WO2023133577A1 - Methods of treating or reducing risk of transplant rejection - Google Patents

Methods of treating or reducing risk of transplant rejection Download PDF

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Publication number
WO2023133577A1
WO2023133577A1 PCT/US2023/060358 US2023060358W WO2023133577A1 WO 2023133577 A1 WO2023133577 A1 WO 2023133577A1 US 2023060358 W US2023060358 W US 2023060358W WO 2023133577 A1 WO2023133577 A1 WO 2023133577A1
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Prior art keywords
transplant
days
administered
hours
months
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PCT/US2023/060358
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English (en)
French (fr)
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John F. Paolini
Muhammad M. MOHIUDDIN
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Kiniksa Phamaceuticals Ltd
University of Maryland Baltimore
University of Maryland College Park
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Kiniksa Phamaceuticals Ltd
University of Maryland Baltimore
University of Maryland College Park
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Application filed by Kiniksa Phamaceuticals Ltd, University of Maryland Baltimore, University of Maryland College Park filed Critical Kiniksa Phamaceuticals Ltd
Priority to EP23737837.7A priority Critical patent/EP4463182A1/en
Priority to CN202380023083.3A priority patent/CN118891285A/zh
Priority to AU2023205152A priority patent/AU2023205152A1/en
Priority to KR1020247026684A priority patent/KR20240131437A/ko
Priority to JP2024541033A priority patent/JP2025502095A/ja
Priority to CA3242941A priority patent/CA3242941A1/en
Publication of WO2023133577A1 publication Critical patent/WO2023133577A1/en
Priority to MX2024008562A priority patent/MX2024008562A/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/577—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 tolerising response
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Tissue and organ transplantation is a powerful therapeutic tool for replacing a damaged or failing organ or tissue in a subject in need thereof.
  • a major problem following transplantation occurs when the recipient’s immune system attacks the transplant, leading to rejection and failure of the transplant.
  • Xenotransplantation which is the transplantation of an organ or tissue from a species other than human into a human recipient, could help to address the shortage of human donor material.
  • Xenotransplantation presents significant obstacles, as certain antigens on a non-human donor organ can elicit an immune response by the human recipient, leading to acute rejection of the transplanted material.
  • new methods are needed to suppress the immune system to treat or reduce the risk or likelihood of transplant rejection or to increase the time before transplant rejection occurs in a human subject that receives a transplant (e.g., an allogeneic or xenogeneic transplant).
  • a transplant e.g., an allogeneic or xenogeneic transplant.
  • a first aspect features a method of treating or reducing the risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a transplant (e.g., a xenotransplant).
  • the method includes administering an anti-CD40 antibody or antigen-binding fragment thereof from about 1 hour to about 24 hours (e.g., from about 3 hours to about 24 hours, or about 10 hours to about 24 hours) prior to the transplant and administering the anti- CD40 antibody or antigen-binding fragment thereof within about 1 hour to about 24 hours following the transplant, for example, once the subject achieves hemostasis.
  • the method treats, reduces the risk of, or increases the duration of time before the occurrence of, hyperacute rejection, acute rejection, or chronic rejection of the transplant.
  • the antibody or antigen-binding fragment thereof may be administered subcutaneously or intravenously.
  • the antibody or antigen-binding fragment thereof includes a heavy chain variable region including a CDRH1 , CDRH2, and CDRH3 as set forth SEQ ID NOs: 1 -3, respectively, and a light chain variable region including a CDRL1 , CDRL2, and CDRL3 as set forth in SEQ ID NOs: 4-6, respectively.
  • the heavy chain variable region includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 7
  • the light chain variable region includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 8.
  • the heavy chain variable region includes the amino acid sequence set forth in SEQ ID NO: 7, and the light chain variable region includes the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the heavy chain includes the amino acid sequence set forth in SEQ ID NO: 9, and the light chain includes the amino acid sequence set forth in SEQ ID NO: 10.
  • the antibody or antigen-binding fragment thereof is administered at a dosage of about 1 mg/kg to about 20 mg/kg (e.g., a dosage of about 5 mg/kg or about 10 mg/kg).
  • a second aspect features a method of treating or reducing the risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a transplant (e.g., a xenotransplant).
  • the method includes administering an anti-CD40 antibody or antigen-binding fragment (e.g., a humanized anti-CD40 antibody or antigen-binding fragment).
  • the method treats, reduces the risk of, or increases the duration of time before the occurrence of hyperacute rejection, acute rejection, and/or chronic rejection of the transplant.
  • the antibody or antigen-binding fragment thereof includes a heavy chain variable region with a CDRH1 , CDRH2, and CDRH3 as set forth SEQ ID NOs: 1 -3, respectively, and a light chain variable region with a CDRL1 , CDRL2, and CDRL3 as set forth in SEQ ID NOs: 4-6, respectively.
  • the antibody or antigenbinding fragment thereof may be administered subcutaneously or intravenously, e.g., at a dosage of about 1 mg/kg to about 20 mg/kg (e.g., a dosage of about 10 mg/kg).
  • the heavy chain variable region includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 7, and the light chain variable region includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 8.
  • the heavy chain variable region includes the amino acid sequence set forth in SEQ ID NO: 7
  • the light chain variable region includes the amino acid sequence set forth in SEQ ID NO: 8.
  • the heavy chain includes the amino acid sequence set forth in SEQ ID NO: 9, and the light chain includes the amino acid sequence set forth in SEQ ID NO: 10.
  • the antibody or antigen-binding fragment thereof is administered prior to the transplant (e.g., from about 1 hour to about 24 hours, e.g., from about 10 hours to about 24 hours prior to the transplant, e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant).
  • the transplant e.g., from about 1 hour to about 24 hours, e.g., from about 10 hours to about 24 hours prior to the transplant, e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the
  • the antibody or antigen-binding fragment thereof is administered on the same day as the transplant.
  • the antibody or antigen-binding fragment thereof is administered after the transplant.
  • the antibody or antigen-binding fragment thereof is administered within about 1 hour to about 24 hours (e.g., within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours) following the transplant, for example, once the subject achieves hemostasis.
  • the antibody or antigen-binding fragment thereof is administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, 11 months, and/or one year after the transplant.
  • the antibody or antigen-binding fragment thereof is administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the antibody or antigen-binding fragment thereof is administered at least once every week, once every two weeks, once every three weeks, or once a month for a treatment period of one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • about 1 mg/kg to about 20 mg/kg (e.g., about 5 mg/kg or about 10 mg/kg) of the antibody or antigen-binding fragment thereof is administered at least once every week, once every two weeks, once every three weeks, or once a month for a treatment period of one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the method includes administering the antibody or antigen-binding fragment thereof as an induction dose that includes two doses: a first dose of about 1 mg/kg to about 20 mg/kg (e.g., a dose of about 10 mg/kg) that is administered prior to the transplant (e.g., from about 1 hour to about 24 hours, e.g., from about 10 hours to about 24 hours prior to the transplant (e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant) and a second dose of about 1 mg/kg to about 20 mg/kg (e.g., a dosage of about 10 mg/kg) that is administered within about 1 hour to about 24 hours (e.g., within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6
  • the second dose is administered once the subject achieves hemostasis.
  • the induction dose administered prior to the transplant is a “conditioning dose” that functions to prophylactically suppress or modulate the subject’s immune system with an anti-CD40 antibody or antigen-binding fragment thereof prior to the transplant.
  • the method further includes treating the subject with subsequent maintenance dosing of the antibody or antigen-binding fragment thereof (e.g., a dose of the antibody or antigen-binding fragment thereof that follows after the induction dose) of about 1 mg/kg to about 20 mg/kg (e.g., a dose of about 10 mg/kg) that is administered once every week, once every two weeks, once every three weeks, or once a month (e.g., once every two or three weeks).
  • maintenance dosing is initiated once the anti-CD40 antibody or antigen-binding fragment thereof has replicable (e.g., within a target therapeutic range) or predictable pharmacokinetics (PK) in the subject.
  • the maintenance dose can be administered to the subject for a treatment period of at least one month (e.g., for a treatment period of at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject).
  • an induction dose includes a single, undivided dose of the antibody or antigen-binding fragment thereof.
  • an induction dose may include a divided dose of the antibody or antigen-binding fragment thereof that includes at least two doses.
  • an induction dose is a divided dose that includes a first dose and a second dose of the antibody or antigen-binding fragment thereof that are administered about 1 hour to about 24 hours apart, e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours apart, such as from about 1 to about 12 hours apart).
  • the first divided dose of the induction dose may involve administration of from about 1 mg/kg to about 20 mg/kg of the antibody or antigen-binding fragment thereof (e.g., a dosage of about 10 mg/kg) and a second divided dose of the induction dose may involve administration of from about 1 mg/kg to about 20 mg/kg of the antibody or antigen-binding fragment thereof (e.g., a dosage of about 10 mg/kg).
  • the second divided dose of the induction dose may be administered about 1 hour to about 24 hours (e.g., within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours, such as from about 1 to about 12 hours) after the subject receives the first divided dose of the induction dose.
  • to the method may involve administration of a divided dose of an induction dose of 20 mg/kg of the anti-CD40 antibody or antigen-binding fragment thereof, in which the first divided dose provides about 10 mg/kg of the antibody or antigen-binding fragment thereof and the second divided dose provides about 10 mg/kg of the antibody or antigen-binding fragment thereof.
  • the method may include administration of multiple induction doses (e.g., either as undivided doses or as divided doses).
  • the method includes administering 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more induction doses (e.g., from about 1 to about 5 induction doses such as, e.g., about 3 or about 4 induction doses).
  • each induction dose (e.g., first induction dose, second induction dose, third induction dose, fourth induction dose, or more) is a divided dose that includes first and second doses of the antibody or antigen-binding fragment thereof (e.g., each of the first or second dose in an amount of about 1 mg/kg to about 20 mg/kg per dose) that are, e.g., administered between 1 and 24 hours apart (e.g., 1 to 12 hours apart)).
  • the first induction dose is a divided dose and any additional induction dose(s) (e.g., first, second, third, fourth, or more induction dose(s)) is/are administered as either a divided dose of the antibody or antigen-binding fragment thereof (e.g., a divided dose of at least two doses that are administered in an amount of about 1 mg/kg to about 20 mg/kg per dose, in which the doses are, e.g., administered between 1 and 24 hours apart (e.g., 1 to 12 hours apart)) or an undivided dose of the antibody or antigen-binding fragment thereof (e.g., a single dose in an amount of about 1 mg/kg to about 20 mg/kg).
  • a divided dose of the antibody or antigen-binding fragment thereof e.g., a divided dose of at least two doses that are administered in an amount of about 1 mg/kg to about 20 mg/kg per dose, in which the doses are, e.g., administered between 1 and 24 hours apart (e.
  • the first induction dose is a divided dose (e.g., a divided dose of at least two doses that are administered in an amount of about 1 mg/kg to about 20 mg/kg per dose, in which the doses are, e.g., administered between 1 and 24 hours apart (e.g., 1 to 12 hours apart)) and any additional induction dose(s) (e.g., first, second, third, fourth, or more induction dose(s)) is/are administered as a divided dose (e.g., including at least two doses in an amount of about 1 mg/kg to about 20 mg/kg per dose).
  • a divided dose e.g., a divided dose of at least two doses that are administered in an amount of about 1 mg/kg to about 20 mg/kg per dose, in which the doses are, e.g., administered between 1 and 24 hours apart (e.g., 1 to 12 hours apart)
  • any additional induction dose(s) e.g., first, second, third, fourth, or more induction
  • a second induction dose is administered from about 1 day to about 14 days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days) following administration of the first induction dose.
  • second, third, fourth, and/or fifth induction doses are administered from about 1 day to about 14 days apart (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days apart) and, optionally, within 1 to 30 days after the first induction dose.
  • the induction dose is provided to attain or maintain a desired minimum blood, plasma, or serum concentration of the antibody or antigen-binding fragment thereof.
  • a minimum concentration e.g., a trough concentration
  • the method may include administering an induction dose and monitoring the concentration of the antibody or antigen-binding fragment thereof in the blood, plasma, or serum over time.
  • concentration approaches the minimum threshold (e.g., about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 110 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, or about 150 pg/mL (or a concentration in the range of from about 20 pg/mL to about 150 pg/mL), e.g., within about 10%, 20%, 30%, 40%, or 50% of the minimum threshold), the method may include administering a further induction dose (e.g., prior to establishment of maintenance dosing e.g., at a dosage of about
  • the subject is administered one of more induction doses until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum (e.g., peak and trough concentrations) is replicable or is predictable (e.g., at the desired therapeutic range, such as when the Ctrough and/or Cmax levels appear consistent between doses).
  • multiple induction doses are administered (as described herein) until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range of about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 110 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/mL, 170 pg/mL, 180 pg/mL, 190
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be about 20%, e.g., within 15%, 10%, 5% or less, of each other.
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Cmax of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range of about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 1 10 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/mL, 170 pg/mL, 180 pg/mL, 190 pg/
  • the Cmax of the antibody or antigen-binding fragment thereof in blood, plasma, or serum may be determined over a period of, e.g., 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 28 days.
  • the method may include administering an induction dose and determining the concentration of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum (e.g., the concentration is determined every six hours, every 12 hours, once per day, once every two days, once every three days, once every four days, once every five days, once every six days or once per week).
  • the subject may transition from induction dosing to maintenance dosing.
  • the subject transitions from induction dosing to maintenance dosing when (i) two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range (e.g., about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 1 10 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/m
  • the Ctrough and/or the Cmax of the antibody or antigen-binding fragment thereof in blood, plasma, or serum may be determined over a period of, e.g., 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 28 days.
  • the method may include administering an induction dose and determining the concentration of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum (e.g., the concentration is determined every six hours, every 12 hours, once per day, once every two days, once every three days, once every four days, once every five days, once every six days, or once per week).
  • the maintenance dose is provided to maintain a desired minimum blood, plasma, or serum concentration of the antibody or antigen-binding fragment thereof.
  • a minimum concentration e.g., a trough concentration
  • the method may include administering an induction or maintenance dose and determining the concentration of the antibody or antigen-binding fragment thereof in the subject's blood, plasma, or serum (e.g., the concentration is determined once per day, once every two days, once every three days, once every four days, once every five days, once every six days or once per week).
  • the method may include administering a maintenance dose (e.g., at a dosage of about 1 mg/kg to about 20 mg/kg, e.g., about 5 mg/kg or about 10 mg/kg) of the antibody or antigen-binding fragment thereof.
  • a maintenance dose e.g., at a dosage of about 1 mg/kg to about 20 mg/kg, e.g., about 5 mg/kg or about 10 mg/kg
  • These maintenance doses can be repeatedly administered following the transplant, e.g., once every week, once every two weeks, once every three weeks, or once a month (e.g., once every two or three weeks), or as needed to maintain in the subject’s blood, plasma, or serum a concentration of the antibody, or antigen-binding fragment thereof, above 150 pg/ml.
  • the maintenance dose can be administered to the subject for a treatment period of at least one month (e.g., for a treatment period of at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject).
