Anti-CD2 antibody treatment in kidney transplantation

Abstract

Provided herein are induction protocols, relating to kidney transplantation in a patient, wherein the method comprises administering an anti-CD2 antibody or antigen binding fragment thereof to the patient.

Description

New International Patent Application February 19, 2026 Zelarion Malta Limited et al. 107805PC METHODS AND COMPOSITIONS FOR CD2-TARGETED INDUCTION CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No.63 / 760,389 filed February 19, 2025, United States Provisional Application No. 63 / 854,926 filed July 31, 2025, United States Provisional Application No. 63 / 890,851 filed September 30, 2025, United States Provisional Application No. 63 / 943,214 filed December 17, 2025, and United States Provisional Application No. 63 / 977,661 filed February 6, 2026, the content of each of which is incorporated by reference in its entirety herein.SEQUENCE LISTING

[0002] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14526-041-228_SEQLISTING.xml”, was created on February 18, 2026, and is 10,731 bytes in size.1. FIELD

[0003] The present application relates to anti-CD2 antibodies (e.g., siplizumab) for CD2 targeted induction.2. BACKGROUND

[0004] Since the first successful human kidney transplantation by Murray et al. in 1954 (Murray etal., Ann Surg. 1958; 148(3): 343-359), numerous immunosuppressive regimens have been developed for clinical application. The ultimate goal of immunosuppression in kidney transplantation is to prevent acute rejection and maintain allograft function while balancing the risk of adverse effects (Tanriover et al., Clin J Am Soc Nephrol. 2015; 10(6): 1041-1049). Immunosuppressive agents are categorized as (1) induction therapy that is administered in the perioperative period and (2) maintenance therapy that transplant recipients require for lifelong use (KDIGO, Am J Transplant. 2009; 9 Suppl 3: S1-S155).

[0005] The contemporary standard of care (SoC) maintenance regimen is based on a calcineurin inhibitor (CNI), such as cyclosporine (CsA, Neoral) or tacrolimus (TAC, Prograf) which inhibits T-cell activation, in combination with a T-cell proliferation inhibitor. CNIs are generally considered the primary immunosuppressant. Immunosuppressive drugs which are typically paired with CNIs include antiproliferative agents such as mycophenolic acid (MPA)-based drugs (mycophenolate mofetil (MMF), CellCept or Myfortic) which block inosine monophosphate dehydrogenase (IMPDH) or mechanistic target of rapamycin (mTOR) inhibitors such as sirolimus (rapamycin, Rapamune) or everolimus (Certican / Zortress).

[0006] Calcineurin inhibitor-based SoC regimens have resulted in excellent 1-year patient and graft survival rates of 94.7% for deceased donor kidneys and 98.1% for living donor kidneys in the United States (US), with low (7-8%) one-year acute rejection rates (Hart et al., Am J Transplant. 2020; 20 Suppl si: 20-130). However, use of currently available immunosuppressive drugs is still limited by mechanism-based side effects and poor long-term graft and patient survival. Side effects such as hypertension, dyslipidemia, and diabetes as well as gastro-, hematologic-, neuro-, and nephrotoxicity are common and result in poor long-term patient survival.

[0007] Induction therapy use varies based on recipient risk and regional preference. There are two broad categories of induction therapies - lymphocyte-depleting antibodies, such as polyclonal rabbit anti-thymocyte globulin (rATG, Thymoglobulin) and nondepleting monoclonal antibodies such as basiliximab (Simulect) and formerly daclizumab (Zenapax; withdrawn from US in 2009) that inhibit T-cell activation (Hardinger et al., Transpl Int. 2013; 26(7): 662-672). In the past, the lymphocyte depleting murine anti-human CD3 monoclonal antibody, muromonab-CD3 (Orthoclone; OKT3, withdrawn 2010) and humanized anti-CD52 antibody alemtuzumab (Campath / Lemtrada) have sometimes been used (off-label) in high-risk transplant patients.

[0008] Siplizumab (TCD601; previously known as MEDI-507) is a non-agonistic, humanized, anti-CD2 monoclonal antibody of the IgG1κ class. Siplizumab binds to a unique epitope on human CD2, distinct from the CD58 binding site, with high affinity (Kd - 5 nM), inhibiting co-stimulation and T-cell activation. In addition, the fragment crystallizable (Fc) portion of the siplizumab antibody binds to fragment crystallizable gamma receptors (FcyR) on NK cells resulting in ADCC and antibody-dependent cellular phagocytosis (ADCP)-mediateddepletion of CD2+ lymphocytes. Siplizumab also demonstrates selective immunomodulatory activity with depletion of Tmems (high CD2 expression) and sparing of regulatory T cells (Treg; low CD2 expression) in vitro and in vivo based on the differential expression of CD2 on lymphocytes. Considering this activity, siplizumab is expected to modulate T-cell memory and immune reactivity in the setting of transplantation.3. SUMMARY

[0009] In one aspect, the present disclosure provides a method of transplanting a kidney from a donor to a subject, wherein the method comprises: (a) administering an anti-CD2 antibody or an antigen binding fragment thereof to the subject, wherein the anti-CD2 antibody is administered at a dose up to 0.2 mg / kg per administration; and (b) transplanting the kidney into the subject.

[0010] In another aspect, the present disclosure provides a method of transplanting a kidney from a donor to a subject, wherein the method comprises: (a) administering an anti-CD2 antibody or an antigen binding fragment thereof to the subject, wherein the anti-CD2 antibody is administered at a dose up to 0.2 mg / kg per administration; and (b) transplanting the kidney into the subject, wherein a first dose of the anti-CD2 antibody or an antigen binding fragment thereof is administered on the day of transplantation.

[0011] In certain embodiments, the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject at a dose of 0.2 mg / kg, 0.15 mg / kg, 0.1 mg / kg, or 0.05 mg / kg per administration.

[0012] In one aspect, the present disclosure provides a method of transplanting a kidney from a donor to a subject, wherein the method comprises: (a) administering an anti-CD2 antibody or an antigen binding fragment thereof to the subject, wherein the anti-CD2 antibody is administered twice in total, at a dose of 0.6 mg / kg per administration; and (b) transplanting the kidney into the subject, wherein the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject on the day of the transplanting step, and 3 days following the transplanting step.

[0013] In one aspect, the present disclosure provides a method of transplanting a kidney from a donor to a subject, wherein the method comprises: (a) administering an anti-CD2 antibody or an antigen binding fragment thereof to the subject, wherein the anti-CD2 antibody isadministered at a dose of 1.2 mg / kg per administration; and (b) transplanting the kidney into the subject. In another aspect, the present disclosure provides a method of transplanting a kidney from a donor to a subject, wherein the method comprises: (a) administering an anti-CD2 antibody or an antigen binding fragment thereof to the subject, wherein the anti-CD2 antibody is administered to the subject at a dose of 1.2 mg / kg per administration; and (b) transplanting the kidney into the subject, wherein a first dose of the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject on the day of the transplanting step.

[0014] In certain embodiments, the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject on the day of transplantation, and 4 days post to the transplantation, and wherein the anti-CD2 antibody or an antigen binding fragment thereof is not administered prior to the day of transplantation. In certain embodiments, the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject on the day of transplantation, and 3 days post to the transplantation, and wherein the anti-CD2 antibody or an antigen binding fragment thereof is not administered prior to the day of transplantation.

[0015] In certain embodiments, the first dose of the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject on the day of transplantation, pre-operatively or intra-operatively.

[0016] In certain embodiments, the anti-CD2 antibody or antigen binding fragment thereof is siplizumab.

[0017] In certain embodiments, the subject is human. In certain embodiments, the donor is human.

[0018] In certain embodiments, the method further comprises administering an immunosuppressive agent. In certain embodiments, the immunosuppressive agent is tacrolimus, mycophenolate mofetil, mycophenolate sodium, and / or corticosteroids.

[0019] In certain embodiments, the method does not comprise administering fludarabine, tocilizumab, an anti-IL6R antibody, a B-cell depleting antibody, cyclophosphamide, total body irradiation, and / or thymic irradiation to the subject.

[0020] In certain embodiments, the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject intravenously.

[0021] In certain embodiments, the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject no more than two times.4. BRIEF DESCRIPTION OF THE FIGURES

[0022] FIG. 1 illustrates quantification of CD45RA+CD197+ naive CD8 T-cells (Tn) in kidney transplant recipients 12 months post-transplant following induction with 1.7 mg / kg siplizumab (black line) or 1.5 mg / kg (rATG) (grey line).

[0023] FIG. 2 illustrates quantification of CD45RA-CD197- effector memory CD8 cells in kidney transplant recipients 12 months post-transplant following induction with 1.7 mg / kg siplizumab (black line) or 1.5 mg / kg (rATG) (grey line).

[0024] FIG. 3 illustrates quantification of NK cells in kidney transplant recipients 12 months post-transplant following induction with 1.7 mg / kg siplizumab (black line) or 1.5 mg / kg (rATG) (grey line).

[0025] FIG. 4 illustrates effects of siplizumab on immunomodulatory activity in kidney transplant recipients 12 months post-transplant following induction with siplizumab at 0.2 mg / kg, 0.6 mg / kg, 1.7 mg / kg, or 5.0 mg / kg, or with rATG at 1.5 mg / kg. FIG. 4 A depicts quantification of CD3+absolute T cells. FIG. 4B depicts quantification of CD8+CD45RA+CD197+naive CD8+T-cells (Tn). FIG. 4C depicts quantification of CD4+CD45RA+CD197+naive CD4+T-cells (Tn). FIG. 4D depicts quantification of CD8+CD45RA CD197‘ effector memory CD8+T cells.

[0026] FIGs. 5A-5B show the study design of Phase 2b study (FIG. 5A) and Phase 3 study (FIG. 5B)

[0027] FIG. 6 shows the schematic of a Phase 2b, randomized, multicenter, double-blind, dose finding, active controlled study of siplizumab compared to rATG in renal transplant recipients requiring induction therapy.

[0028] FIG. 7 illustrates incidence of biopsy-proven acute rejection in kidney transplant recipients following induction with siplizumab at 0.2 mg / kg, 0.6 mg / kg, 1.7 mg / kg, or 5.0 mg / kg, or with rATG at 1.5 mg / kg.5. DETAILED DESCRIPTION

[0029] Described herein are methods for the induction of immunological tolerance of a kidney transplant recipient’s immune system towards the transplanted kidney without the need for ongoing immunosuppressive therapy. The subjects treated in accordance with the methodsdescribed herein are described in Section 5.1. Kidney transplant for use with the methods provided herein in is described in Section 5.2. Initial conditioning regimen and / or post operative treatment for use with the current methods are described in Section 5.3. Kidney transplantation and the methods to assess clinical outcomes are described in Section 5.4 and Section 5.5 respectively. Examples of the methods provided herein are described in Section 6.

[0030] In a specific embodiment, an individual who has been selected to receive or has received a kidney transplant may be treated using the methods described herein. In a specific embodiment, a treatment regimen comprises administering anti-CD2 antibody or antigen binding fragment thereof (e.g., siplizumab at up to 0.2 mg / kg) on the same day of the transplant surgery, and 1 day post transplant surgery. In another specific embodiment, a treatment regimen comprises administering anti-CD2 antibody or antigen binding fragment thereof (e.g., siplizumab at 0.6 mg / kg or 1.2 mg / kg) on the same day of the transplant surgery, and 3 days post transplant surgery. In certain embodiments, the components of the regimen do not comprise administering bone marrow cells to the kidney recipient. In certain embodiment, the components of the regimen can be modified as described herein to achieve induction of tolerance of a kidney transplant recipient’s system towards the transplanted organ without the need for ongoing immunosuppressive therapy.5.1 Recipients

[0031] The terms “subject,” “recipient,” and “patient” are used interchangeably herein. In some embodiments, the subject is a mammal. In some embodiments, a subject or a subject in need is a subject who has or is predicted of having or developing an immune related disorder or disease. In some embodiments, a subject or a subject in need is a subject who has or will undergo transplant surgery. In some embodiments, a subject or a subject in need is a subject who has chronic or acute inflammatory disorder of the immune system. In some embodiments, the subject is a primate. In certain embodiments, the subject is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a child. In some embodiments, the subject is a pediatric patient. In some embodiments, the subject is a juvenile human. In some embodiments, the subject is at least 5 years old, 10 years old, 15 years old, 18 years old, 21 years old, 50 years old, 60 years old, 65 years old, 70 years old, or more than 70 years old. In some embodiments, the subject is at most 5 years old, 10 years old, 15 years old,18 years old, or 21 years old. In some embodiments, the subject has not received prior treatment related to organ transplant or for an immune associated disorder or disease. In some embodiments, the subject is a treatment naive subject. In some embodiments, the subject is treatment naive to a treatment for an immune associated disorder or disease. In some embodiments, the subject has not received prior treatment with an anti-CD2 antibody (e.g. siplizumab) or an antigen-binding fragment thereof and / or with an agent described herein.

