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.
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).
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.
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.
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).
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