Compositions and methods for extending transplant and recipient survival

Abstract

Disclosed is a method for treating transplant rejection by a transplant recipient. It includes a method for prolonging transplant survival in the transplant recipient, prolonging the recipient's survival, delaying and / or suppressing delayed graft function in the recipient, and / or reducing the amount of immunosuppressant administered for transplantation. The method includes providing CHP or a pharmaceutically acceptable salt thereof to the transplant. Also provided is a method for producing a pharmaceutical composition for the treatment of transplantation that allows for regulating transplant survival in the transplant recipient.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 386,531, filed December 8, 2022, the entire contents of which are incorporated by reference.

[0002] Technical Field The present disclosure relates to treatments for prolonging the survival of a transplant in an animal recipient. The present disclosure relates to prolonging the survival of an allograft in a recipient by administering CHP or a pharmaceutically acceptable salt thereof to the recipient. The present disclosure is also directed to methods useful in preventing transplant rejection and / or reducing the amount of immunosuppressant used at the time of transplantation and / or for maintenance after the transplantation. [Background technology]

[0003] background Organ transplantation is the preferred treatment for most patients with chronic organ failure. Kidney, liver, lung, and heart transplants offer excellent opportunities for rehabilitation as recipients return to a more normal lifestyle, but are limited by the medical / surgical suitability of potential recipients, the increasing shortage of donors, and the premature functional failure of transplanted organs.

[0004] Despite significant improvements in therapies to inhibit graft rejection (or transplant rejection), rejection remains the single most significant obstacle to successful organ transplantation. Rejection includes both acute and chronic rejection. According to the OPTN / SRTR Annual Report 2022, 6.8% of adult kidney transplant recipients in 2018–2019 experienced acute rejection by 1 year, including 9.1% of recipients aged 18–34 years and 5.9% of recipients aged 65 years or older. Acute rejection at 1 year occurred in 8.4% of those who received interleukin-2 (IL-2) receptor antibody induction, compared with 6.6% who received T cell depletion induction and 6.4% of a small subgroup whose transplants were managed without induction. For the liver, the 1-year survival rate for transplanted livers is approximately 90%, and the 5-year graft survival rate is approximately 75%, and 11.5% of adult liver transplant recipients in 2018-2019 reported at least one acute rejection within 1 year. See OPTN / SRTR Annual Report, 2022.

[0005] Immunosuppressants (such as cyclosporine A, tacrolimus, and corticosteroids) or antibody therapies (such as anti-T cell antibodies) are typically administered to inhibit harmful immune responses during transplantation and the first few months after transplantation (the induction phase) as well as for extended periods after transplantation (the maintenance phase). Unfortunately, immunosuppression typically has unwanted side effects. For example, cyclosporine can cause reduced kidney function, hypertension, and toxicity, and it must be administered for the patient's lifetime. Corticosteroids can cause decreased resistance to infection, painful arthritis, osteoporosis, and cataracts. Anti-T cell antibodies can cause fever, hypertension, diarrhea, or aseptic meningitis, and are quite expensive.

[0006] Thus, there is a need to develop methods or therapies that induce transplant unresponsiveness or tolerance in the host, and / or prolong survival of the graft and / or transplant recipient, and / or prevent or delay graft loss, and / or inhibit delayed graft function, and / or reduce the amount of immunosuppressive drugs used during and / or after transplantation. Summary of the Invention

[0007] overview According to one embodiment of the present disclosure, a method for suppressing an immune response comprises administering an effective amount of cyclohistidine-proline (cycloHis-Pro or CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to an animal in need of such treatment. In an embodiment, the immune response can include acute and / or chronic rejection of a transplant by the animal recipient. According to another embodiment, the method can further comprise administering an immunosuppressant. In one embodiment, the immune response can be transplant rejection. CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, optionally with the immunosuppressant, can be administered during the transplant surgery and / or induction phase and / or long-term (maintenance) phase after transplant surgery. When used as a combination, CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the immunosuppressant can be administered simultaneously or sequentially and can be formulated into a single formulation or different formulations.

[0008] In another embodiment, the present disclosure provides a method for suppressing an immune response against a transplanted organ, tissue, or cell, comprising administering an effective amount of CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to a mammal in need thereof. In an embodiment, the transplanted organ, tissue, or cell includes an organ, tissue, or cell, such as the lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, or penis. In an embodiment, the immune response may include acute and / or chronic rejection of the transplant by the animal recipient. According to another embodiment, the method may further comprise administering an immunosuppressant. The CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the immunosuppressant may be administered during the transplant surgery and / or induction phase, and / or for an extended period (maintenance phase) after the transplant surgery. When used as a combination, the CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the immunosuppressant may be administered simultaneously or sequentially, and may be formulated into a single formulation or different formulations.

[0009] Yet another aspect of the present disclosure provides a method for prolonging graft survival, delaying or preventing graft loss, and / or suppressing delayed graft function in a recipient animal, comprising treating the transplant with a composition comprising CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In an embodiment, the transplant comprises an organ, tissue, or cell, such as lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, or penis. According to another aspect, the method may further comprise administering an immunosuppressant. When used as a combination, CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and optionally the immunosuppressant, may be administered during the transplant surgery and / or induction phase and / or prolonged (maintenance) phase after transplant surgery. When used as a combination, CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the immunosuppressant may be administered simultaneously or sequentially and may be formulated into a single formulation or different formulations.

[0010] Yet another aspect of the present disclosure provides a method for prolonging the survival of an animal recipient of a transplant, comprising administering to the animal recipient an effective amount of a composition comprising CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In embodiments, the transplant comprises an organ, tissue, or cell, such as lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, or penis. According to another aspect, the method may further comprise administering an immunosuppressant. When used as a combination, CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof may be administered during the transplant surgery and / or induction phase, and / or for an extended period (maintenance phase) after transplant surgery. When used as a combination, CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the immunosuppressant may be administered simultaneously or sequentially and may be formulated into a single formulation or different formulations.

[0011] Another aspect of the present disclosure provides a method for prolonging graft survival, delaying or preventing graft loss, and / or suppressing delayed graft function in an animal recipient by administering to the animal recipient an effective amount of a composition comprising CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In an embodiment, the transplant comprises an organ, tissue, or cell, such as lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, or penis. According to another aspect, the method may further comprise administering an immunosuppressant. When used as a combination, CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof may be administered during the transplant surgery and / or induction phase and / or for an extended period (maintenance phase) after transplant surgery. When used as a combination, CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the immunosuppressant may be administered simultaneously or sequentially and may be formulated into a single formulation or different formulations.

[0012] One aspect of the present disclosure also includes a composition containing CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof for use in suppressing an immune response. The composition may further comprise an immunosuppressant or may be administered in combination with an immunosuppressant. The composition, optionally in combination with an immunosuppressant, may be administered during transplant surgery (induction phase) and / or long-term after transplant surgery (maintenance phase). When used in combination, the composition and the immunosuppressant may be administered simultaneously or sequentially and may be formulated into a single formulation or different formulations.

[0013] One aspect of the present disclosure also includes a composition containing CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, for use in prolonging the survival of a transplant in an animal recipient and / or in prolonging the survival of an animal recipient of a transplant. In embodiments, the transplant comprises an organ, tissue, or cell, such as lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, or penis. The composition may further comprise or be administered in combination with an immunosuppressant. The composition, optionally in combination with an immunosuppressant, may be administered during transplant surgery and / or the induction phase and / or long-term (maintenance) after transplant surgery. When used as a combination, the composition and immunosuppressant may be administered simultaneously or sequentially and may be formulated into a single formulation or different formulations.

[0014] One embodiment of the present disclosure also includes the use of CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof in a method for suppressing an immune response; or in a method for prolonging the survival of a transplant in an animal recipient and / or in a method for prolonging the survival of an animal recipient of a transplant. According to this embodiment, CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof may be used in combination with an immunosuppressant. The composition, optionally in combination with an immunosuppressant, may be administered during the transplant procedure and / or induction phase, and / or for an extended period (maintenance phase) after transplant surgery. When used as a combination, CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the immunosuppressant may be administered simultaneously or sequentially, and may be formulated into a single formulation or different formulations.

[0015] One embodiment of the present disclosure also includes the use of CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, for use in manufacturing a medicament for administration to prolong the survival of a transplant in an animal recipient and / or for use in manufacturing a medicament for administration to prolong the survival of an animal recipient of a transplant. In embodiments, the transplant comprises an organ, tissue, or cell, such as the lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, or penis. According to embodiments, CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, may be used in combination with an immunosuppressant. When used as a combination, CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the immunosuppressant may be administered simultaneously or sequentially and may be formulated into a single agent or different agents. The agent or agents may be administered during the transplant procedure and / or induction phase and / or long-term (maintenance) phase after transplant surgery.

