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ATLG (Anti-T-lymphocyte Globulin)
ATLG (Anti-T-lymphocyte Globulin, brand name Grafalon®) from Neovii Pharmaceuticals AG, Switzerland) is a rabbit-derived polyclonal anti-human T-lymphocyte immunoglobulin preparation applied as an immunosuppressive therapeutic agent targeted against activated T-lymphocytes and used in various transplantation settings.

History of ATLG
ATLG belongs to a family of animal-derived polyclonal anti-T-lymphocyte/ anti-thymocyte immunoglobulin preparations that have been developed in the 1970s and 1980s by academic institutions in Europe and the United States, originally for the purpose of T cell depletion in steroid-resistant organ rejections and subsequently for induction therapy in solid organ transplantation.

ATLG is the only commercially available preparation that is produced by immunization of rabbits against the human T-lymphoblastoid Jurkat cell line. The polyclonal immunoglobulin fraction of the rabbit sera is highly purified and formulated to give the final product, a unique composition of reactive antibodies covering a specific immunological effective range.

ATLG is predominantly used to prevent organ rejection following solid organ transplantations (SOT) and to prevent graft-vs-host-disease (GvHD) following stem cell transplantation (SCT). ATLG is approved for marketing and sold by Neovii in more than 50 countries around the world.

Other commercially-available related preparations are Thymoglobulin®, a rabbit- derived anti-thymocyte immunoglobulin and equine-derived polyclonal anti-T-lymphocyte (ATGAM®). Although these preparations share with ATLG T cell depletion as a common mechanism of action, they materially differ in mechanism of action, their immunosuppressive properties, antibody content, binding specificities and biological and clinical effects mainly due to differences in immunization, purification and formulation (Baron et al. 2017, Popow et al. 2013, Storek et al. 2015).

Mechanism of Immunosuppression
The biological activity of ATLG acts via antibody specificity and mediates its mechanism of action through binding on surface antigens expressed on immune competent cells. ATLG preferentially targets activated T lymphocytes through binding at T cell specific markers, e.g. CD2, CD8, CD28 and leukocyte specific markers e.g. CD11a, CD18, CD45 (Popow et al. 2013, Servais et al. 2015).

The binding of ATLG on cell surface antigens results in T cell induced complement-mediated cytolysis, antibody-dependent cellular cytotoxicity (ADCC), opsonization and phagocytosis by the mononuclear phagocytic system. In addition, immunomodulatory properties contribute to their overall effectiveness (Mohty et al. 2007). ATLG also affects other immune and non-immune key cells and molecules involved in the immunological response (Servais et al. 2015, Grüllich et al. 2009, Werner et al. 2014). This includes for example antigen-presenting cells (APCs) (Naujokat et al. 2007, Fang et al. 2005, Leitner et al. 2010), B cells (Roll et al. 2015), regulatory T cells (Beider et al. 2015, Shimony et al. 2011), natural killer (NK) cells (Penack et al. 2007. ATLG has also been shown to bind adhesion molecules (e.g. E-selectin, ICAM-1) (Kanzler et al. 2013) on endothelial cells leading to inhibition of immune cell adhesion. In summary, the selective targeting of T cells and binding to other cells involved in immune response mechanisms induces a complex and long-lasting immunomodulation and regulation of the immune system through ATLG.

Clinical Applications
ATLG approved indications may be different from one country to the other. ATLG is mainly indicated as an induction and treatment agent as part of various immunosuppressive drug regimens for prevention of acute transplant rejection in patients receiving allogeneic solid organ transplantation (SOT) as well as for treatment of acute corticosteroid-resistant rejection after allogeneic SOT, e.g. renal, heart, liver, lung and pancreas transplantation (Dopazo et al. 2018, Faggian et al. 2010, Cantarovich et al. 2014, Kaden et al. 2009, Kyllönen et al. 2007, Ruan et al. 2017, Jaksch et al. 2013, Martins et al. 2009, Boesmüller et al. 2012, Du et al. 2016). Furthermore, in some countries ATLG is approved for the treatment of moderate and severe aplastic anemia.

