The goal of this clinical trial is to learn if siplizumab can prevent rejection of a kidney transplant in adult participants with end stage kidney disease. The main questions it aims to answer are:

How many adverse events do participants receiving two different doses of siplizumab have compared to rabbit anti-thymocyte globulin (rATG)?

How many participants successfully keep their kidney transplant after receiving siplizumab or rATG? This will be calculated as those participants that did not: die; have their kidney fail to work properly (graft loss); their body rejects their transplant (tissue sample (biopsy)-proven acute rejection: BPAR); or who were lost to follow-up.

How does the body respond to siplizumab after dosing at each of the 2 dose levels?

How does siplizumab work in the body compared to rATG?

Selected participants will be divided into 3 groups. In 2 of the groups, participants will be given siplizumab at one of the two study medicine doses. Participants in the third group will be given rATG. All participants will take the usual anti-rejection medicines given before, during, and after a kidney transplant. All participants will also be given medicines before the study drug to lower the risk of reactions, and medicines used to prevent or treat infections after the transplant.

Participants will be asked to provide their medical history at the first visit at the study site where you will have your kidney transplant. At the first visit and other visits participants will be asked to provide their medication history, have a physical exam, check vital signs, have blood drawn for tests, and have non-invasive tests that record the electrical activity of your heart (ECG) and blood draws.

Participants will be monitored for 12 months after transplant surgery.

Approximately 120 renal transplant candidates requiring induction therapy will be enrolled 1:1:1 to receive 1 of 2 dose levels of siplizumab or to the comparator rATG.

Randomization will be stratified by donor status (living vs donation after brain death vs donation after cardiac death) to ensure similar proportions of donor types in each study arm. All participants will also receive:

• A triple regimen (TAC, MPA, and CS) of background immunosuppressive therapy for the duration of the study.
• Premedication prior to study treatment infusions.
• Infection prophylaxis

This clinical trial will evaluate the safety of an anti-cluster of differentiation 2 (CD2) monoclonal antibody, siplizumab, compared to rATG as induction therapy in renal transplant recipients.

Following hospital discharge, participants will undergo assessments and procedures as indicated in the protocol through Month 12 or EOS, unless more frequent visits are required per local SoC or for laboratory specimen collection.

Safety assessments will include physical examinations, ECGs, vital signs, viral surveillance and monitoring, standard clinical laboratory evaluations completed centrally (hematology, clinical chemistry, urinalysis), and AE/SAE monitoring.

Final analysis will be performed when all participants have completed 12-month follow-up visits post-transplant or have otherwise ended the trial. This analysis will be performed to evaluate the safety of siplizumab at 2 dose levels compared to rATG.

Inclusion Criteria:

• Recipients of a renal allograft from a non-HLA identical living or deceased donor.
• Recipients of a kidney with a cold ischemia time < 30 hours; hypothermic machine perfusion within the same timeframe is acceptable.
• Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, must agree to use highly effective methods of contraception.

Exclusion Criteria:

• Transplant recipients seronegative for EBV.
• Transplant recipients receiving a kidney from a non-heart beating donor (ie, DCD) whose organ is retrieved from an uncontrolled DCD or whose donor age > 55 years of age.
• Multi-organ transplant recipients (eg, kidney-pancreas, organ other than kidney), dual-kidney transplant recipients, recipients with more than one prior kidney transplant, or hematopoietic stem cell transplantation recipients.
• Presence of current or historical DSA via single-antigen bead assay or local SoC. The MFI cut-off value used to determine the presence of DSA will be defined as per the institutional SoC. Results within 3 months prior to transplant are acceptable.
• Crossmatch positive (isolated positive B cell crossmatches are not an exclusion criterion).
• ABO-incompatible recipient.
• Administration of complement inhibitor therapy within 6 months prior to the transplant, or likely to require treatment with complement inhibitor therapy during the study.
• Participants receiving immunosuppressive therapies prior to transplant for pre-existing conditions must be candidates for the protocol-defined regimen.
• History of malignancy of any organ system, except for localized excised non-melanomatous skin lesions or carcinoma in situ of the cervix.
• Seropositive for human immunodeficiency virus or hepatitis B surface antigen. Participants who are seropositive for hepatitis C virus (HCV) are excluded without proof of sustained viral response after anti-HCV treatment.
• Recipient of a kidney from a donor who tests positive for human immunodeficiency virus or hepatitis B surface antigen/hepatitis B core protein.
• History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes (eg, siplizumab, rATG, TAC, MPA derivatives, CS).
• Evidence of active tuberculosis (TB) infection (participants with a history of latent TB may become eligible after treatment with anti-TB therapy according to national guidelines).
• Participants with severe systemic infection(s), at the time of screening or within 2 weeks prior to randomization

Pharmacy will prepare infusion based on randomization code prior to administration by study investigator.

To maintain the blind, matching infusions of normal saline will be administered (IV) as placebo for different dosing regimens.