  • the timing of administration of the maintenance dose and/or the timing between maintenance doses may be selected based on the PK profile of the antibody or antigen-binding fragment thereof in, e.g., the blood, plasma, or serum of the subject.
  • the method further includes treating the subject with a maintenance dose of the antibody or antigen-binding fragment thereof (e.g., after the final induction dose) of about 1 mg/kg to about 20 mg/kg, or about 5 mg/kg to about 10mg/kg (e.g., a dose of about 5mg/kg or about 10 mg/kg) that is administered once every week, once every two weeks, once every three weeks, or once a month (e.g., once every two or three weeks).
  • a maintenance dose of the antibody or antigen-binding fragment thereof e.g., after the final induction dose
  • a maintenance dose of the antibody or antigen-binding fragment thereof e.g., after the final induction dose
  • a maintenance dose of the antibody or antigen-binding fragment thereof e.g., after the final induction dose of about 1 mg/kg to about 20 mg/kg, or about 5 mg/kg to about 10mg/kg (e.g., a dose of about 5mg/kg or about 10 mg/
  • the maintenance dose can be administered to the subject for a treatment period of at least one month (e.g., for a treatment period of at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject).
  • the method further includes including administering a first therapeutic agent that depletes or reduces B cells in the subject (e.g., an anti-CD20 antibody, such as rituximab) and/or a second therapeutic agent that depletes or reduces T cells in the subject (e.g., anti-thymocyte globulin, e.g., THYMOGLOBULIN® or ATGAM®, or an anti-IL-2Ra receptor antibody).
  • a first therapeutic agent that depletes or reduces B cells in the subject e.g., an anti-CD20 antibody, such as rituximab
  • a second therapeutic agent that depletes or reduces T cells in the subject e.g., anti-thymocyte globulin, e.g., THYMOGLOBULIN® or ATGAM®, or an anti-IL-2Ra receptor antibody.
  • the first therapeutic agent may be administered prior to the transplant (e.g., from about 10 hours to about 24, e.g., about 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant).
  • the first therapeutic agent may be administered after the transplant (e.g., one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, and/or four weeks after the transplant).
  • the first therapeutic agent is administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, or four weeks. In some embodiments, the first therapeutic agent is administered daily, weekly, or once every other week for a treatment period of one week, two weeks, three weeks, or four weeks.
  • the first therapeutic agent e.g., an anti-CD20 antibody, such as rituximab
  • the first therapeutic agent is administered at a dosage of about 1 mg/kg to about 40 mg/kg (e.g., about 10 mg/kg).
  • the first therapeutic agent is administered intravenously.
  • the anti-CD20 antibody e.g., rituximab
  • the anti-CD20 antibody is administered at a dosage of about 250 mg/m 2 to about 500 mg/m 2 , e.g., a dosage of about 375 mg/m 2 .
  • the first therapeutic agent is rituximab.
  • the second therapeutic agent may be administered prior to the transplant (e.g., from about 10 hours to about 24 hours prior to the transplant, e.g., about 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant).
  • the second therapeutic agent is administered on the same day as the transplant.
  • the second therapeutic agent may be administered after the transplant (e.g., one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, and/or four weeks after the transplant).
  • the second therapeutic agent is administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, or four weeks.
  • the second therapeutic agent is administered daily, weekly, or once every other week for a treatment period of one week, two weeks, three weeks, or four weeks.
  • the second therapeutic agent is administered within about 1 hour to about 24 hours following the transplant and once the subject achieves hemostasis).
  • the second therapeutic agent e.g., anti-thymocyte globulin, e.g., THYMOGLOBULIN® or ATGAM®, or anti-IL-2Ra receptor antibody
  • the second therapeutic agent is administered at a dosage of about 1 mg/kg to about 10 mg/kg, e.g., about 2 mg/kg or about 5 mg/kg.
  • the second therapeutic agent is THYMOGLOBULIN® and is administered at a dosage of about 2 mg/kg.
  • the second therapeutic agent is ATGAM® and is administered at a dosage of about 5 mg/kg.
  • the second therapeutic agent may be administered intravenously.
  • the second therapeutic agent is anti-thymocyte globulin.
  • the antibody or antigen-binding fragment thereof is administered at a dosage of about 10 mg/kg.
  • the antibody or antigen-binding fragment thereof is administered intravenously.
  • the antibody or antigen-binding fragment thereof is administered subcutaneously.
  • the transplant is an allogeneic transplant. In other embodiments of any of the aspects described herein, the transplant is a xenograft transplant.
  • the transplant may be a cell, tissue, or organ transplant.
  • the transplant may be, or may include, for example, a heart, kidney, lung, liver, pancreas, intestine, thymus, skin, eye, uterus, stem cell, bone, tendon, cornea, heart valve, nerve, vein, or a portion thereof.
  • the xenograft transplant includes an organ or portion thereof from a pig, cow, horse, dog, cat, sheep, goat, non-human primate (e.g., a macaque (e.g., a rhesus macaque or a cynomolgus macaque), a baboon, a marmoset, a monkey, and a chimpanzee), or gorilla.
  • non-human primate e.g., a macaque (e.g., a rhesus macaque or a cynomolgus macaque), a baboon, a marmoset, a monkey, and a chimpanzee
  • gorilla e.g., a porcine heart.
  • the xenograft transplant may include a porcine kidney.
  • the xenograft transplant has been genetically engineered, e.g., to add, modify, or remove one or more xenoreactive antigens.
  • the xenograft transplant includes an organ or portion thereof from a host animal that has been genetically engineered, e.g., to add, modify, or remove one or more xenoreactive antigens.
  • the method further includes administering one or more of a steroid (e.g., methylprednisolone), an antihistamine (e.g., diphenhydramine), an H2 receptor blocker (e.g., famotidine), an antiviral agent (e.g., ganciclovir), a complement inhibitor (e.g., a C1 esterase inhibitor), an immunosuppressive agent (e.g., tocilizumab and/or mycophenolate mofetil), an anti-inflammatory agent (e.g., etanercept, or a non-steroidal anti-inflammatory agent (NSAID, such as aspirin and naproxen), an anticoagulant (e.g., heparin, aspirin or other known agent), and an antibiotic (e.g., ceftriaxone or other known agent).
  • a steroid e.g., methylprednisolone
  • an antihistamine e.g., diphenhydramine
  • the method further includes administering a steroid, such as methylprednisolone.
  • a steroid such as methylprednisolone.
  • the methylprednisolone is administered once per day or twice per day.
  • the methylprednisolone may be administered at a dosage of about 2 mg/kg.
  • the methylprednisolone may be administered prior to the transplant.
  • the methylprednisolone may be administered one day prior to the transplant.
  • the methylprednisolone may be administered on the same day as the transplant.
  • the methylprednisolone may be administered after the transplant.
  • the methylprednisolone may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, and/or six months after the transplant.
  • the methylprednisolone may be administered for a treatment period of 2 months, seven weeks, six weeks, five weeks, four weeks, three weeks, two weeks, one week, six days, five days, four days, three days, two days, or one day.
  • the method further includes administering an antihistamine, such as diphenhydramine.
  • the diphenhydramine may be administered at a dosage of about 50 mg.
  • the diphenhydramine may be administered intravenously.
  • the diphenhydramine may be administered prior to the transplant.
  • the diphenhydramine may be administered one day prior to the transplant.
  • the diphenhydramine may be administered on the same day as the transplant.
  • the diphenhydramine may be administered after the transplant.
  • the diphenhydramine may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, and/or four weeks after the transplant.
  • the diphenhydramine may be administered for a treatment period of 2 months, seven weeks, six weeks, five weeks, four weeks, three weeks, two weeks, one week, six days, five days, four days, three days, two days, or one day.
  • the method further includes administering an H2 receptor blocker, such as famotidine.
  • the famotidine may be administered at a dosage of about 20 mg.
  • the famotidine may be administered once per day or twice per day.
  • the famotidine may be administered prior to the transplant.
  • the famotidine may be administered one day prior to the transplant.
  • the famotidine may be administered on the same day as the transplant.
  • the famotidine may be administered after the transplant.
  • the famotidine may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, and/or eight weeks after the transplant.
  • the famotidine may be administered for a treatment period of 2 months, seven weeks, six weeks, five weeks, four weeks, three weeks, two weeks, one week, six days, five days, four days, three days, two days, or one day.
  • the method further includes administering an antiviral agent, such as ganciclovir.
  • the ganciclovir may be administered at a dosage of about 5 mg/kg.
  • the ganciclovir may be administered prior to the transplant.
  • the ganciclovir may be administered one day prior to the transplant.
  • the ganciclovir may be administered on the same day as the transplant.
  • the ganciclovir may be administered after the transplant.
  • the ganciclovir may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, and/or ten years after the transplant.
  • the ganciclovir may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the ganciclovir may be administered daily for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the method further includes administering a complement inhibitor, such as a C1 esterase inhibitor.
  • a complement inhibitor such as a C1 esterase inhibitor.
  • the C1 esterase inhibitor may be administered at a dosage of about 20 U/kg.
  • the C1 esterase inhibitor may be administered prior to the transplant.
  • the C1 esterase inhibitor may be administered one day prior to the transplant.
  • the C1 esterase inhibitor may be administered on the same day as the transplant.
  • the C1 esterase inhibitor may be administered after the transplant.
  • the C1 esterase inhibitor may be administered one day, two days, three days, four days, five days, six days, and/or one week after the transplant.
  • the method further includes administering an immunosuppressive agent, such as tocilizumab.
  • the tocilizumab may be administered at a dosage of about 8 mg/kg.
  • the tocilizumab may be administered intravenously.
  • the tocilizumab may be administered on the same day as the transplant.
  • the tocilizumab may be administered after the transplant.
  • the tocilizumab may be administered one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, and/or twelve months after the transplant.
  • the tocilizumab may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the tocilizumab may be administered monthly for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the method further includes administering an anti-inflammatory agent, such as etanercept.
  • the etanercept may be administered at a dosage of about 0.7 lU/kg.
  • the etanercept may be administered subcutaneously.
  • the etanercept may be administered on the same day as the transplant.
  • the etanercept may be administered after the transplant.
  • the etanercept may be administered one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, and/or twelve months after the transplant.
  • the etanercept may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the etanercept may be administered weekly for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the method further includes administering an immunosuppressive agent, such as mycophenolate mofetil.
  • an immunosuppressive agent such as mycophenolate mofetil.
  • the mycophenolate mofetil may be administered at a dosage of about 20 mg/kg.
  • the mycophenolate mofetil may be administered intravenously.
  • the mycophenolate mofetil may be administered once per day or twice per day.
  • the mycophenolate mofetil may be administered on the same day as the transplant.
  • the mycophenolate mofetil may be administered after the transplant.
  • the mycophenolate mofetil may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, and/or ten years after the transplant.
  • the mycophenolate mofetil may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the mycophenolate mofetil may be administered daily for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the method further includes administering an anticoagulant, such as heparin.
  • the heparin may be administered on the same day as the transplant.
  • the heparin may be administered after the transplant.
  • the heparin may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, and/or ten years after the transplant.
  • the heparin may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the heparin may be administered daily for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the method further includes administering a non-steroidal antiinflammatory agent (NSAID), such as aspirin.
  • NSAID non-steroidal antiinflammatory agent
  • the aspirin may be administered at a dosage of about 81 mg.
  • the aspirin may be administered after the transplant.
  • the aspirin may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, and/or ten years after the transplant.
  • the aspirin may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the aspirin may be administered daily for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the method further includes administering an antibiotic, such as ceftriaxone.
  • the ceftriaxone may be administered at a dosage of about 50 mg/kg.
  • the ceftriaxone may be administered after the transplant.
  • the ceftriaxone may be administered one day, two days, three days, four days, five days, six days, one week, and/or two weeks after the transplant.
  • the ceftriaxone may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, or two weeks.
  • the ceftriaxone may be administered daily for a treatment period of one week.
  • a third aspect features a method of treating or reducing the risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a porcine heart xenograft transplant.
  • the method includes administering a humanized anti- CD40 antibody or antigen-binding fragment thereof that includes a heavy chain variable region including a CDRH1 , CDRH2, and CDRH3 as set forth SEQ ID NOs: 1 -3, respectively, and a light chain variable region including a CDRL1 , CDRL2, and CDRL3 as set forth in SEQ ID NOs: 4-6, respectively.
  • the heavy chain variable region includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 7, and the light chain variable region includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 8.
  • the heavy chain variable region includes the amino acid sequence set forth in SEQ ID NO: 7
  • the light chain variable region includes the amino acid sequence set forth in SEQ ID NO: 8.
  • the heavy chain includes the amino acid sequence set forth in SEQ ID NO: 9, and the light chain includes the amino acid sequence set forth in SEQ ID NO: 10.
  • the method includes administering the anti-CD40 antibody or antigen-binding fragment thereof from about 1 hour to about 24 hours (e.g., from about 10 hours to about 24 hours) prior to the transplant and administering the anti-CD40 antibody or antigen-binding fragment thereof within about 1 hour to about 24 hours following the transplant, for example, once the subject achieves hemostasis.
  • the antibody or antigen-binding fragment thereof may be administered subcutaneously or intravenously.
  • the antibody or antigen-binding fragment thereof is administered within about 1 hour to about 24 hours (e.g., within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours) following the transplant, for example, once the subject achieves hemostasis.
  • the antibody or antigen-binding fragment thereof is administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, 11 months, and/or one year after the transplant.
  • the antibody or antigen-binding fragment thereof is administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • about 1 mg/kg to about 20 mg/kg (e.g., about 5 mg/kg or about 10 mg/kg) of the antibody or antigen-binding fragment thereof is administered at least once every week, once every two weeks, once every three weeks, or once a month for a treatment period of one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the antibody or antigen-binding fragment thereof is administered at least once every week, once every two weeks, once every three weeks, or once a month for a treatment period of one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the method includes administering the antibody or antigen-binding fragment thereof as a an induction dose, e.g., as a divided dose that includes at least two doses: a first dose of about 1 mg/kg to about 20 mg/kg (e.g., a dose of about 10 mg/kg) that is administered prior to the transplant (e.g., from about 1 hour to about 24 hours, e.g., from about 10 hours to about 24 hours prior to the transplant (e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant) and a second dose of about 1 mg/kg to about 20 mg/kg (e.g., a dosage of about 10 mg/kg) that is administered within about 1 hour to about 24 hours (e.g., within about
  • the induction dose administered prior to the transplant is a “conditioning dose”, which functions to prophylactically suppress the subject’s immune system with an anti-CD40 antibody, or antigen-binding fragment thereof, prior to the transplant.
  • the first induction dose can be administered as a divided dose that includes at least two doses: a conditioning dose of about 1 mg/kg to about 20 mg/kg (e.g., a dose of about 10 mg/kg) that is administered prior to the transplant (e.g., from about 1 hour to about 24 hours, e.g., from about 10 hours to about 24 hours prior to the transplant (e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant) and an induction dose of about 1 mg/kg to about 20 mg/kg
  • the two, divided induction doses administered before and after transplant can be administered as a single, undivided dose of about 1 mg/kg to about 20 mg/kg (e.g., either before the transplant or after the transplant (e.g., after the patient achieves hemostasis)).