ATLG in Graft versus Host Disease
Moreover, ATLG is indicated in certain countries for the prevention of acute and chronic graft vs host disease (GvHD) as part of the conditioning regimen prior to allogeneic SCT from matched, HLA-compatible, unrelated donors in combination with standard therapy (Finke et al. 2009, Finke et al. 2012, Finke et al. 2015, Finke et al. 2017, Socié et al. 2011).

Two prospective, randomized, international multicenter Phase 3 trials in hematopoietic cell transplantation from matched unrelated donors (Finke et al. 2009, Finke et al. 2017) and from HLA-identical siblings* (Kröger et al. 2016), have shown the clear and significant benefit of Grafalon as a GvHD prophylaxis agent when used prior to allogeneic SCT.

The landmark study in unrelated donors demonstrated that the addition of Grafalon to GvHD prophylaxis resulted in a significant reduction of acute and chronic GvHD incidence without an increase in relapse or non-relapse mortality and without compromising overall survival; importantly, the study's long-term follow-up data (median 8.6 years) confirmed the efficacy and safety profile of Grafalon with significant improvements in severe GvHD-free and relapse-free survival and in the probability of surviving free of immunosuppressive therapy (Finke et al. 2009, Finke et al. 2012, Finke et al. 2015, Socié et al. 2011).

An additional large international study demonstrated that Grafalon is efficacious and safe as GvHD prophylaxis in children* undergoing hematopoietic cell transplantation from matched unrelated donors (Peters et al. 2015).

REFERENCE LIST:
1. Baron, F., et al. (2017). "Anti-thymocyte globulin as graft-versus-host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation: a review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation." Haematologica 102(2): 224-234.

2. Beider, K., et al. (2015). "Anti-Human T-Lymphocyte Immunoglobulin (ATG)-Induced T Regulatory Cells and Their Soluble Factors Suppress T Cell Proliferation: Potential Role in Allogeneic Stem Cell Transplantation." Blood 126(23): 1889-1889.

3. Bösmüller, C., et al. (2012). "Tacrolimus monotherapy following alemtuzumab induction in combined kidney-pancreas transplantation: results of a prospective randomized trial." Annals of transplantation 17(4): 45-51.

4. Cantarovich, D., et al. (2014). "Early corticosteroid avoidance in kidney transplant recipients receiving ATG-F induction: 5-year actual results of a prospective and randomized study." Am J Transplant 14(11): 2556-2564.

5. Dopazo, C., et al. (2018). "Low Total Dose of Anti-Human T-Lymphocyte Globulin (ATG) Guarantees a Good Glomerular Filtration Rate after Liver Transplant in Recipients with Pretransplant Renal Dysfunction." Canadian Journal of Gastroenterology and Hepatology 2018: 7.

6. Du, X., et al. (2016). "Meta-analysis on the Safety and Efficacy of the Reperfusion Use of a Single High Dose of Anti–T-Lymphocyte Globulin Fresenius in Kidney Transplantation." Transplantation Proceedings 48(6): 2017-2022.

7. Faggian, G., et al. (2010). “Antithymocyte Globulin Induction Therapy in Heart Transplantation: Prospective Randomized Study of High vs Standard Dosage.” Transplant Proc. 2010 Nov;42(9):3679-87

8. Fang, L., et al. (2005). "Antithymocyte globulin induces ex vivo and in vivo depletion of myeloid and plasmacytoid dendritic cells." Transplantation 79(3): 369-371.

9. Finke, J., et al. (2009). "Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial." Lancet Oncol 10(9): 855-864.

10.  Finke, J., et al. (2012). "Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial." Biol Blood Marrow Transplant 18(11): 1716-1726.

11. Finke, J., et al. (2015). "Randomized Trial on GvHD Prophylaxis with or without Anti-Human T-Lymphocyte Immunoglobulin ATG-Fresenius (ATG-F) in Allogeneic Hematopoietic Cell Transplantation from Matched Unrelated Donors: Final Long-Term Results after 8.6 Years Median Follow-up." Blood 126(23): 853-853.