[0032] Subjects who have undergone or will undergo a kidney transplant can be suitable for treatment with a method provided herein. A recipient treated in accordance with the methods described herein may have required a kidney transplant for any reason. Generally, a patient suffering from end-stage kidney disease whose life expectancy is predicted to be extended by a kidney transplant beyond the life expectancy without the kidney transplant may be considered for a kidney transplant. A recipient may be in need of a kidney transplant due to renal failure or the rejection of a donor kidney. Renal failure can have a number of causes, including but not limited to high blood pressure (hypertension), physical injury, diabetes, kidney disease (polycystic kidney disease, glomerular disease) and autoimmune disorders such as lupus. Renal failure may be acute or chronic. Kidney failure can also be diagnosed by laboratory tests such as glomerular filtration rate, blood urea nitrogen, and serum creatinine, by imaging test (ultrasound, computer tomography) or a kidney biopsy.

[0033] In certain embodiments, a recipient treated in accordance with a method described herein has Stage 1 kidney disease. In certain embodiments, a recipient treated in accordance with a method described herein has Stage 2 kidney disease. In certain embodiments, a recipient treated in accordance with a method described herein has Stage 3 kidney disease. In certain embodiments, a recipient treated in accordance with a method described herein has Stage 4 kidney disease. In certain embodiments, a recipient treated in accordance with a method described herein has Stage 5 kidney disease.

[0034] In certain embodiments, a recipient treated in accordance with a method described herein has a glomerular filtration rate (GFR) of about 90 or higher. In certain embodiments, a recipient treated in accordance with a method described herein has a GFR of about 60-90. In certain embodiments, a recipient treated in accordance with a method described herein has a GFR of about 30-60. In certain embodiments, a recipient treated in accordance with a methoddescribed herein has a GFR of about 15-30. In certain embodiments, a recipient treated in accordance with a method described herein has a GFR of about 15 or less.

[0035] In specific embodiments, the kidney transplant is a living donor kidney transplant. In specific embodiments, the kidney transplant is a deceased donor kidney transplant. In some embodiments, the kidney transplant may be an ABO (major human blood group system type A, type B, type O) compatible transplant. In some embodiments, the kidney transplant may be an ABO incompatible transplant. In some embodiments, the recipient has undergone a splenectomy prior to receiving the transplant. In some embodiments, the recipient has not undergone a splenectomy prior to receiving the transplant.5.2 Transplant and Donors

[0036] As used herein, the donor is the individual from which the kidney to be transplanted is taken. In some embodiments, the donor is of the same species as the recipient and the donor can be alive or deceased. The donor can be related to the recipient or not related to the recipient. As used herein, the recipient is the individual that will receive or has received the transplanted organ or tissue. The recipient can be related or not related to the donor. The recipient can be HLA-matched or HLA-mismatched with the donor. In some embodiments, the kidney to be transplanted is artificially made (e.g., not from a mammal), or made in vitro, or made outside of a body. In some embodiments, the kidney to be transplanted is from a different species as the recipient (e.g., a kidney from a different animal / mammal). In some embodiments, the kidney to be transplanted is not from a human.

[0037] In some embodiments, the kidney transplant may be a whole kidney, a part of a kidney, or cells derived from a kidney. In specific embodiments, a whole kidney is transplanted. In specific embodiments, only a partial kidney is transplanted. In certain embodiments, the method provided herein does not comprise administering bone marrow cells from the donor to the recipient.5.3 Conditioning Regimen and Postoperative Regimen

[0038] The conditioning regimen or use with the methods provided herein can include administration of one or more of the treatments below. In some embodiments, an anti-CD2 antibody or antigen binding fragment thereof (e.g., siplizumab) is provided to a subject. In someembodiments, an anti-CD2 antibody or antigen binding fragment thereof (e.g., siplizumab) is provided to a subject on the day of transplantation.

[0039] The conditioning regimen or use with the methods provided herein can include administration of one or more than one agent described herein e.g., corticosteroid, tacrolimus, mycophenolate sodium, and / or MMF) as described herein. In some embodiments, an agent or more than one agent as described herein is administered with, prior to, or after transplant. In certain embodiments, the conditioning regimen or use with the methods provided herein does not comprise administering fludarabine, tocilizumab, an anti-IL6R antibody, a B-cell depleting antibody, cyclophosphamide, total body irradiation, and / or thymic irradiation to the subject.5.3.1 Anti-CD2 antibody or antigen binding fragment thereof

[0040] In certain embodiments, the methods described herein include administering an anti-CD2 antibody or antigen binding fragment thereof to a subject (e.g., the recipient). In certain embodiments, the anti-CD2 antibody for use with the present methods is siplizumab or an antigen-binding fragment thereof.

[0041] In certain embodiments, the anti-CD2 antibody or antigen binding fragment thereof for use with the present methods comprises:a. a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1;b. a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2;c. a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3;d. a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4;e. a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5; andf. a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0042] In certain embodiments, the anti-CD2 antibody or antigen binding fragment thereof for use with the present methods comprises a heavy chain variable region comprising an aminoacid sequence of SEQ ID NO: 7, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8. In certain embodiments, the anti-CD2 antibody or antigen binding fragment thereof for use with the present methods comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[0043] In certain embodiments, an anti-CD2 antibody or antigen binding fragment thereof is not administered to a recipient prior to the day of transplant. In certain embodiments, an anti-CD2 antibody or antigen binding fragment thereof is administered to a recipient 2 times (or on 2 different days). In certain embodiments, the first dose of an anti-CD2 antibody or antigen binding fragment thereof is administered on the same day as the transplant. In certain embodiments, the first dose of an anti-CD2 antibody or antigen binding fragment thereof is administered on the same day as the transplant pre-operatively. In certain embodiments, the first dose of an anti-CD2 antibody or antigen binding fragment thereof is administered on the same day as the transplant intra-operatively. In a specific embodiment, an anti-CD2 antibody or antigen binding fragment thereof is administered to a recipient on the same day as the transplant, and 4 days after the transplant. In another specific embodiment, an anti-CD2 antibody or antigen binding fragment thereof is administered to a recipient on the same day as the transplant, and 3 days after the transplant.

[0044] In certain embodiments, an anti-CD2 antibody or antigen binding fragment thereof is not administered to a recipient more than 24 hours prior to the transplanting step. In certain embodiments, an anti-CD2 antibody or antigen binding fragment thereof is not administered to a recipient more than 24 hours, more than 23 hours, more than 22 hours, more than 21 hours, more than 20 hours, more than 19 hours, more than 18 hours, more than 17 hours, more than 16 hours, more than 15 hours, more than 14 hours, more than 13 hours, more than 12 hours, more than 11 hours, more than 10 hours, more than 9 hours, more than 8 hours, more than 7 hours, more than 6 hours, more than 5 hours, more than 4 hours, more than 3 hours, more than 2 hours, or more than 1 hour prior to the transplanting step.

[0045] In certain embodiments, an anti-CD2 antibody or antigen binding fragment thereof is administered to a recipient 2 times (or on 2 different days). In certain embodiments, the first dose of an anti-CD2 antibody or antigen binding fragment thereof is administered to the subject about 24 hours, about 23 hours, about 22 hours, about 21 hours, about 20 hours, about 19 hours,about 18 hours, about 17 hours, about 16 hours, about 15 hours, about 14 hours, about 13 hours, about 12 hours, about 11 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour prior to the transplanting step. In certain embodiments, the first dose of an anti-CD2 antibody or antigen binding fragment thereof is administered to the subject concurrently with the transplanting step. In certain embodiments, the second dose of an anti-CD2 antibody or antigen binding fragment thereof is administered to the subject at least 96 hours, and no more than 120 hours following the transplanting step. In certain embodiments, the second dose of an anti-CD2 antibody or antigen binding fragment thereof is administered to the subject at least 72 hours, and no more than 96 hours following the transplanting step.

[0046] In some embodiments, the anti-CD2 antibody or antigen binding fragment thereof is administered to a transplant recipient at a dose up to 0.2 mg / kg. In some embodiments, the anti-CD2 antibody or antigen binding fragment thereof is administered to a transplant recipient at a dose of about 0.2 mg / kg, about 0.15 mg / kg, about 0.1 mg / kg, and / or about 0.05 mg / kg. In certain embodiments, the anti-CD2 antibody or antigen binding fragment thereof is administered to a transplant recipient at a dose of 0.6 mg / kg. In certain embodiments, the anti-CD2 antibody or antigen binding fragment thereof is administered to a transplant recipient at a dose of1.2 mg / kg.

[0047] In certain embodiments, the anti-CD2 antibody or antigen binding fragment thereof is administered through intravenous infusion. In certain embodiments, the anti-CD2 antibody or antigen binding fragment thereof is infused to a transplant recipient over 60 (± 5) minutes. In certain embodiments, the completion of the infusion of the first dose of anti-CD2 antibody or antigen binding fragment thereof is no earlier than 4 hours prior to revascularization and reperfusion of the allograft.5.3.2 Tacrolimus

[0048] In certain embodiments, the conditioning regimen provided herein comprises administering tacrolimus to a transplant recipient. In certain embodiments, tacrolimus is not administered to a recipient prior to day of transplant. In a specific embodiment, the first dose of tacrolimus is administered as soon as possible in the peri-transplant period. In another specific embodiment, the first dose of tacrolimus is administered no later than 24 hours after reperfusionof the allograft. In one embodiment, the first dose of tacrolimus is administered within 24 hours before the transplantation of the allograft. In another embodiment, the first dose of tacrolimus is administered within 24 hours after the transplantation of the allograft. In one specific embodiment, tacrolimus is administered at a frequency of once a day through oral (PO) extended-release. In another specific embodiment, tacrolimus is administered at a frequency of twice a day through PO immediate release. In certain embodiments, a tacrolimus can be administered to a recipient at a sufficient dose amount to obtain the target trough blood levels of 4-11 ng / ml. In certain embodiments, a tacrolimus can be administered to a recipient at a sufficient dose amount to obtain the target trough blood levels of 5-12 ng / ml.

[0049] In certain embodiments, the duration of time a tacrolimus is administered to a transplant recipient can be 1 month, 2 months, 3 months, 4 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more than 12 months after the transplant.

[0050] In certain embodiments, tacrolimus is administered orally. In certain embodiments, tacrolimus is administered intravenously.5.3.3 Mycophenolate mofetil / Mycophenolate sodium

[0051] In certain embodiments, the postoperative treatment regimen provided herein comprises administering Mycophenolic acid (MPA) to a transplant recipient. In certain embodiment, the Mycophenolic acid is Mycophenolate mofetil. In certain embodiment, the Mycophenolic acid is Mycophenolate sodium. In certain embodiments, the postoperative treatment regimen provided herein comprises administering Mycophenolate mofetil (MMF) and / or Mycophenolate sodium (MPS) to a transplant recipient. In certain embodiments, MMF and / or MPS can be administered on the day of the transplant. In certain embodiments, the first dose of MMF or MPS is administered no later than 24 hours after reperfusion of the allograft. In certain embodiments, MMF or MPS is administered to a transplant recipient twice a day.