[0016] Yet another aspect of the present disclosure also includes a method for reducing the amount of immunosuppressant administered to a subject during transplantation, during the induction phase, and / or during post-transplant maintenance by administering an effective amount of CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof to the subject. In one embodiment, the transplant to the subject comprises an organ, tissue, or cell, such as the lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, or penis. The CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the immunosuppressant may be administered simultaneously or sequentially and may be formulated in a single formulation or different formulations. The formulation or formulations may be administered during the transplant procedure (induction phase) and / or for an extended period after the transplant procedure (maintenance phase).

[0017] According to certain aspects, the present disclosure includes the following non-limiting exemplary embodiments.

[0018] Embodiment 1. A method of prolonging survival of a recipient of an allogeneic transplant and / or prolonging survival in said recipient of an allogeneic transplant comprising administering to the recipient an effective amount of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0019] Embodiment 2. The method of embodiment 1, further comprising providing an allograft, wherein the graft is treated with cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, prior to implantation into the recipient.

[0020] Embodiment 3. The method of embodiment 1, further comprising administering an immunosuppressant to said recipient.

[0021] Embodiment 4. The method of embodiment 1, wherein administration of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, begins 0.5 to 18 hours or 18 to 36 hours prior to anesthesia for transplantation of the allograft in the recipient.

[0022] Embodiment 5. The method of embodiment 1, wherein administering cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof comprises administering an effective amount of the cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof as maintenance therapy after transplantation.

[0023] Embodiment 6. The method of embodiment 3, wherein the administration of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the administration of the immunosuppressant are performed simultaneously, concurrently, or sequentially.

[0024] Embodiment 7. The method of embodiment 3, wherein administration of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, begins 0.5 to 18 hours or 18 to 36 hours prior to anesthesia for transplantation of the allograft in the recipient.

[0025] Embodiment 8. The method of embodiment 3, wherein administering cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof comprises administering an effective amount of the cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof as maintenance therapy after transplantation.

[0026] Embodiment 9. The method of embodiment 1, wherein the allograft is lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penile tissue, organ, or cell.

[0027] Embodiment 10. The method of embodiment 3, wherein the allograft is lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penile tissue, organ, or cell.

[0028] Embodiment 11. The method of embodiment 1, wherein administration of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, suppresses an immune response against the allograft in the recipient.

[0029] Embodiment 12. The effective amount of CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof is about 0.001 to 0.005 mg / kg, 0.005 to 0.01 mg / kg, 0.01 to 0.02 mg / kg, 0.02 to 0.04 mg / kg, 0.04 to 0.06 mg / kg, 0.06 to 0.08 mg / kg, 0.08 to 1 mg / kg, 1 to 5 mg / kg, 5 to 6 mg / kg, 6 to 7 mg / kg, 7 to 8 mg / kg. g, 8~10mg / kg, 10~15mg / kg, 15~20mg / kg, 20~25mg / kg, 25~30mg / kg, 30~35mg / kg, 35~40mg / kg, 40~45mg / kg, 45~5 0mg / kg, 50~100mg / kg, 100~150mg / kg, 150~200mg / kg, 200~300mg / kg, 300~400mg / kg, 400~500mg / kg, 500~600mg / kg kg, 600~700mg / kg, 700~800mg / kg, 800~900mg / kg, 900~1000mg / kg, 1000~1100mg / kg, 1100~1200mg / kg, 1200~13 00mg / kg, 1300~1400mg / kg, 1400~1500mg / kg, 1500~1600mg / kg, 1600~1700mg / kg, 1700~1800mg / kg, 1800~1900mg / kg, 1900-2000mg / kg, 2000-2100mg / kg, 2100-2200mg / kg, 2200-2300mg / kg, 2300-2400mg / kg, 2400-2500mg / kg, 2500-2600mg / kg, 2600-2700mg / kg, 2700-2800mg / kg, 2800-2900mg / kg, or 2900-3000mg / kg.

[0030] Embodiment 13. A method of suppressing or reducing an immune response in a recipient of an allograft, reducing rejection of the allograft in the recipient, and / or reducing the amount of immunosuppressant administered during and / or after transplantation of an allograft into the recipient of the allograft, said method comprising administering to the recipient an effective amount of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0031] Embodiment 14. The method of embodiment 13, further comprising providing the allograft, wherein the graft is treated with cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, prior to implantation into the recipient.

[0032] Embodiment 15. The method of embodiment 13, wherein administration of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, begins 0.5 to 18 hours or 18 to 36 hours before anesthesia for transplantation of the allograft in the recipient.

[0033] Embodiment 16. The method of embodiment 13, wherein administering cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof comprises administering an effective amount of the cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof as maintenance therapy after transplantation.

[0034] Embodiment 17. The method of embodiment 13, wherein the administration of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and the administration of the immunosuppressant are performed simultaneously, concurrently, or sequentially.

[0035] Embodiment 18. The method of embodiment 13, wherein the allograft is lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penile tissue, organ, or cell.

[0036] Embodiment 19. The effective amount of CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof is about 0.001 to 0.005 mg / kg, 0.005 to 0.01 mg / kg, 0.01 to 0.02 mg / kg, 0.02 to 0.04 mg / kg, 0.04 to 0.06 mg / kg, 0.06 to 0.08 mg / kg, 0.08 to 1 mg / kg, 1 to 5 mg / kg, 5 to 6 mg / kg, 6 to 7 mg / kg, 7 to 8 mg / kg. g, 8~10mg / kg, 10~15mg / kg, 15~20mg / kg, 20~25mg / kg, 25~30mg / kg, 30~35mg / kg, 35~40mg / kg, 40~45mg / kg, 45~5 0mg / kg, 50~100mg / kg, 100~150mg / kg, 150~200mg / kg, 200~300mg / kg, 300~400mg / kg, 400~500mg / kg, 500~600mg / kg kg, 600~700mg / kg, 700~800mg / kg, 800~900mg / kg, 900~1000mg / kg, 1000~1100mg / kg, 1100~1200mg / kg, 1200~13 00mg / kg, 1300~1400mg / kg, 1400~1500mg / kg, 1500~1600mg / kg, 1600~1700mg / kg, 1700~1800mg / kg, 1800~1900mg / kg, 1900 to 2000 mg / kg, 2000 to 2100 mg / kg, 2100 to 2200 mg / kg, 2200 to 2300 mg / kg, 2300 to 2400 mg / kg, 2400 to 2500 mg / kg, 2500 to 2600 mg / kg, 2600 to 2700 mg / kg, 2700 to 2800 mg / kg, 2800 to 2900 mg / kg, or 2900 to 3000 mg / kg.

[0037] Embodiment 20. A composition for prolonging survival of an allograft recipient and / or prolonging survival of an allograft in said recipient, comprising as an active ingredient an effective amount of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier.

[0038] Embodiment 21. The composition of embodiment 20, wherein the allograft is treated with cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, prior to transplantation into the recipient.

[0039] Embodiment 22. The composition of embodiment 20, which is administered to the recipient in combination with an immunosuppressant.

[0040] Embodiment 23. The composition of embodiment 20, wherein the composition is administered to the recipient 0.5 to 18 hours or 18 to 36 hours prior to anesthesia for transplantation of the allograft in the recipient.

[0041] Embodiment 24. The composition of embodiment 20, wherein the composition is administered to the recipient after transplantation as a maintenance therapy.

[0042] Embodiment 25. The composition of embodiment 22, wherein the composition and the immunosuppressant are administered to the recipient simultaneously, in parallel, or sequentially.

[0043] Embodiment 26. The composition of embodiment 22, wherein the composition is administered to the recipient 0.5 to 18 hours or 18 to 36 hours prior to anesthesia for transplantation of the allograft in the recipient.

[0044] Embodiment 27. The composition of embodiment 22, wherein the composition is administered to the recipient after transplantation as a maintenance therapy.

[0045] Embodiment 28. The composition of embodiment 20, wherein the allograft is lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penile tissue, organ, or cell.

[0046] Embodiment 29. The composition of embodiment 20, wherein the allograft is lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penile tissue, organ, or cell.

[0047] Embodiment 30. The composition of embodiment 20, wherein administration of the composition suppresses an immune response against the allograft in the recipient.

[0048] Embodiment 31. The effective amount of CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof is about 0.001 to 0.005 mg / kg, 0.005 to 0.01 mg / kg, 0.01 to 0.02 mg / kg, 0.02 to 0.04 mg / kg, 0.04 to 0.06 mg / kg, 0.06 to 0.08 mg / kg, 0.08 to 1 mg / kg, 1 to 5 mg / kg, 5 to 6 mg / kg, 6 to 7 mg / kg, 7 to 8 mg / kg. g, 8~10mg / kg, 10~15mg / kg, 15~20mg / kg, 20~25mg / kg, 25~30mg / kg, 30~35mg / kg, 35~40mg / kg, 40~45mg / kg, 45~50 mg / kg, 50~100mg / kg, 100~150mg / kg, 150~200mg / kg, 200~300mg / kg, 300~400mg / kg, 400~500mg / kg, 500~600mg / k g, 600~700mg / kg, 700~800mg / kg, 800~900mg / kg, 900~1000mg / kg, 1000~1100mg / kg, 1100~1200mg / kg, 1200~130 0mg / kg, 1300~1400mg / kg, 1400~1500mg / kg, 1500~1600mg / kg, 1600~1700mg / kg, 1700~1800mg / kg, 1800~1900mg / kg 21. The composition of embodiment 20, wherein the saturation is 1900-2000 mg / kg, 2000-2100 mg / kg, 2100-2200 mg / kg, 2200-2300 mg / kg, 2300-2400 mg / kg, 2400-2500 mg / kg, 2500-2600 mg / kg, 2600-2700 mg / kg, 2700-2800 mg / kg, 2800-2900 mg / kg, or 2900-3000 mg / kg.