12.Finke, J., et al. (2017). “Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial.” The Lancet Haematology, 4(6): 293-30.

13. Grosse-Wilde, H., et al. (1981). "In vitro immunoresponsiveness in recipients of cadaveric renal allografts during ATG therapy." Proc. Eur. Dial. Transplant. Assoc 18: 481-485.

14. Grüllich, C., et al. (2009). "Rabbit anti T-lymphocyte globulin induces apoptosis in peripheral blood mononuclear cell compartments and leukemia cells, while hematopoetic stem cells are apoptosis resistant." Biol Blood Marrow Transplant 15(2): 173-182.

15.Jaksch, P., et al. (2013). "Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis." Transpl Int 26(1): 34-41.

16. Kaden, J., et al. (2009). "Improved long-term survival after intra-operative single high-dose ATG-Fresenius induction in renal transplantation: a single centre experience." Annals of transplantation 14(3): 7-17.

17. Kanzler, I., et al. (2013). "In vitro effects of ATG-Fresenius on immune cell adhesion." Transplant Proc 45(5): 1846-1849.

18. Kröger, N., et al. (2016). "Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease." N Engl J Med 374(1): 43-53.

19.Kröger, N., et al. (2016). "Prevention of Chronic Graft-versus-host Disease and the Unique Role of Anti-human T-lymphocyte Immune Globulin." European Oncology & Haematology 12(2):93–5.

20.Kyllonen, L. E., et al. (2007). "Single bolus antithymocyte globulin versus basiliximab induction in kidney transplantation with cyclosporine triple immunosuppression: efficacy and safety." Transplantation 84(1): 75-82.

21.Leitner, J., et al. (2010). "Interaction of antithymocyte globulins with dendritic cell antigens." Am J Transplant 11(1): 138-145.

22.Martins, L., et al. (2009). "Pancreas-kidney transplantation and the evolution of pancreatic autoantibodies." Transplant Proc 41(3): 913-915.

23.Mohty, M., et al. (2007). "Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond." Leukemia 21(7): 1387-1394.

24.Naujokat, C., et al. (2007). "Antithymocyte globulins suppress dendritic cell function by multiple mechanisms." Transplantation 83(4): 485-497.

25.Penack, O., et al. (2007). “The type of ATG matters -- natural killer cells are influenced differentially by Thymoglobulin, Lymphoglobulin and ATG-Fresenius.” Transpl Immunol. 2007 Nov;18(2):85-7

26.Popow, I., et al. (2013). "A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte globulin preparations." Am J Transplant 13(12): 3103-3113.

27.Peters et al. (2015). “Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J Clin Oncol. 10;33(11):1265-74

28.Roll, P., et al. (2015). "Effect of ATG-F on B-cell reconstitution after hematopoietic stem cell transplantation." Eur J Haematol.

29. Ruan, V., et al. (2017). "Use of Anti-Thymocyte Globulin for Induction Therapy in Cardiac Transplantation: A Review." Transplant Proc 49(2): 253-259.

30.Servais, S., et al. (2015). "Impact of Pre-Transplant Anti-T Cell Globulin (ATG) on Immune Recovery after Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation." PLoS One 10(6): e0130026.

31.Shimony, O., et al. (2011). "Anti-T lymphocyte globulin (ATG) induces generation of regulatory T cells, at least part of them express activated CD44." J Clin Immunol 32(1): 173-188.

32.Socié, G., et al. (2011). "Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius." Blood 117(23): 6375-6382.

33. Storek, J., et al. (2015). "Rabbit anti-T cell globulin in allogeneic hematopoietic cell transplantation." Biol Blood Marrow Transplant 21(6): 959-970.

34. Werner, I., et al. (2014). "ATG-Fresenius inhibits blood circulating cell proliferation in a dose-dependent manner: an experimental study." Transplant Proc 46(9): 3000-3003