[0052] In certain embodiments, MMF is administered to a transplant recipient at an amount of about 2 g / day. In certain embodiments, the MPS administered is enteric-coated mycophenolate sodium (EC -MPS). In a specific embodiment, EC-MPS is administered to a transplant recipient at an amount of about 1.44 g / day.

[0053] In certain embodiments, a single dose amount of MMF can be administered. In certain embodiments, multiple dose amounts of MMF can be administered. In certain embodiments, a constant dose of MMF can be administered. In certain embodiments, a tapering course of MMF can be administered. In certain embodiments, a constant dose of MMF followed by a tapering course of MMF can be administered postoperatively. In certain embodiments, a single dose amount of MPS can be administered. In certain embodiments, multiple dose amounts of MPS can be administered. In certain embodiments, a constant dose of MPS can be administered. In certain embodiments, a tapering course of MPS can be administered. In certain embodiments, a constant dose of MPS followed by a tapering course of MPS can be administered postoperatively.

[0054] In certain embodiments, MMF or MPS can be administered to a transplant recipient at a constant dose. The duration of time a constant dose is administered can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 month, 2 months, 3 months, 4 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more than 12 months after the transplant. In certain embodiments, MMF or MPS is administered to a transplant recipient can be tapered to discontinuation. In certain embodiments, this tapering course can take place over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more than 12 months after the transplant.

[0055] In certain embodiments, MMF or MPS is administered orally. In certain embodiments, the MMF or MPS can be administered intravenously.5.3.4 Corticosteroid

[0056] In certain embodiments, the postoperative treatment regimen provided herein comprises administering corticosteroid to a transplant recipient. In certain embodiments, the first dose of corticosteroid is administered on the day of transplant. In certain embodiments, the corticosteroid is administered to a transplant recipient with a minimum of 2.5 mg / day. In certainembodiments, the corticosteroid is administered to a transplant recipient with a minimum of 5 mg over two days.

[0057] In certain embodiments, the duration of time a corticosteroid is administered can be 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer than 12 months.

[0058] In certain embodiments, the corticosteroid is administered orally. In certain embodiments, the corticosteroid is administered intravenously.5.4 Transplantation

[0059] The procedure for obtaining and implanting the kidney is well-known to the skilled artisan. Any procedure for the surgical removal from the donor and the surgical implantation in the recipient can be used with the methods provided herein. In certain embodiments, the kidney can be treated between removal and implantation.5.5 Outcome assessment

[0060] In certain embodiments, use of a method provided herein induces suppression of CD4+and CD8+effector memory T cells (Tern). In certain embodiments, use of a method provided herein induces at least 20%, at least 50%, or at least 90% reduction in CD4+Tern cells, relative to overall T cell population, compared to pre-administration of anti-CD2 antibody or antigen binding fragment thereof (e.g., siplizumab), wherein the effect lasts for at least 5 weeks, at least 10 weeks, at least 15 weeks, at least 20 weeks, at least 25 weeks, or at least 30 weeks. In certain embodiments, use of a method provided herein induces at least 20%, at least 50%, or at least 90% reduction in CD8+Tern cells, relative to overall T cell population, compared to preadministration of anti-CD2 antibody or antigen binding fragment thereof (e.g., siplizumab), wherein the effect lasts for at least 5 weeks, at least 10 weeks, at least 15 weeks, at least 20 weeks, at least 25 weeks, or at least 30 weeks.

[0061] In certain embodiments, use of a method provided herein minimizes the risk of, duration of, or severity of transplant rejection. In certain embodiments, functional assays can be used to detect biomarkers which are predictive of transplant rejection including the presence of circulating donor-specific antibodies (DS A) and levels of B-cell activating factor (BAFF) in the serum of the recipient which can be determined by ELISA. In certain embodiments, flowcytometric analyses on circulating lymphocytes can be performed to determine status of immune system reconstitution of the recipient. In certain embodiments, mixed lymphocyte reaction (MLR) of the recipient’s peripheral blood mononuclear cells can be performed to assess the response of the recipient’s cells to the donor cells and if the response changes after transplant surgery. In certain embodiments, functional assays can be used to determine if induction of tolerance to the transplanted organ was achieved. These assays can include flow cytometric analysis to determine FoxP3+T cells: CD4+T cells ratio as an indicator for the presence of regulatory T-cells.

[0062] In certain embodiments, assessments of the outcome of the kidney transplant surgery can include the monitoring of the function of the transplanted kidney in the recipient. For example, the glomerular filtration rate (GFR) of the kidney can be monitored as an assessment of the outcome of the transplant surgery. In certain embodiments, other assessments of the outcome of the kidney transplant surgery can include the monitoring of the incidence of infection, the incidence of opportunistic infection, the onset of any treatment-related adverse events, and the patient’s post-transplant quality of life.

[0063] In certain embodiments, the efficacy of a method of treatment described herein can be assessed by determining the survival of the transplanted kidney. In certain embodiments, a biopsy of the transplanted kidney can be performed to examine the health of the transplanted kidney and determine induction of tolerance or evidence of graft rejection. Tissue biopsies can be examined using routine light microscopy, immunofluorescence, and electron microscopy.

[0064] In certain embodiments, the efficacy of a method of treatment described herein can be determined by detecting treated biopsy-proven acute rejection (tBPAR) in a recipient. In specific embodiments, no tBPAR is detected in a recipient at 10 months, 12 months, 15 months, 18 months, 20 months, 25 months, 30 months, 35 months, 40 months, 45 months, 50 months, 55 months, or 60 months post-transplant.

[0065] In certain embodiments, the efficacy of a method of treatment described herein may be assessed by measuring renal function at 10 months, 15 months, 20 months, 25 months, 30 months, 35 months, 40 months, 45 months, 50 months, 55 months, or 60 months post-transplant. Renal function may be determined, for example, by measuring serum creatinine and / or glomerular filtration rate. In particular embodiments, a method described herein can result in a recipient having normal kidney function (as determined by serum creatinine and / or glomerularfiltration rate (GFR)). In particular embodiments, a method described herein can result in a recipient having better kidney function (as determined by serum creatinine and / or glomerular filtration rate) as compared to a patient undergoing standard of care post-liver transplant therapy.

[0066] In certain embodiments, a method of treatment described herein results in a recipient having serum creatinine values of 0.5-1.5 mg / mL, 0.6-1.4 mg / mL, 0.7-1.3 mg / mL, 0.8-1.2 mg / mL, or 0.9- 1.1 mg / mL for at least 10 months, at least 15 months, at least 20 months, at least 25 months, at least 30 months, at least 35 months, at least 40 months, at least 45 months, at least 50 months, at least 55 months, or at least 60 months post-transplant.

[0067] In certain embodiments, a method of treatment described herein results in a recipient having a GFR of 40-90, 45-85, 50-80, 55-75, 60-70, or above 90 for at least 10 months, at least 15 months, at least 20 months, at least 25 months, at least 30 months, at least 35 months, at least 40 months, at least 45 months, at least 50 months, at least 55 months, or at least 60 months posttransplant.6. EXAMPLES6.1 Example 1. Study of Siplizumab Induction: Effect of an anti-CD2 mAb on T-cell Subsets in Kidney Transplant Recipients

[0068] Siplizumab (TCD601) is an antagonistic, humanized, anti-CD2 IgGlk monoclonal antibody that binds to a unique epitope with high affinity. Cell surface CD2 is differentially expressed on T- and NK-cells with low constitutive expression on naive T-cells (Tn) and high expression on activated and memory T-cell (Tmem) subsets. CD2 receptors play an important role in co-stimulation, immune surveillance and lymphocyte activation. Siplizumab demonstrates selective, concentration dependent, immunomodulatory activity in vitro, including Tmem depletion, Tn sparing and expansion of regulatory T-cells (Treg). Early enrichment of Tn and concomitant depletion of Tmem in kidney transplant recipients may favorably shift the balance of antigenic priming and alloreactive responses, potentially further mitigating the early risks of acute rejection.

[0069] A Phase 2 trial was conducted using a dose escalation methodology. Adult recipients of a living or deceased donor renal allograft at 11 centers in the US and EU were randomly assigned to induction with siplizumab or rATG. All subjects received background maintenance immunosuppression with tacrolimus, MPA and glucocorticoids. Multi-color flow cytometry wasconducted with samples collected at baseline and 26 time points throughout the 12 months posttransplant.

[0070] A total of 45 participants were randomized to the siplizumab (n=33) or rATG (n=12) induction arms. Siplizumab was administered in four cohorts (0.2 mg / kg, 0.6 mg / kg, 1.7 mg / kg, and 5 mg / kg) and rATG was dosed at 1.5 mg / kg. Flow cytometry delineated key lymphocyte subsets, including CD45RA+CD197+ Tn cells and CD45RA-CD197- TEM cells.

[0071] The CD8 Tn-cell subsets were largely preserved through 12 weeks post-transplant and demonstrated rapid redistribution and homeostatic expansion to levels exceeding baseline in the siplizumab cohorts; in contrast to rATG. Additionally, NK-cell counts were reduced through 12 weeks compared to ATG. Siplizumab administration resulted in suppression of both CD4+ and CD8+ TEM cell populations.

[0072] Increasing doses of siplizumab were associated with durable Tmem depletion while preferentially sparing Tn populations, leading to an immunophenotypic shift in CD4+ and CD8+ T-cells toward a naive-dominant and memory depleted profile in the post-transplant period compared to rATG. These findings suggest that CD2-targeted induction with siplizumab provides a specific, differentiated, immunomodulatory response warranting continued development for the treatment of kidney transplant recipients.6.2 Example 2. Study of Siplizumab Induction: Effect of an anti-CD2 mAb on T-cell Subsets in Kidney Transplant Recipients

[0073] Example 2 is an update of Example 1. A Phase 2 study was conducted using a dose escalation methodology. Adult recipients of a living or deceased donor renal allograft at 11 centers in the US and EU were randomly assigned to induction with siplizumab or rATG. All subjects received background maintenance immunosuppression with tacrolimus, mycophenolic acid (MPA), and glucocorticoids. A total of 45 participants were randomized to the siplizumab (n = 33) or rATG (n = 12) induction arms. Siplizumab was administered in 4 cohorts (0.2 mg / kg, 0.6 mg / kg, 1.7 mg / kg, and 5 mg / kg) and rATG was dosed at 1.5 mg / kg. Multi-color flow cytometry was conducted with samples collected at baseline and 26 time points through 12 months post-transplant. Flow cytometry delineated key lymphocyte subsets, including CD45RA+CD197+Tn cells and CD45RA-CD197-Tem cells.

[0074] As shown in FIGs. 4A-4D, the CD8 and CD4 Tn-cell subsets were largely preserved through 12 weeks post-transplant and demonstrated rapid redistribution and homeostaticexpansion to levels exceeding baseline in the siplizumab cohorts, in contrast to rATG. All T cells were significantly suppressed after administration of induction therapy, with a negative relationship between increased siplizumab dose, and rate of repopulation across T-cell subtypes. Naive CD4+and CD8+T cells maintained a higher proportion of the overall helper and cytotoxic T cell population, respectively, through 1 year post-transplant, with low dose siplizumab subjects (0.2 mg / kg and 0.6 mg / kg) showing a higher naive population than high dose siplizumab (1.7 mg / kg and 5.0 mg / kg). In addition to naive T cells, Tern depletion was also sustained longer than subjects receiving rATG, correlating with the preclinical in vitro findings. This significant suppression was sustained through 12 weeks post-transplant, compared to 1-week repopulation in rATG.