[0049] Embodiment 32. A composition for suppressing or reducing an immune response in a recipient of an allograft, for reducing rejection of the allograft in the recipient, and / or for reducing the amount of immunosuppressant administered for and / or after transplantation of the allograft into the recipient of the allograft, the composition comprising an effective amount of cyclo-his-pro (CHP) as an active ingredient, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier.

[0050] Embodiment 33. The composition of embodiment 32, wherein the transplant is treated with cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, prior to transplantation into the recipient.

[0051] Embodiment 34. The composition of embodiment 32, wherein the composition is administered to the recipient 0.5 to 18 hours or 18 to 36 hours prior to anesthesia for transplantation of the allograft in the recipient.

[0052] Embodiment 35. The composition of claim 32, wherein the composition is administered to the recipient as a maintenance therapy after transplantation.

[0053] Embodiment 36. The composition of embodiment 32, wherein the composition and the immunosuppressant are administered simultaneously, in parallel, or sequentially.

[0054] Embodiment 37. The composition of embodiment 32, wherein the allograft is lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penis tissue, organ, or cell.

[0055] Embodiment 38. The effective amount of CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof is about 0.001 to 0.005 mg / kg, 0.005 to 0.01 mg / kg, 0.01 to 0.02 mg / kg, 0.02 to 0.04 mg / kg, 0.04 to 0.06 mg / kg, 0.06 to 0.08 mg / kg, 0.08 to 1 mg / kg, 1 to 5 mg / kg, 5 to 6 mg / kg, 6 to 7 mg / kg, 7 to 8 mg / kg , 8~10mg / kg, 10~15mg / kg, 15~20mg / kg, 20~25mg / kg, 25~30mg / kg, 30~35mg / kg, 35~40mg / kg, 40~45mg / kg, 45~50 mg / kg, 50~100mg / kg, 100~150mg / kg, 150~200mg / kg, 200~300mg / kg, 300~400mg / kg, 400~500mg / kg, 500~600mg / k g, 600~700mg / kg, 700~800mg / kg, 800~900mg / kg, 900~1000mg / kg, 1000~1100mg / kg, 1100~1200mg / kg, 1200~130 0mg / kg, 1300~1400mg / kg, 1400~1500mg / kg, 1500~1600mg / kg, 1600~1700mg / kg, 1700~1800mg / kg, 1800~1900mg / kg 33. The composition of embodiment 32, wherein the saturation is 1900-2000 mg / kg, 2000-2100 mg / kg, 2100-2200 mg / kg, 2200-2300 mg / kg, 2300-2400 mg / kg, 2400-2500 mg / kg, 2500-2600 mg / kg, 2600-2700 mg / kg, 2700-2800 mg / kg, 2800-2900 mg / kg, or 2900-3000 mg / kg.

[0056] Embodiment 39. Use of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, in the manufacture of a medicament for (i) prolonging survival of an allograft recipient; (ii) prolonging survival of an allograft in said recipient; (iii) suppressing or reducing the immune response to an allograft in said recipient; (iv) reducing rejection of an allograft in said recipient; and / or (v) reducing the amount of immunosuppressant administered during and / or after transplantation of an allograft into said allograft recipient.

[0057] Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. [Brief explanation of the drawings]

[0058] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Figure 1] Figure 1 is a photograph of the transplanted kidney after reperfusion. After reperfusion, blood flowed smoothly and the kidney was in good condition. [Figure 2] FIG. 2 shows an exemplary experimental flow of rat allogeneic kidney transplantation. [Figure 3] Figures 3A and 3B show the survival rates of kidney transplants in the positive control and CHP-treated groups during the first 80 days (Figure 3A) and 1 year (Figure 3B) after transplantation. [Figure 4] Figure 4 is an ultrasound image showing the smooth flow of blood in the transplanted body. [Figure 5]FIG. 5 shows histological images of transplanted kidneys in the positive control group (Syngenic TPL) and in the CHP treatment group (TPL+CHP). [Figure 6] Figures 6A-6D show the changes in body weight (g), blood urea nitrogen (BUN) (mg / dL), creatine (mg / dL), and Uproc / Crea ratio (mg / mg) over a 46-week period after transplantation in the syngeneic (Syngenic) and CHP-treated transplant groups (TPL+CHP), respectively. [Figure 7] Figures 7A and 7B are graphs presenting a quantitative comparison of blood urea nitrogen (BUN) (Figure 7A) and serum creatinine levels (Figure 7B) in recipient rats on day 5 after transplantation. Individual data points represent the following groups: syngeneic transplant recipients (Syngenic; n=3), kidney transplant recipients without CHP administration (TPL; n=5), and CHP-treated transplant recipients (TPL+CHP; n=5). [Figure 8] Figure 8 shows representative immunohistochemical images of PAS and Nrf2 staining (at 100x magnification) with the scale bar indicating 100 μm. All animals were sacrificed on day 5 after kidney transplantation. DETAILED DESCRIPTION OF THE INVENTION

[0059] Detailed Description definition Unless otherwise defined, all terms and phrases used herein include the meaning that the term or phrase has acquired in the art unless expressly indicated to the contrary or clearly apparent from the context in which the term or phrase is used. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, particular methods and materials are now described.

[0060] Unless otherwise stated, the use of individual numerical values ​​is stated as an approximation, as if the value were preceded by the word "about" or "approximately." Similarly, numerical values ​​in various ranges specified in this application are stated as approximations, as if the minimum and maximum values ​​within the stated range were both preceded by the word "about" or "approximately," unless explicitly stated otherwise. In this manner, variations above and below the stated range can be used to achieve substantially the same results as values ​​within the range. As used herein, the terms "about" and "approximately," when referring to numerical values, shall have their obvious and ordinary meaning to those of ordinary skill in the art to which the disclosed subject matter most closely pertains or to the range or element in question. The amount of spread from an exact numerical boundary depends on many factors. For example, some of the factors that may be considered include the importance of the element and / or the effect that a given amount of variation has on the performance of the claimed subject matter, as well as other considerations known to those of ordinary skill in the art. As used herein, the use of different amounts of significant figures for different numerical values ​​does not imply a limitation on how the use of the word "about" or "approximately" serves to broaden a particular numerical value or range. That is, as a general matter, "about" or "approximately" broadens the numerical value. Also, the disclosure of a range is intended as a continuous range that includes every value between the minimum and maximum values ​​plus the breadth of the range given by the use of the term "about" or "approximately." Thus, the recitation of a range of values ​​herein is intended merely to serve as a shorthand method of individually referring to each individual value within the range, and each individual value is incorporated into the specification as if it were individually listed herein. In one aspect, the word "about," when used in reference to a numerical value, is intended to include a 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% difference from the numerical value(s).

[0061] As used herein, the term "animal" includes all members of the animal kingdom, including humans. The term "mammal" includes both human and non-human mammals. Similarly, the term "subject" includes both human and veterinary subjects.

[0062] As used herein, the term "active agent" or "active ingredient" or "drug" or "medicament" or "drug formulation" refers to any chemical substance that induces a biochemical reaction when administered to a human or animal. A drug may act as a substrate or product of a biochemical reaction, or a drug may interact with a cellular receptor to induce a physiological response, or a drug may bind to a receptor and block the receptor from inducing a physiological response.

[0063] As used herein, the phrase "consisting essentially of" with respect to a composition or formulation means that the composition or formulation contains the recited compound(s) as the only active ingredient(s) and may further contain pharmaceutically acceptable inert additive(s), excipient(s), or carrier(s). Such inert additives, excipients, or carriers are known in the art.

[0064] The terms "parenteral administration" and "administering parenterally" are art-recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intradermal, intraarticular, subcapsular, intrathecal, intraspinal, and intrasternal injection.

[0065] As used herein, the term "treatment" or "treating" refers to an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, diminishment of the extent of disease, stabilized (i.e., not worsening) disease, preventing the spread of disease, delaying or slowing the progression of disease, improvement or palliation of the disease state, and remission (whether partial or total). "Treating" can also mean prolonging the survival of a recipient or transplant compared to the expected survival if not receiving treatment.

[0066] As used herein, the term "pharmaceutically acceptable" additives, excipients, or carriers includes those well known in the art. Generally, the nature of the carrier will depend on the particular mode of administration being used. For example, parenteral formulations usually comprise injectable fluids containing pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol, or the like as a vehicle. For solid compositions (such as powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers may include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions to be administered may contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents, for example, sodium acetate or sorbitan monolaurate.

