A Comprehensive Clinical and Pharmacological Review of Anti-T-Lymphocyte Immunoglobulin (Rabbit), ATG-Fresenius S (Grafalon)

Executive Summary

This report provides a comprehensive clinical and pharmacological review of ATG-Fresenius S, an immunosuppressive agent identified by DrugBank Accession Number DB05320. Contrary to its classification in some databases as a small molecule, ATG-Fresenius S is a complex biologic therapeutic. It is a purified, concentrated preparation of polyclonal rabbit-derived immunoglobulin G (IgG) antibodies. Its primary clinical applications are as an induction agent for the prophylaxis and treatment of acute rejection in solid organ transplantation (SOT), particularly kidney transplantation; the prevention of Graft-versus-Host Disease (GVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT); and as an immunosuppressive therapy for acquired aplastic anemia (AA).

The principal mechanism of action of ATG-Fresenius S is the profound and rapid depletion of circulating T-lymphocytes, the key mediators of allogeneic immune responses. This is achieved through a multifaceted process involving complement-dependent cytotoxicity (CDC) and the induction of apoptosis. Beyond simple cell depletion, its polyclonal nature allows it to modulate a wide array of cell surface molecules, thereby impairing leukocyte adhesion and trafficking, and exerting effects on other immune cell populations, including B-lymphocytes and dendritic cells.

ATG-Fresenius S is distinguished from other antithymocyte globulin (ATG) preparations by its source antigen; it is produced by immunizing rabbits with the Jurkat human T-lymphoblast cell line. This contrasts with Thymoglobulin®, which uses human thymocytes, and Atgam®, which is equine-derived. These differences in manufacturing result in distinct antibody profiles, which in turn lead to variations in clinical potency, dosing regimens, and safety profiles. Notably, in the treatment of aplastic anemia, horse-derived ATG is considered the superior first-line agent, whereas rabbit-derived ATGs like ATG-Fresenius S are central to transplantation medicine.

The safety profile of ATG-Fresenius S is characterized by a high incidence of infusion-associated reactions, hematologic toxicities such as leukopenia and thrombocytopenia, and an increased risk of opportunistic infections due to profound immunosuppression. Its global regulatory status is complex; it is widely approved and used in Europe and other regions under the brand name Grafalon®, but it is not approved for marketing by the U.S. Food and Drug Administration (FDA). This regulatory divergence has significant implications for global standards of care and the cross-applicability of clinical research. This report synthesizes the available evidence on its pharmacology, clinical efficacy, safety, and comparative standing to provide a definitive resource for clinicians and researchers.

Section 1: Product Identification and Pharmaceutical Characteristics

A precise understanding of a therapeutic agent's identity, classification, and origin is fundamental to its safe and effective clinical use. This section delineates the nomenclature, classification, and manufacturing characteristics of ATG-Fresenius S, clarifying common points of confusion that have significant clinical relevance.

1.1. Nomenclature and Synonyms

The agent is identified in the DrugBank database by the Accession Number DB05320.[1] Its generic name is anti-T-lymphocyte immunoglobulin (rabbit).[3] Historically and in much of the clinical literature, it is referred to as ATG-Fresenius S or the abbreviated form, ATG-F.[1] In 2015, the product was globally rebranded and is now marketed under the trade name Grafalon®.[3] Other synonyms found in literature and databases include US-ATG-F, reflecting its investigational use in the United States.[3]

The evolution of its nomenclature is a critical point of awareness for both clinicians and researchers. Clinical trials and publications spanning several decades may use different names for the same product, creating a potential for confusion. For instance, a study from 2008 refers to the product as "ATG-Fresenius" [9], whereas a 2019 study refers to "grafalon (formerly ATG-Fresenius)".[10] This can complicate literature reviews and, more critically, may lead to medication errors. Given that dosing regimens differ substantially between various ATG products, confusing Grafalon® with another rabbit ATG like Thymoglobulin® could result in clinically significant under- or over-dosing.[5]

1.2. Classification: A Polyclonal Antibody Biologic

Despite being categorized as a "Small Molecule" in some database entries, ATG-Fresenius S is unequivocally a biologic therapeutic agent.[1] It is a purified, concentrated preparation of polyclonal immunoglobulin G (IgG) antibodies.[12] This distinction is not merely semantic; it carries profound implications for the drug's entire profile. Unlike small molecules, which are typically chemically synthesized, have low molecular weights, and often target intracellular pathways, biologics like ATG-Fresenius S are large, complex proteins derived from living organisms. Their mechanism of action is typically extracellular, their administration is parenteral, and they possess inherent immunogenicity, meaning they can elicit an immune response in the recipient. Its pharmacological classification is that of a potent immunosuppressive and lymphodepleting agent.[1] The misclassification as a small molecule can be misleading, as it fails to account for the characteristic risks of biologics, such as infusion-associated reactions and serum sickness.

1.3. Source and Manufacturing Process: The Jurkat Cell Line Immunization Method

The specific antibodies constituting ATG-Fresenius S are produced in rabbits following immunization with the Jurkat cell line, a human T-lymphoblastoid cell line that resembles activated T-cells.[1] This manufacturing process is a key differentiator from the other major rabbit-derived ATG, Thymoglobulin®, which is produced by immunizing rabbits with human thymocytes (T-cell precursors).[5] This fundamental difference in the immunizing antigen is the primary determinant of the final antibody composition. The Jurkat cell line presents a more limited and specific set of antigens compared to the diverse population of cells within the human thymus. Consequently, ATG-Fresenius S recognizes a narrower spectrum of antigens than Thymoglobulin®, a fact that directly influences its relative potency, required clinical dosage, and immunomodulatory effects.[5]