[0075] Siplizumab was associated with durable Tmem depletion while preferentially sparing Tn populations, leading to an immunophenotypic shift in CD4+and CD8+T cells toward a naive-dominant and memory-depleted profile in the post-transplant period compared to rATG. These findings suggest that CD2-targeted induction with siplizumab provides a specific differentiated immunomodulatory response warranting continued development for the treatment of kidney transplant recipients.6.3 Example 3. Siplizumab as Induction Therapy in Renal Transplant Recipients

[0076] A phase 2b / 3, 12-month, randomized, active-controlled, double-blind study is conducted to evaluate the safety and efficacy of an anti-CD2 monoclonal antibody, siplizumab, compared to rabbit anti thymocyte globulin (rATG) as induction therapy in renal transplant recipients. In addition to either siplizumab or rATG, all participants receive background immunosuppression with standard-exposure tacrolimus (TAC), mycophenolic acid (MPA), and corticosteroids (CS).6.3.1 Study Design

[0077] When the last Phase 2b participant reaches 3 months post-transplant, an interim analysis is performed, and the decision to initiate Phase 3, including selection of the Phase 3 siplizumab dose (from the two doses of Phase 2b) is made based upon an evaluation of adverse events of special interest (AESIs), biopsy-proven acute rejection (BPAR), pharmacokinetics (PK) / pharmacodynamics (PD), and composite biomarker panel (abbreviated iBox).

[0078] Participants are randomized to receive either siplizumab or rATG (see Table 1). Participants randomized to siplizumab receive 2 intravenous (IV) doses. The first dose is administered on Day 0, pre- or intra-operatively, and is completed prior to revascularization / reperfusion of the allograft. The second dose is administered on post-operative Day 3. Participants randomized to rATG receive 4 IV doses (Days 0, 1, 2, 3). In Phase 2b study, siplizumab 0.6 mg / kg and 1.2 mg / kg dose levels are selected for testing and to confirm a preferred dose to take into the Phase 3 study (see Table 1 and FIGs. 5A-5B).Table 1. Phase 2b / 3 Cohort Assignment and Dosing RegimenPhase 2b Investigational Product (IP) Administration Arm Dosing RegimenSiplizumab 0.6 0.6 mg / kg (Days 0 and 3); 1.2 mg / kg cumulative mg / kgSiplizumab 1.2 1.2 mg / kg (Days 0 and 3); 2.4 mg / kgmg / kgrATG 1.5 mg / kg (Days 0, 1, 2, and 3); 6.0 mg / kg cumulative Phase 3 Investigational Product (IP) AdministrationArm Dosing RegimenSiplizumab0.6 mg / kg 0.6 mg / kg (Days 0 and 3); 1.2 mg / kg cumulativeOR ORSiplizumab 1.2 mg / kg (Days 0 and 3); 2.4 mg / kg cumulative1.2 mg / kgrATG 1.5 mg / kg (Days 0, 1, 2, and 3); 6.0 mg / kg cumulative

[0079] To maintain the blind, matching infusions of normal saline is administered as placebo (see Table 2).Table 2. Placebo (Normal Saline) AdministrationTreatment Day 0 Day 1 Day 2 Day 3Siplizumab and Siplizumab and Siplizumab Placebo PlaceboPlacebo PlaceborATG rATG and Placebo rATG rATG rATG and Placebo6.3.2 Concomitant Treatment

[0080] As shown in Table 3, all participants also receive:a. a triple regimen of background immunosuppressive therapy for the duration of the study;b. premedication prior to study treatment infusions; and c. infection prophylaxisTable 3. Concomitant Treatment and Dosing Regimen Background Dosing RegimenImmunosuppressive TherapyTacrolimus (TAC) Oral (PO) extended-release once-daily (QD) or immediate- release (PO) twice-daily (BID)Administration is started within 24 hours post-transplant Serum concentrations maintained per local practice and consistent with applicable labelling (5-12 ng / mL).Mycophenolic acid (MPA) Administration is started within 24 hours post-transplant • Mycophenolate mofetil (MMF; CellCept® or generic; 2 g PO [QD]) in 2 divided doses; or• Enteric-coated mycophenolate sodium (EC-MPS;Myfortic® or generic; 1.44 g PO [QD]) in 2 divided doses Corticosteroids (CS) • IV at time of transplant per local practice then tapering to maintain a minimum of 5 mg oral prednisone equivalent / dayPremedication for Study Dosing RegimenTreatment InfusionsPremedication • Hl antagonist (e.g., diphenhydramine), paracetamol / acetaminophen, and corticosteroids• Use of a 5-HT3 antagonist (e.g., ondansetron) for emesis prophylaxis is considered as neededInfection Prophylaxis Dosing RegimenInfection prophylaxis • Cytomegalovirus (CMV): for donor positive / recipient negative (D+ / R-) and recipient positive (R+) candidates for 6 months; treatment selection per local practice. No CMV prophylaxis for donor negative / recipient negative (D- / R-) candidates required per protocol.• Pneumocystis pneumonia (PCP) prophylaxis for 6 months; treatment selection per local practice• Candida treatment, per local practice6.3.3 Study Enrollment

[0081] Participants who meet all the following inclusion criteria are eligible to participate in the study:1) Adults >18 and <70 years of age.2) Recipients of a renal allograft from a non-human leukocyte antigen (HLA) identical living or deceased donor.3) Recipients of a kidney with a cold ischemia time (CIT) <30 hours; hypothermic machine perfusion within the same timeframe is acceptable.4) Women of childbearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must agree to use highly effective methods of contraception during dosing and for 24 weeks after the study medications have been stopped.a. Postmenopausal females must not have experienced regular menstrual bleeding for >1 year prior to initial dosing. Menopause will be confirmed by a plasma follicle-stimulating hormone (FSH) level of >40 IU7L at screening. b. Female participants who are surgically sterile must have undergone the procedure >6 months prior to initial dosing. Surgical sterilization procedures should be supported with clinical documentation made available to the Sponsor.c. All WOCBP must have negative pregnancy test results at screening / baseline.

[0082] Participants must not meet any of the following exclusion criteria:1) Transplant recipients seronegative for Epstein-Barr virus (EBV).2) Transplant recipients receiving a kidney from a non-heart beating donor (i.e., donation after cardiac death [DCD])3) Multi-organ transplant recipients (e.g., kidney-pancreas, organ other than kidney), dual-kidney transplant recipients, recipients with more than one prior kidney transplant, or hematopoietic stem cell transplantation (HSCT) recipients.4) Presence of current or historical donor-specific anti-HLA antibody (DSA) via singleantigen bead assay or local standard of care. The mean fluorescence intensity (MFI) cutoff value used to determine the presence of DSA are defined as per the institutional standard of care. Results within 3 months prior to transplant are acceptable.5) Complement-dependent cytotoxicity (CDC), virtual-crossmatch (VXM), or flowcrossmatch (FCXM) positive transplant.6) ABO-incompatible recipient7) Requirement for additional immunosuppression / complement inhibitor within 6 months prior to the transplant, or likely requirement within 6 months post-transplant.) History of malignancy of any organ system, except for localized excised non- melanomatous skin lesions or carcinoma in situ of the cervix.) Participants with clinically significant laboratory abnormality that would preclude participation in the study.0) Participant with any of the following:a. Hemoglobin (Hgb) < 8 g / dL (< 80 g / L)b. White blood cell (WBC) count <2,000 / mm3 (<2 x 109 / L)c. Platelet count <50, 000 / mm3 (<50 x 109 / L)1) Seropositive for human immunodeficiency virus (HIV) or hepatitis B surface antigen (HBsAg). Participants who are seropositive for hepatitis C virus (HCV) are excluded without proof of sustained viral response (SVR) after anti-HCV treatment.2) Recipient of a kidney from a donor who tests positive for HIV or HBsAg / hepatitis B core protein (HBc). Recipients of a kidney from an HCV-positive deceased donor are excluded, and recipients of a kidney from an HCV-positive living donor are excluded without proof of SVR in the donor.3) History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes (e.g., siplizumab, rATG, tacrolimus [TAC], mycophenolic acid [MPA] derivatives, corticosteroids [CS]).4) Any additional contraindication to the use of TAC or MPA according to the national labeling information of these products (refer to the local product label).5) Evidence of tuberculosis (TB) infection (after anti-TB therapy, participants with a history of latent TB may become eligible if treated according to national guidelines).6) Participants with severe systemic infection(s), current or within 2 weeks prior to randomization.7) Participants with any other clinically significant medical condition, active infection, or laboratory abnormality that would, in the judgment of the Investigator, interfere with the participant’s ability to participate in the study.8) Participants who, in the opinion of the Investigator, are incapable of providing informed consent for the study, or are unable or unwilling to adhere to the study requirements. 9) Use of other investigational products or enrollment in another investigational drug study within 30 days of screening or 5 half-lives of the medication, whichever is longer.20) Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by human chorionic gonadotropin (hCG) laboratory test.6.4 Example 4. Study of Siplizumab Induction: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of escalating doses of Siplizumab in de novo Reno Transplant Patients

[0083] Example 4 is an update of Example 2. A Phase 2 study (NCT06365437) was conducted using a dose escalation methodology. A 12-month, multicenter, randomized, controlled, open-label, dose escalation study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of siplizumab, compared to rATG, as induction therapy in de novo renal transplant recipients. All subjects received triple regimen background immunosuppression with standard exposure tacrolimus (TAC), mycophenolate mofetil (MMF), and corticosteroids (CS).

[0084] Eligible subjects were randomized to the siplizumab or rATG induction arms.Siplizumab was administered in 4 cohorts (0.2 mg / kg (Arm 1), 0.6 mg / kg (Arm 2), 1.7 mg / kg (Arm 3), and 5 mg / kg (Arm 4)) and rATG was dosed at 1.5 mg / kg (Arm 5). Subjects randomized to receive siplizumab received 2 intravenous (IV) doses. The first dose was administered on Day 0, pre- or intra-operatively. The second dose of siplizumab was administered on Day 4 post-transplant. Subjects randomized to rATG received 1.5 mg / kg IV doses on Days 0, 1, and 2.

[0085] Number of participants with treatment-related adverse events was investigated and the results are shown in table below.Arm / Group Title Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Overall Number of Participants Analyzed.6. |. 5.1.8. |. 8..5.F.'eas.ure Type Count of PurtlLiptfilhUnit uH.'WiW psKtlupjlillRuw Titl« TitfeAt least 1 TEAE Ws 6 5 ■ 8: 8 5I No 0 0 0 0 Ic 0 At least 1 TEAE Related Yes 61.. 4 8 8 5to Study Medication i N00 J 1. 0 0 i 0At least1SAE i Yes 3 c 1. 4. 4 0No 3 ■>: 4 ■ ' 4 4 r 5 At least 1 TEAE leading to O O ' 1 ’ • ‘ 'Study Discontinuation NO6 5 7. 7At least 1 TEAE leading to Y« 0 0 0 0!Dose Adjustment i NO 6 " 5 • 8 8 ’ ■ >At toast 1 TEAE leading to 0 O ' 0 c10 Dose Interruption N06. 5 "18 ’ 7 5 At least 1 TEAE leading to Yes 0 0 1 2 0 Study MedicationMDiscontinuation iNs6 il»% 1 5 too*. \ 7 | 6 5 At toast 1 Infection > Yes 6 > 2.. 8 2 2[ No 0 3 > O 6 3 At least 1 Serious vei, 0 t 0. 1 O i 0 Infection i NO 6 5, -. i 7:? “ 8 5 At least 1 SAE related to Yes O r 0 2 3 0Study Medication NO 6 5 ' 6 5 '. 5

[0086] The peak plasma concentration (Cmax) was measured. The results are shown in table below.Arm / Group Title Arm 1 Arm 2 Arm 3 Arm 4 Overall Number of | 6 j 5 [ 8 | 7 Participants Analyzed i i i 1(Standard 4.3 (0.578)fl2.8 (1.96) 506 (9.79) 135 (11.8)Unit of Measure: ug / mL i

[0087] The area under the plasma concentration versus time curve (AUC) were measured. The results are shown in table below.Arm / Group Title Arm 1 Arm 2 Arm 3 Arm C o t onn 4 Overall Number of 6 5 | 8 | 7 Participants Analyzed > i iiiiirs VeamSiandatd Dev.atan’ 26.2 (4.67) 95.4 (29.3) j. 627 (249) 1910 (389)Unit of Measure: ug.'tnLxday;