[0067] As used herein, "pharmaceutically acceptable salt" refers to a salt that can be used pharmaceutically among substances having a cation and anion bound by electrostatic attraction.Typically, it can include metal salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Examples of metal salts can include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, barium salts, etc.), aluminum salts, etc.; examples of salts with organic bases can include salts with triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.; examples of salts with inorganic acids can include salts with methyl methyl amine, ... Examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc.; and examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0068] As used herein, the term "therapeutically effective amount" or "effective amount," or "effective dose" refers to the amount of active agent(s) present in the compositions described herein required to provide a prolonged effect in the transplant or animal recipient of the transplant. The exact amount will depend on numerous factors, such as the specific activity of the composition, the delivery device used, the physical characteristics of the composition, its intended use, and patient considerations such as the severity of the condition and patient cooperation.

[0069] The terms "increased" or "increasing" or "prolonging" are used herein to generally mean an increase or prolongation by a statically significant amount; in some embodiments, the terms "increased" or "increasing" or "prolonging" refer to an increase or prolongation of at least 10% compared to a reference level (e.g., without a treatment or administration described herein), for example, an increase (or prolongation) of at least about 10%, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including a 100% increase, or any increase (or prolongation) between 10 and 100% compared to the reference level. Other examples of "increasing" or "prolonging" include an increase or prolongation of at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold or more compared to the reference level.

[0070] The terms "inhibit" or "inhibited" are used generally herein to mean that the progression of a disease or the development of a symptom(s) is slowed or reduced compared to the absence of the intervention described herein.

[0071] The terms "reduced" or "reducing" or "lowering" or "reduced" are generally used herein to mean a statistically significant reduction. In some embodiments, "reduced" or "reducing" refers to a reduction of at least 10% compared to a reference level (e.g., without the treatment or administration described herein), for example, a reduction of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% compared to a reference level, or up to and including a 100% reduction (e.g., an absent or undetectable level compared to a reference level), or any reduction between 10% and 100%. In the context of a marker or symptom, these terms refer to a statistically significant reduction in such level. The decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and preferably is below the level that is considered to be within the normal range for a given disease-free individual.In the context of the reduced amount of immunosuppressant, the term refers to a statistically significant decrease in such level.The decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and preferably is below the level that is considered to be within the normal range for a given disease-free individual.

[0072] As used herein, the term "induction phase" can refer to the period before surgery, during surgery (intubation, incision, implantation, completion of surgery), and / or after surgery. The preoperative period can cover 0-3 days, 1 day, 2 days, 3 days, 0 days, 24 hours, 18 hours, 15 hours, 12 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 0.5 hours before surgery. The post-operative period can include about 0.5 days after, about 1 day after, about 2 days after, about 3 days after, about 4 days after, about 5 days after, about 6 days after, about 7 days after, about 10 days after, about 14 days after, about 1 month after, about 0-7 days after, about 0-1 month after, about 1 day to 1 month after, about 1-10 days after, about 0-14 days after, about 1-7 days after, about 1-10 days after, or about 1-14 days after the implantation surgery.

[0073] As used herein, the term "induction therapy" refers to immunosuppressive therapy administered during the induction phase to reduce the risk of graft rejection. Generally, induction strategies can include (i) strategies using high doses of conventional immunosuppressants, or (ii) more commonly used strategies utilizing either T cell-depleting antibodies or interleukin (IL) 2 receptor-blocking antibodies in combination with lower doses of conventional agents.

[0074] As used herein, the term "maintenance phase" can be the period following the induction phase.

[0075] The term "maintenance therapy" refers to immunosuppressive therapy administered after the induction phase (when the risk of acute rejection is reduced) to suppress the immune response to the graft. Maintenance therapy is generally administered at lower levels than induction therapy and is tapered over time to help reduce the overall risk of infection and malignancy. Traditional maintenance regimens include a combination of immunosuppressive agents that differ by mechanism of action. This strategy minimizes the morbidity and mortality associated with each class of agent while maximizing overall efficacy.

[0076] The term "in combination with" includes administration of two therapeutic agents (e.g., CHP and an immunosuppressant (other than CHP)) either simultaneously, concurrently, or sequentially without any specific time restriction. In one embodiment, both agents are present in a cell or in a patient's body at the same time or exert their biological or therapeutic effects simultaneously. In one embodiment, the two therapeutic agents are in the same composition or unit dosage form. In another embodiment, the two therapeutic agents are in separate compositions or unit dosage forms.

[0077] As used herein, the term "recipient" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. In embodiments, the term "recipient" refers to a mammalian subject, such as a human subject. In one embodiment, the recipient is a human.

[0078] Rejection of the transplant or graft In one aspect, the disclosure relates to the prevention and treatment of rejection of a transplant by the recipient of the transplant, particularly acute and / or chronic rejection.

[0079] Transplants include tissues and organs such as kidney, pancreas, liver, intestine, heart, lung, and / or vascularized composite allograft (VCA) transplants (e.g., uterus, abdominal wall, penis, face / scalp, other upper extremities).

[0080] Hyperacute rejection occurs within minutes to hours after transplantation and is due to preformed antibodies against transplanted tissue antigens. It is characterized by hemorrhage and thrombotic occlusion of the graft vasculature. Antibody binding to the endothelium activates complement, and the antibodies and complement induce numerous changes in the graft endothelium that promote intravascular thrombosis and lead to vascular occlusion, resulting in irreversible ischemic damage to the transplanted organ. Hyperacute rejection is often mediated by preexisting IgM alloantibodies, such as those directed against ABO blood group antigens expressed on red blood cells. This type of rejection, mediated by natural antibodies, is the primary reason for the rejection of xenografts. Because allografts are typically selected to match the ABO types of the donor and recipient, hyperacute rejection due to natural IgM antibodies is no longer a major problem with allografts.

[0081] Acute rejection is a process of vascular and parenchymal damage mediated by T cells, macrophages, and antibodies that usually begins after the first week of transplantation. T lymphocytes play a central role in acute rejection by responding to alloantigens, including MHC molecules, present on vascular endothelial cells and parenchymal cells. Activated T cells produce cytokines that either cause direct lysis of graft cells or recruit and activate inflammatory cells, which cause necrosis. Both CD4+ and CD8+ cells can contribute to acute rejection. Destruction of allogeneic cells in the graft is highly specific and characteristic of CD8+ cytotoxic T lymphocyte killing. CD4+ T cells may be important in mediating acute graft rejection by secreting cytokines and inducing delayed-type hypersensitivity-like reactions in the graft, and some evidence is available indicating that CD4+ T cells are sufficient to mediate acute rejection. Antibodies can also mediate acute rejection after the transplant recipient mounts a humoral immune response to vessel wall antigens and the antibodies produced bind to the vessel wall and activate complement.

[0082] Chronic rejection (CR) or chronic allograft dysfunction (CAD) of solid organ allografts or transplants, regardless of type, evolves slowly over a period of months or years. The process is characterized by narrowing and occlusion of the lumen of arteries and arterioles secondary to proliferation of intimal smooth muscle cells.

[0083] Several studies have shown that acute rejection episodes, especially severe, recurrent, and late rejection episodes, are major risk factors for chronic rejection.

[0084] For a transplant to be successful, several modes of rejection must be overcome. Multiple approaches are utilized to prevent rejection. This includes the administration of several types of immunosuppressants, often to prevent various modes of attack, such as inhibition of T cell attack, antibodies, and cytokine and complement effects. Immunoadsorption of anti-HLA antibodies prior to transplantation can reduce hyperacute rejection. Prior to transplantation, the recipient or host may be administered an anti-T cell reagent, such as monoclonal antibody OKT3, antithymocyte globulin (ATG), cyclosporin A, or tacrolimus (FK 506). Additionally, glucocorticoids and / or azathioprine (or other purine analogs) may be administered to the recipient or host prior to transplantation. Drugs used to assist in preventing transplant rejection include, but are not limited to, ATG or antilymphocyte globulin (ALG), OKT3, daclizumab, basiliximab, corticosteroids, 15-deoxyspergualin, LF15-0195, cyclosporine, tacrolimus, purine analogs such as azathioprine, methotrexate, mycophenolate mofetil, 6-mercaptopurine, bredinin, brequinar, leflunamide, cyclophosphamide, sirolimus, everolimus, anti-CD4 monoclonal antibodies, CTLA4-Ig, Rituxan, anti-CD154 monoclonal antibodies, anti-LFA1 monoclonal antibodies, anti-LFA-3 monoclonal antibodies, anti-CD2 monoclonal antibodies, and anti-CD45.

[0085] Delayed graft function Delayed graft function (DGF) is defined as the need for dialysis during the first week after transplantation and is the most frequent early posttransplant complication. DGF is one of the main predictors of poor graft survival in deceased-donor kidney transplants. DGF is common, affecting between 20 and 60 of every 100 kidneys transplanted from deceased donors. DGF is a manifestation of acute kidney injury (AKI) with characteristics unique to the transplant process. Furthermore, DGF is a major obstacle to allograft survival because it can be exacerbated by acute rejection and chronic allograft nephropathy (CAN).

