Thymoglobulin® [Anti-thymocyte Globulin (Rabbit)] is a
purified, pasteurized, gamma immune globulin, obtained by immunization of rabbits with
human thymocytes. This immunosuppressive product contains cytotoxic antibodies
directed against antigens expressed on human T-lymphocytes.
Thymoglobulin is a sterile, freeze-dried product for intravenous
administration after reconstitution with Sterile Water for Injection, USP (SWFI).
Each 10 mL vial contains 25 mg anti-thymocyte globulin (rabbit) as well as 50
mg glycine, 50 mg mannitol, and 10 mg sodium chloride.
After reconstitution with 5 mL SWFI, each vial of reconstituted product
contains approximately 5 mg/mL of Thymoglobulin, of which >90% is
rabbit gamma immune globulin (IgG). The reconstituted solution has a pH of 6.5 - 7.2.
Human red blood cells are used in the manufacturing process to deplete cross-reactive
antibodies to non-T-cell antigens. The manufacturing process is validated to remove or
inactivate potential exogenous viruses. All human red blood cells are from US
registered or FDA licensed blood banks. A viral inactivation step (pasteurization,
i.e., heat treatment of active ingredient at 60°C/10 hr) is performed for
each lot. Each Thymoglobulin lot is released following potency testing
(lymphocytotoxicity and E-rosette inhibition assays), and cross-reactive antibody
testing (hemagglutination, platelet agglutination, anti-human serum protein antibody,
antiglomerular basement membrane antibody, and fibroblast toxicity assays on every
Mechanism of Action
The mechanism of action by which polyclonal antilymphocyte preparations
suppress immune responses is not fully understood. Possible mechanisms by which
Thymoglobulin may induce immunosuppression
include: T-cell clearance from the circulation and modulation of T-cell
activation, homing, and cytotoxic activities. Thymoglobulin includes antibodies
against T-cell markers such as CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45,
HLA-DR, HLA Class I heavy chains, and Ÿ2 micro-globulin.
Thymoglobulin (concentrations >0.1 mg/mL) mediates T-cell
suppressive effects via inhibition of proliferative responses to several mitogens.
In patients, T-cell depletion is usually observed within a day from initiating
Thymoglobulin therapy. Thymoglobulin has not been shown to be effective
for treating antibody (humoral) mediated rejections.
Pharmacokinetics and Immunogenicity
After an intravenous dose of 1.25 to 1.5 mg/kg/day (over 4 hours for 7-11
days) 4-8 hours post-infusion, Thymoglobulin levels were on average 21.5 mcg/mL
(10-40 mcg/mL) with a half-life of 2-3 days after the first dose, and 87 mcg/mL
(23-170 mcg/mL) after the last dose. During the Thymoglobulin Phase 3
randomized trial, of the 108 of 163 patients evaluated, anti-rabbit antibodies
developed in 68% of the Thymoglobulin-treated patients, and anti-horse antibodies
developed in 78% of the Atgam -treated patients (p=n.s.). No controlled studies have been
conducted to study the effect of anti-rabbit antibodies on repeat use of
Thymoglobulin. However, monitoring the lymphocyte count to ensure that T-cell
depletion is achieved upon retreatment with Thymoglobulin is recommended. Based on
data collected from a limited number of patients (Clinical study Phase 3, n=12),
T-cell counts are presented in the chart below. These data were collected using
flow cytometry (FACSCAN, Becton-Dickinson).
US Phase 3 Study
A controlled, double-blind, multicenter, randomized clinical trial
comparing Thymoglobulin and Atgam was conducted at 28 US transplant centers in
renal transplant patients (n=163) with biopsy-proven Banff Grade II (moderate),
Grade III (severe), or steroid-resistant Grade I (mild) acute graft rejection.
This clinical trial rejected the null hypothesis that Thymoglobulin was more than
20% less effective in reversing acute rejection than Atgam. The overall
weighted estimate of the treatment difference (Thymoglobulin Atgam
success rate) was 11.1% with a lower 95% confidence bound of
0.07%. Therefore, Thymoglobulin was at least as effective as Atgam in
reversing acute rejection episodes.
In the study, patients were randomized to receive 7 to 14 days of
Thymoglobulin (1.5 mg/kg/day) or Atgam (15 mg/kg/day). For the entire study, the
two treatment groups were comparable with respect to donor and recipient
characteristics. During the trial, the FDA approved new maintenance
immunosuppressive agents (tacrolimus and mycophenolate). Off-protocol use of these
agents occurred during the second half of the study in some patients without
affecting the overall conclusions (Thymoglobulin 22/43, Atgam 20/37; p=0.826). The
results, however, are presented for the first and second halves of the study
(Table 1). In
successful treatment is presented as those patients whose serum creatinine levels
(14 days from the diagnosis of rejection) returned to baseline and whose graft was
functioning on day 30 after the end of therapy.
Table 1: Response to Study Treatment by Rejection Severity and Study Half
|| 4/5 (80.0%)
Weighted estimate of difference
95% confidence bound
| p Value
There were no significant differences between the two treatments with
respect to (i) day 30 serum creatinine levels relative to baseline, (ii)
improvement rate in post-treatment histology, (iii) one-year post-rejection
Kaplan-Meier patient survival (Thymoglobulin 93%, n=82 and Atgam
96%, n=80), (iv) day 30 and (v) one-year post-rejection graft survival
(Thymoglobulin 83%, n=82; Atgam 75%, n=80).