[0088] The change in renal function after transplantation was evaluated and the results are shown in table below. 1 -month post-transplant was defined as baseline.Arm / Group Title | Arm 1 | Arm 2 Arm 3 Arm 4 Arm 5 Overall Number of Participants Analyzed 6 5 8 8 5 Mean (Standard Deviation) iUnit of Measure mL-min / 1 73mA2 / Rew Title iBaseline NumherAnalyzed n j l vji I 32-9§ (15.671) j 6li g0.521) 51.85 (12.011 ) 59.45 (12.676) 51.17 (8.370) Month 3 Number Analyzed n |ui—imr 8 participants..."i 5 participants j 40.51 (14.339) [ 67.11 (21.028) 52.53 (9.416) 57.92 (9.412) 53.48 (4.918) Month 6 Number Analyzed(. v. - n- 8 participants I 8 participants | 5 participants |) 37.98 (8.236) ( 63.75 (11 501) 53.64 (8.727 ) 54 64 (21.590) 58.93 (7 13) Month 12 Number Analyzed,,, 8 participants 0 participants 5 participantsI 45.15 (9.295)s70.06 (16 051 ) 56.96 (8.411) j — |.61.23 (9.02) i

[0089] Adverse events were evaluated among each treatment arm. Results are shown in table below.All-Cause MortalityArm 1 Arm 2 Arm 3 Arm 4 Arm 5 Total | 0 / 6 (0%) I 0 / 5 (0%) ( 0 / 8 (0%) | 0 / 8 (0%) I 0 / 5 (0%) Serious Adverse EventsArm 1 Arm 2 Arm 3 Arm 4 Arm 5 j Total I 3 / 6 (50%) | 1 / 5 (20%) I 4 / 8 (50%) | 4 / 8 (50%) | 0 / 5 (0%)! Gastrointestinal disorders i s > > > 'buodenZuEr haemorrh^.:"A. T.6 / 6 (6%).6. J.1 / 5 (26%).1. ).6S'(6%).6. f.6 / 8 (6%).6. |.6 / 5 (6%). I. Pancreatitis. -A. I..0 / 6. (6%).6. j.6 / 5 (6%).6. j.6 / 8. (6%).6. |i. W(l25%j.1. j.6 / 5 (6%). Immune system disorders> > > > > > Transplant Rejection *A0 / 6 (0%) 0 i.6 / 5 (6%).6. F 0 / 8 (o%) 0 1 / 8 (12 5%) 1 0 / 5 (0%) Infections and infestations > > > > > > | > Appendicitis ' * | 6 / 6 (6%) > 0 j 0 / 5 (0%) 0 > | 1 / 8 (12.5%) 1 > > > > > Cerebral Nocardiosis- A0 / 6 (0%) > 0.1.6 / 5 (6%).6.1.178 (125%). 1 >I > Pneumonia * * I 0 / 6 (0%) > 0 0 / 5 (0%) > 0 > 1 / 8 (12.5%) 1 > > _ Pulmonary Nocardiosis *A0 / 6 (0%) 6. |.6 / 5 (6%).6. |.1 / 8 "(12'5%). 1j Injury, poisoning and procedural |i complications > i > > > > > j > Delayed Graft Function •A| 2 / 6 (33.33%) 2 | 0 / 5 (0%) 0 0 / 8 (0%) 0 1.0 / 8 (6%).6. [.6 / 5 (6%). | > Graft Thrombosis •A| > 0 / 6 (6%) > > > 6 / 5 (6%) 0 l78 p2i5%) i > > 6 / 5 (6%) > | Infusion Related Reaction ’A| 0 / 6 (6%) 6’.1. > 6S'(6%) 0.6S"(6%). o 1 / 8 (12 5%) 1 0 / 5 (0%) >Renal Lymphocele, A0 / 6 (0%) 0 T.6 / 5 (6%j‘ 0 0 / 8 (0%) 0 '[ 1 / 8 (12'5%)". i r 6 / 5 (6%y1 Investigationsi’ - - - - - - - ’ ’1 Blood creatinine Increased, A61 (6%j 6 | 6 / 5 (6%) 6 | 61 (6%j 6 1 / 8 (12.5%) 1 0 / 5 (0%) Metabolism and nutrition disordersNew onset diabetes after 1 / 6 (16.67%) i 1 6 / 5 (6%) 6 i 6 / 8 (6%) 6 0 / 8 (0%) 0 0 / 5 (0%) 1 transplantation "AI Neoplasms benign, malignant andunspecified (incl cysts and polyps)Renal cell carcinoma •A0 / 6 (0%). Q / 5 (0%^ 0 / 8 (0%) 0 0 / 5 (0%) Renal and urinary disordersFocal segmental i / 6 (16.67%) i | 6 / 5 (6%j 6 1 61 (6%j 6 0 / 8 (0%) 0 0 / 5 (0%) glomerulosclerosis ’Ai Hydronephrosis 'A0 / 6 (0%) 0 0 / 5 (0%) 0 0 / 8 (0%) 0 1 / 8 (12.5%) 1 0 / 5 (0%) < Renal Impairment •A1 / 6 (16.67%) 1 I 6 / 5 (6%) 6 I 6 / 8 (6%) 6 0 / 8 (0%) 0 0 / 5 (0%) i Vascular di sorderss Deep vein thrombosis ’A.. 6 / 5 (6^.1 / 8 0 / 8 (0%) 0. 015 (0%) | Hypotension 'A61 (6%) 6 | 6 / 5 (6%) 6 | 6fi (6%j 6 1 / 8 (12.5%) 1 6 / 5 (6%). VS (l6J&^... Offi (6%). 0 / 8 (0%) 0 6 / 5 ^1 Lymphocele *S’ - - - - -A■ * Indicates events were collected by non-systematic methods.A Term from vocabulary, MedDRA v27.1Other (Not Including Serious) Adverse Events Frequency Threshold for Reporting ( 0% Other Adverse Events Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 i ITotal [ 6 / 6 (100%) 5 / 5 i 8 / 8 (100%) 8 / 8 (100%) 5 / 5(100%) ( (100%) Blood and lymphatic system I disorders Anemia 'A0 / 6 (0%) 0 / 5 (0%) 1 / 8 (12.5%) 1 / 8 (12.5%) 0 / 5 (0%) Iron Deficiency Anemia ‘Aj 0 / 6 (0%) 6 / 5 (6%) | 1 / 8 (125%). ns8 (6%j. 0 / 5 (0%).. TWW==T......... r’wiw5’’......... Twwr J. Neutropenia 'A. j.0 / 6 (0%). j.6 / 5 (6%). (.6 / 8 (6%). j.1 / 8 (1Z5%). {’.6 / 5 (6%).[. ~Pojycythaemia~7T.61 (6%). j'l) / 5 (6%)'^^~'f.6 / 8 (6%). [.6 / 8 (6%). p / 5 (20%)~" Cardiac disorders Palpitations "Aj 61 (6%), 1 / 5 (20%) | 1 / 8 (125%), 1 / 8 (12.5%), 0 / 5 (6%) Tachycardia ’A0 / 6 (0%) 0 / 5 (0%) 0 / 8 (0%) 1 / 8 (12.5%) 0 / 5 (0%) Ear and labyrinth disordersVertigo ■A1 / 6 (16.67%) 0 / 5 (0%) 1 / 8 (125%) 0 / 8 (0%) 0 / 5 (0%)> I Endocrine disorders I Hyperparathyroidism tertiary, A| 0 / 6 (0%) | 0 / 5 (0%) 178 (12.5%) 1 6 / 8 (6%) | 0 / 5 (0%)Hypothyroidism ’A1 / 6 (16.67%) 0 / 5 (0%) 6 / 8 (6%) | 678 (6%) | 26 (6%) Eye disorders i i < > i >Dry eye "A1 / 6 (16.67%) 0 / 5 (0%) 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%) >. Eye pain.:’A. f.6 / 6 (0%).....6 / 5 (6%). I'.672(6%). j..6 / 8 (6%)’. |.1 / 5 (26%).> 6 / 5 (6%). scleral. hemorrhage.:’A.1 ' 1 / 6 (16’67%). [.6 / 5 (6%). |.6 / 8. (6%). [.6 / 8. (6%). [.6 / 5 ’(6%). Gastrointestinal disorders i I!! I >. Abdominal discomfort. •’*. i.6 / 6 ”(6%j. j.6 / 5. (6%). |. l78 (125%). [.6 / 8 ”(6%). j.6 / 5 (6%). > Abdominal pain ’A| 2 / 6 (33.33%) | 0 / 5 (0%) | 1 / 8 (12.5%) J / 80Z5^ Abdominal pain upper *AI 0 / 6 (0%) ii 0 / 5 (0%) 0 / 8 (0%) 7 1 / 8 (12.5%) p 0 / 5 (0%)> >. Aphthous ulcer.:’A.1.6 / 6 (6%). I.6 / 5 (6%). [.6 / 8 (6%). |.1 / 8. (125%). j.6 / 5. (6%).. Constipation.:’A. I.1 / 6 (1667%). j. l75 (20%j. |.6 / 8 (6%). |.1 / 8 (125%). >Diarrhoea.: A.1.2 / 6 (3353%). j.675(6%)'.1.4 / 8 (50%). i. Il'(l25%j’. I.21 (40%)> > Faeces hard •* | 1 / 6 (16.67%) I 0 / 5 (0%) | 0 / 8 (0%) ( 0 / 8 (0%) [ 0 / 5 (0%). Haematochezia.:’A. J.6 / 6 (6%). |.1 / 5 (20%). j.6 / 8. (6%). j.6 / 8. (6%). |.6 / 5 (6%).. Haemorrhoids.:’A. FWWj. j.6 / 5'(6%j.. |..6 / 8. (6%j.2~ > Intra-abdominal haematoma *A7 0 / 6 (0%) 7 6 / 5 (0%) 1 / 8 (12.5%) § 6 / 8 (6%) 6 / 5 (6%) > Mouth ulcera^ 6 / 5 >. Nausea.:‘A. |.3 / 6 (50%). j.6 / 5 (6%). j.2 / 8 "(25%). j.6 / 8 (6%).. Oesophagitis.:’A. j.6 / 6 (0%). J.6 / 5 (6%). (”'.61”(6%j. j”.1 / 8 (125%). J”.6 / 5 (6%).Vomiting 'A1 / 6 (16.67%) 0 / 5 (0%) 1 / 8 (12.5%) 0 / 5 (0%) > General disorders |.... '”"...... Fatigue. -A. j.2 / 6 (3333%)..1.675 (6%).. |.6 / s. (o%j. j.6 / 8 (6%). | 0 / 5 (0%) i General physical health 1 / 6 (1667%) 0 / 5 (0%) I. "6^.. 6 / 8’(6p" 1.25 (6%) > deterioration ‘A»Malaise ’A1 / 6 (1667%) 0 / 5 (0%). J.6 / §. (0%). f.6 / §”(6%j. T.675 (6%j. > Oedema peripheral ’A3 / 6 (50%). [’.675 (6%)’.. I”.28 (25%). J.678 (6%). 7.675 (6%).> Pain< A1 / 6 (1667%).1.6 / 5 (6%) 0 / 8 (0%) 0 / 8 (0%) ‘j.675'(6%).> Peripheral swelling ’A0 / 6 (0%) ].1 / 5 (20%)..1.6 / 8 (6%). f.6 / s ’’(6%). 1.675 (6%). > Puncture site haematoma ’A0 / 6 (0%) “j.675 (6%)’’ 0 / 8 (0%) 0 / 8 (0%) > 1. il”(26%j. | >. " Pyrexia.:’A. pffi pHS?).. |. V5’(26%)”. n / 8p25%) f.178 (125%) | chills *A0 / 6 (0%) 0 / 5 (0%) 0 / 8 (0%) 0 / 8 (0%) 1 / 5 (20%) > Hepatobiliary disorders > > > Hyperbilirubinaemia ’A0 / 6 (0%) 0 / 5 (0%). i.6 / 8. (o%). [.678 (6%). Immune system disorders i > > >Transplant Rejection ’A1 / 6 (16 67%). j.1 / 8 (12.5%).1.6 / 8. (6%).Infections and infestationsI... ”.. BK virus infection. *A”l| 3 / 6 (50%) 0 / 5 (0%) 1 / 8 (12.5%) | 0 / 8 (0%) | 1 / 5 (20%) Bacterial disease carrier 0 / 6 (0%).63”(0%). |.13(125%) ' j. o3 (6%). F.63(6%)'.Bacteriuria *AI 1 / 6 (16.67%) "|.0 / 5 (0%). |.6S””3%)'. j’ 0 / 5 (6%). Bronchitis •A| 63 (6%) 1.0 / 5 (0%). j.1 / 8 (123%). ”j.633%).. r.63(6%). COVID-19 *A( 13 (16.67%) 1.1 / 5 (20%). j.1 / 8 (123%).. |.63 (6%). 0 / 5 (0%) Conjunctivitis, AI 13 (16,67%) f. owr. F"’”633%J. ”j.63'3%). Cytomegalovirus infection • * | 1 / 6 (16,67%).1.33(20%) F.2 / 8 (25%). ”J. l / 8”(12’5%F ”j. i / 536%). Cytomegalovirus viraemia ’A3 / 6 (50%). |.63(6%).1.5 / 8 (623%) 1 / 8 (125%).1.63(6%). Device related infection, A| 13 (16.67%) 0 / 5 (0%) 0 / 8 (0%) |.63 (6%).. Il.63(6%). Epstein-Barr viraemia ■AI 0 / 6 (6%). F.1 / 5 (20%). f".0 / 8 (0%). " I".63F6%). | 63 (6%) Epstein-Barr virus infection ”AI 6 / 6 (6%) 1.13 (26%). I 2 / 8 (25%) | 0 / 8 (0%) 1.1 / 5 (20%) Genital herpes 'A| 63 (6%) ”l.1ffi (20%). |.0 / 8 (6%). 0 / 8 (0%).63(6%j. Lyme disease •AI 0 / 6 (0%) ”T.633%)" i.6 / 8 (6%). 1 / 8 (12.5%) j 0 / 5 (0%) Nasal herpes ‘A0 / 6 (0%) j 0 / 5 (6%). j 63 (0%) j.38 (6%). |i. I3(20%) Nasopharyngitis ' -Ai 33 / / 66 (50%). i.6 / 3(6%). 1.3 / 8 (373%) )|.63 (6%) I. I3”(26%) Oral candidiasisA" 1 / 6 (16 67%).1.6 / 3(6%). 1.63(6%).. ||.633%). 0 / 5 (0%) | Oral herpes *Af 2 / 63333%) 1 / 5 (20%) Polyomavirus viraemia "A4 / 6 (66.67%) 1.6 / 5 (6%). i. iS”(m%)”” | 1 / 8 (12.5%) II 13 (20%) Postoperative wound infection 'A0 / 6 (0%) 0 / 5 (0%) 1 / 8 (12.5%) 0 / 8 (0%) 0 / 5 (0%) Respiratory tract infection viral •A0 / 6 (0%) ”j.0 / 5 (0%y. {. W(123%). 