Status: approved; marketed

Organizations involved:

Pfizer, Inc. – Manuf.; Tech.; World. mark.; Parent

Upjohn Co. – R&D; Tech.; Former

Pharmacia & Upjohn Co. – Former

Cross ref: See the Immune Globulin Products entry (#743) in the Blood Products, Human section. See the entry above for Thymoglobulin, a similar T lymphocyte immune globulin product obtained from rabbits.

Description: Anti-thymocyte Globulin (Equine) or Atgam is an aqueous solution of horse (equine) immune globulin containing high levels of polyclonal immunoglobulin G (IgG) antibodies with specificity for human T lymphocytes (T-cells), fractionated from horses inoculated with human T lymphocytes (thymocytes; T-cells). Atgam primary contains monomeric IgG.

Atgam is packaged in 5 mL vials containing 50 mg/mL of equine IgG stabilized in 0.3 M glycine at a pH of about 6.8. Thimerosal (mercury derivative; sodium ethylmer-curi-thio-sali-cylate; see entry #939) 0.01% is added as an antimicrobial preservative.

Nomenclature: Lymphocyte Immune Globulin/Pfizer [BIO]; ATGAM Sterile Solution [TR]; Anti-thymocyte Globulin (Equine) [FDA]; Lymphocyte Immune Globulin [FDA]; Antilymphocyte Immunoglobulin (Horse) [BAN]; horse anti-thymocyte globulin [SY]

Biological.: The equine human thymocyte-induced antibodies in Atgam are used for immune suppression. The antibodies markedly deplete the patient’s pool of T-cells through a variety of mechanisms. See also the Thymoglobulin entry above for information about the mechanisms of action of these similar products. Atgam particularly interferes with cell-mediated rejection of foreign tissues, making it useful to reduce the risk for chronic rejection and graft loss. Atgam is also among the few therapeutics useful for treatment of aplastic anemia. Atgam is generally used in conjunction with androgenic steroids, corticosteroids, and/or cyclosporine. Atgam has an in vivo half-life of 5.7 ±3 days measured as horse IgG.

Companies.: Atgam is manufactured and marketed in the U.S. by Pharmacia Corp. (a subsidiary of Pfizer; originally Upjohn Co., later Pharmacia & Upjohn Co., later Pharmacia Corp.), CBER/FDA est. no. 1216, at facilities in Kalamazoo, MI. Pharmacia merged into Pfizer Corp. in April 2003. Atgam was originally developed, manufactured, and marketed by Upjohn Co. It is currently marketed by Pharmacia Corp. (Pfizer) in the U.S., and internationally by Pharmacia/Pfizer affiliates. Officially, it is manufactured by the Pharmacia & Upjohn Co., CBER/FDA est. no. 1216, Kalamazoo, MI.

Manufacture: Purified suspensions of human thymic (T) lymphocytes are mixed with unspecified adjuvant(s) and used to repeatedly immunize groups of horses over a 120 day period. The human thymic tissue is normally obtained from children (malignancy- and infection-free) undergoing thoracic surgery in which a partial thymectomy has been required to clear the operating field. Each immunization pool of T-cells is obtained from at least five donors. The horses are quarantined, maintained, immunized, and bled according to specifications outlined in the Code of Federal Regulations (CFR).

Horses producing antibodies with adequate T-cell rosette inhibiting activity are bled repeatedly over time. Immune globulin is purified from separated blood plasma by an acrinol precipitation procedure. The supernatant is incubated with human red blood cell solids (stroma) and a human IgG-free plasma protein precipitate fraction (to remove and reduce equine antibodies to associated red blood cells and human proteins). The equine immune globulin is precipitated with cold ethanol, reconstituted, and passed through silica gel chromatography columns to remove residual acrinol. Diafiltration of the effluent is conducted as a buffer-exchange step in diethyl-aminoethyl (DEAE) cellulose ion chromatography. The immune globulin fraction is collected, sterile filtered (0.2 µm filter), and lyophilized. Unspecified viral inactivation/removal processes are used during manufacture. The company claims Atgam attains “state-of-the art quality and purity” in this and other respects.