[0086] CHP and compositions containing CHP Cyclohistidine-proline (Cyclo His-Pro, CHP) is a naturally occurring cyclic dipeptide structurally related to thyrotropin-releasing hormone (TRH). It is a unique peptide in animal and human tissues and body fluids. It is found in blood, semen, the gastrointestinal tract, urine, etc., and is a particularly abundant metabolite in the prostate. It is known to have various physiological functions, including antidiabetic, antiobesity, anti-inflammatory, and antioxidant effects.

[0087] According to one aspect of the disclosure, CHP or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof is used as the active agent or ingredient for the methods and compositions. It should be understood that the term "CHP," as used in this disclosure, sometimes collectively refers to CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0088] According to the embodiments described herein, CHP is used broadly to include CHP of the above formula, its pharmaceutically acceptable salts, stereoisomers, and solvates thereof, unless otherwise specified.

[0089] cyclo(-His-Pro)(CHP) is exemplified below:

[0090] [ka]

[0091] A non-limiting example of a CHP solvate is CHP monohydrate, as illustrated below:

[0092] [ka]

[0093] In one embodiment, the CHP is substantially pure.

[0094] In one embodiment, the CHP is a CHP hydrate. In yet another embodiment, the CHP hydrate is characterized by an XRPD diffractogram containing peaks at about 17±0.2° and about 27.3±0.2° in two-theta. One embodiment of a substantially pure CHP hydrate is characterized by an XRPD diffractogram containing at least three peaks selected from the following list: 13.7, 17, 18.1, 20.2, and 27.3 degrees (±0.2° in two-theta). Another embodiment is characterized by an XRPD diffractogram containing at least two peaks selected from the following list: 10, 13.7, 17, 18.1, 20.2, and 27.3 degrees (±0.2° in two-theta). CHP hydrate, as one of the CHP solvates, can be made by the process described in U.S. Application No. 16 / 448,083, the contents of which are incorporated herein by reference in their entirety.

[0095] CHP is synthesized from a variety of biochemical sources, including histidine-proline rich glycoproteins. High levels of CHP are present in many food sources and are readily absorbed in the intestine without chemical or enzymatic destruction.

[0096] A composition suitable for reducing or preventing rejection of a transplant in a recipient animal, treating a recipient animal to prolong its survival, and / or treating a transplant (prior to transplantation) to prolong its survival in the recipient animal may comprise or consist essentially of CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and may include a pharmaceutically acceptable carrier or excipient. The composition may be administered alone or used to reduce or prevent rejection of a transplant in a recipient animal, to treat a recipient animal to prolong its survival, to treat a recipient animal to prolong the survival of the graft in the recipient animal, and / or to treat a transplant to prolong its survival in the recipient animal. The composition may be administered or used in combination with an immunosuppressant (different from CHP) to reduce or prevent rejection of the graft in the recipient animal, to treat the recipient animal to prolong survival of the recipient animal, and / or to treat the graft to prolong survival of the graft in the recipient animal, and / or to delay or prevent graft loss, and / or to prevent or treat delayed graft function, and / or to reduce the amount of immunosuppressant administered during the induction and / or maintenance phases. Compositions comprising or consisting essentially of CHP and an immunosuppressant (different from CHP) may be administered simultaneously, concurrently, or sequentially.

[0097] The compositions may be used to lower or reduce the amount of immunosuppressant (other than CHP) administered to a transplant recipient during or for transplantation or for maintenance (post-transplant) purposes. Compositions comprising or consisting essentially of CHP and immunosuppressant (other than CHP) may be administered simultaneously, concurrently, or sequentially.

[0098] In one embodiment, CHP may be present in the composition in an amount ranging from about 0.5 to about 10,000 mg, about 1 to 5,000 mg, about 1 to 2,000 mg, or about 10 to about 1,000 mg. In another embodiment, the amount of CHP present in the administered pharmaceutical composition, calculated in terms of anhydrous CHP, may range from about 5 to about 3,000 mg, about 50 to about 2,000 mg, about 100 to about 2,000 mg, about 50 to about 1,000 mg, about 100 to about 1,000 mg, about 150 to about 2,000 mg, about 200 to about 1,000 mg, about 50 to about 800 mg, about 100 to about 700 mg, about 50 to about 600 mg, or about 100 to about 1,500 mg. The composition may be a pharmaceutical composition, a food product, or a dietary supplement. In certain embodiments, the composition is a pharmaceutical composition.

[0099] In another embodiment, the composition is suitable for treating a transplant in a recipient animal to prolong its survival. The composition can be a liquid into which the transplant is infused. In one embodiment, the concentration of the liquid formulation is about 1 mg / liter to about 200 mg / ml, about 5 mg / ml to about 150 mg / ml, or about 10 mg / ml to about 100 mg / ml. In another embodiment, the concentration of the liquid formulation is about 1 mg / liter, about 2 mg / liter, about 3 mg / liter, about 4 mg / liter, about 5 mg / liter, about 6 mg / liter, about 7 mg / liter, about 8 mg / liter, about 9 mg / liter, about 10 mg / liter, about 11 mg / liter, about 12 mg / liter, about 13 mg / liter, about 14 mg / liter, about 15 mg / liter, about 20 mg / liter, about 25 mg / liter, about 30 mg / liter, about 35 mg / liter, about 40 mg / liter, about 45 mg / liter, about 50 mg / liter, about 65 mg / liter, about 70 mg / liter, about 75 mg / liter, about 80 mg / liter, about 90 mg / liter, about 100 mg / liter, about 11 mg / liter, about 120 mg / liter, about 130 mg / liter, about 140 mg / liter, about 150 mg / liter, about 150 mg / liter, about 160 mg / liter, about 170 mg / liter, about 180 mg / liter, about 190 mg / liter, about 210 mg / liter, about 220 mg / liter, about 230 mg / liter, about 240 mg / liter, about 250 mg / liter, about 260 mg / liter, about 270 mg / liter, about 280 mg / liter, about 290 mg / liter, about 300 mg / liter, about 310 mg / liter 0 mg / liter, about 55 mg / liter, about 60 mg / liter, about 65 mg / liter, about 70 mg / liter, about 75 mg / liter, about 80 mg / liter, about 85 mg / liter, about 90 mg / liter, about 95 mg / liter, about 100 mg / liter, about 110 mg / liter, about 120 mg / liter, about 130 mg / liter, about 140 mg / liter, about 150 mg / liter, about 160 mg / liter, about 170 mg / liter, about 180 mg / liter, about 190 mg / liter, or about 200 mg / liter.

[0100] In yet another embodiment, the composition is suitable for administration to a recipient animal that is about to receive, has received, or has received a transplant. The composition may contain a known immunosuppressant. Alternatively, CHP and the immunosuppressant may be administered simultaneously or sequentially in separate formulations. In another embodiment, the composition may consist essentially of CHP. In yet another embodiment, a composition comprising CHP alone or optionally with an immunosuppressant may further comprise another therapeutically active agent. Alternatively, a composition comprising CHP alone or optionally with an immunosuppressant may be administered or used separately from another composition comprising another therapeutically active agent.

[0101] In some embodiments, the other therapeutically active agent may include a biomolecule, a bioactive agent, a small molecule, a drug, a prodrug, a drug derivative, a protein, a peptide, a vaccine, an adjuvant, an imaging agent (e.g., a fluorescent moiety), a polynucleotide, or a metal. In yet other embodiments, the active agent is a metal element, a metal cation, a metal complex, or a metal compound, wherein the metal may be copper, zinc, magnesium, manganese, iron, cobalt, chromium, or a combination thereof. In one embodiment, the metal is zinc, and the zinc compound may be zinc gluconate, zinc acetate, zinc sulfate, zinc picolinate, zinc orotate, or zinc citrate. In another embodiment, the metal is magnesium, and a magnesium compound such as magnesium oxide, magnesium citrate, magnesium chloride, magnesium glycinate, magnesium biglycinate, magnesium aspartate, magnesium lactate, or magnesium chloride may be used. In another embodiment, the metal is manganese, and the manganese compound can include an amino acid manganese chelate (e.g., manganese bisglycinate chelate, manganese glycinate chelate, manganese aspartate, manganese gluconate, manganese picolinate, manganese sulfate, manganese citrate, or manganese chloride. In one embodiment, the metal is copper, and the copper compound can include cupric oxide, cupric sulfate, amino acid copper chelate, and copper gluconate. In yet another embodiment, the metal is iron, and Iron can be present in various forms, such as ferrous and ferric salts (e.g., ferrous sulfate, ferrous gluconate, ferric citrate, or ferric cobalt sulfate). In one embodiment, the metal is cobalt, and the cobalt compound can include cobalt acetate, cobalt sulfate, cobalt picolinate, cobalt orotate, or cobalt citrate. In one embodiment, the metal is chromium, and the chromium compound can include chromium chloride, chromium nicotinate, chromium picolinate, high chromium yeast, or chromium citrate.