  • a subject is administered a conditioning dose of about 1 mg/kg to about 20 mg/kg before the transplant (e.g., from about 1 hour to about 24 hours, e.g., from about 10 hours to about 24 hours prior to the transplant (e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant).
  • a conditioning dose of about 1 mg/kg to about 20 mg/kg before the transplant (e.g., from about 1 hour to about 24 hours, e.g., from about 10 hours to about 24 hours prior to the transplant (e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18
  • the method may optionally include administering a second induction dose of the antibody or antigen-binding fragment thereof (e.g., as a divided dose with at least two separate doses administered 1 - 24 hours apart (e.g., 1 -12 hours apart) or as an undivided dose) in an amount of from about 1 mg/kg to about 20 mg/kg (e.g., a dose of about 10 mg/kg) from about 1 day to about 10 days (e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days) following the transplant (e.g., after administration of a first induction dose).
  • a second induction dose of the antibody or antigen-binding fragment thereof e.g., as a divided dose with at least two separate doses administered 1 - 24 hours apart (e.g., 1 -12 hours apart) or as an undivided dose
  • a second induction dose of the antibody or antigen-binding fragment thereof e.
  • the method may optionally include administering a third induction dose (e.g., as a divided dose with at least two separate doses administered, e.g., 1 -24 hours apart (e.g., 1 -12 hours apart) or as an undivided dose) in an amount of from about 1 mg/kg to about 20 mg/kg (e.g., a dose of about 5 mg/kg or about 10 mg/kg).
  • the second and/or third induction doses may be administered, e.g., at days 2, 3, 4, 5, 6, 7, 8, 9, and/or 10 following the transplant (e.g., the second induction dose following administration of the first induction dose and the third induction dose following administration of the second induction dose).
  • Additional induction doses may also be administered as a divided or undivided dose (e.g., in an amount of from about 1 mg/kg to about 20 mg/kg per dose (e.g., a dose of about 5 mg/kg or about 10 mg/kg)).
  • the second, third, fourth, and/or fifth induction doses, etc. may be administered in an amount of about 1 mg/kg to about 20 mg/kg per dose (e.g., a dose of about 5 mg/kg or about 10 mg/kg).
  • the subject is administered one of more induction doses until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum (e.g., peak and trough concentrations) is replicable or is predictable (e.g., at the desired therapeutic range).
  • multiple induction doses are administered (as described herein) until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Ctrough of the antibody or antigenbinding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range of about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 110 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/mL, 170 pg/mL, 180 pg/mL, 190
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be about 20%, e.g., within 15%, 10%, 5% or less, of each other.
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Cmax of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range of about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 110 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/mL, 170 pg/mL, 180 pg/mL, 190 pg/m
  • the Cmax of the antibody or antigen-binding fragment thereof in blood, plasma, or serum may be determined over a period of, e.g., 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 28 days.
  • the method may include administering an induction dose and determining the concentration of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum (e.g., the concentration is determined every six hours, every 12 hours, once per day, once every two days, once every three days, once every four days, once every five days, once every six days or once per week).
  • the subject may transition from induction dosing to maintenance dosing.
  • the subject transitions from induction dosing to maintenance dosing when (i) two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range (e.g., about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 1 10 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/m
  • the Ctrough and/or the Cmax of the antibody or antigen-binding fragment thereof in blood, plasma, or serum may be determined over a period of, e.g., 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 28 days.
  • the method may include administering an induction dose and determining the concentration of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum (e.g., the concentration is determined every six hours, every 12 hours, once per day, once every two days, once every three days, once every four days, once every five days, once every six days or once per week).
  • the method further includes, for example, treating the subject with a subsequent maintenance dose (e.g., after administration of the last induction dose) of the antibody or antigen-binding fragment thereof of about 1 mg/kg to about 20 mg/kg (e.g., a dose of about 5 mg/kg or about 10 mg/kg) that is administered once every week, once every two weeks, once every three weeks, or once a month (e.g., once every two or three weeks).
  • a subsequent maintenance dose e.g., after administration of the last induction dose
  • the antibody or antigen-binding fragment thereof of about 1 mg/kg to about 20 mg/kg (e.g., a dose of about 5 mg/kg or about 10 mg/kg) that is administered once every week, once every two weeks, once every three weeks, or once a month (e.g., once every two or three weeks).
  • the maintenance dose can be administered to the subject for a treatment period of at least one month (e.g., for a treatment period of at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject).
  • the maintenance dose is provided to maintain a desired minimum blood, plasma, or serum concentration of the antibody or antigen-binding fragment thereof.
  • a minimum concentration e.g., a trough concentration
  • the method may include administering an induction dose or a maintenance does and monitoring the concentration of the antibody or antigen-binding fragment thereof in the blood, plasma, or serum.
  • concentration approaches the minimum threshold (e.g., about 150 gg/mL or about 20 gg/mL, or, e.g., within about 10%, 20%, 30%, 40%, or 50% of the minimum threshold)
  • the method may include administering a maintenance dose (e.g., at a dosage of about 1 mg/kg to about 20 mg/kg, e.g., about 10 mg/kg) of the antibody or antigen-binding fragment thereof.
  • maintenance doses can be repeatedly administered following the transplant, e.g., once every week, once every two weeks, once every three weeks, or once a month (e.g., once every two or three weeks).
  • the maintenance dose can be administered to the subject for a treatment period of at least one month (e.g., for a treatment period of at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject).
  • the timing of administration of the maintenance dose and/or the timing between maintenance doses may be selected based on the PK profile of the antibody or antigen-binding fragment thereof in, e.g., the blood, plasma, or serum of the subject.
  • the subject may have been administered a therapeutic agent (e.g., an anti-CD20 antibody, such as rituximab) that depletes or reduces B cells in the subject.
  • a therapeutic agent e.g., an anti-CD20 antibody, such as rituximab
  • the subject may have been administered a therapeutic agent (e.g., anti-thymocyte globulin or anti-IL-2Ra receptor antibody) that depletes or reduces T cells in the subject.
  • the method further includes administering one or more of a steroid (e.g., methylprednisolone), an antihistamine (e.g., diphenhydramine), an H2 receptor blocker (e.g., famotidine), an antiviral agent (e.g., ganciclovir), a complement inhibitor (e.g., a C1 esterase inhibitor), an immunosuppressive agent (e.g., tocilizumab and/or mycophenolate mofetil), an anti-inflammatory agent (e.g., etanercept, or a non-steroidal anti-inflammatory agent (NSAID, such as aspirin and naproxen), an anticoagulant (e.g., heparin and aspirin or other known agent), and an antibiotic (e.g., ceftriaxone or other known agent) to the subject before and/or after the transplant.
  • a steroid e.g., methylprednisolone
  • an antihistamine e
  • a fourth aspect features a method of treating or reducing the risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a xenograft transplant.
  • the method includes administering a humanized anti-CD40 antibody or antigen-binding fragment thereof having a heavy chain variable region with the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region with the amino acid sequence set forth in SEQ ID NO: 8.
  • the antibody or antigen-binding fragment thereof may be administered subcutaneously or intravenously, e.g., at a dosage of about 1 mg/kg to about 20 mg/kg (e.g., about 10 mg/kg), e.g., from about 10 hours to about 24 hours prior to the transplant.
  • the method may further include administering the antibody or antigen-binding fragment thereof on the same day as the transplant.
  • the method may further include administering the antibody or antigen-binding fragment thereof after the transplant.
  • the antibody or antigen-binding fragment thereof may be administered within about 1 hour to about 24 hours after the subject reaches hemostasis following the transplant.
  • the method may further include administering the antibody or antigen-binding fragment thereof once a week, once every other week, once every three weeks, or once a month after the transplant.
  • the method may further include intravenously administering an anti-CD20 antibody, such as rituximab, e.g., at a dosage of about 1 mg/kg to about 40 mg/kg, e.g., from about 10 hours to about 24 hours prior to the transplant.
  • the anti-CD20 antibody e.g., rituximab
  • the method may further include intravenously administering anti-thymocyte globulin or anti-IL-2Ra receptor antibody at a dosage of about 1 mg/kg to about 10 mg/kg on the same day as the transplant.
  • the method further includes administering one or more of a steroid (e.g., methylprednisolone), an antihistamine (e.g., diphenhydramine), an H2 receptor blocker (e.g., famotidine), an antiviral agent (e.g., ganciclovir), a complement inhibitor (e.g., a C1 esterase inhibitor), an immunosuppressive agent (e.g., tocilizumab and/or mycophenolate mofetil), an anti-inflammatory agent (e.g., etanercept, or a non-steroidal anti-inflammatory agent (NSAID, such as aspirin and naproxen), an anticoagulant (e.g., heparin and aspirin or other known agent), and an antibiotic (e.g., ceftriaxone or other known agent) to the subject before and/or after the transplant.
  • a steroid e.g., methylprednisolone
  • an antihistamine e
  • the xenograft transplant includes a cell, tissue, or organ, or portion thereof from a pig, cow, horse, dog, cat, sheep, goat, non-human primate (e.g., a macaque (e.g., a rhesus macaque or a cynomolgus macaque), a baboon, a marmoset, a monkey, and a chimpanzee), or gorilla.
  • the xenograft transplant may be or includes a heart, kidney, lung, liver, pancreas, intestine, thymus, skin, eye, uterus, stem cell, bone, tendon, cornea, heart valve, nerve, vein, or a portion thereof.
  • the xenograft transplant includes a porcine heart. In some embodiments, the xenograft transplant has been genetically engineered to add, remove, or modify one or more xenoreactive antigens. In some embodiments, the xenograft transplant includes an organ or portion thereof from a host animal that has been genetically engineered to add, remove, or modify one or more xenoreactive antigens.
  • a fifth aspect features a method of treating or reducing a risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a transplant (e.g., an allogeneic or xenogeneic transplant).
  • the method includes a) administering intravenously or subcutaneously an induction dose of a humanized anti-CD40 antibody or antigen-binding fragment thereof as a divided dose, which includes a first dose of about 1 mg/kg to about 20 mg/kg from about 10 hours to about 24 hours prior to the transplant and a second dose of about 1 mg/kg to about 20 mg/kg, after the transplant once the subject achieves hemostasis, and b) administering subcutaneously or intravenously a maintenance dose of the humanized anti-CD40 antibody or antigen-binding fragment thereof at a dosage of about 1 mg/kg to about 20 mg/kg for treatment period of at least one month.
  • An induction dose may, alternatively, be administered as a single undivided dose (e.g., of from about 1 mg/kg to about 20 mg/kg, e.g., about 10 mg/kg or 20 mg/kg)).
  • an induction dose e.g., first induction dose
  • the subject is administered one of more additional induction doses (e.g., as a divided dose or an undivided dose, such as 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional induction doses), as described herein, until the PK of the anti-CD40 antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum (e.g., peak and trough concentrations) is replicable or predictable (e.g., in the desired therapeutic range).
  • additional induction doses e.g., as a divided dose or an undivided dose, such as 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional induction doses
  • multiple induction doses are administered (as described herein) until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range of about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 110 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/mL, 170 pg/mL, 180 pg/mL, 190
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be about 20%, e.g., within 15%, 10%, 5% or less, of each other.
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Cmax of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range of about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 110 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/mL, 170 pg/mL, 180 pg/mL, 190 pg/m
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Cmax of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be about 20%, e.g., within 15%, 10%, 5% or less, of each other.
  • the Cmax of the antibody or antigen-binding fragment thereof in blood, plasma, or serum may be determined over a period of, e.g., 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 28 days.
  • the method may include administering an induction dose and determining the concentration of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum (e.g., the concentration is determined every six hours, every 12 hours, once per day, once every two days, once every three days, once every four days, once every five days, once every six days or once per week).
  • the subject may transition from induction dosing to maintenance dosing.
  • the subject transitions from induction dosing to maintenance dosing when (i) two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range (e.g., about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 1 10 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/m
  • the Ctrough and/or the Cmax of the antibody or antigen-binding fragment thereof in blood, plasma, or serum may be determined over a period of, e.g., 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 28 days.
  • the method may include administering an induction dose and determining the concentration of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum (e.g., the concentration is determined every six hours, every 12 hours, once per day, once every two days, once every three days, once every four days, once every five days, once every six days or once per week).
  • the method further includes treating the subject with a maintenance dose of the antibody or antigen-binding fragment thereof (e.g., after the final induction dose) of about 1 mg/kg to about 20 mg/kg, or about 5 mg/kg to about 10mg/kg (e.g., a dose of about 5mg/kg or about 10 mg/kg) that is administered once every week, once every two weeks, once every three weeks, or once a month (e.g., once every two or three weeks).
  • a maintenance dose of the antibody or antigen-binding fragment thereof e.g., after the final induction dose
  • a maintenance dose of the antibody or antigen-binding fragment thereof e.g., after the final induction dose
  • a maintenance dose of the antibody or antigen-binding fragment thereof e.g., after the final induction dose of about 1 mg/kg to about 20 mg/kg, or about 5 mg/kg to about 10mg/kg (e.g., a dose of about 5mg/kg or about 10 mg/
  • the maintenance dose can be administered to the subject for a treatment period of at least one month (e.g., for a treatment period of at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject).
  • the maintenance dose is provided to maintain a minimum blood, plasma, or serum concentration of the humanized anti-CD40 antibody or antigen-binding fragment thereof of at least 150 pg/mL. In some embodiments, the maintenance dose is provided to maintain a minimum blood, plasma, or serum concentration of the humanized anti-CD40 antibody or antigen-binding fragment thereof within the range of at least about 20 pg/mL to about 200 pg/mL, such as at least 20 pg/ml.
  • a blood, plasma, or serum concentration of the humanized anti-CD40 antibody or antigen-binding fragment thereof is used to guide redosing during maintenance dosing. For example, if a serum concentration drops below a desired or predetermined threshold or range (e.g., from about 20 pg/mL to about 300 pg/mL, e.g., from about 50 pg/mL to about 200 pg/mL, from about 50 pg/mL to about 150 pg/mL, or from about 80 pg/mL to about 150 pg/mL), the subject can be administered a maintenance dose.
  • a desired or predetermined threshold or range e.g., from about 20 pg/mL to about 300 pg/mL, e.g., from about 50 pg/mL to about 200 pg/mL, from about 50 pg/mL to about 150 pg/mL, or from about 80 pg/mL to about 150 p
  • the subject can be administered one or more “reloading dose(s)” to increase the serum concentration to a desired therapeutic level (e.g., to a concentration of from about 20 pg/mL to about 300 pg/mL, e.g., from about 50 pg/mL to about 200 pg/mL, from about 50 pg/mL to about 150 pg/mL, or from about 80 pg/mL to about 150 pg/mL).
  • a desired therapeutic level e.g., to a concentration of from about 20 pg/mL to about 300 pg/mL, e.g., from about 50 pg/mL to about 200 pg/mL, from about 50 pg/mL to about 150 pg/mL, or from about 80 pg/mL to about 150 pg/mL.