0 / 8 (0%) 0 / 5 (0%) |... Rhinitis. *A. [.6 / 6 (6%) 0 / 5 (0%) 0 / 8 (0%) 0 / 8 (0%) 1 / 5 (20%) f Suspected COVID-19 *AI 0 / 6 (6%) 1 / 5 (20%) 0 / 8 (0%) | 0 / 8 (0%)I Tooth infection, A| 1 / 6 (16.67%) T.63(6%). f.63 (6%). f.38’3%) 0 / 5 (0%) | Transmission of an infectious 0 / 6 (0%) 0 / 5 (0%) > 0 / 8 (0%) 0 / 8 (0%) 1 / 5 (20%) I agent via product ’A|Urinary tract infection bacterial 'A0 / 6 (0%) 1 / 5 (20%) 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%) Urinary tract infection enterococcal 0 / 6 (0%) 63(6%) W(i2'5%)' 0 / 8 (0%) 0 / 5 (0%)Injury, poisoning and procedural IcomplicationsArteriovenous fistula occlusion 'A0 / 6 (0%) I 0 / 5 (0%) 1 / 8 (12.5%) 0 / 8 (0%) 1 / 5 (20%)Clavicle fracture *A0 / 6 (0%). J.13(26%)’ 63 (6%) I ois 3%).63(6%)” Complications of transplanted 0 / 6 (0%).1.63(6%). 1 / 8 (12.5%) | 0 / 8 (0%) 0 / 5 (0%) kidney ■ A jDrain site complication •A1 / 6 (16.67%) | 0 / 5 (0%) II.633%). [I.63(6%). f.35 (6%) Incision site pain ”:”A. I. W (1637%). r.63 (6%). 0 / 8 (0%) 1 / 8 (12.5%) 1 / 5 (20%) Incision site swelling. I.13 (16167%). I. oi5 (o%i. 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%) Infusion related reaction ”• *. F.63(6%)'”. |~63. (6%) 0 / 8 (0%) 0 / 8 (0%) 1 / 5 (20%) Limb injury *Ai ’63(6%).. j.63(6%).. I. ira pSFFj.1.633%). 1.63(6%). Po.st p -ro -c -edural hae.m. orrha -g -e ■A‘63(6%)'. ”F“.63(6%).. F. i3”(i23%F. J.63'3%). r’63'3%).Procedural pain "A0 / 6 (0%) F.63(6%) 1. ii8 (iz5^..115 ^0^ Renal lymphocele, A| 13 (16.67%) 1.633%)’ 0 / 8 (0%) 1 / 8 (12.5%) 0 / 5 (0%). Rib fractureA. j.63(6%).. [. V5 (2O%) 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%)Skin abrasionA. |. V6 (W~67%). J.633%).. [.63’3%). II.63”(6%). li.633%). Subcutaneous haematoma 1.63(6%) j. 633%).. 63 (6%)..1 / 5 (20%) Wound complicationA. i.6i”3%)”.. [.633%)’ 0 / 8 (0%) 1 / 8 (12.5%) 0 / 5 (0%)Wound dehiscence A 0 / 6 (0%) 0 / 5 (0%) 1 / 8 (12.5%) 63’3^..0 / 5 (0%)>Investigations > > >Acidosis -A* 0 / 6 (0%) 0 / 5 (0%% 1 / 8 (125%) 0 / 8 (0%) 0 / 5 (0%% Anti factor Vll! am, bocy increased 06 (0"% 0 5 (0”% 1 8 (125"% 0'8 (0"% 0.5 (0"%•ABlood aibumm decreased ■ '% 0 / 6 (0%) %5 (201% 0'8 {0%) 0 / 8 (0%) 0 / 5 (0%% Biooc b.carbontite decreased ’ 0'6 (0% >' 0-5 (0%)> 1 / 8 (125%) 0 / 8 (0%) 0 / 5 (0%) Blood creatinine incteaseci *A2 / 6 (3333%) 2 / 5 (401.), 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%) > Blood glucose increased- A0’6 (0%.) 1 / 5 (20%.) 0 / 8 (0%) 0 / 8 (0% >) 0 / 5 (0%) Blood magnesium decreased 'A0 / 6 (0%) 2 / 5 (40%) 0 / 8 (0%) 0 / 8 (0%) 1 / 5 (201% Blood phosphorus decreased 'A0’6 (0%) 0 / 5 (O’ / .) 0'8 (0%) 2 / 8 (25%) 0 / 5 (0%) Blood phosphorus increased -A0 / 6 (0%) 0 / 5 (0%.) 0 / 8 (0%) 0 / 8 (0%) 1 / 5 (2088) B'ood urea increased ‘ “ %6 ( 1667"% 0-5 (0"% 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%) Blood unc acid increased 'A1 / 6 (1667%) 0'5 (0% ) 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%) C-reactive protein increased 1 / 6 (16.67%) 0'5 (0".) 0 / 8 (0%) 1 / 8 (125%) 0 / 5 (0%) > 3'abetes mo' to ' ''' 26 (3333'’% 1.5 (20",-) 0 / 8 (0%) > 1 / 8 (125%) 0 / 5 (0%) Epstein-Barr virus antibody 0<’S (01% 0 5 (0"% 0'8 (0%-) 0 / 8 (0%) 1 5 (20’.,) > positive 'A> > >> Fluid retention ■ * > 0 / 6 (0%) 0-5 (0"%> 1 / 8 (125%) 0 / 8 (0%,) 0 / 5 (0%) > Folate deficiency ■A 16 ( 1667"% > 0 / 5 (0%) > 0 / 8 (0%) 0 / 8 (0% >) 0 / 5 (0%) Glucose tolerance impaired ‘A0 / 6 (0%,) 0'5 (0", ) 2 / 8 (25%) 0 / 8 (0%) 0 / 5 (0%,) Haemoglobin decreased 'A0’6 (0%) ’>5 (20%) 0 / 8 (0%) 1 / 8 (12.5%) 0 / 5 (0%) Hepatic enzyme increased •A2>6 (3333%) 1 / 5 (20%l 0 / 8 (0%), 0 / 8 (0% >) 1.5 (20%) Hypercalcaemia "A0 / 6 (0%) 0-5 <0". ) ■ 0® (0%) 0 / 8 (0%) 1 / 5 (20%) Hypercholesterolaemia 'A0 / 6 (0%) 0 / 5 (0%% 2 / 8 (25%) 0 / 8 (0%) 1 / 5 (20%,) Hyperglycaemia ‘A0 / 6 (01% 0 5 (0“%> 1 / 8 (125%) 1 / 8 (12 5%.) 0 / 5 (0%) > Hyperkalaemia ‘A26 (3333"% 0 5 (0%,) 4 / 8 (50%) 2 / 8 (25%) i 2 / 5 (40%) > 0'6 (01% 0 / 8 (0%) 0 / 8 (0%) 1 / 5 (20%)•A2.6 (3333%)> > 0 / 8 (0%) 0 / 8 (0% >) 0 / 5 (0%.) 0 / 6 (0%.) > 0 / 8 (0%' 0-8 (0%) 1 '5 (20%,) > Hyperphosphatemia 'A■ 2 / 6 (3333%% 1 / 5 (20%) 0 / 8 (0%) 0'8 (0°.) 0'5 (0",-) J Hwen / ricaemia ’ * 2 / 6 (3333%)> 1 / 5 (20%) 0 / 8 (0%)> 0 / 8 (0%,) 0 / 5 (0%)2 / 6 (3333%,) 2 / 5 (40%) 0 / 8 (0%) 0 / 8 (0%) 0 5 (0% I 2 / 6 (3333% >) 0 / 5 (0% ) 2'8 ( 25%, ) 2 8 (25%) 0.5 (0% ) 1 / 6 (1667%) 0 / 5 (0%) 0 / 8 (0%) 0 / 8 (05.) 0 / 5 (0%) 1 / 6 (1667%) 0 / 5 (0%) >13 / 8 (37 5%)> 2 / 8 (25%) 0 / 5 (0%,) 0 / 6 {0%l) 0 / 5 (0%) 0 / 8 (0%) 0 / 8 (0"%) 1 / 5 (20%% 0 / 6 (0%) * 0 / 5 (0%) 0 / 8 (0%) > 0 / 8 (0%) 1 / 5 (20%) 1 / 5 (1667%) 0'5 (0%) 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (03% 1 / 6 (1667°% 0 / 5 (0%,) 0 / 8 (0%% 0 / 8 (0%) 0,'5 i0%)>0 / 6 (0%) 1 '5 (20%.) 0.8.0"% 0.8 (01% 0 5 (0%) > > >> Obesity -A0 / 6 (0"% 0 / 5 (0%) 0 / 8 (0%% 1 / 8 (125%) 0 / 5 (0»% > Renal function test abnormal •A1 / 6 (1667%) 0 / 5 (0%) 0 / 8 (0%) 0’8 (0%% 0 / 5 (0%) > Transaminases increased "A0 / 6 (0%) 0 / 5 (0%) 0 / 8 (0%) 1 / 8 (125%) 0 / 5 (0%) White bbod cell count decreased 0 / 6 (0%)10 / 5 (0%) " 0 / 8 (0%% 0’8 (0%) 1 / 5 (201%Musculoskeletal and connective> tissue disorders; >f......2 / 6 (33.6 / 5 (0%) j. ^6^ ^ j. 0 / 8 (0%)|. Muscuioskeietai pain. •*. T.1 / 6.06767%)'. ||.6 / 5 (6%).. j.6 / 8. (o%j.. (.678 (6%). 0 / 5 (0%) ||". Osteopenia.:'A. ||.0 / 6 (6%). j.6B’(6%)". 0 / 8 (0%) I 1 / 8 (12.5%) 0 / 5 (0%)Osteoporosis ’A0 / 6 (0%) 0 / 5 (0%). |.6785%). "|. i78"(1275^ 1.67s (6%) I Pain in extremity, A| 1 / 6 (16.67%) [ 6 / 5 (6%) 1 / 8 (12.5%) " J. o / 8 'ifi%). j.675 (6%). Nervous system disordersDizziness, A1 / 6 (16.67%) 0 / 5 (0%). |.6S"(6%j. j.6 / 8 (6%). [.6 / 5 (6%j. Dysaesthesia ’A1 / 6 (16.67%) 0 / 5 (0%) 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%) |. Headache.: A. ||.1 / 6 (16^67%). J.6 / 5 (6%).. |.6 / 8 (6%). i.1 / 8 (125%). i.6 / 5 (6%). | Hypoaesthesia, AI 6 / 6 (6%) | 6 / 5 (6%) ( 6 / 8 (6%) 6 / 5 (6%) II. intentton'tremor.:"A. I.6 / 6 (6%). J.6 / 5 (6%).. F.6 / 8 "(o%)"'"".1.6 / 8 (6%)'. (.6 / 5 (20%). | Paraesthesia >A[ 1 / 6 (16.67%) | 0 / 5 (0%). T. K 6Km / 8 (6%). F.6 / 8 (6%). li..6 / 5 ■'(6%..j.” ■ - ■ ■ I. Syncope.:'A. |l.0 / 6 (0%). 1.0 / 5 (6%). | 1 / 8 (12.5%) | 0 / 8 (0%) | 0 / 5 (0%) _ Tremor ‘A2 / 6 (33.33%) _ 1 / 5 (20%) 1. 2 / 8 (25%)..1 / 8 (127^. i / 5 (20%)! Psychiatric disorders; iI Adjustment disorder *AI 1 / 6 (16.67%) | 6 / 5 (6%) 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%) |. Anxiety.: AriS"(iei67%). || 6 / 5 (6%) 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%). Insomnia >AT 3 / 6 (50%). ] 6 / 5 (6%) T" 2 / 8 (25%j. f 6 / a "(6%). I 6 / 5 (6%) Restlessness< A1 / 6 (16.67%) 0 / 5 (0%) ).6 / 8I Sleep disorder *AI 0 / 6 (0%) | 1 / 5 (20%) 1 6 / 8 (6%). I 1 / 8 (125%). || 6 / 5 (6%)Stress -A1 / 6 (16.67%) 0 / 5 (0%) 0 / 8 (0%) 0 / 8 (0%) 0 / 5 (0%) Renal and urinary disorders I Dysuria ’A| 0 / 6 (0%) | 0 / 5 (0%) | 0 / 8 (0%) | 0 / 8 (0%) J 1 / 5 (20%) |. Haematuria..1.0 / 6 (6%). |.6 / 5 (6%). f. V8 (625%). |.6 / 8. (6%). |.6 / 5 (6%). |. Hjtoronep^^.1 / 60667%).6 / 5 p%^.. 6 / 8 ||. ' Leukocyturia -A|| 1 / 6 (1657%). T " 6 / 5 (6%). f 6 / 8 (6%). '{.6 / 8 (6%). '! 6 / 5 (6%).. w ^e& K).. 6^.1661 / 6%^^. 6 / 5 (6^ I. Perinephric collection.:’A. f".6 / 5 (6%). j.6 / 5. (6%). J.6 / 8. (6%). i.6 / 8 (6%). j.1 / 5 (20%). |. Polyuria”^. 6^ ^. 6 / 8. f. Proteinuria.:"Ar26’(33'33%). || o7F(6%). I"' 178 (125%). T 6 / 8 (6%). Tl / 5 (26%j. _ Urinary incontinence ~A1 / 6 (1667%) _ 0 / 5 (0%). '6 / 8' (6%). 0 / 8 (0%) | Reproductive system and breast! l i l t disorders I. Penile haematoma:"A|.0 / 6 (6%). || 6 / 5 "(6%). [ 6 / 8 (6%). |[.678 (6%). || 1 / 5 (26%) I Respiratory, thoracic and mediastinal | disorders I.....216 ^... 6 / 8 ^. 6 / ^ |. increased. bronchial secretion.:"A. |.676 (6%)... j".675 (6%). j.0 / 8 ' (6%). J’.6 / 8. (6%). | iS (20%).[... "". Oropharyngeaipain. •'*. j.1 / 606767%). [.675 (6%j". j..6 / 8 (6%)'. |.67f‘(6%). | 175 (26%) |. Pleural effusion. -A. |.676 (6%)... |.6 / 5 (6%). j.6ffi"(6%). j.6 / 8 (6%). | 1 / 5 (20%). |. Productive cough^^.6 / 5 (6%)..0t51fl%^.. 6 / 8’(6^ ||. ThroJirritation. -"A. j.17606767%). i.6 / 5. (6%). ['.0 / 8 " (6%). J.6 / 8. (6%). f " 6 / 57(6%). Skin and subcutaneous tissue disorders Actinic keratosis 0 / 6 (0%) J 0 / 5 (0%) I 2 / 8 (25%) j 0 / 8 (0%) | 0 / 5 (0%) Dermatosis 176’06767%). || 675 (0%)' i 6S‘|(6%). | 0 / 8 (6%). { 0 / 5 (0%)' Diffuse alopecia 1 / 6 (16.67%) 0 / 5 (0%) j.6 / 8 (6%) 0 / 8 (0%) 0 / 5 (0%) ' Pruritus 'A1 / 6 (16.67%) 0 / 5 (0%)11 / 8 (12.5%) 0 / 8 (0%) 0 / 5 (0%) I... RaSrTrT...6 / 6 (6%)’.. j. o / B'W)^—“ j. t78025%)'^^—.. o / IW). ir6 / 5 (6%)—[’ Skin hyperpigmentation'.7a. r~'~6S‘(0%). j.6 / 5 (6%)* |.1 / 80275%). [”' 0 / 8 (6%) r67g’(O%r~~ ‘ Vascular disorders > i i! I. nushir^i. -A1.176 06767%). J.675 (6%). |.678 (6%). |.078 (0%). 1.6 / 5|)%|j7Haematoma • '%AI i 1 / / c6 V(-1tR6. «677%%i). | I. ri 0 / / ri5 r(ri0o%Zi). 7. n 0 / / s8 n(6w%.)) I |. ri 6 / / 8s m(6%%\) I. i 1 / rri5 r (2dr0w%.’)i Hypertension, A4 / 6 (66.67%) 3 / 5 (60%) 4 / 8 (50%) 2 / 8 (25%).1 / 5 (26%). Hypotension 'A0 / 6 (0%) J 0 / 5 (0%) 2 / 8 (25%) I 0 / 8 (0%) 0 / 5 (0%)Poor peripheral circulation ’A0 / 6 (0%) I 0 / 5 (0%) 0 / 8 (0%) 1 / 8 (125%) 0 / 5 (0%) » Indicates events were collected by non-systematic methods.[ A Term from vocabulary, MedDRA v27.16.5 Example 5. Siplizumab as Induction Therapy in Renal Transplant Recipients

