Use of Immune Globulin Plus Rituximab for Desensitization in Highly HLA Sensitized Patients Awaiting Deceased Donor Kidney Transplantation

Organ transplantation offers the only hope for a normal life for patients with end-stage
renal disease on dialysis. For patients with antibodies to human leukocyte antigens (HLA),
transplantation is extremely difficult or impossible since pre-formed antibodies will cause
severe rejection and loss of transplanted organs. Intravenous gamma globulin (IVIG) can
reduce or eliminate these antibodies in most patients and allow for successful
transplantation. This breakthrough has allowed patients previously considered not
transplantable to receive life-saving transplants. However, IVIG alone does not always
eradicate the anti-HLA antibodies to a degree that will allow transplantation.

In this study, the investigators propose additional treatment with rituximab, a humanized
antibody directed at the CD20 antigen that is present on most B-cells. Both IVIG and
rituximab are approved by the U.S. Food and Drug Administration (FDA) for numerous
immunologic disorders and Non-Hodgkin's lymphoma, respectively. However, neither is approved
by the FDA for desensitization of highly-HLA sensitized transplant patients. A previously
conducted pilot study demonstrated IVIG + Rituximab can fill an important gap in the current
therapeutic approach for management of highly sensitized patients and may become the standard
therapy.

Update: Study updated after observation that subjects transplanted after desensitization with
IVIG alone experienced higher rates of antibody rejection and graft loss. The primary
objective of this revised protocol will be to examine the safety and efficacy of IVIG 2gm/kg
(maximum 140g) given on day#0 & day #30 plus Rituximab 1gm given on day #15. Transplanted
patients will receive additional doses of Rituximab 1gm at 3 months post-transplant if donor
specific antibody (DSA) levels remain or become positive or at 6M if de novo DSA occur. All
transplanted patients who remain DSA negative, will not receive additional Rituximab. All
transplanted patients will have a protocol biopsy at transplant and 12 months. All subjects
will complete 5 visits in the pre-transplant phase of the study. Patients who are
transplanted will have additional 5 post-transplant visits. The following are
research-related procedures:

1. Rituximab infusion.

2. Kidney allograft biopsies (Intra-op, 12 months post-transplant)

3. Rituximab level, HACA levels

4. Immunologic biomarkers (CD19+, CD38+, CD27+)

Although the investigator commonly uses both treatment regimens at Cedars-Sinai Medical
Center, only the IVIG treatment is considered to be standard of care for highly
HLA-sensitized patients. The investigational component of this study is the addition of the
rituximab. Currently the study has been amended to a safety and efficacy study focusing on
decreasing HLA antibodies pre-transplant and minimizing DSA post-transplant.

Inclusion Criteria:

1. End-stage renal disease.

2. No known contraindications for therapy with IGIV10%/Rituximab.

3. Age 18-70 years at the time of screening.

4. PRA> 30% demonstrated on 3 consecutive samples, UNOS wait time sufficient to allow DD
offers, history of sensitizing events, positive crossmatch with the intended donor.

5. Subject/Parent/Guardian must be able to understand and provide informed consent.

Exclusion Criteria:

1. Lactating or pregnant females.

2. Pediatric patients <18 years of age

3. Women of child-bearing age who are not willing or able to practice FDA-approved forms
of contraception.

4. HIV-positive subjects.

5. Subjects who test positive for HBV infection [positive HBVsAg, HBVcAg, or HBVeAg/DNA]
or HCV infection [positive Anti-HCV (EIA) and confirmatory HCV RIBA].

6. Subjects with active TB.

7. Subjects with selective IgA deficiency, those who have known anti-IgA antibodies, and
those with a history of anaphylaxis or severe systemic responses to any part of the
clinical trial material.

8. Subjects who have received or for whom multiple organ transplants are planned.

9. Recent recipients of any licensed or investigational live attenuated vaccine(s) within
two months of the screening visit (including but not limited to any of the following:

- Adenovirus [Adenovirus vaccine live oral type 7]

- Varicella [Varivax]

- Hepatitis A [VAQTA]

- Rotavirus [Rotashield]

- Yellow fever [Y-F-Vax]

- Measles and mumps [Measles and mumps virus vaccine live]

- Measles, mumps, and rubella vaccine [M-M-R-II]

- Sabin oral polio vaccine

- Rabies vaccines [IMOVAX Rabies I.D., RabAvert])

10. A significantly abnormal general serum screening lab result defined as a WBC < 3.0 X
103/ml, a Hgb < 8.0 g/dL, a platelet count < 100 X 103/ml, , an SGOT > 5X upper limit
of normal, and an SGPT >5X upper limit of normal range.

11. Individuals deemed unable to comply with the protocol.

12. Subjects with active CMV or EBV infection as defined by CMV-specific serology (IgG or
IgM) and confirmed by quantitative PCR with or without a compatible illness.

13. Subjects with a known history of previous myocardial infarction within one year of
screening.

14. Subjects with a history of clinically significant thrombotic episodes, and subjects
with active peripheral vascular disease.

15. Use of investigational agents within 4 weeks of participation.