[0102] In exemplary embodiments, the pharmaceutical compositions of the embodiments can be administered in a variety of ways, including orally, topically, parenterally, intravenously, intradermally, colonically, rectally, intramuscularly, or intraperitoneally.

[0103] The pharmaceutical composition can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion.The injection preparation can be provided in a unit dosage form in an ampule or in a multi-dose container with an optional preservative added.The parenteral preparation can be enclosed in an ampule, a disposable syringe, or a multi-dose vial made of glass, plastic, etc.The preparation can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain agents such as suspending agents, stabilizing agents, and / or dispersing agents.

[0104] For example, a parenteral formulation can be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be used are water, 0.9% saline, or other suitable aqueous media.

[0105] In one embodiment, the concentration of the intravenous solution formulation is from about 1 mg / liter to about 200 mg / ml, from about 5 mg / ml to about 150 mg / ml, or from about 10 mg / ml to about 100 mg / ml. In another embodiment, the concentration of the intravenous solution formulation is from about 1 mg / liter, about 2 mg / liter, about 3 mg / liter, about 4 mg / liter, about 5 mg / liter, about 6 mg / liter, about 7 mg / liter, about 8 mg / liter, about 9 mg / liter, about 10 mg / liter, about 11 mg / liter, about 12 mg / liter, about 13 mg / liter, about 14 mg / liter, about 15 mg / liter, about 20 mg / liter, about 25 mg / liter, about 30 mg / liter, about 35 mg / liter, about 40 mg / liter, about 45 mg / liter, or about 50 mg / liter, about 55 mg / liter, about 60 mg / liter, about 65 mg / liter, about 70 mg / liter, about 75 mg / liter, about 80 mg / liter, about 85 mg / liter, about 90 mg / liter, about 95 mg / liter, about 100 mg / liter, about 110 mg / liter, about 120 mg / liter, about 130 mg / liter, about 140 mg / liter, about 150 mg / liter, about 160 mg / liter, about 170 mg / liter, about 180 mg / liter, about 190 mg / liter, or about 200 mg / liter.

[0106] In another embodiment, the pharmaceutical composition may be formulated for diffusion (slow drip) or intravenous bolus injection.

[0107] In yet another embodiment, the pharmaceutical composition can be administered or formulated for oral administration. Administration can be via immediate release tablets and capsules or enteric-coated tablets, etc. In preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient can usually be diluted with an excipient and / or enclosed in such a carrier, which can be in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. That is, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment, soft gelatin capsule and hard gelatin capsule, sterile injectable solution, and sterile packaged powder.

[0108] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, cellulose, USP or sterile water, syrup base, and methylcellulose. The formulation may further include: lubricating agents such as talc, magnesium stearate, and stearic acid; wetting agents; emulsifying and suspending agents; preservatives such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.

[0109] In some embodiments, the pharmaceutical composition is formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount (therapeutically effective amount) of active substance calculated to produce a desired therapeutic effect in association with an appropriate pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharmaceutically effective amount. In some embodiments, each dosage unit contains about 1 mg to about 100 mg of the CHP compound. In some embodiments, each dosage unit contains about 2 mg to about 60 mg, about 3 mg to about 50 mg, about 4 mg to about 40 mg, about 5 mg to about 30 mg, about 6 mg to about 20 mg, about 8 mg to about 15 mg, or about 8 mg to about 10 mg of the CHP compound.

[0110] In other embodiments, each dosage unit contains about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of the CHP compound.

[0111] To prepare solid compositions such as tablets, the active ingredient is mixed with pharmaceutical excipients to form a solid mixed blend composition containing a homogeneous mixture of the compounds of the present disclosure. When these mixed blend compositions are referred to as homogeneous, it means that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0112] The tablets or pills of the present disclosure may be powder coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablets or pills may comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope covering the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release. A variety of materials may be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. In one embodiment, the film coating is a polyvinyl alcohol-based coating.

[0113] Compounds useful in the compositions and methods include those described herein in any of their pharmaceutically acceptable forms, including, where applicable, isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs of the compounds described herein, as well as racemic mixtures and pure isomers.

[0114] Suitable excipients include binders, fillers, disintegrants, lubricants, antioxidants, chelating agents, and colorants.

[0115] In yet another embodiment, the compositions disclosed herein can be a food or dietary supplement. The food or dietary supplement composition can contain pharmaceutically acceptable excipients as described herein for pharmaceutical compositions.

[0116] method According to one aspect of the present disclosure, there is disclosed a method for suppressing an immune response comprising or consisting essentially of administering to an animal in need of such treatment an effective amount of cyclohistidine-proline (cyclo His-Pro or CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In embodiments, the immune response may include acute and / or chronic rejection of a transplant by the animal recipient.

[0117] In another embodiment, the present disclosure provides a method for suppressing an immune response against a transplanted organ, tissue, or cell, comprising or consisting essentially of administering an effective amount of CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof to a mammal in need thereof. In embodiments, the transplanted organ, tissue, or cell comprises an organ, tissue, or cell, such as the lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, or penis. In embodiments, the immune response may include acute and / or chronic rejection of the transplant by the animal recipient.

[0118] Yet another aspect of the present disclosure provides a method for prolonging the survival of a transplant in a recipient animal, comprising or consisting essentially of treating the transplant with a composition comprising CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In embodiments, the transplant comprises an organ, tissue, or cell, such as lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc.

[0119] Yet another aspect of the present disclosure provides a method for prolonging survival of an animal recipient of a transplant, comprising or consisting essentially of administering to the animal recipient an effective amount of a composition comprising CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In embodiments, the transplant comprises an organ, tissue, or cell, such as lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc.

[0120] For any of the methods discussed above, CHP may be administered to the recipient in an amount of about 0.001 to about 3000 mg / kg. In some embodiments, an effective amount of CHP is about 0.001-0.005 mg / kg, 0.005-0.01 mg / kg, 0.01-0.02 mg / kg, 0.02-0.04 mg / kg, 0.04-0.06 mg / kg, 0.06-0.08 mg / kg, 0.08-1 mg / kg, 1-5 mg / kg, 5-6 mg / kg, 6-7 mg / kg, 7-8 mg / kg, 8-10 mg / kg, 10 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, ~15mg / kg, 15~20mg / kg, 20~25mg / kg, 25~30mg / kg, 30~35mg / kg, 35~40mg / kg, 40~45mg / kg, 45~50mg / kg, 50~ 100mg / kg, 100~150mg / kg, 150~200mg / kg, 200~300mg / kg, 300~400mg / kg, 400~500mg / kg, 500~600mg / kg, 600 ~700mg / kg, 700~800mg / kg, 800~900mg / kg, 900~1000mg / kg, 1000~1100mg / kg, 1100~1200mg / kg, 1200~1300 mg / kg, 1300~1400mg / kg, 1400~1500mg / kg, 1500~1600mg / kg, 1600~1700mg / kg, 1700~1800mg / kg, 1800~1900 mg / kg, 1900-2000 mg / kg, 2000-2100 mg / kg, 2100-2200 mg / kg, 2200-2300 mg / kg, 2300-2400 mg / kg, 2400-2500 mg / kg, 2500-2600 mg / kg, 2600-2700 mg / kg, 2700-2800 mg / kg, 2800-2900 mg / kg, or 2900-3000 mg / kg. The amount is based on the amount of anhydrous CHP.

[0121] For any of the methods discussed above, CHP may be administered to the animal recipient in an amount of about 1 to about 3000 mg / day. In some embodiments, an effective amount of CHP is about 1-10 mg / day, 10-50 mg / day, 50-100 mg / day, 100-150 mg / day, 150-200 mg / day, 200-300 mg / day, 300-400 mg / day, 400-500 mg / day, 500-600 mg / day, 600-700 mg / day, 700-800 mg / day, 800-900 mg / day, 900-1000 mg / day, 1000-1100 mg / day, 1100-1200 mg / day, 1200-1300 mg / day, 1300-1400 mg / day, 1500-1600 mg / day, 1600-1700 mg / day, 1700-1800 mg / day, 1800-2000 mg / day, 1900-2100 mg / day, 2000-2200 mg / day, 2100-2200 mg / day, 2300-2400 mg / day, 2400-2500 mg / day, 2500-2600 mg / day, 2600-2700 mg / day, 2700-2800 mg / day, 2800-2900 mg / day, 2900-3000 mg / day, 3000-3100 mg / day, 3100-3200 mg / day, 3200-3300 mg / day, 3300-3400 mg / day, 3400 The dose may range from 400-1500 mg / day, 1500-1600 mg / day, 1600-1700 mg / day, 1700-1800 mg / day, 1800-1900 mg / day, 1900-2000 mg / day, 2000-2100 mg / day, 2100-2200 mg / day, 2200-2300 mg / day, 2300-2400 mg / day, 2400-2500 mg / day, 2500-2600 mg / day, 2600-2700 mg / day, 2700-2800 mg / day, 2800-2900 mg / day, or 2900-3000 mg / day. The amount is based on the amount of anhydrous CHP.

