The purpose of this study is to evaluate the safety and efficacy of carfilzomib and belatacept, administered with steroids and maintenance immunosuppression, in kidney transplant recipients with donor-specific antibody (DSA)-associated graft injury. Participants will be followed for 52 weeks after starting investigational therapy, including protocol biopsies at 3 months and 12 months after start of investigational therapy. The study will also assess changes in immune cell responses, blood and urine biomarkers, and biopsy-based pathomic features associated with antibody-mediated graft injury.

This is a prospective, multicenter, open-label study evaluating the safety and efficacy of carfilzomib and belatacept in kidney transplant recipients with donor-specific antibody-associated graft injury. Twenty-five participants will receive steroid pulse/taper, carfilzomib, belatacept, tacrolimus, mycophenolate, and prednisone according to protocol-defined dosing and maintenance immunosuppression. Participants will be followed for 12 months after initiation of investigational therapy, with protocol biopsies performed at 3 months and 12 months after start of investigational therapy. Participants who discontinue study treatment without withdrawing informed consent will continue follow-up to end of study.

Inclusion Criteria:

1. Able to understand and agree to participate in the study.
2. Have received a kidney transplant from a living or deceased donor (including re-transplants).
3. Men and women must agree to use birth control during the study and for 3 months after the last dose of study drugs, or be surgically sterile or post-menopausal.
4. Heart function must be good enough (LVEF of at least 40%) without severe heart issues or high blood pressure in the lungs.
5. Must have been previously exposed to the Epstein-Barr Virus (EBV).
6. Diagnosed with specific types of kidney transplant rejection based on criteria, with certain conditions on timing and treatment history.
7. Kidney function must be at a certain level (eGFR of at least 30 ml/min/1.73 m²).
8. Specific scores related to kidney biopsy results must be within certain limits.
9. Patient is ≥6-months post-transplant or is <6 months post-transplant but has documentation that they have been offered and/or received the local standard of care treatment prior to enrollment.
10. Must have a measurable level of specific antibodies against the donor kidney (HLA DSA) with a certain intensity.
11. Up-to-date vaccinations according to guidelines for transplant patients.
12. Must have a negative tuberculosis (TB) test and chest x-ray before enrollment, no symptoms or known contact with TB, and not have recently traveled to or lived in areas with high TB rates. If previously infected with TB, must have completed treatment and have a recent negative chest x-ray.
13. If previously infected with COVID-19, must be fully recovered for at least 21 days before joining the study. No COVID-19 test required for those without symptoms.

Exclusion Criteria:

1. Unable or unwilling to give consent or follow study rules.

2. Kidney transplant with incompatible blood types.

3. Very high levels of protein in urine, indicating severe kidney issues.

4. Previously had a non-kidney organ or bone marrow transplant.

5. Any other medical issues that might increase risk, make following the study rules hard, or affect study results, as judged by the study doctor.

6. Heart attack within the last year, uncontrolled chest pain, or signs of a recent heart problem on an ECG.

7. Severe heart failure (Class 3 or higher).

8. Irregular heartbeats that can't be controlled with medication.

9. Participants who are actively receiving any of the therapies listed below, or who have previously received these therapies without meeting the required washout period prior to the qualifying biopsy and donor-specific antibody (DSA) assessment:

   • ≥4 weeks since last dose: IVIG (intravenous immunoglobulin), therapeutic plasma exchange (TPE)
   • ≥6 weeks since last dose: Proteasome inhibitors
   • ≥3 months since last dose: Eculizumab; lymphocyte-depleting agents (e.g., rabbit anti-thymocyte globulin, alemtuzumab); anti-CD20 agents
   • ≥6 months since last dose: Anti-CD38 agents; anti-IL-6 agents

10. Used any experimental drug not specified within the last 4 weeks or longer if the drug stays in the body longer.

11. Serious medical or mental health issues that could interfere with the study.

12. Cancer diagnosis or treatment within the past 2 years, except for certain skin cancers or cancers with a high cure rate.

13. Known allergy to Captisol® (used in the study drug).

14. Very low blood counts (hemoglobin, neutrophils, or platelets).

15. Positive for HIV, Hepatitis B, or Hepatitis C, unless Hepatitis C was successfully treated.

16. Severe infections needing treatment in the last 4 weeks.

17. Specific kidney infection (BK nephropathy) or high levels of BK virus.

18. Certain kidney biopsy results indicating other types of rejection or kidney diseases.

19. Treated for a specific viral infection (CMV) in the last 90 days or resistant to certain CMV treatments.

20. Received a live vaccine in the last 4 weeks.

21. Severe liver disease or abnormal liver tests.

22. Pregnant or breastfeeding women. Women who can become pregnant must have a negative pregnancy test or proof they are not pregnant.

23. Any other significant medical condition that could interfere with the study according to the doctor.

24. Received certain antibody treatments in the last 3 months.

25. Kidney rejection within 6 months post-transplant without standard care.

26. Confirmed severe protein levels in urine.

27. Underwent certain treatments from the time of entry DSA result and biopsy screening.

28. History of multiple unprovoked blood clots.

29. Diagnosed with Atypical Hemolytic Uremic Syndrome (aHUS).