The production and testing of a batch of Atgam can take from 10-16 months. Overall, each batch is subjected to about 880 hours of testing for quality, potency, and safety, including comparison to an Atgam reference standard. Each lot is assayed for T lymphocyte immunosuppressant activity by measuring inhibition of rosette formation by sheep red blood cells and fresh human peripheral blood lymphocytes (PBLs). Titers are expressed as the reciprocal dilution of Atgam required to give specific reduction in rosette numbers relative to buffer controls. More precise assays for immunosuppressant activity of Atgam have not been established (and, thus, clinical activity may vary from lot to lot). Atgam is also analyzed by high-performance size-exclusion chromatography to determine the amount of aggregates and fragments of equine IgG, in addition to the active monomeric (IgG), the desired product, and dimeric IgG. Fragments indicate potential protease contamination, and aggregates indicate potential protein conformational stability problems. Aggregates may activate comp-lement by attaching to lymphocyte surfaces, promoting release of inflammatory peptides. Agarose electrophoresis is used to assess protein purity and the exclusive presence of equine IgG.

Lots of Atgam are tested for absence of human platelet and red blood cell equine antibodies, and assays must detect no reactivity with human serum proteins or glomerular basement membrane (GBM). Atgam is tested for anti-human platelet activity using a complement fixation assay. Residual equine antibody to human red blood cells is assayed using a hemagglutination assay with type O red blood cells. An Ouchterlony double-diffusion assay determines the presence of equine antibodies to human plasma proteins. Equine antibodies to kidney glomerular basement membrane (GBM) are assayed by fluorescent dye-labeled equine anti-horse IgG staining of kidney sections from rats injected with Atgam.

FDA class: Biologic PLA

CBER class: Blood And Blood Derivatives

Approvals: Date = 19811117; first approval, PLA, granted to Upjohn Co.; Indication = immune suppressant for treatment of moderate to severe aplastic anemia in patients who are unstable for bone marrow transplantation

Date = 19850924; PLA supplement; Indication = treatment of moderate to severe aplastic anemia in patients who are unsuitable for bone marrow transplantation

Date =19961204; PLA/ELA revoked and granted (reissued) to new owner, Pharmacia & Upjohn Co.

Date = 19981117; PLA supplement; Indication = for the management of allograft transplantation in renal transplant patients; also as an adjunct to other immunosuppressive therapy to delay the onset of the first rejection episode

Indications: [portions of the "INDICATIONS AND USAGE” section of product insert/labeling]:

Renal Transplantation: ATGAM Sterile Solution is indicated for the management of allograft rejection in renal transplant patients. When administered with conventional therapy at the time of rejection, it increases the frequency of resolution of the acute rejection episode. The drug has also been administered as an adjunct to other immunosuppressive therapy to delay the onset of the first rejection episode. Data accumulated to date have not consistently demonstrated improvement in functional graft survival associated with therapy to delay the onset of the first rejection episode.

Aplastic Anemia: ATGAM is indicated for the treatment of moderate to severe aplastic anemia in patients who are unsuitable for bone marrow transplantation. When administered with a regimen of supportive care, ATGAM may induce partial or complete hematologic remission. In a controlled trial, patients receiving ATGAM showed a statistically significantly higher improvement rate compared with standard supportive care at 3 months. Improvement was defined in terms of sustained increase in peripheral blood counts and reduced transfusion needs.

Medical: The recommended dose of Atgam is 10-15 mg/kg administered intravenously, in conjunction with other therapy, e.g., corticosteroids. When used for initial renal transplant rejection, the recommended dose is given daily for 14 days. Additional alternate day therapy may be given for up to a total of 21 doses in 28 days.

Market: The 2007 Average Wholesale Price (AWP) is $2,015.22/kit ($1,729.94 in 2005, $1,647.56 in 2004), with a Direct Price (Manufacturer’s discount price) of $1,679.35/kit ($1,372.97 in 2004) (Red Book, 2007).

Competition: In the U.S., Atgam competes with other immune suppressants for kidney transplant rejection-related indications: including OKT 3 from Ortho/Johnson & Johnson (entry #303) and Thymoglobulin (rabbit anti-thymocyte immune globlulin entry #917) from Genzyme Transplant.

Internationally, competition includes Lympho-glo-buline, equine anti-thymocyte immune globulin, formerly manufactured and marketed by SangStat Medical Corp., now Genzyme Transplant, in Europe; by Sanofi-Aventis S.A. in Japan; and by other distributors in various countries. Lymphoglobuline is primarily used in conjunction with immunosuppressive drugs to treat acute rejection in renal transplant patients.