1.4. Originator and Developer

The product was originally developed by Fresenius Biotech. In 2013, Fresenius Biotech was acquired and became Neovii Biotech, which is the current developer and manufacturer of the product, now marketed as Grafalon®.[3]

Table 1: Summary of Product Characteristics

Characteristic	Description
DrugBank ID	DB05320 1
Generic Name	Anti-T-lymphocyte immunoglobulin (rabbit) 3
Brand Name	Grafalon® 7
Synonyms	ATG-Fresenius S, ATG-F, US-ATG-F 3
Classification	Biologic, Polyclonal Immunoglobulin G (IgG), Immunosuppressive Agent 12
Source	Rabbit serum after immunization with the Jurkat human T-lymphoblast cell line 1
Originator/Developer	Fresenius Biotech (Originator) / Neovii Biotech (Current Developer) 3

Section 2: Comprehensive Pharmacological Profile

The therapeutic utility of ATG-Fresenius S stems from its profound and multifaceted interactions with the human immune system. While its primary effect is the depletion of T-lymphocytes, its polyclonal nature endows it with a range of secondary mechanisms that contribute to its overall immunosuppressive potency.

2.1. Primary Mechanism of Action: T-Lymphocyte Depletion

The central pharmacological action of ATG-Fresenius S is the induction of profound and rapid T-lymphocyte (T-cell) depletion.[18] T-cells are the principal orchestrators and effectors of the adaptive immune response responsible for recognizing and attacking foreign tissues, making them the primary targets in preventing allograft rejection and GVHD.[21] As a polyclonal preparation, ATG-Fresenius S consists of a diverse mixture of antibodies that recognize and bind to a wide array of antigens expressed on the surface of T-cells.[18] This multi-target approach is a significant advantage over monoclonal antibodies, as it makes it difficult for T-cells to evade destruction by downregulating a single surface protein. The clinical effect is swift, with significant T-cell depletion typically observed within 24 hours of initiating therapy.[22]

2.2. Secondary and Ancillary Mechanisms

The efficacy of ATG-Fresenius S is not solely a function of cell killing but also involves a more sophisticated disruption of the immune response through several parallel mechanisms. This combination of "depletion and dysfunction" likely explains its high potency, particularly in challenging clinical scenarios like steroid-resistant rejection, where simply reducing T-cell numbers may be insufficient.

2.2.1. Complement-Dependent Cytotoxicity (CDC) and Apoptosis

The two primary effector mechanisms for T-cell elimination are CDC and apoptosis. Upon binding to T-cell surface antigens, the IgG antibodies in ATG-Fresenius S activate the classical complement pathway. This cascade culminates in the formation of the membrane attack complex (MAC), which perforates the cell membrane, leading to rapid cell lysis. This process, known as CDC, is believed to be the dominant mechanism of depletion within the bloodstream.[18] In parallel, the binding of ATG antibodies to certain T-cell receptors can trigger intracellular signaling pathways that lead to programmed cell death, or apoptosis. This mechanism is thought to be particularly important for eliminating T-cells within secondary lymphoid tissues such as the spleen and lymph nodes.[13]

2.2.2. Modulation of Cell Surface Adhesion and Trafficking Molecules

A crucial step in any T-cell mediated immune attack, whether on a transplanted organ or host tissues, is the migration of T-cells from the circulation into the target tissue. This process is mediated by a complex interplay of adhesion molecules (e.g., integrins, selectins) on the surface of leukocytes and their corresponding ligands on endothelial cells lining the blood vessels. ATG-Fresenius S contains antibodies that bind to and modulate these key molecules.[12] This action can physically block the interaction between T-cells and the endothelium or induce the downregulation of these adhesion molecules from the cell surface. The functional consequence is a marked reduction in T-cell infiltration into the graft, effectively disarming the T-cells that escape immediate depletion and preventing them from reaching their target.[20]

2.2.3. Impact on Other Immune Cells

While T-cells are the primary target, the polyclonal nature of ATG-Fresenius S results in effects on other critical immune cell populations:

• B-Lymphocytes: The preparation contains antibodies that recognize B-cell surface proteins such as CD19 and CD20. Binding to these targets can trigger caspase- and cathepsin-dependent apoptosis in B-cells, contributing to the overall immunosuppressive effect and potentially mitigating antibody-mediated rejection.[19]
• Dendritic Cells (DCs): As professional antigen-presenting cells (APCs), DCs are essential for initiating the primary T-cell response. ATG-Fresenius S can inhibit the maturation and migration of DCs by targeting surface molecules like MHC class I and II, thereby blunting the very first step of the rejection cascade.[19]
• Regulatory T-Cells (Tregs): There is compelling evidence that rabbit-derived ATGs, in contrast to horse-derived ATG, may selectively spare or even promote the expansion and function of regulatory T-cells (Tregs).[23] Tregs are a specialized subset of T-cells that actively suppress immune responses and are crucial for maintaining immunological tolerance. This differential effect—depleting pathogenic effector T-cells while potentially enhancing the "peacekeeper" Treg population—represents a more refined immunomodulatory action than indiscriminate lymphodepletion. It suggests a mechanism that shifts the immune balance away from rejection and towards a state of tolerance, which could be a key factor in achieving long-term graft survival and preventing chronic GVHD.

2.3. Pharmacodynamic Effects on the Immune System

The cumulative result of these varied mechanisms is a state of profound, multifaceted immunosuppression.[1] By depleting key effector cells, disrupting their ability to migrate to target tissues, impairing the antigen presentation that initiates the response, and potentially promoting regulatory pathways, ATG-Fresenius S effectively dismantles the host's ability to mount an effective alloimmune response. In the long term, this profound initial perturbation of the immune system leads to an altered T-cell homeostasis, characterized by the expansion of specific T-cell subsets that may exhibit regulatory functions, contributing to sustained immunosuppression.[18]

Section 3: Clinical Pharmacokinetics

The pharmacokinetic profile of ATG-Fresenius S—its absorption, distribution, metabolism, and elimination—dictates its concentration over time at the site of action and is essential for designing rational dosing regimens. As a complex biologic, its pharmacokinetics differ substantially from those of small-molecule drugs.