[0090] A phase 2b, randomized, multicenter, double-blind, dose-finding, active-controlled study is conducted to evaluate the safety and efficacy of an anti-CD2 monoclonal antibody, siplizumab, compared to rabbit anti thymocyte globulin (rATG) as induction therapy in renal transplant recipients. In addition to either siplizumab or rATG, all participants receive background immunosuppression with standard-exposure tacrolimus (TAC), mycophenolic acid (MPA), and corticosteroids (CS).6.5.1 Study Design

[0091] The schematic of the study is as shown in FIG. 6. Renal transplant candidates requiring induction therapy are enrolled to receive siplizumab at dose level of 0.6 mg / kg, or 1.2 mg / kg, or to receive the comparator, rATG at dose level of 1.5 mg / kg (see Table. 4).Randomization is stratified by donor status (living vs donation after brain death vs donation after cardiac death [DCD]) to ensure similar proportions of donor types in each study arm.Participants randomized to siplizumab receive 2 intravenous (IV) doses. The first dose is administered on Day 0, pre- or intra-operatively, and is completed prior to revascularization / reperfusion of the allograft. The second dose is administered on post-operative Day 3. Participants randomized to rATG receive either 3 or 4 IV doses (Days 0, 1, 2 or Days 0, 1, 2, 3). To maintain the blind, matching infusions of normal saline are administered as placebo.Table 4. Investigational Product AdministrationArm Dosing RegimenSiplizumab 0.6 mg / kg 0.6 mg / kg (Days 0 and 3); 1.2 mg / kg cumulative Siplizumab 1.2 mg / kg 1.2 mg / kg (Days 0 and 3); 2.4 mg / kg cumulative1.5 mg / kg (Days 0, 1, and 2); 4.5 mg / kg cumulative rATG or1.5 mg / kg (Days 0, 1, 2, and 3); 6.0 mg / kg cumulative

[0092] An interim analysis is performed when 75% of subjects have been followed for 6 months post-transplant, including the selection of a siplizumab dose for further development based upon evaluation of efficacy and safety outcomes including AESIs, BP AR, PK / PD, and composite biomarker panel (abbreviated iBox). Final analysis is performed when all participants have completed 12 month follow-up visits post-transplant or have otherwise ended the trial. Thisanalysis is performed to evaluate the safety of siplizumab at 2 dose levels (0.6 mg / kg; 1.2 mg / kg) compared to rATG.6.5.2 Concomitant Treatment

[0093] As shown in Tables 5-7 below, all participants also receive:d. a triple regimen of background immunosuppressive therapy for the duration of the study;e. premedication prior to study treatment infusions; andf. infection prophylaxisTable 5. Background Immunosuppressive TherapyBackground Dosing RegimenImmunosuppressive TherapyTacrolimus (TAC) • Oral (PO) extended-release once-daily (QD) or immediate- release (PO) twice-daily (BID).• Administration is started within 24 hours (±) of the transplant.• Serum concentrations maintained per local practice and consistent with applicable labelling (5-12 ng / mL).Mycophenolic acid (MPA) • Administration is started within 24 hours post-transplant • Mycophenolate mofetil (MMF; CellCept® or generic; 2 g PO [QD]) in 2 divided doses; or• Enteric-coated mycophenolate sodium (EC-MPS;Myfortic® or generic; 1.44 g PO [QD]) in 2 divided doses. Corticosteroids (CS) • IV at time of transplant per local practice then tapering to maintain a minimum of 5 mg oral prednisoneequivalent / dayTable 6. Infusion PremedicationPremedication for Study Dosing RegimenTreatment InfusionsPremedication • Hl antagonist (e.g., diphenhydramine),paracetamol / acetaminophen, and corticosteroids• Use of a 5-HT3 antagonist (e.g., ondansetron) for emesisprophylaxis is considered as neededTable 7. Infusion PremedicationInfection Prophylaxis Dosing RegimenInfection prophylaxis • Cytomegalovirus (CMV): for donor positive / recipient negative (D+ / R-) and recipient positive (R+) candidates for 6 months; treatment selection per local practice. No CMV prophylaxis for donor negative / recipient negative (D- / R-) candidates required per protocol.• Pneumocystis pneumonia (PCP) prophylaxis for 6 months; treatment selection per local practice• Candida treatment, per local practice6.5.3 Study Objectives and Endpoints