  • the maintenance dose may be administered at a greater dosage than a prior maintenance dose (e.g., a dose of greater than 10 mg/kg or 20 mg/kg) if it is administered following a drop below a desired minimum blood, plasma, or serum concentration (e.g., below about 150 pg/mL or below about 20 pg/mL).
  • one or more maintenance dose(s) may be administered at a shorter dosing interval than the prior maintenance doses if it is administered following a drop below a desired minimum blood, plasma, or serum concentration (e.g., below about 150 pg/mL or below about 20 pg/mL).
  • the subject can be administered (i) one or more rescue dose(s) of an anti-CD40 antibody or antigen-binding fragment thereof; (ii) one or more increased dose(s) of the anti-CD40 antibody or antigen-binding fragment thereof relative to the dose level administered to the subject prior to the signs or symptoms of transplant rejection; or (iii) the anti-CD40 antibody or antigen-binding fragment thereof at an increased dose frequency relative to the dose frequency administered to the subject prior to relative to the dose level administered to the subject prior to the signs or symptoms of transplant rejection, or combinations of (i)-(iii).
  • the rescue dose(s) of an anti-CD40 antibody or antigen-binding fragment thereof e.g., one or more rescue dose(s) of an anti-CD40 antibody or antigen-binding fragment thereof
  • one or more increased dose(s) of the anti-CD40 antibody or antigen-binding fragment thereof relative to the dose level administered to the subject prior to the signs or symptoms of transplant rejection
  • a subject receiving a dose of about 10 mg/kg once per week may receive an increased dose of, for example, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, or 20 mg/kg once per week.
  • the treatment frequency may be increased, such as from 10 mg/kg once per one or two weeks to 10 mg/kg twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week (e.g., once per day).
  • the antibody or antigen-binding fragment thereof includes a heavy chain variable region with a CDRH1 , CDRH2, and CDRH3 as set forth SEQ ID NOs: 1 -3, respectively, and a light chain variable region with a CDRL1 , CDRL2, and CDRL3 as set forth in SEQ ID NOs: 4-6, respectively.
  • the heavy chain variable region includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 7, and wherein the light chain variable region includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 8.
  • the heavy chain variable region includes the amino acid sequence set forth in SEQ ID NO: 7, and the light chain variable region includes the amino acid sequence set forth in SEQ ID NO: 8.
  • the heavy chain includes the amino acid sequence set forth in SEQ ID NO: 9, and the light chain includes the amino acid sequence set forth in SEQ ID NO: 10.
  • the method further includes including administering a first therapeutic agent that depletes or reduces B cells in the subject (e.g., anti-CD20 antibody, such as rituximab) and/or a second therapeutic agent that depletes or reduces T cells in the subject (e.g., anti-thymocyte globulin, e.g., THYMOGLOBULIN® or ATGAM®, or anti-IL-2Ra receptor antibody).
  • a first therapeutic agent that depletes or reduces B cells in the subject e.g., anti-CD20 antibody, such as rituximab
  • a second therapeutic agent that depletes or reduces T cells in the subject e.g., anti-thymocyte globulin, e.g., THYMOGLOBULIN® or ATGAM®, or anti-IL-2Ra receptor antibody.
  • the first therapeutic agent may be administered prior to the transplant (e.g., from about 1 hour to about 24 hours, e .g., from about 10 hours to about 24, e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant).
  • the first therapeutic agent may be administered after the transplant (e.g., one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, and/or four weeks after the transplant).
  • the first therapeutic agent is administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, or four weeks. In some embodiments, the first therapeutic agent is administered daily, weekly, or once every other week for a treatment period of one week, two weeks, three weeks, or four weeks.
  • the first therapeutic agent e.g., anti-CD20 antibody, such as rituximab
  • the first therapeutic agent is administered at a dosage of about 1 mg/kg to about 40 mg/kg (e.g., about 10 mg/kg).
  • the first therapeutic agent is administered intravenously.
  • the first therapeutic agent is rituximab.
  • the second therapeutic agent may be administered prior to the transplant (e.g., from about 10 hours to about 24 hours prior to the transplant, e.g., about 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant).
  • the second therapeutic agent is administered on the same day as the transplant.
  • the second therapeutic agent may be administered after the transplant (e.g., one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, and/or four weeks after the transplant).
  • the second therapeutic agent is administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, or four weeks.
  • the second therapeutic agent is administered daily, weekly, or once every other week for a treatment period of one week, two weeks, three weeks, or four weeks.
  • the second therapeutic agent is administered within about 1 hour to about 24 hours following the transplant and after the subject achieves hemostasis (e.g., once the subject achieves hemostasis).
  • the second therapeutic agent e.g., anti-thymocyte globulin, e.g., THYMOGLOBULIN® or ATGAM®, or anti-IL-2Ra receptor antibody
  • the second therapeutic agent is administered at a dosage of about 1 mg/kg to about 10 mg/kg, e.g., about 2 mg/kg or about 5 mg/kg.
  • the second therapeutic agent is THYMOGLOBULIN® and is administered at a dosage of about 2 mg/kg.
  • the second therapeutic agent is ATGAM® and is administered at a dosage of about 5 mg/kg.
  • the second therapeutic agent may be administered intravenously.
  • the second therapeutic agent is anti-thymocyte globulin.
  • a sixth aspect features a method of treating or reducing the risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a porcine kidney xenograft transplant.
  • the method includes administering a humanized anti- CD40 antibody or antigen-binding fragment thereof that includes a heavy chain variable region including a CDRH1 , CDRH2, and CDRH3 as set forth SEQ ID NOs: 1 -3, respectively, and a light chain variable region including a CDRL1 , CDRL2, and CDRL3 as set forth in SEQ ID NOs: 4-6, respectively (e.g., as an induction dose (e.g., as a conditioning dose) or maintenance dose).
  • the heavy chain variable region includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 7, and the light chain variable region includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 8.
  • the heavy chain variable region includes the amino acid sequence set forth in SEQ ID NO: 7
  • the light chain variable region includes the amino acid sequence set forth in SEQ ID NO: 8.
  • the heavy chain includes the amino acid sequence set forth in SEQ ID NO: 9, and the light chain includes the amino acid sequence set forth in SEQ ID NO: 10.
  • the method includes administering the anti-CD40 antibody or antigen-binding fragment thereof (e.g., as an induction dose that is a conditioning dose) from about 1 hour to about 24 hours (e.g., from about 10 hours to about 24 hours) prior to the transplant and administering the anti-CD40 antibody or antigen-binding fragment thereof within about 1 hour to about 24 hours following the transplant, for example, once the subject achieves hemostasis.
  • the antibody or antigen-binding fragment thereof may be administered subcutaneously or intravenously.
  • the induction dose of the anti-CD40 antibody or antigen-binding fragment thereof may be administered as a divided dose (e.g., of at least two doses, in which each dose is about 1 mg/kg to about 20 mg/kg (e.g., about 5 mg/kg or about 10 mg/kg)) or as an undivided dose (e.g., a dose of about 1 mg/kg to about 20 mg/kg (e.g., about 5 mg/kg or about 10 mg/kg)).
  • a divided dose e.g., of at least two doses, in which each dose is about 1 mg/kg to about 20 mg/kg (e.g., about 5 mg/kg or about 10 mg/kg)
  • an undivided dose e.g., a dose of about 1 mg/kg to about 20 mg/kg (e.g., about 5 mg/kg or about 10 mg/kg)).
  • the antibody or antigen-binding fragment thereof is administered within about 1 hour to about 24 hours (e.g., within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours) following the transplant (e.g. as an induction dose), for example, once the subject achieves hemostasis.
  • the transplant e.g. as an induction dose
  • the antibody or antigen-binding fragment thereof is administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, 11 months, and/or one year after the transplant.
  • the antibody or antigen-binding fragment thereof is administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the antibody or antigen-binding fragment thereof is administered at least once every week, once every two weeks, once every three weeks, or once a month for a treatment period of one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • about 1 mg/kg to about 20 mg/kg (e.g., about 5 mg/kg or about 10 mg/kg) of the antibody or antigen-binding fragment thereof is administered at least once every week, once every two weeks, once every three weeks, or once a month for a treatment period of one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the subject is administered one of more additional induction doses (e.g., as a divided dose or an undivided dose, such as 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional induction doses), as described herein, until the pharmacokinetics (PK) of the antibody or antigen-binding fragment thereof.
  • the subject is administered one of more induction doses until the PK of the anti- CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum (e.g., peak and trough concentrations) is replicable or is predictable (e.g., in the desired therapeutic range).
  • multiple induction doses are administered (as described herein) until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range of about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 110 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/mL, 170 pg/mL, 180 pg/mL, 190
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be about 20%, e.g., within 15%, 10%, 5% or less, of each other.
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Cmax of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range of about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 110 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/mL, 170 pg/mL, 180 pg/mL, 190 pg/m
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Cmax of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be about 20%, e.g., within 15%, 10%, 5% or less, of each other.
  • the Cmax of the antibody or antigen-binding fragment thereof in blood, plasma, or serum may be determined over a period of, e.g., 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 28 days.
  • the method may include administering an induction dose and determining the concentration of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum (e.g., the concentration is determined every six hours, every 12 hours, once per day, once every two days, once every three days, once every four days, once every five days, once every six days or once per week).
  • the subject may transition from induction dosing to maintenance dosing.
  • the subject transitions from induction dosing to maintenance dosing when (i) two or more Ctrough of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range (e.g., about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 1 10 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/m
  • the Ctrough and/or the Cmax of the antibody or antigen-binding fragment thereof in blood, plasma, or serum may be determined over a period of, e.g., 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 28 days.
  • the method may include administering an induction dose and determining the concentration of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum (e.g., the concentration is determined every six hours, every 12 hours, once per day, once every two days, once every three days, once every four days, once every five days, once every six days or once per week).
  • a maintenance dose is provided to maintain a minimum blood, plasma, or serum concentration of the humanized anti-CD40 antibody or antigen-binding fragment thereof of at least 150 pg/mL. In some embodiments, the maintenance dose is provided to maintain a minimum blood, plasma, or serum concentration of the humanized anti-CD40 antibody or antigen-binding fragment thereof within the range of at least about 20 pg/mL to about 200 pg/mL, such as at least 20 pg/ml.
  • a serum concentration of the humanized anti-CD40 antibody or antigenbinding fragment thereof is used to guide redosing during maintenance dosing. For example, if a serum concentration drops below a desired or predetermined threshold or range (e.g., from about 20 pg/mL to about 300 pg/mL, e.g., from about 50 pg/mL to about 200 pg/mL, from about 50 pg/mL to about 150 pg/mL, or from about 80 pg/mL to about 150 pg/mL), the subject can be administered a maintenance dose.
  • a desired or predetermined threshold or range e.g., from about 20 pg/mL to about 300 pg/mL, e.g., from about 50 pg/mL to about 200 pg/mL, from about 50 pg/mL to about 150 pg/mL, or from about 80 pg/mL to about 150 pg/mL
  • the subject can be administered one or more “reloading dose(s)” to increase the serum concentration to a desired therapeutic level (e.g., to a concentration of from about 20 pg/mL to about 300 pg/mL, e.g., from about 50 pg/mL to about 200 pg/mL, from about 50 pg/mL to about 150 gg/mL, or from about 80 gg/mL to about 150 gg/mL).
  • a desired therapeutic level e.g., to a concentration of from about 20 pg/mL to about 300 pg/mL, e.g., from about 50 pg/mL to about 200 pg/mL, from about 50 pg/mL to about 150 gg/mL, or from about 80 gg/mL to about 150 gg/mL.
  • the maintenance dose may be administered at a greater dosage than a prior maintenance dose (e.g., a dose of greater than 10 mg/kg or 20 mg/kg) if it is administered following a drop below a desired minimum blood, plasma, or serum concentration (e.g., below about 150 gg/mL or below about 20 gg/mL).
  • a prior maintenance dose e.g., a dose of greater than 10 mg/kg or 20 mg/kg
  • serum concentration e.g., below about 150 gg/mL or below about 20 gg/mL
  • one or more maintenance dose(s) may be administered at a shorter dosing interval than the prior maintenance doses if it is administered following a drop below a desired minimum blood, plasma, or serum concentration (e.g., below about 150 gg/mL or below about 20 gg/mL).
  • the subject can be administered (i) one or more rescue dose(s) of an anti-CD40 antibody or antigen-binding fragment thereof; (ii) one or more increased dose(s) of the anti-CD40 antibody or antigen-binding fragment thereof relative to the dose level administered to the subject prior to the signs or symptoms of transplant rejection; (iii) the anti-CD40 antibody or antigen-binding fragment thereof at an increased dose frequency relative to the dose frequency administered to the subject prior to relative to the dose level administered to the subject prior to the signs or symptoms of transplant rejection, or combinations of (i)- (iii).
  • a subject receiving a dose of about 10 mg/kg once per week may receive an increased dose of, for example, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, or 20 mg/kg once per week.
  • the treatment frequency may be increased, such as from 10 mg/kg once per one or two weeks to 10 mg/kg twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week (e.g., once per day).
  • the method may include administering an antibody or antigen-binding fragment thereof that targets CD40 ligand (CD40L, i.e., CD154) or an antagonist that targets CD154 in place of the anti-CD40 antibody or antigen-binding fragment thereof.
  • CD40L CD40 ligand
  • Suitable antibodies or antigen-binding fragments thereof and antagonists that target CD154 include, for example, dapirolizumab, VIB4920, AT-1501 , and SAR441344 (INX021 ).
  • the method may include monitoring and/or adjusting a dosage of the anti-CD40 antibody or antigen-binding fragment thereof in response to loss or dilution thereof as a result of a procedure during or following a transplant procedure, such as during peri- or postoperative care of the subject.
  • the subject may experience a reduction in the blood, plasma, or serum concentration of the anti-CD40 antibody or antigen-binding fragment thereof as a result of volume shifts due to a loss or infusion of blood or other fluids.
  • the method may include redosing of the anti-CD40 antibody or antigen-binding fragment thereof to increase the blood, plasma, or serum concentration of the anti-CD40 antibody or antigen-binding fragment thereof in the subject.
  • the subject may be treated with an additional therapeutic intervention(s), such as dialysis, extracorporeal membrane oxygenation (ECMO), continuous veno-venous hemofiltration (CVVHW), renal replacement therapy (e.g., continuous hemofiltration and hemodialysis, intermittent hemodialysis and peritoneal dialysis) and the like, or infusion of liquids, e.g., albumin or crystalloid, that may reduce the level of the anti-CD40 antibody or antigen-binding fragment thereof in the blood, plasma, or serum of the subject or may dilute the blood, plasma, or serum concentration of the anti-CD40 antibody or antigen-binding fragment thereof.
  • an additional therapeutic intervention(s) such as dialysis, extracorporeal membrane oxygenation (ECMO), continuous veno-venous hemofiltration (CVVHW), renal replacement therapy (e.g., continuous hemofiltration and hemodialysis, intermittent hemodialysis and peritoneal dialysis) and the like, or infusion of liquids, e.g., albumin or crystalloid
  • the subject may experience a pleural effusion and may, for example, undergo a procedure, such as thoracentesis, to remove the fluid from the lungs.