3.1. Absorption and Distribution

ATG-Fresenius S is administered exclusively by intravenous infusion, ensuring 100% bioavailability in the systemic circulation.[25] Following administration, the antibodies distribute throughout the plasma and into the interstitial fluid. Pharmacokinetic studies have reported an apparent volume of distribution of approximately twice the plasma volume, which indicates that a significant portion of the drug distributes outside the vascular compartment, likely into lymphoid tissues where target T-cells reside.[27]

3.2. Metabolism and Elimination

As a protein-based therapeutic, ATG-Fresenius S is not metabolized by the cytochrome P450 enzyme system in the liver, which is the primary route for small-molecule drugs. Instead, its clearance is governed by biological processes. The primary route of elimination is target-mediated drug disposition: the antibodies bind to T-lymphocytes and other cells expressing the target antigens, and these antibody-cell complexes are then cleared from circulation by the reticuloendothelial system (RES), primarily in the spleen and liver.[22] A secondary elimination pathway involves the development of human anti-rabbit antibodies (HARA). The recipient's immune system can recognize the rabbit IgG as foreign and mount an immune response, producing HARA that bind to, neutralize, and accelerate the clearance of ATG-Fresenius S.[22]

3.3. Half-Life and Serum Concentration Dynamics

A critical nuance in the pharmacokinetics of ATG-Fresenius S is the distinction between the half-life of the total rabbit IgG protein and the half-life of the biologically active fraction of antibodies capable of binding to human T-cells.

• The elimination half-life of total rabbit IgG can be quite long, with values of 2-3 days reported, potentially increasing with multiple doses.[22] One study reported a terminal elimination half-life for total, unspecific rabbit IgG (RIgG) of 67 days.[13]
• However, the functionally relevant component—the T-cell specific rabbit IgG (SRIgG)—has a significantly shorter terminal elimination half-life, reported in one study to be approximately 14 days.[13]

This discrepancy is of high clinical importance. While rabbit protein may be detectable in a patient's serum for many weeks, the potent, specific anti-T-cell activity may diminish much more rapidly. This has direct implications for the timing of subsequent immunotherapies, such as donor lymphocyte infusions (DLI) for treating relapse after HSCT. Administering DLI while active ATG levels are still high would result in the immediate destruction of the therapeutic cells, rendering the treatment futile. Clinical decisions should therefore be guided by the clearance of the active drug fraction, which supports the use of functional assays over simple ELISA tests for total protein.

Peak serum concentrations are typically reached at the end of the infusion course.[13] Studies have also suggested a non-linear relationship between the administered dose and the resulting plasma concentration. For instance, one pharmacokinetic study observed that doubling the dose from 10 mg/kg to 20 mg/kg resulted in a four-fold increase in peak levels of active SRIgG, suggesting that clearance mechanisms may become saturated at higher doses, leading to a disproportionate increase in drug exposure.[13]

3.4. Factors Influencing Pharmacokinetic Variability

The standard practice of weight-based (mg/kg) dosing for ATG-Fresenius S is a crude approach that does not account for significant inter-patient variability. One of the most important factors influencing its pharmacokinetics is the patient's baseline immune status, specifically the absolute lymphocyte count (ALC).[5] Since the primary clearance mechanism is binding to T-cells, a patient with a low ALC has a smaller "sink" for the drug. In such a patient, a standard weight-based dose will result in higher concentrations of free, unbound antibody and a longer duration of action. This can lead to an "overdosing" effect, causing excessively profound and prolonged T-cell depletion, which has been associated with inferior clinical outcomes, including an increased risk of severe infections.[5] This highlights a fundamental limitation of weight-based dosing and provides a strong rationale for developing more personalized, pharmacodynamically-guided approaches. To this end, individualized dosing strategies combined with therapeutic drug monitoring (TDM) of active ATG levels are being actively investigated as a means to optimize drug exposure, thereby maximizing efficacy while minimizing toxicity.[28]

Section 4: Clinical Efficacy and Therapeutic Applications

ATG-Fresenius S is a cornerstone immunosuppressive agent with established efficacy in three major clinical domains: solid organ transplantation, hematopoietic stem cell transplantation, and the treatment of aplastic anemia. However, its role, optimal use, and standing relative to other therapies are highly dependent on the specific clinical context.

4.1. Solid Organ Transplantation: Prophylaxis and Treatment of Acute Rejection

The original and most widespread application of ATG-Fresenius S is in solid organ transplantation (SOT), where it is used both as an induction therapy to prevent acute rejection and as a treatment for established rejection episodes.[1] Developed over three decades ago for this purpose, it is approved for SOT in more than 45 countries.[20]

• Induction Therapy: It is frequently used to provide potent initial immunosuppression in the peri-transplant period, particularly for patients deemed to be at high immunological risk (e.g., highly sensitized recipients, re-transplantations).[6] This initial profound T-cell depletion allows for the delayed introduction or dose reduction of other maintenance immunosuppressants like calcineurin inhibitors, thereby sparing the newly transplanted kidney from their nephrotoxic effects.
• Treatment of Acute Rejection: ATG-Fresenius S is a highly effective therapy for treating acute T-cell mediated rejection, especially for severe cases (e.g., those with vascular involvement) or for rejection episodes that have proven resistant to first-line high-dose corticosteroid therapy.[12]

Comparative efficacy data against Thymoglobulin®, the other major rabbit ATG, are complex. A large Bayesian network meta-analysis of randomized controlled trials in kidney transplantation concluded that ATG-Fresenius S appeared to be more effective than Thymoglobulin® in improving short-term outcomes, showing superiority in preventing delayed graft function, patient death, and graft loss.[29] However, the same analysis found that Thymoglobulin® was superior in preventing biopsy-proven acute rejection (BPAR).[29] Conversely, a single-center retrospective study reported a significantly higher rate of BPAR in patients receiving Grafalon® (at a total dose of 6 mg/kg) compared to those receiving Thymoglobulin® (3 mg/kg), although patient and graft survival were comparable.[10] These conflicting results underscore the need for large, prospective, head-to-head trials.