[0122] For any of the methods described above, the method may further comprise administering an immunosuppressant, as described below. The immunosuppressant may be contained in the same or a different formulation as the composition containing CHP. When the immunosuppressant is contained in a separate formulation, the immunosuppressant may be administered simultaneously with or sequentially to CHP.

[0123] With regard to the administration methods discussed above, the recipient may be administered the pharmaceutical compositions described herein before, during, and / or after the transplant procedure, at the dosages described above, by one or more of the administration routes discussed above. In some embodiments, CHP may be administered to the recipient via a first administration route 0.5 to 24 hours, 0.5 to 18 hours, 0.5 to 12 hours, 0.5 to 9 hours, 0.5 to 6 hours, or 0.5 to 3 hours before transplantation. In some embodiments, CHP may be administered starting 0.5 to 3 hours before anesthesia and ending 0 to 12 hours, 1 to 8 hours, or 2 to 6 hours after emergence from anesthesia. The recipient may further be administered CHP via a second administration route for 1 to 30 days. The first and second administration routes may be the same or different from each other. In non-limiting exemplary embodiments, the first route of administration can be intravenous, and the second route of administration can be intraperitoneal, intravenous, oral, or of a combination thereof.

[0124] With respect to the administration methods discussed above, the methods may further include administering CHP to a donor of a transplant before the transplant is removed from the donor, and / or providing CHP to the transplant removed from the donor before transplantation into a recipient.

[0125] immunosuppressants The various drugs available to delay transplant rejection (i.e., prolong their survival) work in different ways. Immunosuppressants are widely used.

[0126] Examples of biological immunosuppressants used in induction therapy can include, but are not limited to, various polyclonal or monoclonal antibodies.

[0127] ALG (antilymphocyte globulin), ATG (anti-T lymphocyte globulin), thymoglobulin (TG)-antithymocyte globulin (obtained by immunization of rabbits), lymphoglobulin (LG)-antithymocyte globulin (obtained by immunization of horses), etc. These polyclonal antibodies, directed against various T cell markers, exhibit cytotoxicity and lymphocyte depletion from peripheral blood. Polyclonal antibodies can cause leukopenia and thrombocytopenia.

[0128] Muromonab (OKT3) is a lymphocyte-depleting monoclonal antibody produced by hybridization of mouse antibody-secreting B lymphocytes with a non-secretory myeloma cell line. Potentially life-threatening adverse reactions can occur on the first and second days of treatment with OKT3, which is why it is currently only used when thymoglobulin is contraindicated due to leukopenia or thrombocytopenia. Lemtuzumab (Campath 1H) is a recombinant DNA-derived humanized monoclonal antibody directed against the cell surface glycoprotein CD52. A humanized anti-CD25 monoclonal antibody, basiliximab (SIMULECT TM ) and daclizumab (ZENAPAX TM These antibodies target the alpha chain of the IL-2 receptor and block IL-2-mediated responses. TM , MABTHERA TM ) is a monoclonal anti-CD20 antibody that targets the CD20 antigen on B lymphocytes. Efalizumab (RAPTIVA), a humanized CD11a-specific IgG1, targets the lymphocyte-associated function 1 (LFA-1) molecule. TM alefacept (AMEVIVE), a humanized LFA-3-IgG1 fusion protein that binds to CD2 in T lymphocytes and prevents T cell activation TM bortezomib (VELCADE), a proteosome inhibitor that suppresses T cell function; TM ) etc. are also used in the induction phase.

[0129] During the maintenance phase, calcineurin inhibitors (CNIs) (e.g., cyclosporine (CsA) and tacrolimus (Tac)), mycophenolate mofetil (MMF), mycophenolic acid (MPA), mTOR inhibitors (e.g., sirolimus (RAPAMUNE)), TM ), everolimus (CERTICAN TM A variety of immunosuppressants may be used, including, but not limited to, steroids (e.g., prednisone and methylprednisolone), corticosteroids (e.g., prednisone and methylprednisolone), etc. These immunosuppressants may be administered alone or in combination.

[0130] Inhibitors of purine or pyrimidine biosynthesis are also used to inhibit transplant rejection (or graft rejection). They interfere with DNA synthesis and thereby inhibit cell division, including the ability of T cells to divide. The result is inhibition of T cell activity by preventing the formation of new T cells. Inhibitors of purine synthesis include azathioprine, methotrexate, mycophenolate mofetil (MMF), and mizoribine (MZB, BREDININ). TM ). Inhibitors of pyrimidine synthesis include brequinar sodium and leflunomide. Cyclophosphamide is an inhibitor of both purine and pyrimidine synthesis.

[0131] Many other drugs and methods for delaying allograft rejection are known and used by those skilled in the art. Administration of inhibitors (blockers) of CD40 ligand-CD40 interaction and / or blockers of CD28-B7 interaction to the recipient has been proposed (U.S. Patent No. 6,280,957). Published PCT patent application WO01 / 37860 teaches the administration of anti-CD3 monoclonal antibodies and IL-5 to inhibit Th1 immune responses. Published PCT patent application WO00 / 27421 teaches a method for preventing or treating corneal transplant rejection by administering a tumor necrosis factor α antagonist. U.S. Patent Application Publication No. 2003 / 0180301 discloses the treatment of chronic transplant rejection by administering an antagonist of TGF-β.

[0132] Side effects of CNIs include, for example, nephrotoxicity, early enhanced post-transplant graft dysfunction, dose-related reversible renal vasoconstriction, chronic interstitial fibrosis, acute microvascular disease, hypertension, gastrointestinal dysfunction, anorexia, nausea, vomiting, diarrhea and abdominal discomfort, and hair loss. TM ) and enteric-coated MPA (MYFORTIC TM Adverse effects of sirolimus include gastrointestinal adverse effects such as diarrhea, varying degrees of nausea, bloating, dyspepsia, vomiting, apparent esophagitis, and gastritis. Most of these symptoms respond to a reduction in drug dosage. Adverse effects of sirolimus include renal tubular toxicity, hypokalemia, hypomagnesemia, proteinuria, and nephritic syndrome. Corticosteroids inhibit dendritic cells, inhibiting cytokine gene transcription and all stages of T cell activation; and a nonspecific immunosuppressive effect is lymphopenia. The following non-limiting examples illustrate the present disclosure. [Example]

[0133] Example 1: Allogeneic kidney transplantation in rats Donor surgery: After removing abdominal hair from the donor rat under general anesthesia, the surgical area was disinfected and draped. After a midline incision in the abdominal wall, one kidney was exposed and 8 iu / kg heparin was administered intravenously, followed by nephrectomy.

[0134] Table surgery: unnecessary tissues were removed to anastomose the artery, vein, and ureter of the excised kidney to the recipient's blood vessels and ureter, and the kidney was covered with gauze soaked in saline and stored at 4°C.

[0135] Recipient surgery: After removing the abdominal hair of the recipient rat under general anesthesia, the surgical area was disinfected and draped. After a midline incision in the abdominal wall, the right kidney was exposed, excised, and the donor's renal artery and vein were anastomosed end-to-side to the abdominal vena cava. The donor's ureter was sutured after the bladder was incised. After confirming good renal perfusion (Figure 1), the abdominal wall was closed, and the animal was placed on a blanket at 37°C to recover.

[0136] Example 2. Survival rates of the control group and CHP-treated group As a minor MHC incompatibility model, kidney transplantation model F344 rats were used as donors and Lewis rats were used as recipients. After resection of the right kidney of the recipient on day 0 (D0), the donor kidney was transplanted into the recipient. The left kidney of the recipient was resected on day 3 (D3). The schedule of transplantation and CHP treatment is shown in Figure 2. CHP was administered intravenously at a dose of 40 mg / kg one hour before kidney transplantation, and then intraperitoneally administered at 40 mg / kg three times a week.

[0137] The mean survival time in days (SMD) for the seven control animals not administered CHP was 9 days, and the SMD for the four animals administered CHP was 326 days (n=4) (Figures 3A and 3B). Recipient animals treated with CHP one day before the transplant procedure, on the day of surgery, and during the postoperative period (i.e., induction phase) and maintenance phase, were confirmed to exhibit significantly prolonged survival.

[0138] The results show that CHP could significantly extend the median survival of recipients.

[0139] Example 3. Representative ultrasound images of the control group, CHP-treated group, and inbred (syngeneic) transplant group In the control group, CHP-treated group (F344-to-LEWIS rats), and inbred (LEWIS-to-LEWIS rat) kidney transplant models, ultrasound examinations were performed weekly to check for smooth blood flow to the transplanted kidney. As can be seen from the images in Figure 4, blood flow to the kidney was smooth in the CHP-treated group, indicating normal functioning of the transplanted kidney, while kidney transplant recipients without CHP treatment ("Syngenic PL") showed significantly reduced blood flow to the kidney. When the transplanted kidney function was smooth, blood flow to the kidney was confirmed by color Doppler, and the RI index also showed values ​​between 0.5 and 0.7. When the function of the transplanted kidney decreased, blood flow to the kidney decreased, and the RI index also showed values ​​of 0.7 or higher.