  • the anti-CD40 antibody or antigen-binding fragment thereof may be present in the pleural effusion, thus removing the anti-CD40 antibody or antigen-binding fragment from circulation.
  • the subject may require plasmapheresis, which removes plasma (and antibodies contained therein) that is separated from the blood of the subject.
  • These therapeutic interventions, and/or the use of external instrumentation may (directly or indirectly) reduce the blood, plasma, or serum cumulative amount or concentration of the anti-CD40 antibody or antigen-binding fragment thereof in the subject, which may require redosing or adjustment of the dose level or dosing frequency of the anti-CD40 antibody or antigen-binding fragment thereof, or of other therapeutic agents.
  • the anti-CD40 antibody or antigen-binding fragment thereof may be re-administered to the subject, or the dosage and/or dosing frequency of the anti-CD40 antibody or antigen-binding fragment thereof may be increased, as needed, to restore or increase the blood, plasma, or serum concentration of the anti-CD40 antibody or antigenbinding fragment thereof in the subject to account for the loss of blood or other fluids, or dilution thereof, due to one or more of these procedures and/or the usage of the external instrumentation.
  • administering is meant a method of giving a dosage of a pharmaceutical composition (e.g., an antibody or antigen-binding fragment thereof as described herein or any of the other agents described herein).
  • a pharmaceutical composition e.g., an antibody or antigen-binding fragment thereof as described herein or any of the other agents described herein.
  • the compositions utilized in the methods described herein can be administered, for example, intravenously and subcutaneously, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbil ically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, by gavage, in cremes, or in lipid compositions, according to methods known in the art for the particular agent.
  • the method of administration can vary depending on various factors (e.g., the components of the composition being administered and the severity of the condition being treated) and by using known guidance
  • antibody and “immunoglobulin (lg)” are used interchangeably in the broadest sense and include monoclonal antibodies (e.g., full-length or intact monoclonal antibodies) and polyclonal antibodies, and may also include certain antibody fragments.
  • An antibody typically comprises both “light chains” and “heavy chains.”
  • the light chains of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (K) and lambda (A), based on the amino acid sequences of their constant domains.
  • hemostasis is meant a status of a subject after a surgical procedure (e.g., following transplant surgery (e.g., after the thoracic cavity is sewn up by a surgeon) in which the flow of blood has substantially or completely ceased (e.g., no bleeding is apparent).
  • a surgical procedure e.g., following transplant surgery (e.g., after the thoracic cavity is sewn up by a surgeon) in which the flow of blood has substantially or completely ceased (e.g., no bleeding is apparent).
  • composition any composition that contains a therapeutically or biologically active agent, such as an antibody or antigen-binding fragment thereof as described herein or any of the other agents described herein.
  • pharmaceutical compositions include the active agent and one or more pharmaceutically acceptable carriers, excipients, or diluents known in the art to be suitable for delivering a therapeutic or biologically active agent.
  • sequence identity or “sequence similarity” is meant that the identity or similarity, respectively, between two or more amino acid sequences, or two or more nucleotide sequences, is expressed in terms of the identity or similarity between the sequences.
  • Sequence identity can be measured in terms of “percentage (%) identity,” in which a higher percentage indicates greater identity shared between the sequences.
  • Sequence similarity can be measured in terms of percentage similarity (which takes into account conservative amino acid substitutions); the higher the percentage, the more similarity shared between the sequences.
  • Homologs or orthologs of nucleic acid or amino acid sequences possess a relatively high degree of sequence identity/similarity when aligned using standard methods.
  • Sequence identity may be measured using sequence analysis software on the default setting (e.g., Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wl 53705). Such software may match similar sequences by assigning degrees of homology to various substitutions, deletions, and other modifications. Sequence identity/similarity can be determined across all or a defined portion of the two or more sequences compared.
  • the phrase “specifically binds” refers to a binding reaction which is determinative of the presence of an antigen in a heterogeneous population of proteins and other biological molecules that is recognized, e.g., by an antibody or antigen-binding fragment thereof, with particularity.
  • An antibody or antigen-binding fragment thereof that specifically binds to an antigen will bind to the antigen with a KD of less than 100 nM.
  • an antibody or antigen-binding fragment thereof that specifically binds to an antigen will bind to the antigen with a KD of up to 100 nM (e.g., between 1 pM and 100 nM).
  • An antibody or antigen-binding fragment thereof that does not exhibit specific binding to a particular antigen or epitope thereof will exhibit a KD of greater than 100 nM (e.g., greater than 500 nm, 1 pM, 100 pM, 500 pM, or 1 mM) for that particular antigen or epitope thereof.
  • a variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein or carbohydrate.
  • solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein or carbohydrate.
  • a “subject” is a vertebrate, such as a mammal (e.g., a primate and a human, in particular a human with underlying health conditions (e.g., cardiovascular disease) that necessitates transplantation of a cell, tissue, or organ).
  • a subject to be treated according to the methods described herein e.g., a human, is one in need of a cell, tissue, or organ transplant. Diagnosis may be performed by any suitable means.
  • a subject to be treated according to the disclosure may have been subjected to standard tests or may have been identified, without examination, as one with suspected tissue or organ failure or one in need of restoration of cellular, tissue, or organ function.
  • Day -1 Rituximab 375mg/m 2 ; Day 0: status post (s/p): Rituximab 375mg/m 2 ; Day 1 : s/p: Rituximab 375mg/m 2 and s/p 1 mg/kg ATG; Day 3: s/p Rituximab 375mg/m 2 , s/p 2 mg/kg ATG.
  • FIG. 2 is a graph showing flow cytometric analysis of lymph nodes performed prior to chest closure following a xenograft heart transplant (day 2). At time of chest closure: s/p cumulative dose administered: Rituximab 375mg/m 2 , s/p 2 mg/kg ATG.
  • FIG. 5 is a graph showing a time course of KPL-404 serum concentrations as a function of time relative to the heart transplant (horizonal line corresponding to xenotransplantation). Also shown as horizontal lines are time courses of abdominal surgery, continuous veno-venous hemofiltration (CVVHW) (hemofiltration), and extracorporeal membrane oxygenation (ECMO).
  • CVVHW continuous veno-venous hemofiltration
  • ECMO extracorporeal membrane oxygenation
  • FIG. 7 is a graph showing an extended time course (relative to FIG. 5) of KPL-404 serum concentrations as a function of time relative to the heart transplant (horizonal line corresponding to xenotransplantation). Also shown as horizontal lines are time courses of abdominal surgery, continuous veno-venous hemofiltration (CVVHW) (hemofiltration), and extracorporeal membrane oxygenation (ECMO).
  • CVVHW continuous veno-venous hemofiltration
  • ECMO extracorporeal membrane oxygenation
  • FIGS. 8A and 8B are graphs showing B cell and T cell counts in peripheral blood following the heart transplant in the human subject.
  • FIG. 8A shows percentage of T cell (CD3+) and B cells (CD20+) in peripheral blood relative to total blood lymphocyte count.
  • FIG. 8B shows percentages of CD4+ and CD8+ T cells in peripheral blood relative to total blood CD4+ and CD8+ T cell count.
  • FIG. 9 show clinical details during postoperative course, labeled in the upper x-axis in relation to donor specific endothelial IgM, IgG and Troponin I levels.
  • the disclosure features methods of treating or reducing the risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject.
  • the subject may have received or is receiving a transplant, such as a cell, organ or tissue transplant.
  • the transplant may be an allogeneic transplant or a xenograft transplant.
  • the methods include administration of an antagonist that targets CD40 or CD154.
  • the methods may include administration of an anti-CD40 antibody or antigen binding fragment thereof, e.g., prior to, on the day of, and/or following the transplant.
  • the antagonists may be anti-CD40 antibodies or antigen-binding fragments thereof or the antagonists may be, e.g., antibodies or antigen-binding fragments thereof that bind to CD154.
  • the methods described herein include administration of an antagonist (e.g., an antibody or antigen-binding fragment thereof) that disrupts the CD40-CD154 interaction.
  • the antagonist may target CD40 or may target CD154.
  • the methods described herein include administration of an antibody or antigen-binding fragment thereof, e.g., derived from the murine 2C10 antibody.
  • the heavy chain variable regions, light chain variable regions, and CDRs of certain anti-CD40 antibodies described herein are shown in Table 1.
  • the antibody or antigen-binding fragment thereof includes (e.g., consists of) a heavy chain variable region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to the heavy chain variable region amino acid sequence as set forth in SEQ ID NO: 7.
  • the antibody or antigen-binding fragment thereof includes (e.g., consists of) a light chain variable region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to a light chain variable region amino acid sequence as set forth in SEQ ID NO: 8.
  • the antibodies or antigen-binding fragments thereof include (e.g., consists of) both a heavy chain variable region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to a heavy chain variable region amino acid sequence as set forth in SEQ ID NO: 7, and a light chain variable region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 8
  • the antibodies or antigen-binding fragments thereof include (e.g., consists of) a heavy chain region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to a heavy chain with the amino acid sequence as set forth in SEQ ID NO: 9, and a light chain region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about
  • anti-CD40 antibodies or antibody fragments thereof are, e.g., Bl 55064, which is described in US Patent No. 8,591 ,900, iscalimab, which is described in US Patent No. 8,828,396, bleselumab, which is described in US Patent No. 9,125,893 and PCT Pub. No. WQ2017100305, BMS- 986325, which is described in US Pub. No. US20210054090 and PCT Pub. No. WQ2021236546, each of the foregoing are hereby incorporated by reference in their entirety, including the amino acid and nucleic acid sequences described therein.
  • polypeptides described herein may be a functionally active variant of the antibodies or antigen-binding fragments thereof disclosed herein, e.g., with less than about 30%, about 25%, about 20%, about 15%, about 10%, about 5% or about 1 % amino acid residues substituted or deleted but that retain essentially the same immunological properties including, but not limited to, binding to CD40.
  • the dissociation constant (KD) of the antibody or antigen-binding fragment thereof is less than about 1 x 10 8 M, e.g., less than about 1 x 10 9 M.
  • the antibodies or antigen-binding fragments thereof may also include one or more analogs of an amino acid (including, for example, non-naturally occurring amino acids, amino acids which only occur naturally in an unrelated biological system, modified amino acids from mammalian systems etc.), polypeptides with substituted linkages, as well as other modifications known in the art.
  • an amino acid including, for example, non-naturally occurring amino acids, amino acids which only occur naturally in an unrelated biological system, modified amino acids from mammalian systems etc.
  • polypeptides with substituted linkages as well as other modifications known in the art.
  • the methods may inhibit transplant rejection for at least one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the methods described herein may include administering to a subject an induction therapy during which the subject is administered one or more doses (e.g., induction doses) of an anti-CD40 antibody or antigen-binding fragment thereof in the perioperative period to cover the immediate post-transplant phase as the period with the highest risk of hyper acute and acute rejection of the transplant.
  • the induction therapy includes a fixed dosing regimen, wherein the subject is administered an anti-CD40 antibody or antigen-binding fragment thereof at a fixed or weight-based dose level, and at a fixed or predetermined dosing interval.
  • the induction therapy includes a pharmacokinetics (PK) target-based dosing regimen, wherein the subject is administered an anti-CD40 antibody or antigen-binding fragment thereof to achieve a desired blood, plasma, or serum concentration (e.g., peak and/or trough concentration) of the anti-CD40 antibody or antigen-binding fragment thereof sufficient to inhibit or suppress CD40 activity in the subject.
  • PK pharmacokinetics
  • the induction therapy continues until the anti-CD40 antibody or antigen-binding fragment thereof achieves replicable or predictable PK in the subject.
  • PK PK behavior in a subject
  • NCA non-compartmental analysis
  • a pharmacokineticist identifies data that are insufficient to generate a PK model and should therefore be excluded.
  • Reasons for excluding data include, for example, an anomalous concentration value, lack of exposure when exposure was expected, and dose failure.
  • the antibody or antigen-binding fragment thereof may be administered prior to the transplant, e.g., from about 1 hour to about 24 hours, e.g., from about 10 hours to about 24 hours prior to the transplant, e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant.
  • the antibody or antigen-binding fragment thereof may be administered on the same day as the transplant.
  • the antibody or antigenbinding fragment thereof may be administered after the transplant.
  • the antibody or antigenbinding fragment thereof may be administered following the transplant within about 1 hour to about 24 hours (e.g., within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours) following the transplant and, for example, once the subject achieves hemostasis.
  • the antibody or antigen-binding fragment thereof is administered after the transplant once the subject achieves hemostasis
  • the antibody or antigen-binding fragment thereof is administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the antibody or antigen-binding fragment thereof is administered at least once per week, once every two weeks, once every three weeks, or once a month for a treatment period of one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the methods described herein may include administering the antibody or antigen-binding fragment thereof as a an induction dose that includes two doses: a first dose of about 1 mg/kg to about 20 mg/kg (e.g., a dose of about 5 mg/kg or about 10 mg/kg) that is administered prior to the transplant (e.g., from about 1 hour to about 24 hours, e.g., from about 10 hours to about 24 hours prior to the transplant (e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant) and a second dose of about 1 mg/kg to about 20 mg/kg (e.g., a dosage of about 5 mg/kg or about 10 mg/kg) that is administered within about 1 hour to about 24 hours (e.g., within about 1 hour
  • an induction dose is administered as a single, undivided dose or a divided dose will depend on the dosing restrictions of the anti-CD40 antibody or antigen-binding fragment thereof, e.g., limits set by the drug’s prescribing information, or as otherwise imposed by relevant clinical experience or restrictions imposed by applicable regulatory authorities.
  • the drug can be administered as a divided dose to achieve the target concentration.
  • an induction dose that is a divided dose may be administered as a first dose and a second dose of the antibody or antigen-binding fragment thereof that are administered about 1 hour to about 24 hours apart, e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours apart, such as from about 1 to about 12 hours apart).
  • the first divided dose of the induction dose may involve administration of from about 1 mg/kg to about 20 mg/kg of the antibody or antigen-binding fragment thereof (e.g., a dosage of about 10 mg/kg) and a second divided dose of the induction dose may involve administration of from about 1 mg/kg to about 20 mg/kg of the antibody or antigen-binding fragment thereof (e.g., a dosage of about 10 mg/kg).
  • the second divided dose of the induction dose may be administered about 1 hour to about 24 hours (e.g., within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours, such as from about 1 to about 12 hours) after the subject receives the first divided dose of the induction dose.
  • the method may involve administration of a divided dose of an induction dose of 20 mg/kg of the antibody or antigen-binding fragment thereof, in which the first divided dose provides about 10 mg/kg of the antibody or antigen-binding fragment thereof and the second divided dose provides about 10 mg/kg of the antibody or antigen-binding fragment thereof.
  • the method may include administering 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more induction doses (e.g., from about 1 to about 5 induction doses, such as, e.g., about 3 or about 4 induction doses).