4.2. Hematopoietic Stem Cell Transplantation: Prophylaxis of Graft-versus-Host Disease (GVHD)

In the setting of allogeneic HSCT, ATG-Fresenius S is a key component of the conditioning regimen used to prevent GVHD, a life-threatening complication where donor immune cells attack the recipient's tissues.[5] Its use is particularly established in transplants from matched unrelated donors (MUD).[20] The mechanism involves in-vivo depletion of both residual host T-cells, which reduces the risk of graft failure, and the T-cells present in the donor graft, which are the primary mediators of GVHD.[23]

The efficacy of this approach was demonstrated in a pivotal prospective, randomized, multi-center study involving 201 patients. The addition of ATG-Fresenius S to standard GVHD prophylaxis resulted in a statistically significant reduction in the incidence of severe acute GVHD (grade III-IV) from 25.5% to 11.7% and a dramatic reduction in extensive chronic GVHD from 45% to 12.2%.[20]

The use of ATG in HSCT, however, requires a delicate balance. The same donor T-cells that cause GVHD are also responsible for the beneficial Graft-versus-Leukemia (GVL) effect, which helps to eliminate residual malignant cells and prevent relapse.[23] Therefore, the goal is not maximal T-cell depletion but an optimal level that sufficiently suppresses GVHD without completely abrogating the GVL effect. Overly aggressive immunosuppression with high-dose ATG can increase the risk of disease relapse and fatal infections due to delayed immune reconstitution.[5] This has led to extensive investigation into dose optimization. Studies have evaluated total doses ranging from 15 mg/kg to 60 mg/kg, with evidence suggesting that lower doses may be associated with better overall survival in some patient populations by striking a more favorable balance between the risks of GVHD, relapse, and infection.[5]

4.3. Aplastic Anemia and Other Hematological Disorders

ATG-Fresenius S is also used as a first-line immunosuppressive therapy (IST) for patients with acquired severe aplastic anemia (SAA), an autoimmune disorder where T-cells destroy the patient's own hematopoietic stem cells in the bone marrow.[21] In this context, the therapeutic goal is to eliminate these autoreactive T-cell clones, allowing the bone marrow to recover and resume normal blood cell production.[32] It is almost always administered in combination with cyclosporine, another immunosuppressant. This combination therapy has been shown to be effective, inducing a hematologic response in approximately 55-70% of patients.[32]

However, the choice of ATG product is of paramount importance in this disease. A landmark randomized trial conducted by the National Institutes of Health (NIH) and other subsequent studies have conclusively shown that horse-derived ATG (h-ATG, Atgam®) is superior to rabbit-derived ATG (r-ATG, which includes both ATG-Fresenius S and Thymoglobulin®) for the first-line treatment of SAA.[24] Patients treated with h-ATG demonstrate higher response rates and better overall survival.[24] The reason for this difference is thought to lie in the distinct antigenic profiles of the preparations; the broader spectrum of antibodies in h-ATG may be more effective at targeting the specific pathogenic T-cell clones responsible for AA. While r-ATG is considered an inferior first-line choice, ATG-Fresenius S remains an effective therapy for children with SAA and serves as an important alternative in regions where h-ATG is difficult to acquire.[33] This starkly illustrates that the optimal ATG formulation is highly context-dependent and dictated by the underlying pathophysiology of the disease being treated.

Section 5: Safety and Tolerability Profile

The potent immunosuppressive activity of ATG-Fresenius S is accompanied by a significant and predictable spectrum of adverse effects. Effective management requires a thorough understanding of these risks, proactive monitoring, and appropriate prophylactic and supportive care measures.

5.1. Infusion-Associated Reactions and Cytokine Release Syndrome

Infusion-associated reactions (IARs) are the most common adverse events, occurring frequently, especially during the first infusion.[35] These reactions are a direct consequence of the drug's mechanism of action and are driven by the massive release of cytokines (e.g., TNF-α, IL-6) from lymphocytes and monocytes as they are activated and destroyed by the ATG antibodies.[11] Symptoms typically include fever, chills, rigors, headache, nausea, vomiting, diarrhea, rash, and tachycardia.[32]

In its most severe form, this phenomenon is known as Cytokine Release Syndrome (CRS). Severe CRS, which has been associated with rapid infusion rates, can lead to life-threatening complications, including hypotension, capillary leak, acute respiratory distress syndrome (ARDS), and other serious cardiorespiratory events, which can be fatal.[11] Management is centered on prevention through premedication with corticosteroids, antihistamines, and acetaminophen, and adherence to slow infusion rates, particularly for the first dose.[26]

5.2. Immunologic Reactions: Serum Sickness and Anaphylaxis

As a foreign protein, ATG-Fresenius S can elicit specific immunologic reactions in the recipient.

