The Impact of Velcade(TM)on Antibody Secreting Cells in Sensitized Renal Allograft Candidates

The study is designed to assess the impact of in vivo treatment of bortezomib on anti-HLA
production by normal antibody secreting cells (ASC) in sensitized renal allograft
candidates. The design involves in vivo treatment with bortezomib for one 4 dose cycle
(days 1, 4, 8 and 11). Using novel assays, anti-HLA production is determined by bone marrow
derived ASC at baseline (prior to therapy) and after treatment (at day 14, 3 days after the
last bortezomib dose). Paired data are used with patients serving as their own controls.
Finally, the safety of bortezomib is evaluated by monitoring total serum antibody levels and
the incidence of side effects (primarily neuropathy) at 1 month, the final follow-up point.

Inclusion Criteria:

- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.

- Female subject is post-menopausal, surgically sterilized, or she and/or sexual
partner are willing to use an acceptable method of birth control (i.e., a
hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom
with spermicide, or abstinence) for the duration of the study.

- Male subject agrees to use an acceptable method for contraception for the
duration of the study.

- Renal transplant candidates who otherwise meet our acceptance criteria.

- Evidence of alloantibody in their serum (panel reactive antibody >20% and
specificities determined by single antigen flow bead assay.

- Sensitized patients with no living donors or have donor-specific antibody levels
too high to undergo successful transplantation using our current protocols (T or
B cell crossmatch channel shift >500).

Exclusion Criteria:

- Patient has a platelet count of <30 x 109/L within 14 days before enrollment.

- Patient has an absolute neutrophil count of ANC<1.0 x 109/L within 14 days
before enrollment.

- Patient has >Grade 2 peripheral neuropathy within 14 days before enrollment.

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic
evidence of acute ischemia or active conduction system abnormalities. Prior to
study entry, any ECG abnormality at Screening has to be documented by the
investigator as not medically relevant.

- Patient has hypersensitivity to bortezomib, boron or mannitol.

- Female subject is pregnant or breast-feeding. Confirmation that the subject is
not pregnant must be established by a negative serum B-human chorionic
gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy
testing is not required for post-menopausal or surgically sterilized women.

- Patient has received other investigational drugs within14 days before
enrollment.

- Serious medical or psychiatric illness likely to interfere with participation in
this clinical study.

- Diagnosed or treated for malignancy within 5 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell
carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after
curative therapy.

- Contraindication to kidney transplantation—active infection, comorbid medical
conditions, etc.