  • each induction dose e.g., first induction dose, second induction dose, third induction dose, and/or fourth induction dose, or more
  • the first induction dose is a divided dose and any additional induction dose(s) (e.g., first, second, third, and/or fourth, or more induction dose(s)) is/are administered as either a divided dose of the antibody or antigen-binding fragment thereof (e.g., each induction dose including at least two doses in an amount of about 1 mg/kg to about 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg) of the antibody or antigen-binding fragment thereof per dose) or an undivided dose of the antibody or antigen-binding fragment thereof (e.g., each induction dose being a single dose in an amount of about 1 mg/kg to about 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg) of the antibody or antigen-binding fragment thereof).
  • each induction dose including at least two doses in an amount of about 1 mg/kg to about 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg) of the antibody or antigen-bind
  • the first induction dose is a divided dose and any additional induction dose(s) (e.g., first, second, third, and/or fourth, or more induction dose(s)) is/are administered as a divided dose (e.g., each induction dose including at least two doses in an amount of about 1 mg/kg to about 20 mg/kg of the antibody or antigenbinding fragment thereof per dose).
  • any additional induction dose(s) e.g., first, second, third, and/or fourth, or more induction dose(s)
  • each induction dose including at least two doses in an amount of about 1 mg/kg to about 20 mg/kg of the antibody or antigenbinding fragment thereof per dose.
  • the first induction dose is a divided dose and any additional induction dose(s) (e.g., first, second, third, and/or fourth, or more induction dose(s)) is/are administered as an undivided dose (e.g., each induction dose being a single dose in an amount of about 1 mg/kg to about 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg) of the antibody or antigen-binding fragment thereof).
  • any additional induction dose(s) e.g., first, second, third, and/or fourth, or more induction dose(s)
  • each induction dose being a single dose in an amount of about 1 mg/kg to about 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg) of the antibody or antigen-binding fragment thereof).
  • a second induction dose is administered from about 1 day to about 14 days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days) following administration of the first induction dose.
  • second, third, fourth, and/or fifth induction doses are administered from about 1 day to about 14 days apart (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days apart).
  • the subject is administered one of more induction doses until the pharmacokinetics (PK) of the anti-CD40 antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum (e.g., peak and trough concentrations) is replicable or predictable (e.g., the desired therapeutic range).
  • PK pharmacokinetics
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Cmax of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be, the same or in a similar range of about 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 110 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/mL, 170 pg/mL, 180 pg/mL, 190 pg/m
  • multiple induction doses are administered until the PK of the anti-CD40 antibody, or antigen-binding fragment thereof, in the subject’s blood, plasma, or serum is replicable or is predictable, wherein two or more Cmax of the antibody or antigen-binding fragment thereof in the subject’s blood, plasma, or serum determined after two or more administrations are, or can predicted to be about 20%, e.g., within 15%, 10%, 5% or less, of each other.
  • the Cmax of the antibody or antigen-binding fragment thereof in blood, plasma, or serum may be determined over a period of, e.g., 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 28 days.
  • the maintenance dose can be administered to the subject for a treatment period of at least one month (e.g., for a treatment period of at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject).
  • the maintenance dose can be repeatedly administered following the transplant, e.g., once every week, once every two weeks, once every three weeks, or once a month (e.g., once every two or three weeks).
  • the maintenance dose can be administered to the subject for a treatment period of at least one month (e.g., for a treatment period of at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject).
  • the timing of the maintenance dose and/or time between maintenance doses may be selected based on the PK profile of the anti-CD40 antibody or antigen-binding fragment thereof in transplant patients, or the PK profile in a particular subject being treated. Furthermore, the dose amount and/or timing can be titrated as needed or desired.
  • a blood, plasma, or serum concentration of the humanized anti-CD40 antibody or antigen-binding fragment thereof may be used to guide maintenance dosing.
  • a serum concentration drops below a desired or predetermined threshold or range (e.g., from about 20 pg/mL to about 300 pg/mL, e.g., from about 50 pg/mL to about 200 pg/mL, from about 50 pg/mL to about 150 pg/mL, or from about 80 pg/mL to about 150 pg/mL)
  • the subject can be administered a maintenance dose.
  • the maintenance dose may be administered at a greater dosage than a prior maintenance dose (e.g., a dose of greater than 10 mg/kg or 20 mg/kg) if it is administered following a drop below a desired minimum blood, plasma, or serum concentration (e.g., below about 150 pg/mL or below about 20 pg/mL).
  • one or more maintenance dose(s) may be administered at a shorter dosing interval than the prior maintenance doses if it is administered following a drop below a desired minimum blood, plasma, or serum concentration (e.g., below about 150 pg/mL or below about 20 pg/mL).
  • the subject can be administered (i) one or more rescue dose(s) of an anti-CD40 antibody or antigen-binding fragment thereof; (ii) one or more increased dose(s) of the anti-CD40 antibody or antigen-binding fragment thereof relative to the dose level administered to the subject prior to the signs or symptoms of transplant rejection; (iii) the anti-CD40 antibody or antigen-binding fragment thereof at an increased dose frequency relative to the dose frequency administered to the subject prior to relative to the dose level administered to the subject prior to the signs or symptoms of transplant rejection, or combinations of (i)- (iii).
  • the blood, plasma, or serum concentration of the antibody or antigen-binding fragment thereof may be measured following administration of the antibody using an immunoassay.
  • the immunoassay may employ plates coated with an anti-ID antibody as the capture antigen.
  • Calibration standards and quality control (QC) samples may be prepared by diluting stock solutions of the antibody or antigenbinding fragment thereof into undiluted human serum, followed by subsequent serial dilution with undiluted human serum to the desired antibody concentration.
  • Prepared calibrators, quality control samples and study human serum samples may be diluted to a minimum required dilution (MRD) of 1 :200 using Assay Diluent prior to loading onto the pre-coated plates.
  • MRD minimum required dilution
  • the calibration curve range of this method may be, for example, 8000 ng/mL to 80.0 ng/mL in 100% human serum. Calibrators outside the evaluated range of the assay at 10000 ng/mL and 40.0 ng/mL in 100% human serum may be included as anchor points to facilitate curve-fitting.
  • the methods described herein may include adjusting a dosage of the anti-CD40 antibody or antigen-binding fragment thereof in response to loss following administration.
  • the subject may experience significant blood loss (e.g., as a result of the transplant surgery or another surgical procedure) that could require redosing to mitigate a reduced concentration of the anti- CD40 antibody or antigen-binding fragment thereof in the subject.
  • the subject may be treated with an additional therapeutic intervention(s), such as dialysis, extracorporeal membrane oxygenation (ECMO), continuous veno-venous hemofiltration (CVVHW), mechanical ventilation, and the like, or infusion of liquids, e.g., albumin or crystalloid, that may dilute the blood, plasma, or serum concentration of the anti-CD40 antibody or antigen-binding fragment thereof.
  • an additional therapeutic intervention such as dialysis, extracorporeal membrane oxygenation (ECMO), continuous veno-venous hemofiltration (CVVHW), mechanical ventilation, and the like
  • liquids e.g., albumin or crystalloid
  • the subject may experience a pleural effusion and, for example, may undergo thoracentesis to remove the fluid from the lungs.
  • the anti-CD40 antibody or antigen-binding fragment thereof may be present in the pleural effusion.
  • the subject may require plasmapheresis, which removes plasma (and antibodies contained therein) that is separated from the blood of the subject.
  • These therapeutic interventions, and/or the use of external instrumentation may (directly or indirectly) reduce the blood, plasma, or serum concentration of the anti-CD40 antibody or antigen-binding fragment thereof in the subject, which may require redosing or adjustment of the dose level or dosing frequency of the anti-CD40 antibody or antigen-binding fragment thereof, or of other therapeutic agents. Accordingly, it is possible that the serum levels of the anti-CD40 antibody or antigen-binding fragment thereof are drastically reduced during or as a result of one or more of these procedures.
  • the blood, plasma, or serum concentration of the anti-CD40 antibody or antigen-binding fragment thereof may be monitored prior to, during, or following one or more of these procedures.
  • the anti-CD40 antibody or antigen-binding fragment thereof may be re-administered to the subject, or the dosage and/or dosing frequency of the anti-CD40 antibody or antigen-binding fragment thereof may be increased, as needed, to restore or increase the blood, plasma, or serum concentration of the anti-CD40 antibody or antigen-binding fragment thereof, to account for the loss of blood or other fluids, blood dilution or loss due to one or more of these procedures and/or the usage of the external instrumentation.
  • the level of other therapeutic agents may also be monitored for loss and re-administered, as needed.
  • the methods described herein include performing a transplant (e.g., a cell, organ, or tissue transplant) in a subject.
  • a transplant e.g., a cell, organ, or tissue transplant
  • Methods of transplantation are well known and can be performed by a physician skilled in the art.
  • the transplant may be an allogeneic transplant.
  • the transplant may be a xenograft transplant, e.g., a cell, organ, or tissue from a different species.
  • the transplant may include a heart, kidney, lung, liver, pancreas, intestine, thymus, skin, eye, uterus, stem cell, bone, tendon, cornea, heart valve, nerve, vein, or a portion thereof.
  • the xenograft transplant may a cell, organ, or tissue that has been genetically engineered, e.g., to add, modify, or remove one or more xenoreactive antigens.
  • the transplant is a xenograft transplant that includes a cell, organ (or portion thereof), or tissue from a pig, cow, horse, dog, cat, sheep, goat, non-human primate (e.g., a macaque (e.g., a rhesus macaque or a cynomolgus macaque), a baboon, a marmoset, a monkey, and a chimpanzee), or gorilla.
  • a macaque e.g., a rhesus macaque or a cynomolgus macaque
  • gorilla e.g., a baboon, a marmoset, a monkey, and a chimpanzee
  • the xenograft transplant may be a porcine heart.
  • the xenograft transplant may be a porcine kidney.
  • the xenograft transplant includes a cell, organ or portion thereof, or tissue from a host animal that has been genetically engineered, e.g., to add, modify, or remove one or more xenoreactive antigens.
  • Such genetically engineered animals are described, for example, in Lu, et al. Front. Immunol. 10, 3060, 2020, which is herein incorporated by reference in its entirety (see also Table 2). See also, for example, U.S. Pat. Nos. 10,912,863 and 11 ,179,496 and US 2018/0249688, each of which is incorporated herein by reference in their entirety.
  • a cell, tissue, or organ transplant can be prepared according to methods known in the art.
  • the organ transplant is a xenotransplant, e.g., an organ (e.g., heart) from a pig, and the host animal has been genetically engineered.
  • the host may have been engineered to add, remove, or modify one or more xenoreactive antigens, e.g., to prevent transplant rejection.
  • Suitable systems and methods are known in the art, e.g., as described in U.S. Pat. Nos. 11 ,179,496 and 10,912,863 and US Pub. No. 2018/0249688, the disclosures of which are hereby incorporated by reference in their entirety.
  • certain pharmaceutical compositions e.g., the anti-CD40 antibody or antigen-binding fragment thereof or any other therapeutic agent described herein, e.g., an anti-CD20 antibody, such as rituximab, and/or anti-thymocyte globulin and/or anti-IL-2Ra receptor antibody
  • an anti-CD20 antibody such as rituximab
  • hemostasis may include a visual or qualitative assessment by the surgeon. Following hemostasis, the subject may be able to leave the operating room and go to recovery.
  • transplant rejection can be characterized as hyperacute rejection, acute rejection, or chronic rejection.
  • Hyperacute rejection occurs immediately after the transplant to about 48 hours after the transplant (e.g., when the transplant contains antigens that are mismatched relative to the recipient).
  • Acute rejection occurs from about 2 days to about 3 months after the transplant.
  • Chronic rejection occurs when the immune system continually attacks the transplant over time, ultimately reducing or permanently damaging the functionality of the transplant.
  • the methods described herein can be used treat or reduce the risk of hyperacute transplant rejection.
  • the methods described herein can also be used to treat or reduce the risk of acute transplant rejection and/or chronic transplant rejection.
  • the subject can be administered (i) one or more rescue induction dose or maintenance dose, respectively, of the antibody or antigen-binding fragment in addition to the scheduled or anticipated doses; (ii) one or more increased dose(s) of the antibody or antigen-binding fragment relative to the dose level administered to the subject prior to the increase in troponin levels; (iii) the antibody or antigen-binding fragment at an increased dose frequency relative to the dose frequency administered to the subject prior to the increase in troponin levels.
  • the subject can be administered (i) a rescue induction dose or maintenance dose, respectively, of the antibody or antigen-binding fragment in addition to the scheduled or anticipated doses; (ii) one or more increased dose(s) of the antibody or antigen-binding fragment relative to the dose level administered to the subject prior to the signs or symptoms of transplant rejection; (iii) the antibody or antigen-binding fragment at an increased dose frequency relative to the dose frequency administered to the subject prior to relative to the dose level administered to the subject prior to the signs or symptoms of transplant rejection, or combinations of (i)-(iii).
  • Other biomarkers evidencing rejection of the transplanted tissue are well known in the art.
  • the methods described herein may further include administering a therapeutic agent that depletes or reduces B cells in the subject.
  • the therapeutic agent may be, for example, rituximab.
  • the therapeutic agent may be administered prior to the transplant (e.g., from about 1 hour to about 24, e.g., about 3 hours to about 24 hours, such as at about 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant).
  • the therapeutic agent may be administered after the transplant (e.g., one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, and/or four weeks after the transplant).
  • the methods described herein may further include administering a therapeutic agent that depletes or reduces T cells in the subject.
  • the therapeutic agent may be, for example, anti-thymocyte globulin, e.g., THYMOGLOBULIN® or ATGAM®.
  • the therapeutic agent may be administered prior to the transplant (e.g., from about 1 hour to about 24 hours prior to the transplant, e.g., about 3 hours to about 24 hours, such as about 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours prior to the transplant).
  • the therapeutic agent is administered on the same day as the transplant.
  • the therapeutic agent e.g., anti-thymocyte globulin, e.g., THYMOGLOBULIN® or ATGAM®, or anti-IL-2Ra receptor antibody
  • the therapeutic agent is administered at a dosage of about 1 mg/kg to about 10 mg/kg, e.g., about 2 mg/kg or about 5 mg/kg.
  • the therapeutic agent is THYMOGLOBULIN® and is administered at a dosage of about 2 mg/kg.
  • the therapeutic agent is ATGAM® and is administered at a dosage of about 5 mg/kg.
  • the therapeutic agent may be administered intravenously.
  • the methods described herein may further include administration of an additional therapeutic agent, e.g., prior to, on the same day as, or following the transplant.
  • the method may include administration of any drug required to maintain suppression of the immune system or promote recovery following surgery.
  • the method may further include administering one or more of a steroid (e.g., methylprednisolone), an antihistamine (e.g., diphenhydramine), an H2 receptor blocker (e.g., famotidine), an antiviral agent (e.g., ganciclovir), a complement inhibitor (e.g., a C1 esterase inhibitor), an immunosuppressive agent (e.g., an anti-IL-6R antibody, such as tocilizumab, and/or mycophenolate mofetil), an anti-inflammatory agent (e.g., TNFa protein, such as etanercept, or a non-steroidal antiinflammatory agent (NSAID, such as aspirin and naproxen), an anticoagulant (
  • the methods described herein may further include administering a steroid, such as methylprednisolone, or other steroid known in the art.