• Anaphylaxis: This is a rare, but potentially fatal, Type I hypersensitivity reaction to the rabbit proteins. It is an absolute contraindication to further use of the drug.[11] The drug should only be administered in a setting equipped to manage anaphylaxis, and patients with a known allergy to rabbit proteins must not receive it.[35]
• Serum Sickness: This is a Type III hypersensitivity reaction caused by the deposition of immune complexes (rabbit IgG-human anti-rabbit antibody) in tissues. Symptoms typically develop 7 to 21 days after the initiation of therapy and include the classic triad of fever, rash (often urticarial or morbilliform), and polyarthralgia or polyarthritis.[11] The reaction is usually self-limiting but can be treated with corticosteroids for severe cases.

5.3. Hematologic Adverse Events

Dose-dependent cytopenias are a very common and expected consequence of ATG therapy.

• Leukopenia and Thrombocytopenia: Low white blood cell and platelet counts are frequently observed. These effects are generally transient and reversible upon dose reduction or completion of the course.[6]
• Anemia: Anemia is also a common finding during and after treatment.6 These hematologic toxicities necessitate vigilant monitoring of daily blood counts throughout the treatment period. Specific thresholds for dose reduction or temporary cessation of therapy are well-defined to mitigate the risk of severe, prolonged cytopenias.25

5.4. Infectious Complications and Prophylactic Strategies

The profound and prolonged T-cell depletion induced by ATG-Fresenius S renders patients highly susceptible to a wide range of opportunistic infections, including bacterial, fungal, viral, and protozoal pathogens.[11] Reactivation of latent viruses is a particularly significant concern, most notably Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV).[23] EBV reactivation is linked to the development of Post-Transplant Lymphoproliferative Disorder (PTLD). Due to this high risk, prophylactic anti-infective therapy (e.g., antibacterial, antifungal, and antiviral agents like valganciclovir for CMV) is a standard component of care for patients receiving ATG.[25] Regular surveillance, such as weekly PCR monitoring for CMV and EBV DNAemia, is crucial for early detection and pre-emptive treatment.[38]

5.5. Risk of Malignancy

As with all potent immunosuppressive agents, long-term therapy with regimens including ATG is associated with an increased risk of developing malignancies. This is primarily due to the impairment of immune surveillance, which normally eliminates nascent cancer cells. The most commonly associated malignancies are PTLD (often EBV-driven) and other lymphomas, as well as an increased incidence of solid tumors.[11] It is important to note that this risk is related to the overall intensity and duration of the combined immunosuppressive regimen rather than being solely attributable to ATG.[37]

5.6. Contraindications and High-Risk Populations

The primary contraindications for the use of ATG-Fresenius S are:

• A history of a severe systemic reaction, allergy, or anaphylaxis to rabbit proteins or any other component of the formulation.[11]
• The presence of an active acute or chronic infection for which additional profound immunosuppression would be contraindicated.[11]

Additionally, patients who have recently received ATG therapy should not be administered live attenuated vaccines, as their compromised immune system may be unable to mount an appropriate response and could be at risk of developing vaccine-strain disease.[11]

Table 4: Summary of Common and Serious Adverse Events

System Organ Class	Adverse Reaction	Typical Onset/Frequency	Clinical Management/Monitoring
General/Immune System	Infusion-Associated Reactions (IARs) / Cytokine Release Syndrome (CRS)	Common, especially with first dose	Premedicate (corticosteroids, antihistamines, acetaminophen). Infuse slowly. Monitor vital signs closely during infusion. 26
	Anaphylaxis	Rare	Immediate termination of infusion. Emergency medical treatment. Contraindicated in patients with known rabbit protein allergy. 11
	Serum Sickness	Uncommon; 7-21 days post-initiation	Monitor for fever, rash, arthralgia. Usually self-limiting; may require corticosteroids for severe cases. 11
Hematologic	Leukopenia / Neutropenia	Common, dose-dependent	Monitor daily FBC. Dose reduction or cessation based on established thresholds. 25
	Thrombocytopenia	Common, dose-dependent	Monitor daily FBC. Platelet transfusions as needed. Dose modification as for leukopenia. 25
	Anemia	Common	Monitor hemoglobin/hematocrit. Red blood cell transfusions as required. 38
Infections	Bacterial, Fungal, Viral Infections	Common; risk persists during period of immunosuppression	Administer prophylactic anti-infective agents. Monitor for signs/symptoms of infection. 25
	CMV/EBV Reactivation	Common	Weekly PCR monitoring post-transplant. Pre-emptive therapy if viremia detected. 23
Neoplasms	Post-Transplant Lymphoproliferative Disorder (PTLD), Other Malignancies	Rare; long-term risk	Long-term patient monitoring. Risk is associated with overall immunosuppression. 11

Section 6: Dosage, Administration, and Clinical Monitoring

The clinical application of ATG-Fresenius S requires strict adherence to indication-specific dosing protocols, meticulous administration procedures, and vigilant patient monitoring to maximize efficacy while mitigating its significant toxicity profile.

6.1. Dosing Regimens by Indication

A critical point of clinical safety is the recognition that dosing is not interchangeable between different ATG products. The protein composition and antibody concentrations vary significantly depending on the source and manufacturing process, meaning the dose for Grafalon® is different from that for Thymoglobulin® or Atgam®.[11] Prescribers must ensure they are referencing the correct dosing information for the specific product being administered. Dosing for ATG-Fresenius S varies widely depending on the clinical context:

• Solid Organ Transplantation (SOT): In kidney transplant rejection prophylaxis, dosing regimens have varied in clinical studies. One protocol investigated a single high perioperative dose of 9 mg/kg.[41] A more recent retrospective study in India used a total induction dose of 6 mg/kg, typically administered as 3 mg/kg on the day of transplant and on post-operative day 2.[10]
• Hematopoietic Stem Cell Transplantation (HSCT): For GVHD prophylaxis, total doses have ranged from 15 mg/kg to 60 mg/kg.[5] A common regimen evaluated in a large randomized trial was a total dose of 60 mg/kg, administered as 20 mg/kg per day on days -3, -2, and -1 prior to stem cell infusion.[5] However, studies have shown that lower total doses (e.g., 30 mg/kg) may lead to better overall outcomes by reducing transplant-related mortality without compromising GVHD control.[9]
• Aplastic Anemia (AA): In a retrospective study of pediatric patients with severe AA, the immunosuppressive regimen consisted of ATG-Fresenius S at a dose of 5 mg/kg per day for 5 consecutive days (total dose of 25 mg/kg), in combination with cyclosporine.[33]

6.2. Intravenous Administration Protocol and Premedication

ATG-Fresenius S is intended for intravenous (IV) infusion only and should be administered into a high-flow central or peripheral vein to minimize the risk of phlebitis and thrombosis.[25]

• Premedication: To reduce the incidence and severity of IARs and CRS, premedication is universally recommended. This typically involves the administration of intravenous corticosteroids, an oral or IV antihistamine (e.g., diphenhydramine), and an antipyretic (e.g., acetaminophen) approximately one hour prior to the start of the infusion.[26]
• Infusion Rate: Adherence to recommended infusion rates is a critical safety measure. The first dose should always be administered slowly, over a minimum of 6 hours. If the first dose is well-tolerated, subsequent doses may be infused over a shorter period, but not less than 4 hours.[26] Slowing the infusion rate is a primary strategy for minimizing the risk and severity of CRS.[11]

6.3. Essential Monitoring Parameters and Dose Modification Criteria

Patients receiving ATG-Fresenius S require intensive monitoring in a hospital setting, particularly during the infusion period.[26]

• Clinical Monitoring: Continuous monitoring of vital signs is essential during the infusion to detect early signs of anaphylaxis or CRS. Patients should also be monitored for signs of infection, bleeding, and other adverse effects throughout the treatment course.
• Laboratory Monitoring: Daily monitoring of a full blood count (FBC), with particular attention to the total white blood cell (WBC) count, absolute neutrophil count, and platelet count, is mandatory during and for a period after therapy.[25]
• Dose Modification Criteria: Dose adjustments are based on hematologic parameters to prevent profound and dangerous myelosuppression. While specific institutional protocols may vary slightly, generally accepted guidelines are as follows [17]:
• Reduce the daily dose by 50% if the WBC count is between 2,000 and 3,000 cells/mm³ or if the platelet count is between 50,000 and 75,000 cells/mm³.
• Consider stopping or withholding treatment if the WBC count falls below 2,000 cells/mm³ or if the platelet count falls below 50,000 cells/mm³.

Table 3: Recommended Dosing Regimens for Key Clinical Indications

Clinical Indication	ATG Product	Recommended Dose & Schedule	Key Clinical Pearls/References
Prophylaxis of Kidney Transplant Rejection	ATG-Fresenius S (Grafalon®)	Regimens vary. Examples include: • Total dose of 6 mg/kg (e.g., 3 mg/kg on Day 0 and Day 2). • Single perioperative dose of 9 mg/kg.	Must be used with concomitant immunosuppressants. Data is less standardized than for Thymoglobulin®. 10
Prophylaxis of GVHD (MUD-HSCT)	ATG-Fresenius S (Grafalon®)	Total doses range from 15-60 mg/kg. • Example: 20 mg/kg/day for 3 days (Days -3 to -1).	Lower total doses (e.g., 30 mg/kg) may improve survival by reducing infection risk. 5
Treatment of Aplastic Anemia	ATG-Fresenius S (Grafalon®)	5 mg/kg/day for 5 days (Total dose: 25 mg/kg).	Used in combination with cyclosporine. Horse ATG is preferred for first-line therapy. 33
Prophylaxis of Kidney Transplant Rejection	Thymoglobulin® (for comparison)	1.5 mg/kg/day for 4-7 days. First dose prior to reperfusion.	FDA-approved indication. Dosing is distinct from Grafalon®. 25

Section 7: Comparative Analysis with Other Antithymocyte Globulins

The therapeutic landscape of potent lymphodepleting agents is dominated by three main ATG preparations: ATG-Fresenius S (Grafalon®), Thymoglobulin® (both rabbit-derived), and Atgam® (equine-derived). The choice between these agents is a critical clinical decision, as they are not interchangeable and possess distinct profiles in terms of source, potency, efficacy, and safety.

7.1. ATG-Fresenius S (Grafalon) vs. Thymoglobulin (Rabbit ATG)

These two products represent the most commonly used rabbit-derived ATGs, and their comparison is central to decision-making in transplantation.

