Some kidney transplant candidates have a very low chance of getting a kidney transplant because their immune systems are "highly sensitized" to most kidney donors. Being "highly sensitized" means that they will likely have to wait a long time (more than 5 years) before an acceptable donor is found for them or, they never receive a compatible donor, and die on waitlist. The purpose of this study is to find out whether two drugs, daratumumab (Darzalex®), and belatacept (Nulojix®), can make these kidney transplant candidates less sensitized, and make it easier and quicker to find a kidney donor for them.

This study will enroll 15 eligible adult participants with end stage renal failure on dialysis who are on the waiting list for a deceased donor transplant with calculated panel reactive antibodies (cPRA) ≥99.9% or >98% (with >5 years of waiting time) or, those with cPRA >98% and an human leukocyte antigen (HLA)-incompatible approved living donor who have not received a transplant after 1 year in a paired kidney exchange program. The study will evaluate whether the study treatment is safe and can lower the participant's immune system's sensitization to kidney donors, making it easier to find a well-matched kidney for them.

The study treatment is comprised of two drugs, Darzalex® (daratumumab) and Nulojix® (belatacept). Daratumumab is licensed for treatment of multiple myeloma and belatacept is licensed for prevention of rejection after kidney transplant. Eligible participants will receive infusions of daratumumab and belatacept over a 10-week period in Cohort 1. Eligible participants will receive infusions of daratumumab and belatacept over a 14-week period in Cohort 2. An interim safety and efficacy analysis will occur after the first 5 participants have received study treatment. All subjects will undergo HLA antibody assessments and bone marrow aspiration prior to and after completion of treatment and receive 42 weeks of follow up after completing treatment. Participants who prematurely discontinue study therapy will receive follow up through 56 weeks after their baseline visit. Subjects who receive a kidney transplant while in the study will receive standard of care immunosuppression and undergo 52 weeks of follow up. Living donors will participate for one study visit to provide blood collection.

Inclusion Criteria:

Individuals who meet all of the following criteria are eligible for enrollment as study subjects-

1. Subject must be able to understand and provide informed consent

2. End stage renal disease (ESRD) on dialysis

3. United Network for Organ Sharing (UNOS) listed listed with current calculated panel reactive antibodies (cPRA) ≥99.9% or >98% (with >5 years of waiting time) awaiting deceased donor transplant

   --Note: Those with cPRA >98% with human leukocyte antigen (HLA)-incompatible approved living donor who have not received a transplant after 1 year in a paired kidney exchange program are also eligible

4. Evidence of established immunity to Epstein-Barr Virus (EBV) as demonstrated by serologic testing

5. Negative result of most recent tuberculosis (TB) testing or appropriately completed latent TB infection (LTBI) therapy.

   • Testing should be conducted using either a PPD or interferon-gamma release assay (i.e., QuantiFERON-TB, T-SPOT.TB)
   • Results from tests performed within 12 months prior to study entry are acceptable in the absence of any intervening exposure to TB
   • Subjects with a positive test for LTBI must complete appropriate therapy for LTBI ---LTBI treatment regimens should be among those endorsed by the Centers for

   Disease Control and Prevention (CDC), Division of TB Elimination, url:

   https://www.cdc.gov/tb/topic/treatment/ltbi.htm

6. Negative Food and Drug Administration (FDA)-approved test for human immunodeficiency virus (HIV) diagnosis (at screening or as documented in medical record, up to 12 months prior to screening)

7. Negative Hepatitis C antibody test at screening or as documented in medical record, up to 12 months prior to screening

   --If there is a history of treated hepatitis C then documentation of two consecutive negative HCV quantitative ribonucleic acid (RNA) Polymerase chain reaction (PCR) tests separated by at least 6 months is required. Untreated subjects with HCV RNA are eligible.

8. Negative result for SARS-CoV-2 by an FDA-authorized molecular diagnostic test. Examples include, but are not limited to RT-PCR, LAMP, TMA, and qSTAR.

9. Female subjects of reproductive potential must have a negative pregnancy test upon study entry

10. All subjects of reproductive potential must agree to use of contraception for the duration of the study

11. Subjects must have current vaccinations or documented immunity to varicella, measles, hepatitis B, pneumococcus, influenza, and zoster (if ≥50 years old)

    • If subjects require administration of vaccines to meet eligibility requirements, they must wait at least 2 weeks between vaccination and the baseline (Visit 0) visit

Exclusion Criteria:

Individuals who meet any of these criteria are not eligible for enrollment as study subjects-

1. Inability or unwillingness of a subject to give written informed consent or comply with study protocol

2. Known active current or history of invasive fungal infection or non-tuberculous mycobacterial infection

3. Hepatitis B surface antigen or core antibody positive

4. Serious uncontrolled concomitant major organ disease excluding kidney failure

5. Previous non-kidney solid organ or bone marrow transplant

6. Any infection requiring hospitalization and intravenous (IV) antibiotics within 4 weeks of screening or by mouth (PO) antibiotics within 2 weeks

7. Primary or secondary immunodeficiency

8. History of active tuberculosis (TB), even if treated

9. History of positive result for 2019-novel Coronavirus (2019-nCoV) by real-time reverse transcriptase (RT-PCR)

10. Malignancy within the last 5 years except treated basal and squamous cell cancer of the skin or treated in situ cervical cancer

11. History of plasma cell dyscrasia

12. Alcohol, drug, or chemical abuse within 1 year

13. Difficult peripheral venous access

14. Need for uninterrupted anticoagulation

15. Neutropenia (absolute neutrophil count <1000/uL) or thrombocytopenia (platelet count <100,000/uL) within 4 weeks prior to study enrollment

16. Women who are currently pregnant or nursing

17. Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational drug, whichever is longer) of screening

18. Current treatment with other biological drug

19. Immunization with live vaccine within 2 weeks of study baseline (Visit 0) visit

20. Past or current medical problems or findings from physical examination or laboratory testing not listed above, which, in the opinion of the investigator, may:

    • pose additional risks from participation in the study,
    • interfere with the subject's ability to comply with study requirements, or
    • impact the quality or interpretation of the data obtained from the study

The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.

On average, within 24 months after database lock for the trial.

Open access.