  • a steroid such as methylprednisolone, or other steroid known in the art.
  • the methylprednisolone is administered once per day or twice per day.
  • the methylprednisolone may be administered at a dosage of about 2 mg/kg.
  • the methylprednisolone may be administered prior to the transplant.
  • the methylprednisolone may be administered one day prior to the transplant.
  • the methylprednisolone may be administered on the same day as the transplant.
  • the methylprednisolone may be administered after the transplant.
  • the methylprednisolone may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, and/or six months after the transplant.
  • the methylprednisolone may be administered for a treatment period of 2 months, seven weeks, six weeks, five weeks, four weeks, three weeks, two weeks, one week, six days, five days, four days, three days, two days, or one day.
  • the methods described herein may further include administering an antihistamine, such as diphenhydramine, or other antihistamine known in the art.
  • the diphenhydramine may be administered at a dosage of about 50 mg.
  • the diphenhydramine may be administered intravenously.
  • the diphenhydramine may be administered prior to the transplant.
  • the diphenhydramine may be administered one day prior to the transplant.
  • the diphenhydramine may be administered on the same day as the transplant.
  • the diphenhydramine may be administered after the transplant.
  • the diphenhydramine may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, and/or four weeks after the transplant.
  • the diphenhydramine may be administered for a treatment period of 2 months, seven weeks, six weeks, five weeks, four weeks, three weeks, two weeks, one week, six days, five days, four days, three days, two days, or one day.
  • the methods described herein may further include administering an H2 receptor blocker, such as famotidine, or other H2 receptor blocker known in the art.
  • the famotidine may be administered at a dosage of about 20 mg.
  • the famotidine may be administered once per day or twice per day.
  • the famotidine may be administered prior to the transplant.
  • the famotidine may be administered one day prior to the transplant.
  • the famotidine may be administered on the same day as the transplant.
  • the famotidine may be administered after the transplant.
  • the famotidine may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, and/or eight weeks after the transplant.
  • the famotidine may be administered for a treatment period of 2 months, seven weeks, six weeks, five weeks, four weeks, three weeks, two weeks, one week, six days, five days, four days, three
  • the methods described herein may further include administering an antiviral agent, such as ganciclovir, or another antiviral agent known in the art.
  • the ganciclovir may be administered at a dosage of about 5 mg/kg.
  • the ganciclovir may be administered prior to the transplant.
  • the ganciclovir may be administered one day prior to the transplant.
  • the ganciclovir may be administered on the same day as the transplant.
  • the ganciclovir may be administered after the transplant.
  • the ganciclovir may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the ganciclovir may be administered daily for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the methods described herein may further include administering a complement inhibitor, such as C1 esterase inhibitor, or other complement inhibitor known in the art.
  • a complement inhibitor such as C1 esterase inhibitor, or other complement inhibitor known in the art.
  • the C1 esterase inhibitor may be administered at a dosage of about 20 U/kg.
  • the C1 esterase inhibitor may be administered prior to the transplant.
  • the C1 esterase inhibitor may be administered one day prior to the transplant.
  • the C1 esterase inhibitor may be administered on the same day as the transplant.
  • the C1 esterase inhibitor may be administered after the transplant.
  • the C1 esterase inhibitor may be administered one day, two days, three days, four days, five days, six days, and/or one week after the transplant.
  • the methods described herein may further include administering an immunosuppressive agent, such as tocilizumab, or another immunosuppressive agent known in the art.
  • the tocilizumab may be administered at a dosage of about 8 mg/kg.
  • the tocilizumab may be administered intravenously.
  • the tocilizumab may be administered on the same day as the transplant.
  • the tocilizumab may be administered after the transplant.
  • the tocilizumab may be administered one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, and/or twelve months after the transplant.
  • the tocilizumab may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the tocilizumab may be administered monthly for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the methods described herein may further include administering an anti-inflammatory agent, such as etanercept or another anti-inflammatory agent known in the art.
  • the etanercept may be administered at a dosage of about 0.7 I U/kg .
  • the etanercept may be administered subcutaneously.
  • the etanercept may be administered on the same day as the transplant.
  • the etanercept may be administered after the transplant.
  • the etanercept may be administered one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, and/or twelve months after the transplant.
  • the etanercept may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the etanercept may be administered weekly for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the methods described herein may further include administering an immunosuppressive agent, such as mycophenolate mofetil, or another immunosuppressive agent known in the art.
  • the mycophenolate mofetil may be administered at a dosage of about 20 mg/kg.
  • the mycophenolate mofetil may be administered intravenously.
  • the mycophenolate mofetil may be administered once per day or twice per day.
  • the mycophenolate mofetil may be administered on the same day as the transplant.
  • the mycophenolate mofetil may be administered after the transplant.
  • the mycophenolate mofetil may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the mycophenolate mofetil may be administered daily for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the heparin may be administered for a treatment period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the heparin may be administered daily for a treatment period of at least one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject.
  • the methods described herein may further include administering a non-steroidal antiinflammatory agent (NSAID), such as aspirin.
  • NSAID non-steroidal antiinflammatory agent
  • the aspirin may be administered at a dosage of about 81 mg.
  • the aspirin may be administered after the transplant.
  • the aspirin may be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, and/or ten years after the transplant.
  • an anti-CD40 antibody or antigen-binding fragment thereof such as those described herein (e.g., an antibody or antigen-binding fragment thereof that includes a heavy chain variable region including a CDRH1 , CDRH2, and CDRH3 as set forth SEQ ID Nos: 1 -3, respectively, and a light chain variable region including a CDRL1 , CDRL2, and CDRL3 as set forth in SEQ ID Nos: 4-6, respectively, such as an antibody or antigen-binding fragment thereof with a heavy chain that includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 7 or 9, and a light chain that includes an amino acid sequence having at least 85% (e.g., at least 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO:
  • the antibody or antigenbinding fragment thereof can be formulated in a pharmaceutical composition in a concentration of about 50 to about 300 mg/mL, and optionally, in a volume of about 0.5 mL to about 2.0 mL (e.g., about 1 .0 mL).
  • the amino acid is one or more of alanine, arginine, aspartic acid, asparagine, carnitine, citrulline, ornithine, glycine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.
  • the composition may also include acetate may include, for example, sodium acetate (e.g., in salt form) or acetate in its ionic form.
  • the composition includes, for example, sucrose, arginine, glutamate, or sorbitol, or a combination thereof.
  • the excipient is sucrose. In some embodiments the polar excipient is arginine. In some embodiments the excipient is glutamate. In some embodiments, the excipient is a mixture of arginine and glutamate. In some embodiments, the excipient is sorbitol.
  • the antibody or antigen-binding fragment thereof may be provided in a container including a pharmaceutical composition as described herein.
  • suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds a pharmaceutical composition as described herein, e.g., that is effective for treating the condition, and may have a sterile access port.
  • the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle.
  • the label on or associated with the container indicates that the composition is used for treating the condition of choice.
  • the kit may further include a second container with a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • a pharmaceutically acceptable buffer such as phosphate-buffered saline, Ringer's solution, and dextrose solution.
  • a pharmaceutically acceptable buffer such as phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • the antibody or antigen-binding fragment thereof may be present in the container at a concentration of from about 50 mg/mL to about 300 mg/mL (e.g., 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, 200 mg/mL, 210 mg/mL, 220 mg/mL, 230 mg/mL, 240 mg/mL, 250 mg/mL, 260 mg/mL, 270 mg/mL, 280 mg/mL, 290 mg/mL, or 300 mg/mL), such as at a concentration of about 100 mg/mL or about 200 mg/mL.
  • a concentration of from about 50 mg/mL to about 300 mg/mL e.g., 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL
  • the composition may be formulated in a single use vial with about 1 .0 mL or 2.0 mL extractable volume.
  • the composition can be formulated in a volume of about 0.1 mL to about 2.0 mL (e.g., 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1 .0 mL, 1 .1 mL, 1 .2 mL, 1 .3 mL, 1 .4 mL, 1 .5 mL, 1 .6 mL, 1 .7 mL, 1 .8 mL, 1 .9 mL, or 2.0 mL), such as a volume of about 1 .0 mL.
  • An anti-CD40 antibody, KPL-404 can be used to treat or reduce the risk of (e.g., inhibit or prevent) xenotransplantation rejection, and the treatment may be performed in conjunction with additional immunosuppressive treatments.
  • the method was performed in a pig-to-baboon orthotopic cardiac xenotransplantation model using a baboon that received transplantation of a heart from a pig that was genetically modified to include 10 gene modifications that eliminated expression of antigens that are known to provoke humoral and cellular immune responses.
  • a conventional Papio anubis baboon weighing 15-30 kg was screened to eliminate specific pathogens of interest and used as a recipient.
  • a weight-matched German Landrace pig, with the genetics described in Table 2, was used as a cardiac donor (supplied by Revivicor Inc. Blacksburg, VA).
  • An orthotopic porcine heart transplant was performed in the baboon.
  • the immunosuppressive regimen for the recipient baboon included induction therapy and maintenance therapy, as shown in Table 3.
  • Induction immunotherapy includes anti-thymocyte globulin (THYMOGLOBULIN®), anti-CD20 antibody (RITUXAN®) for T and B cell suppression and humanized anti-CD40 antibody (KPL-404); for blocking the CD40/CD154 co-stimulation pathway, and antiinflammatory drugs, Tociluzimab and Etanercept.
  • C1 Esterase Inhibitor (Berinert) was used to inhibit complement activation.
  • Maintenance immunotherapy included administration of Mycophenolate Mofetil (MMF) and the anti-CD40 antibody (KPL-404) and the anti-inflammatory drugs, Tociluzimab and Etanercept.
  • the baboon received continuous heparin infusion to keep the activated clotting time (ACT) level twice the baseline.
  • Ganciclovir was administered daily to prevent Cytomegalovirus (CMV) infection.
  • Other medications include Ep
  • the baboon is recovering with no signs of transplant rejection, as measured by echnocardiography and Troponin levels, which is are markers of cardiac function.
  • the echocardiogram showed normal function, and the troponin plasma levels were normal.
  • T-cell cytotoxicity e.g., via CD40 blockade on antigen presenting cells.
  • THYMOGLOBULIN® would be expected to reduce T cells to about 1 -10% in an equivalent procedure performed in humans.
  • anti-CD40 treatment in a human subject that undergoes a transplant would mitigate transplant rejection caused by any remaining B- or T-cells, given that the treatments do not completely ablate these cells in the subject.
  • Anti-CD40 treatment would also be expected to reduce or inhibit transplant rejection as the B- and T-cells begin to regenerate after B- and T-cell reducing agent treatment is ceased or titrated downward.
  • the baboon received a high dose of the KPL-404 antibody (e.g., 25-50 mg/kg), this was done to ensure an excess of the antibody over what would likely be required to treat or reduce the risk of transplant rejection. Accordingly, it would be understood that a reduction in the risk of transplant rejection could be achieved in a subject (e.g., a human subject) that receives a dosage of KPL-404 of less than 25- 50 mg/kg, such as a dosage of about 1 mg/kg to about 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg).
  • a subject e.g., a human subject
  • a dosage of KPL-404 of less than 25- 50 mg/kg, such as a dosage of about 1 mg/kg to about 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg).
  • FIGS 6A-6C show percentages of B cells and T cells counts in peripheral blood relative to total blood lymphocyte count
  • FIGS. 6D-6F show absolute numbers of B and T cells in peripheral blood.
  • LVEF left ventricular ejection fraction
  • the patient did not meet criteria for allotransplantation or for a ventricular assist device (VAD) due to severe sarcopenia and a three-week non-ambulatory status. There was also concern about the effectiveness of a VAD due to his severe biventricular failure with ventricular arrythmias. Given single organ failure, the patient was considered for experimental xenotransplantation. Despite his biventricular failure, the patient exhibited preserved renal function and required only intermittent nasal cannula for mild hypoxia. His pre-transplant ICU course was notable for adrenal insufficiency, gastrointestinal bleeding, bacteremia, which cleared with antimicrobial therapy, and drug induced leukopenia. He underwent cardiac xenotransplantation from a genetically modified pig source animal. The human subject received a porcine heart xenograft transplant generally according to the following protocol.
  • the pig was supplied by Revivicor, Inc. and was clonally derived from fibroblasts, a cell line that included 10 gene edits (see, e.g., U.S. Pat. Nos. 10,912,863 and 1 1 ,179,496 and US 2018/0249688, each of which is incorporated herein by reference in their entirety) to render the cardiac xenograft more compatible for transplantation into a human.
  • 10 gene edits see, e.g., U.S. Pat. Nos. 10,912,863 and 1 1 ,179,496 and US 2018/0249688, each of which is incorporated herein by reference in their entirety
  • the pig heart was procured from the source animal. Non-ischemic perfusion of the 328 gm pig heart using the XVIVO system lasted 114 minutes. Perfusate was cooled to 8 degrees centigrade. It consisted of 4 parts Steen cardiac solution mixed with one part human blood which was type-matched to the recipient. Perfusion was fixed at 20mmHg in the aortic root. Flow increased from 148 cc/min to 194 cc/min suggesting coronary relaxation. Total cold ischemia time was 150 minutes. The implant required 63 minutes and was interrupted three times for intermittent cardioplegia with XVIVO perfusate harvested from the circuit.
  • the XVIVO system was transported into the hospital’s operating room from the laboratory operating room.
  • the redo sternotomy in the anesthetized patient was delayed until the donor heart was delivered.
  • Implantation was performed using a biatrial anastomosis followed by separation from cardiopulmonary bypass following the xenotransplantation.
  • PBMCs were monitored by flow cytometry for B (CD20+) and T (CD3+) lymphocytes.
  • KPL-404 levels were monitored at peak, trough, and longitudinally over time. Prior to transplantation, donor-specific IgM and IgG antibody levels were acceptably low.
  • TTE Serial transthoracic echocardiography
  • embx Endomyocardial biopsies
  • H&E Hematoxylin & Eosin
  • IHC immunohistochemistry
  • xd- cfDNA Xenograft-derived cell free DNA
  • Heat-inactivated patient serum was incubated with 10GE source animal aortic endothelial cells (pAEC) for 2 hrs at 4°C. Untreated pAECs were used as a negative assay control. Heat inactivated serum samples from healthy subjects known to have high (High Human) and low (Low Human) levels of anti- non-gal antibodies, served as controls. After incubation, pAEC were washed twice with PBS and nonspecific protein-binding sites were blocked with 10% normal goat serum (Abeam, MA, USA) for 20 min at 4°C.
  • pAEC 10GE source animal aortic endothelial cells
  • the organ transplant was successful, and the subject recovered from the surgery and was observed to have no signs of xenotransplant hyperacute rejection or acute rejection three days after surgery.
  • blood loss was estimated to be >3 liters (KPL-404 was administered after hemostasis).
  • cell saver 1800 cc (washed packed red cells) were administered.