• Source and Antigen Profile: As previously noted, this is their most fundamental difference. ATG-Fresenius S is derived from the Jurkat T-cell line, while Thymoglobulin® is derived from human thymocytes.[5] This results in Thymoglobulin® having a broader antibody profile, recognizing a wider array of T-cell, B-cell, and adhesion molecule antigens.[29] In contrast, ATG-Fresenius S has a more limited antigen recognition spectrum.[5]
• Potency and Dosing: The broader reactivity of Thymoglobulin® is believed to make it a more potent lymphodepleting agent on a milligram-per-milligram basis. Consequently, higher total doses of ATG-Fresenius S are generally required to achieve a comparable level of immunosuppression. For example, in HSCT, a 60 mg/kg total dose of ATG-Fresenius S has been compared against much lower doses of Thymoglobulin®.[5] One recent study directly compared a 20 mg/kg total dose of ATG-F to a 10 mg/kg total dose of ATG-T.[16]
• Efficacy Comparison: The clinical evidence is mixed and lacks a definitive, large-scale head-to-head trial.
• In kidney transplantation, a Bayesian meta-analysis suggested ATG-Fresenius S was associated with better patient and graft survival but a higher rate of acute rejection compared to Thymoglobulin®.[29] However, a prospective randomized controlled trial in immunologically high-risk kidney recipients found no significant differences in safety or efficacy between the two agents.[17]
• In HSCT, a retrospective comparison of low-dose ATG-Fresenius S (15 mg/kg) and a relatively high dose of Thymoglobulin® (10 mg/kg) for GVHD prevention found no significant differences in the incidence of GVHD, relapse, or overall survival. Interestingly, this study noted a significantly higher rate of EBV reactivation in the Thymoglobulin® group.[5]
• Safety Profile: There appear to be subtle but potentially important differences in their safety profiles. Some evidence suggests Thymoglobulin® induces a more profound and sustained lymphopenia, while ATG-Fresenius S may be associated with a higher incidence of post-transplantation thrombocytopenia.[6] The meta-analysis in kidney transplant recipients suggested a higher risk of infection and malignancy with Thymoglobulin®.[29]

7.2. Rabbit-Derived ATG vs. Horse-Derived ATG (Atgam)

This comparison is most critical in the context of aplastic anemia, where the choice of animal source has a clear impact on outcomes.

• Efficacy in Aplastic Anemia: As established in Section 4.3, horse ATG (h-ATG) is the superior agent for the first-line treatment of severe aplastic anemia. Randomized trials have demonstrated higher hematologic response rates and improved overall survival with h-ATG compared to rabbit ATG (r-ATG).[24]
• Efficacy in HSCT: The situation is reversed in the transplant setting. The more potent lymphodepletion and potential Treg-enhancing effects of r-ATG are advantageous for preventing GVHD and graft rejection.[23] A large registry study showed that while h-ATG was associated with higher rates of both acute and chronic GVHD compared to r-ATG, survival was similar in matched sibling transplants and was significantly better with r-ATG in unrelated donor transplants.[24]
• Mechanistic Rationale: The differing efficacy profiles are believed to stem from their distinct immunobiology. The broader, less specific antibody profile of h-ATG may be more effective at eliminating the particular T-cell clones driving the autoimmune attack in aplastic anemia. Conversely, the potent and deep T-cell depletion provided by r-ATG is more desirable for overcoming the robust alloimmune response in transplantation.[24]

7.3. Clinical Implications of Formulation Differences

The available evidence strongly indicates that ATG preparations are distinct biological drugs, not interchangeable commodities. The selection of an ATG product must be a deliberate clinical decision based on the specific indication, the available clinical evidence for that indication, institutional experience and protocols, and cost-effectiveness considerations. A "one-size-fits-all" approach to ATG therapy is inappropriate and potentially suboptimal for patient care.

Table 2: Head-to-Head Comparison of Antithymocyte Globulin Preparations

Feature	ATG-Fresenius S (Grafalon®)	Thymoglobulin®	Atgam® (Equine ATG)
Animal Source	Rabbit 4	Rabbit 5	Horse 21
Source of Immunogen	Jurkat T-lymphoblast cell line 5	Human thymocytes 5	Human thymocytes 21
Antigen Profile	More limited spectrum 5	Broad spectrum (T-cells, B-cells, adhesion molecules) 29	Broad spectrum 24
Relative Potency	Less potent than Thymoglobulin® on a mg/mg basis 5	Highly potent lymphodepleting agent 6	Less potent lymphodepletion than r-ATG 24
Preferred Indication (Evidence-Based)	SOT, HSCT 12	SOT, HSCT 21	Aplastic Anemia (First-line), SOT 21
Key Efficacy Findings	Effective in GVHD/rejection prevention. May have better graft/patient survival but higher BPAR vs. Thymoglobulin® in SOT.20	Highly effective in GVHD/rejection prevention. May have lower BPAR but higher infection/malignancy risk vs. ATG-F in SOT.29	Superior response and survival vs. r-ATG in first-line treatment of aplastic anemia.24
Distinct Safety Concerns	Higher incidence of thrombocytopenia reported in some studies.6	More profound/prolonged lymphopenia. Higher EBV reactivation in one HSCT study.6	Generally considered to have a higher incidence of serum sickness compared to r-ATG.

Section 8: Global Regulatory Landscape and Development History

The clinical availability and use of ATG-Fresenius S (Grafalon®) are significantly influenced by its varied regulatory status across the globe. This fragmentation, particularly its lack of approval in the United States, has led to divergent standards of care and complicates the global application of clinical trial data.

8.1. Regulatory Status in the United States (FDA)

ATG-Fresenius S / Grafalon® is not currently approved for marketing by the U.S. Food and Drug Administration (FDA).21 The two ATG products that are licensed for clinical use in the United States are Thymoglobulin® (rabbit ATG, manufactured by Sanofi) and Atgam® (equine ATG, manufactured by Pfizer).11

In 2010, the FDA did grant ATG-Fresenius S an orphan drug designation and a fast track designation for its development program in the prevention of GVHD.8 These designations are intended to facilitate the development and expedite the review of drugs for serious conditions but do not constitute marketing approval. As such, the product remains an investigational agent in the U.S.