[0094] The study objectives and endpoints are presented in the table below.Primary Objective Primary EndpointTo assess the safety of 2 dose levels Number and percentage of participants at 12 months of siplizumab versus rATG. post-transplant experiencing AEs, SAEs, and AESIs. Secondary Objectives Secondary EndpointsTo assess the incidence of • Composite incidence of BP AR, death, graft loss, composite efficacy failure (defined and loss-to-follow-up.as death, graft loss, BP AR, or loss- • Incidence of participants who experienced BP AR as to-follow-up) and their individual defined by central pathology (blinded independent components. central review using Banff Allograft Pathology Scoring).• Grade and severity of BP AR.• Time to first BP AR for each participant.• Incidence of treated BP AR and steroid-resistant BPAR.• Participant survival at 12 months.• Graft survival at 12 months.• Time to graft loss for each participant.• Time to death for each participant.• Number of participants requiring for-cause renal allograft biopsy assessments over 12 months post-transplant.To assess the PK of 2 dose levels of Siplizumab Cmaxand AUC over 12 weeks siplizumab. post-transplant.To assess the PD of 2 dose levels of Depletion and recovery of lymphocyte count by subset siplizumab versus rATG. (total lymphocytes; CD3+, CD4+, and CD8+ T cells;CD19+ B cells; CD56+ NK cells) over 12 monthspost-transplant.Exploratory Objectives Exploratory EndpointsTo assess composite biomarker Composite biomarker panel (abbreviated iBox) score at panel (abbreviated iBox) scoring of 6 and 12 months post-transplant.long-term allograft outcomes inparticipants receiving siplizumabcompared to rATG at 12 monthspost-transplant.To assess the effect of siplizumab • eGFR calculated using the Chronic Kidney Disease compared to rATG when combined Epidemiology Collaboration formula at 12 months with a TAC, MPA, and CS-based post-transplant.regimen on renal function as • eGFR slope from 1 month to 12 months assessed by eGFR. post-transplant.To assess the incidence of • Number, type (Class I / II), and mean fluorescence treatment-emergent de novo, DS A intensity of de novo anti-HLA DSA at 12 months in participants receiving siplizumab post-transplant.compared to rATG. • Proportion of participants who have developed de novo DSA at 6 and 12 months post-transplant. To assess quality of life, life Patient Reported Outcome Measures comparisons participation, and symptom severity between arms (see Tong etal., Transpl Int. 2022; measures relative to control by 35:10134):validated instruments over • Quality of Life - EQ-5D-5L (see Cleemput et 12 months. al., Value Health. 2004;7:499-509).• Life Participation - Patient-Reported Outcomes Measurement Information System, Short Form (PROMIS) Short Form v2.0 (see PROMIS 2018).• Symptom Severity - End Stage Renal Disease- Symptom Checklist Transplantation Module (see Franke etal., Nephron. 1999;83:31-9). To assess the incidence of dd- Quantification of dd-cfDNA at 12 monthscfDNA in participants receiving post-transplant.siplizumab compared to rATG at12 months post-transplant.To assess the immunogenicity of Quantification of siplizumab anti-drug antibodies and siplizumab. neutralizing antibodies at 12 months post-transplant. To explore the incidence of BP AR by treatment according to degree of rejection by treatment and HL A eplet-mismatch.mismatch at the molecular level.6.5.4 Study Enrollment

[0095] Participants who meet all the following inclusion criteria are eligible to participate in the study:1) Adults >18 and <70 years of age.2) Recipients of a renal allograft from a non-HLA identical living or deceased donor.3) Recipients of a kidney with a cold ischemia time < 30 hours; hypothermic machine perfusion within the same timeframe is acceptable.4) Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, must agree to use highly effective methods of contraception during dosing and for 24 weeks after the study medications have been stopped.a. Postmenopausal females must not have experienced any menstrual bleeding for > 1 year prior to initial dosing.b. Female participants who are surgically sterile must have undergone the procedure > 6 months prior to initial dosing. Surgical sterilization procedures should be supported with clinical documentation made available to the Sponsor.c. All women of childbearing potential must have negative pregnancy test results at screening / baseline.

[0096] Participants must not meet any of the following exclusion criteria:1) Transplant recipients seronegative for EBV.2) Transplant recipients receiving a kidney from a non-heart beating donor (ie, DCD) who fulfills any of the following criteria:a. Organ is retrieved from an uncontrolled DCD.b. Donor age >55 years of age.3) 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.4) Presence of current or historical DSA via single-antigen bead assay or local standard of care. The MFI cut-off value used to determine the presence of DSA will be defined as per the institutional standard of care. 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. For instance, a participant receiving maintenance immunosuppressive therapy including cyclosporine, azathioprine, sirolimus or related medication must be, in the opinion of the Investigator, eligible to discontinue treatment and initiate the protocol-defined TAC-based regimen. ) History of malignancy of any organ system, except for localized excised non- melanomatous skin lesions or carcinoma in situ of the cervix.0) Participant with any of the following:a. Hemoglobin < 8 g / dL (< 80 g / L)b. White blood cell count ≤ 2,000 / mm3(≤ 2 × 109 / L)c. Platelet count ≤ 50,000 / mm3(≤ 50 × 109 / L).1) 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.2) Recipient of a kidney from a donor who tests positive for human immunodeficiency virus or hepatitis B surface antigen / hepatitis B core protein. Recipients of a kidney from an HCV-positive deceased donor are excluded, and recipients of a kidney from an HCV- positive living donor are excluded without proof of sustained viral response in the donor.3) History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes (eg, siplizumab, rATG, TAC, MPA derivatives, CS).4) Any additional contraindication to the use of TAC or MPA according to the national labeling information of these products (refer to the local product label).5) 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).6) Participants with severe systemic infection(s), at the time of screening or within 2 weeks prior to randomization.17) Participants with any other clinically significant medical condition, active infection, or laboratory abnormality that would, in the judgment of the Investigator, may impact participant’s safety or may interfere with the participant’s ability to participate in the study.18) Participants who, in the opinion of the Investigator, are incapable of providing informed consent for the study, or are unable or unwilling to adhere to the study requirements. 19) Use of other investigational products or enrollment in another investigational drug study within 30 days of screening or 5 half-lives of the medication, whichever is longer.20) Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by human chorionic gonadotropin laboratory test.6.6 Example 6. Study of Siplizumab Induction: Safety and Efficacy of Siplizumab Induction in de novo Renal Transplant Recipients

[0097] A multicenter, open-label, dose-escalation Phase 2 trial was conducted. Adult recipients of living or deceased donor renal allografts were randomized to induction with siplizumab in four cohorts (0.2 mg / kg, 0.6 mg / kg, 1.7 mg / kg, and 5.0 mg / kg; IV on the day of transplantation and on post operative Day 4) or rATG (1.5 mg / kg; IV on the day of transplantation and on post operative Day 1, 2). Forty-five participants were randomized to siplizumab (n=33) or rATG (n=12). All subjects received maintenance immunosuppression with tacrolimus, my cophenolate, and glucocorticoids. Key endpoints included incidence of biopsy-proven acute rejection (BPAR), safety / tolerability, and renal function at 48 weeks.

[0098] Siplizumab was well tolerated in recipients; adverse events leading to dose reduction or discontinuation were rare (n=2). Grade IA tBPAR occurred in 6% (n=2) siplizumab subjects across all dosing arms. In the rATG arm, 8% (n=l) subject developed IIA mixed rejection (see FIG. 7). For-cause biopsy incidence was 18.2% (n=6) in siplizumab and 25% (n=3) in rATG arms. Renal function was preserved across all groups and eGFR trajectories were comparable.

[0099] In this Phase 2 study, siplizumab was well-tolerated and demonstrated successful prevention of acute rejection comparable to an rATG based regimen. These findings support the continued development of siplizumab for renal transplant recipients.SEQUENCESSEQ DESCRIPTION SEQUENCE ID NO1 heavy chain EYYMYvariable regionCDR 12 heavy chain RIDPEDGSIDYVEKFKKvariable regionCDR 23 heavy chain GKFNYRFAYvariable regionCDR 34 light chain RSSQSLLHSSGNTYLNvariable regionCDR 15 light chain LVSKLESvariable regionCDR 26 light chain MQFTHYPYTvariable regionCDR 37 heavy chain QVQLVQSGAEVQRPGAS VKVS CKASGY I FTE YYMYWVRQAPGQG variable region LELVGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTS DDTAVYYCARGKFNYRFAYWGQGTLVTVS S8 light chain DVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQR variable region PGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDV GVYYCMQFTHYPYTFGQGTKLEIK9 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYMYWVRQAPGQG variable region LELMGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTS DDTAVYYCARGKFNYRFAYWGQGTLVTVS S

Claims

What is claimed is:

1. A method of transplanting a kidney from a donor to a subject, wherein the method comprises:a. administering an anti-CD2 antibody or an antigen binding fragment thereof to the subject, wherein the anti-CD2 antibody is administered at a dose up to 0.2 mg / kg per administration; andb. transplanting the kidney into the subject.

2. A method of transplanting a kidney from a donor to a subject, wherein the method comprises:a. administering an anti-CD2 antibody or an antigen binding fragment thereof to the subject, wherein the anti-CD2 antibody is administered at a dose up to 0.2 mg / kg per administration; andb. transplanting the kidney into the subject,wherein a first dose of the anti-CD2 antibody or an antigen binding fragment thereof is administered on the day of transplantation.

3. A method of transplanting a kidney from a donor to a subject, wherein the method comprises:a. administering an anti-CD2 antibody or an antigen binding fragment thereof to the subject, wherein the anti-CD2 antibody is administered twice in total, at a dose of 0.6 mg / kg per administration; andb. transplanting the kidney into the subject,wherein the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject on the day of the transplanting step, and 3 days following the transplanting step.

4. A method of transplanting a kidney from a donor to a subject, wherein the method comprises:a. administering an anti-CD2 antibody or an antigen binding fragment thereof to the subject, wherein the anti-CD2 antibody is administered at a dose of 1.2 mg / kg per administration; andb. transplanting the kidney into the subject.

5. A method of transplanting a kidney from a donor to a subject, wherein the method comprises:a. administering an anti-CD2 antibody or an antigen binding fragment thereof to the subject, wherein the anti-CD2 antibody is administered at a dose of 1.2 mg / kg per administration; andb. transplanting the kidney into the subject,wherein a first dose of the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject on the day of transplanting step.

6. The method of claim 1 or 2, wherein the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject at a dose of 0.2 mg / kg, 0.15 mg / kg, 0.1 mg / kg, or 0.05 mg / kg per administration.

7. The method of claim 1 or 2, wherein the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject on the day of transplantation, and 4 days post to the transplantation, and wherein the anti-CD2 antibody or an antigen binding fragment thereof is not administered prior to the day of transplantation.

8. The method of any one of claims 1-6, wherein the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject on the day of transplantation, and 3 days post to the transplantation, and wherein the anti-CD2 antibody or an antigen binding fragment thereof is not administered prior to the day of transplantation.

9. The method of any one of claims 1-8, wherein the first dose of the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject on the day of transplantation, pre-operatively or intra-operatively.

10. The method of any one of claims 1-9, wherein the anti-CD2 antibody or antigen binding fragment thereof is siplizumab.

11. The method of any one of claims 1-10, wherein the subject is human.

12. The method of any one of claims 1-11, wherein the donor is human.

13. The method of any one of claims 1-12, wherein the method further comprises administering an immunosuppressive agent.

14. The method of claim 13, wherein the immunosuppressive agent is tacrolimus, mycophenolate mofetil, mycophenolate sodium, and / or corticosteroids.

15. The method of any one of claims 1-14, wherein the method does not comprise administering bone marrow cells to the subject.

16. The method of any one of claims 1-15, wherein the method does not comprise administering fludarabine, tocilizumab, an anti-IL6R antibody, a B-cell depleting antibody, cyclophosphamide, total body irradiation, and / or thymic irradiation to the subject.

17. The method of any one of claims 1-16, wherein the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject intravenously.

18. The method of any one of claims 1-17, wherein the anti-CD2 antibody or an antigen binding fragment thereof is administered to the subject no more than two times.

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