[0140] Example 4. Representative graft tissue findings in the control group and CHP-treated group In the CHP-treated group (TPL+CHP), not only were focal glomerular necrosis and severe tubulointerstitial changes reduced, but findings with borderline changes suggestive of acute cell-mediated rejection and microvascular inflammation also rapidly diminished.

[0141] From an overall renal histological perspective, significant changes, such as acute tubular injury, i.e., acute inflammatory cell infiltration around the renal tubules or glomeruli, thrombus formation in capillaries, and inflammation of the arterial wall, were observed in the CHP-treated group. These phenomena are thought to be the effect of CHP, which may suppress acute rejection that occurs within a few days after transplantation. Figure 5 shows the graft kidney histological findings on the 7th day of rejection in the positive control group (Syngenic TPL) and on the 45th day in the CHP-treated group (TPL + CHP).

[0142] Example 5. Evaluation of graft function Body weight (g), blood urea nitrogen (BUN) (mg / dL), creatine (mg / dL), and Uproc / Crea ratio (mg / mg) of the CHP-treated (TPL+CHP) and syngeneic (Syngenic) groups were measured weekly for a period of 46 weeks after transplantation, and the results are shown in Figures 6A-6D, respectively. Serum creatinine in the inbred negative control (Syngenic) group was 0.71 mg / dL at 3 weeks, and a similar value of 0.82 mg / dL was observed in the CHP-treated group (TPL+CHP).

[0143] The results show that the transplanted organs of CHP-treated animals functioned fully after transplantation for the entire life of the recipient animals.

[0144] Figure 7 shows a graph providing a quantitative comparison of BUN and serum creatinine levels in recipient rats 5 days after transplantation. Individual data points represent the following groups: syngeneic transplant recipients (Syngenic; n = 3), transplant recipients without CHP administration (TPL; n = 5), and CHP-treated transplant recipients (TPL + CHP; n = 5). Recipients treated with CHP showed significant reductions in both BUN (from 193.5 ± 8.54 to 41.98 ± 5.69; p < 0.0001) and serum creatinine levels (from 7.23 ± 0.39 to 1.32 ± 0.13; p < 0.0001). This significant improvement in key renal function indicators highlights promising advances in posttransplant care that reduce dependency on immunosuppressive therapy and prolong recipient and graft survival.

[0145] Figure 8 shows representative immunohistochemical images of PAS and Nrf2 staining (at 100x magnification) with a scale bar indicating 100 μm. All animals were sacrificed on day 5 after kidney transplantation. Administration of CHP to transplant recipients reduced tubular atrophy, tubulitis, endotheliitis, and leukocyte infiltration, while increasing levels of the antioxidant stress marker Nrf2 (nuclear factor erythroid 2-related factor). These findings highlight the potential for CHP to exert protective (e.g., anti-inflammatory and antioxidant) effects in a rat transplant model.

[0146] While the invention has been described with reference to what are presently considered to be the preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

[0147] All publications, patents, and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

Claims

1. A composition for prolonging survival in a recipient of an allograft and / or for prolonging survival of an allograft in said recipient, comprising an effective amount of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof as an active ingredient, and a pharmaceutically acceptable carrier.

2. 10. The composition of claim 1, wherein the allograft is treated with cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, prior to transplantation into the recipient.

3. 10. The composition of claim 1, administered to said recipient in combination with an immunosuppressant.

4. 10. The composition of claim 1, wherein the composition is administered to the recipient 0.5 to 18 hours or 18 to 36 hours prior to anesthesia for transplantation of the allograft in the recipient.

5. 10. The composition of claim 1, wherein the composition is administered to the recipient after transplantation as a maintenance therapy.

6. The composition of claim 3, wherein the composition and the immunosuppressant are administered to the recipient simultaneously, concurrently, or sequentially.

7. 4. The composition of claim 3, wherein the composition is administered to the recipient 0.5 to 18 hours or 18 to 36 hours prior to anesthesia for transplantation of the allograft in the recipient.

8. 4. The composition of claim 3, wherein the composition is administered to the recipient after transplantation as a maintenance therapy.

9. 10. The composition of claim 1, wherein the allograft is lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penile tissue, organ, or cell.

10. 4. The composition of claim 3, wherein the allograft is lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penile tissue, organ, or cell.

11. The composition of claim 1 , wherein administration of the composition suppresses an immune response to the allograft in the recipient.

12. The effective amount of CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof is about 0.001 to 0.005 mg / kg, 0.005 to 0.01 mg / kg, 0.01 to 0.02 mg / kg, 0.02 to 0.04 mg / kg, 0.04 to 0.06 mg / kg, 0.06 to 0.08 mg / kg, 0.08 to 1 mg / kg, 1 to 5 mg / kg, 5 to 6 mg / kg, 6 to 7 mg / kg, 7 to 8 mg / kg, 8 to 10mg / kg, 10-15mg / kg, 15-20mg / kg, 20-25mg / kg, 25-30mg / kg, 30-35mg / kg, 35-40mg / kg, 40-45mg / kg, 45-50mg / kg kg, 50-100mg / kg, 100-150mg / kg, 150-200mg / kg, 200-300mg / kg, 300-400mg / kg, 400-500mg / kg, 500-600mg / kg, 600-700mg / kg, 700-800mg / kg, 800-900mg / kg, 900-1000mg / kg, 1000-1100mg / kg, 1100-1200mg / kg, 1200-1300 mg / kg, 1300-1400mg / kg, 1400-1500mg / kg, 1500-1600mg / kg, 1600-1700mg / kg, 1700-1800mg / kg, 1800-1900mg / 2. The composition of claim 1, wherein the serotonin-releasing hormone (SHR) is 1900-2000 mg / kg, 2000-2100 mg / kg, 2100-2200 mg / kg, 2200-2300 mg / kg, 2300-2400 mg / kg, 2400-2500 mg / kg, 2500-2600 mg / kg, 2600-2700 mg / kg, 2700-2800 mg / kg, 2800-2900 mg / kg, or 2900-3000 mg / kg.

13. A composition for suppressing or reducing the immune response in a recipient of an allograft, for reducing rejection of the allograft in the recipient, and / or for reducing the amount of immunosuppressant administered for and / or after transplantation of the allograft into the recipient, the composition comprising an effective amount of cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, as an active ingredient, and a pharmaceutically acceptable carrier.

14. 14. The composition of claim 13, wherein the transplant is treated with cyclo-his-pro (CHP), a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, prior to implantation into the recipient.

15. 14. The composition of claim 13, wherein the composition is administered to the recipient 0.5 to 18 hours or 18 to 36 hours prior to anesthesia for transplantation of the allograft in the recipient.

16. 14. The composition of claim 13, wherein the composition is administered to the recipient as a maintenance therapy after transplantation.

17. 14. The composition of claim 13, wherein the composition and the immunosuppressant are administered simultaneously, concurrently, or sequentially.

18. 14. The composition of claim 13, wherein the allograft is lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penile tissue, organ, or cell.

19. The effective amount of CHP, its pharmaceutically acceptable salt, stereoisomer, or solvate thereof is about 0.001 to 0.005 mg / kg, 0.005 to 0.01 mg / kg, 0.01 to 0.02 mg / kg, 0.02 to 0.04 mg / kg, 0.04 to 0.06 mg / kg, 0.06 to 0.08 mg / kg, 0.08 to 1 mg / kg, 1 to 5 mg / kg, 5 to 6 mg / kg, 6 to 7 mg / kg, 7 to 8 mg / kg, 8 to 10mg / kg, 10-15mg / kg, 15-20mg / kg, 20-25mg / kg, 25-30mg / kg, 30-35mg / kg, 35-40mg / kg, 40-45mg / kg, 45-50mg / kg kg, 50-100mg / kg, 100-150mg / kg, 150-200mg / kg, 200-300mg / kg, 300-400mg / kg, 400-500mg / kg, 500-600mg / kg, 600-700mg / kg, 700-800mg / kg, 800-900mg / kg, 900-1000mg / kg, 1000-1100mg / kg, 1100-1200mg / kg, 1200-1300m g / kg, 1300-1400mg / kg, 1400-1500mg / kg, 1500-1600mg / kg, 1600-1700mg / kg, 1700-1800mg / kg, 1800-1900mg / k 14. The composition of claim 13, wherein the serotonin concentration is 1900-2000 mg / kg, 2000-2100 mg / kg, 2100-2200 mg / kg, 2200-2300 mg / kg, 2300-2400 mg / kg, 2400-2500 mg / kg, 2500-2600 mg / kg, 2600-2700 mg / kg, 2700-2800 mg / kg, 2800-2900 mg / kg, or 2900-3000 mg / kg.

20. (ii) prolonging survival of an allograft in said recipient; (iii) suppressing or reducing the immune response in said recipient to an allograft; (iv) reducing rejection of an allograft in said recipient; and / or (v) reducing the amount of immunosuppressant administered during and / or after transplantation of an allograft into said allograft recipient.

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