  • Blood products that were infused included 8 units of PRBCs, 4 units of platelets, 6 units FFP (with extra C1 Esterase Inhibitor (Berinert)) to account for infused complement), 341 cc Cryo, 24 mcg desmopressin (DDAVP®), and 2226 mg fibrinogen (Table 7 and 8).
  • the following dosages indicate the cumulative dose of the respective drugs administered to the subject at the indicated time of blood sample collection for flow cytometry: Day -1 : prior to induction; Day 0: s/p Total: Rituximab 375mg/m 2 ; Day 1 : s/p Total: Rituximab 375mg/m 2 and s/p 1 mg/kg anti-thymocyte globulin; Day 3: s/p Rituximab 375mg/m 2 , s/p 2 mg/kg anti-thymocyte globulin.
  • Flow cytometry analysis of the peripheral bloodstream indicated depletion of B cells by Day 0 (see quadrant 3) and depletion of T cells by Day 3 (see quadrant 1 ).
  • T cells were still present immediately following surgery, as shown in quadrant 1 of FIG. 1 on Day 0 and Day 1 as, in this case, ATG was not administered until after surgery (day 1 ).
  • B-cells were largely ablated in the periphery, other sources of CD40 exist that could contribute to transplant rejection.
  • CD40 is present on several other cell-types, including antigen presenting cells (APCs), which could contribute to T-cell activation and transplant rejection.
  • APCs antigen presenting cells
  • platelet-derived CD154 (CD40L) release as a result of surgery may be sufficient to initiate transplant rejection independent of any cellular source of this molecule (Xu et al., J. Clin. Invest. 2006; 116(3):769- 774).
  • CD154 is a cell surface molecule expressed on activated T-cells that binds CD40, an activating molecule on APCs, which are believed to promote graft rejection. Together, this supports the role for CD40 blockade to reduce the risk of transplant rejection even in a subject who has undergone ablation of peripheral B-cells and/or T-cells.
  • Flow cytometric analysis was performed on lymph nodes that were removed from the subject on the day the subject’s chest was closed (day 2) following the heart transplant.
  • the cumulative dose of the respective drugs administered to the subject were as follows: s/p Total: Rituximab 375mg/m 2 , s/p 2 mg/kg anti-thymocyte globulin (FIG. 2).
  • flow cytometry analysis shows the presence of B-cells (quadrant 3) and T-cells (quadrant 1 ) in the lymph nodes immediately before chest closure on Day 2, suggesting that (as expected) the rituximab and anti-thymocyte globulin did not fully deplete the B-cells or T-cells in solid tissue, even though the cells were depleted in the bloodstream (FIG. 1 ).
  • CD3 23 absolute
  • CD4 17 absolute
  • CD8 ⁇ 10
  • KPL-404 preparation nine vials for each dose were used, drawn up 8.5 ml for 850 mg (10 mg/kg). Heparin was given on Day 0 (30,000 units Bolus) and 250 mg protamine was administered prior to leaving operating room. Running partial thromboplastin time (PTT) was 45-55 seconds. 1 .5x ULN was administered for the last 3 days with Bivalrudin ⁇ 0.06mcg/kg/min. Extracorporeal membrane oxygenation (ECMO) was removed on Day 4.
  • PTT partial thromboplastin time
  • Troponin levels were measured in the subject (FIG. 3).
  • Troponin is a biomarker for transplant rejection and is released by the heart’s myocytes in response to injury.
  • the subject exhibited an increase in serum troponin I levels postoperatively, but these levels decreased to baseline by POD24 suggesting that the heart recovered from the surgical procedure and that no transplant rejection occurred following the transplantation procedure.
  • Troponin I levels began increasing by POD 35, although it was later determined by endomyocardial biopsy (POD 50) that this did not appear to be a result of rejection, as there were no signs of antibody or acute cellular rejection (International Society for Heart and Lung Transplantation (ISHLT) Grade 0).
  • LVEF Left ventricular ejection fraction
  • RV right ventricular
  • GLS global longitudinal strain
  • embx demonstrated no evidence of rejection and the heart revealed a right atrial pressure of 5 mmHg, pulmonary artery pressure of 25/15 mmHg, cardiac index of 2.7 (L/min/BSA) and a mixed venous saturation of 65% (Hgb 8.1 gm/dL).
  • the patient was able to rehabilitate without any cardiovascular support and the xenograft functioned normally without evidence of rejection.
  • Endomyocardial biopsy did not demonstrate antibody or acute cellular rejection (International Society for Heart and Lung Transplantation (ISHLT) Grade 0). There was focal capillary damage with extravasated erythrocytes and edema. Antibody staining, IgG greater than IgM, in capillaries was present but was negative for C3d or C4d. There was a single ischemic myocyte and no cellular infiltrates either on H&E or IHC by CD3+ or CD68+ staining. Troponin I was rising (FIG. 9) and it was also determined that xd-cfDNA and serum levels of xenograft-specific IgG, and to lesser extent, IgM were peaking.
  • Biventricular wall thickening improved slightly.
  • the patient was slowly able to be weaned from 4.5 Umin of VA-ECMO flows down to 3 L/min without the need for catecholamine support. Further echocardiographs did not demonstrate improvement of wall thickness or GLS and ECMO could not be weaned below 2 L/min.
  • KPL-404 blood serum concentration was measured following administration of the antibody (FIG. 4). Following dose 1 (part 1 of the first induction dose), the blood serum concentration reached maximum (peak) concentration of about 100 pg/mL and a minimum (trough) concentration of ⁇ 20 pg/mL before a subsequent second dose (part 2 of the first induction dose) was administered. This contrasts with previous phase 1 studies in which the normalized blood serum concentration was over 250 pg/mL at a similar time point.
  • FIG. 5 An extended time course is shown in FIG. 5, illustrating a minimum KPL-404 concentration of 20 pg/mL was sufficient to prevent transplant rejection.
  • the serum concentration of KPL-404 was determined using an immunoassay.
  • the KPL-404 immunoassay employed plates coated with an anti-ID antibody as the capture antigen.
  • Calibration standards and quality control (QC) samples are prepared by diluting stock solutions of KPL-404 into undiluted human serum, followed by subsequent serial dilution with undiluted human serum to the desired KPL-404 concentration.
  • Prepared calibrators, quality control samples and study human serum samples were diluted to a minimum required dilution (MRD) of 1 :200 using Assay Diluent prior to loading onto the pre-coated plates. The plates were incubated to allow the KPL-404 present in the samples to bind to the target and subsequently washed to remove unbound material.
  • MRD minimum required dilution
  • Mouse anti-Hu lgG4 pFc HRP was then added to the plate to bind the KPL-404.
  • the plates were further incubated, and then washed to remove any unbound materials.
  • TMB substrate was then added to the plates and then the reaction was stopped by adding 1 N H2SO4.
  • the plate was read immediately using a SPECTRAMAX® Plus 384 (450 nm for detection and 650 nm for background) microplate reader.
  • the resulting OD values (detection OD at 450 nm minus background OD at 650 nm) obtained from the calibration standards were fitted using a 4-PL logistic equation with 1 Zy2 to calculate the KPL-404 concentrations in the quality control and study samples.
  • the calibration curve range of this method was 8000 ng/mL to 80.0 ng/mL in 100% human serum. Calibrators outside the evaluated range of the assay at 10000 ng/mL and 40.0 ng/mL in 100% human serum may be included as anchor points to facilitate curve-fitting.
  • FIG. 7 An updated extended time course over 60 days is shown in FIG. 7, and no signs of transplant rejection were observed in the subject at this time.
  • a time course of therapeutic administrations corresponding to the times shown in FIG. 7 is provided in Table 9.
  • the dotted line in FIG. 7 corresponds to the original calculation of concentration of KPL-404 (e.g., as shown in FIG. 5). Due to minor inconsistencies in the assay, these samples were re-run using the same protocol but with different machines. The result of the re-analysis is shown by the solid line. The overall trend is similar between the dotted and solid lines, but with slight variation of the peaks. One hypothesis for the discrepancy may be that the original assay was less sensitive and, thus, resulted in a higher readout than was actually present.
  • Antibody mediated rejection was not detected by ISHLT criteria, with the exception of mild C4d staining POD 56 (which includes IgM/IgG staining and C4d staining of intact myocardium, monocellular infiltrate and endotheliitis with myocardial thickening from fibrosis).
  • C4d staining POD 56 which includes IgM/IgG staining and C4d staining of intact myocardium, monocellular infiltrate and endotheliitis with myocardial thickening from fibrosis.
  • microthrombi, massive intracellular hemorrhage, myocyte necrosis with pyknotic nuclei and occasional cellular infiltrate are generally present in xenografts with antibody mediated rejection, which was absent in this case. No evidence of pathology outside of the heart related to the xenotransplantation and associated therapeutics were observed on preliminary autopsy.
  • IVIg was administered twice during the patient’s postoperative course (FIG. 7 and Table 9).
  • the first dose on POD 43 for infectious concerns.
  • the second dose on POD 50 for treatment of presumed antibody mediated rejection after initial therapeutic plasma exchange.
  • both doses coincided with an increase in recipient donor-specific IgG and to a lesser extent IgM.
  • IVIg contributed to xenograft capillary injury.
  • IVIg has not shown to have complement dependent cytotoxicity to pig xenogeneic tissues in vitro or in vivo (Yamamoto et al., Sci Rep 2020;10(1 ):11747).
  • binding to donor specific cells was observed in two laboratories, including ours.
  • lots should be tested to select those that exhibit minimal xenograft specific antibody-mediated cytotoxicity.
  • Postoperative monitoring of both the xenograft and zoonoses were performed using traditional clinical monitoring and included novel highly sensitive cfDNA assays.
  • Longitudinal xenograft-specific antibody assays were also used to aid in detecting elicited donor-specific antibody responses. These results were generally delayed by 1 week, as they are dependent on growing cell cultures of the source animal’s aortic endothelial cells, incubating these cells with recipient serum and analyzing antibody binding by flow cytometry.
  • Point-of-care troponin I testing was most useful for detecting early xenograft injury largely because the data was instantaneous and previously validated by NHP work (FIG. 9).
  • the donor spleen tested positive for pCMV indicating that the donor was likely latently infected with pCMV.
  • Recipient PBMCs were also positive. It is uncertain whether the detection of pCMV via plasma mcf-DNA and/or PCR testing represents 1 ) replicating virus in the xenograft or 2) replicating virus in the recipient or 3) shedding of genetic material from the xenograft.
  • the presence of pCMV in explanted xenografts from NHP recipients has been correlated with worse outcomes than those without pCMV, for reasons that are currently unclear (Denner et al., Sci Rep 2020;10(1 ):17531 ).
  • HHV6 human herpes virus 6
  • a human subject is selected for an allogeneic liver transplant.
  • the subject may be administered a therapeutic regimen (e.g., induction therapy) before the transplant (e.g., within 1 -24 hours before the transplant) that includes 125 mg methylprednisolone, 10 mg/kg rituximab, 20 U/kg C1 esterase inhibitor and 10 mg/kg of KPL-404.
  • a therapeutic regimen e.g., induction therapy
  • the subject undergoes the transplant and may receive 1000 mg methylprednisolone during the operation. Once the subject reaches hemostasis following the transplant, the subject may also receive a therapeutic regimen (e.g., maintenance therapy) that includes 10 mg/kg KPL-404, 20 U/kg C1 esterase inhibitor, and 2 mg/kg anti-thymocyte globulin.
  • a therapeutic regimen e.g., maintenance therapy
  • the subject may receive an additional therapeutic regimen that includes 20 U/kg C1 esterase inhibitor and 2 mg/kg anti-thymocyte globulin.
  • the subject may receive a periodic intravenous infusion of KPL-404 at a dosage of 10 mg/kg (e.g., at least one dose every two or three weeks).
  • the blood of the subject is periodically assayed to measure his blood serum concentration of KPL-404.
  • a maintenance dose of KPL-404 may be intravenously administered to boost the subject’s KPL- 404 blood serum concentration.
  • the time between maintenance doses may be determined empirically based on the PK profile of the subject and the peak and trough values of KPL-404.
  • Kidney transplantation can include induction therapy with a biologic lymphocyte-depleting agent begun before, at the time of, or immediately after transplantation.
  • the subject may be treated with an immunosuppressive standard of care as described, e.g., in Yin et al. Chin. Med. J. 124:1928-1932, 2011 , or Amer. J. Transplantation, 9: Suppl 3, 2009, S1 -155, each of which is hereby incorporated by reference in its entirety, which includes rituximab and anti-thymocyte globulin therapy.
  • the subject may be administered a therapeutic regimen (e.g., induction therapy) before the transplant (e.g., within 1 -24 hours before the transplant) that includes a B cell and/or T-cell depleting agent.
  • a therapeutic regimen e.g., induction therapy
  • the subject may be subcutaneously or intravenously administered a first induction dose (i.e., a conditioning dose) of between 1 and 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg) of KPL-404.
  • a first induction dose i.e., a conditioning dose
  • the subject may be administered one or more additional agents during the transplant (e.g., methylprednisolone (e.g., -1000 mg)) during the operation.
  • the subject may also subcutaneously or intravenously be administered a second dose (e.g., an induction dose) of KPL-404 of between 1 and 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg), and, optionally, 20 U/kg C1 esterase inhibitor and/or a T cell depleting agent.
  • a second dose e.g., an induction dose
  • KPL-404 of between 1 and 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg), and, optionally, 20 U/kg C1 esterase inhibitor and/or a T cell depleting agent.
  • the subject may optionally receive an additional therapeutic regimen that includes a T cell depleting agent.
  • the subject may also receive intravenous or subcutaneous administration of a second induction dose of KPL-404, as either a divided dose of at least two doses of between 1 and 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg per dose) administered 1 to 24 hours apart, or as a single, undivided dose of between 1 and 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg per dose)) that is administered between 2-10 days after surgery.
  • a second induction dose of KPL-404 as either a divided dose of at least two doses of between 1 and 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg per dose) administered 1 to 24 hours apart, or as a single, undivided dose of between 1 and 20 mg/kg (e.g., 5 mg/kg or 10 mg/kg per dose)) that is administered between 2-10 days after surgery.
  • KPL-404 PK of KPL-404 is replicable or predictable in the subject (as determined by periodic measurement of KPL-404 concentration in the subject’s blood, plasma, or serum), additional induction doses of KPL-404 are delivered to the subject as needed to maintain Ctrough of KPL-404 at or above therapeutic levels.
  • the subject may receive a periodic intravenous infusion of KPL-404 at a dosage of 10 mg/kg (i.e., a maintenance dose, e.g., at least one dose every one, two or three weeks).
  • a maintenance dose e.g., at least one dose every one, two or three weeks.
  • the blood of the subject is periodically assayed to measure the blood, plasma, or serum concentration of KPL-404.
  • a maintenance dose of KPL-404 may be intravenously administered to boost the subject’s KPL-404 blood, plasma, or serum concentration.
  • the optimal time between maintenance doses may be determined empirically based on the PK profile of the subject and the peak and trough values of KPL-404.
  • the subject can be periodically measured to determine a level of transplant rejection. If the troponin levels increase, the subject can be administered an infusion of KPL-404 or an increased dosage of KPL-404 as further described herein.

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