8.2. Regulatory Status in Europe (EMA and National Authorizations)

In contrast to the U.S., ATG-Fresenius S / Grafalon® is widely used in Europe. It is authorized for use through national approvals in numerous member states of the European Union rather than through a centralized European Medicines Agency (EMA) procedure.[46] A 2016 EMA document cataloged national authorizations for "Atg-Fresenius S (future name: Grafalon)" or similar names in Germany, Austria, Slovenia, Latvia, Lithuania, Cyprus, Hungary, the Netherlands, Portugal, Slovakia, Sweden, Croatia, and Ireland.[8] It received approval for the specific indication of GVHD prevention in Germany in 2011 and subsequently in Austria and other countries.[8]

8.3. Regulatory Status in Australia (TGA) and Other Regions

The regulatory status in Australia appears to be similar to that in the U.S. A search of the Australian Register of Therapeutic Goods (ARTG) does not show a current, active registration for ATG-Fresenius S or Grafalon® under its sponsors.47 Furthermore, a drug development database indicates that a Phase III clinical trial for GVHD prevention in Australia was discontinued in February 2021, suggesting that the product is not currently marketed there.3

Beyond these major regulatory regions, ATG-Fresenius S is approved for use in over 45 countries worldwide, including Argentina, Portugal, Thailand, and India, where it was introduced in 2016.10

This divergent regulatory landscape is a crucial factor for clinicians and researchers. A physician practicing in the U.S. will have extensive experience with Thymoglobulin® and Atgam® but none with Grafalon®, while the opposite may be true for a physician in Germany. This reality means that clinical trial results from one region may have limited direct applicability in another, as the comparator drugs and standard-of-care protocols differ significantly.

8.4. Key Milestones in Product Development and Branding

The history of ATG-Fresenius S spans over four decades, marked by key milestones in its clinical application and corporate identity [8]:

• 1979: First manufactured under the name ATG-Fresenius® S.
• 1981: First clinical use in the field of solid organ transplantation.
• 1989: First clinical use in hematopoietic stem cell transplantation.
• 2010: Granted orphan drug and fast track designation by the U.S. FDA for GVHD prevention development.
• 2011: Approved by German health authorities for GVHD prevention in adults.
• 2013: The originator company, Fresenius Biotech, becomes Neovii Biotech.
• 2015: The product is globally re-branded and launched as Grafalon®.

Section 9: Concluding Analysis and Future Directions

ATG-Fresenius S, now marketed as Grafalon®, is a potent polyclonal anti-T-lymphocyte immunoglobulin that holds a significant place in the immunosuppressive armamentarium for transplantation medicine. Its development and clinical application over several decades have established its efficacy but have also highlighted important nuances regarding its use, safety, and standing relative to other therapies.

9.1. Synthesis of Efficacy, Safety, and Clinical Positioning

The primary clinical value of ATG-Fresenius S lies in its ability to induce profound T-cell depletion, making it a highly effective agent for preventing acute rejection in solid organ transplantation and for prophylaxis against Graft-versus-Host Disease in allogeneic stem cell transplantation. Its unique manufacturing process, utilizing the Jurkat T-cell line as an immunogen, fundamentally distinguishes it from its main competitor, Thymoglobulin®, resulting in a different antibody profile, distinct dosing requirements, and a subtly different balance of efficacy and safety. While clinical data from direct comparisons are mixed, ATG-Fresenius S appears to be a robust and effective option in these settings.

Its clinical positioning is, however, highly indication-specific. In the treatment of severe aplastic anemia, strong evidence supports the superiority of horse-derived ATG as the first-line agent, relegating rabbit-derived preparations like ATG-Fresenius S to a second-line or alternative role. The selection and dosing of this powerful agent must therefore be meticulously tailored to the specific disease pathophysiology, patient risk factors, and institutional protocols.

9.2. Unresolved Questions and Areas for Future Research

Despite its long history of clinical use, several key questions remain, pointing to important avenues for future research:

• Head-to-Head Comparative Trials: There is a clear and pressing need for large-scale, prospective, randomized controlled trials to directly compare Grafalon® and Thymoglobulin® across various transplant settings. Such trials are essential to definitively resolve the conflicting data from retrospective studies and meta-analyses and to provide clear guidance on which agent may be superior for specific patient populations.[5]
• Mechanisms of Tolerance: Further investigation is warranted into the long-term immunomodulatory effects of ATG-Fresenius S, particularly its impact on immune reconstitution and its potential to induce a state of operational tolerance. Elucidating its differential effects on effector T-cells versus regulatory T-cells could pave the way for more sophisticated immunomodulatory strategies.
• Personalized Dosing: The limitations of weight-based dosing are evident. Future research should focus on the development, validation, and implementation of standardized therapeutic drug monitoring (TDM) protocols that measure the biologically active fraction of the drug. Personalized dosing based on TDM or baseline immunological parameters (like ALC) holds the promise of optimizing the therapeutic index, thereby improving the benefit-risk ratio by avoiding both over- and under-immunosuppression.[28]

9.3. Final Recommendations for Clinical Practice

Based on the available evidence, the following recommendations are crucial for the safe and effective use of ATG-Fresenius S (Grafalon®):

1. Vigilant Product Identification: Clinicians must be acutely aware of the specific ATG product being used (Grafalon® vs. Thymoglobulin® vs. Atgam®) and must apply only product-specific dosing regimens to prevent potentially catastrophic medication errors.
2. Indication-Driven Selection: The choice of ATG must be driven by the clinical indication. For first-line therapy of severe aplastic anemia, horse-derived ATG remains the standard of care. In transplantation, the choice between rabbit ATGs should be based on a careful evaluation of the available evidence and institutional guidelines.
3. Rigorous Monitoring and Prophylaxis: Given the predictable and significant risks of hematologic toxicity and opportunistic infections, rigorous patient monitoring, including daily blood counts and viral surveillance, is non-negotiable. Universal implementation of anti-infective prophylaxis is essential.
4. Adherence to Administration Safety: The risk of severe infusion-associated reactions necessitates strict adherence to safety protocols, including appropriate premedication and slow, controlled infusion rates, especially for the initial dose. Administration should only occur in a hospital setting equipped to manage severe hypersensitivity reactions.

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