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Muromonab-CD3
Monoclonal antibody
TypeWhole antibody
SourceMouse
TargetCD3
Clinical data
Trade namesOrthoclone OKT3
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa605011
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC6460H9946N1720O2043S56
Molar mass146189.98 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Muromonab-CD3 (brand name Orthoclone OKT3, marketed by Janssen-Cilag) is an immunosuppressant medication given to reduce acute rejection in people with organ transplants.[1][2] It is a monoclonal antibody targeted at the CD3 receptor,[3] a membrane protein on the surface of T cells. It is the first monoclonal antibody to be approved for clinical use in humans.[2]

Medical uses

[edit]

Muromonab-CD3 is approved for the therapy of acute, glucocorticoid-resistant rejection of allogeneic kidney, heart, and liver transplants.[4] Unlike the monoclonal antibodies basiliximab and daclizumab, it is not approved for prophylaxis of transplant rejection, although a 1996 review has found it to be safe for that purpose.[5]

Contraindications

[edit]

Except under special circumstances, the drug is contraindicated for patients with an allergy against mouse proteins, as well as patients with uncompensated heart failure, uncontrolled arterial hypertension or epilepsy. It should not be used during pregnancy or lactation.[2][4]

Adverse effects

[edit]

Especially during the first infusion, the binding of muromonab-CD3 to CD3 can activate T cells to release cytokines like tumor necrosis factor and interferon gamma. This cytokine release syndrome, or CRS, includes side effects like skin reactions, fatigue, fever, chills, myalgia, headaches, nausea and diarrhea,[6] and could lead to life-threatening conditions like apnoea, cardiac arrest, and flash pulmonary edema.[4] To minimize the risk of CRS and to offset some of the minor side effects patient experience, glucocorticoids (such as methylprednisolone), acetaminophen, and diphenhydramine are given before the infusion.[7]

Other adverse effects include leucopenia, as well as an increased risk for severe infections and malignancies typical of immunosuppressive therapies. Neurological side effects like aseptic meningitis and encephalopathy have been observed. Possibly, they are also caused by the T cell activation.[4]

Repeated application can result in tachyphylaxis (reduced effectiveness) due to the formation of anti-mouse antibodies in the patient, which accelerates elimination of the drug. It can also lead to an anaphylactic reaction against the mouse protein,[2] which may be difficult to distinguish from a CRS.

Pharmacology

[edit]

T cells recognise antigens primarily via the T cell receptor (TCR).[8]: 160  CD3 is one of the proteins that make up the TCR complex.[8]: 166  The TCR transduces the signal for the T cell to proliferate and attack the antigen.[8]: 160 

Muromonab-CD3 is a murine (mouse) monoclonal IgG2a antibody which was created using hybridoma technology.[9] It binds to the T cell receptor-CD3-complex (specifically the CD3 epsilon chain) on the surface of circulating T cells, initially leading to an activation,[7] but subsequently inducing the clearance of TCR complex from cell surface and apoptosis of the T cells.[10] This protects the transplant against the T cells.[2][4] When administered for transplant induction, the drug is administered daily thereafter for up to 7 days.[7]

Newer monoclonal antibodies in development with the same mechanism of action include otelixizumab (also known as TRX4), teplizumab (also known as hOKT3γ1(Ala-Ala) ), visilizumab and foralumab. They are being investigated for the treatment of other conditions like Crohn's disease, ulcerative colitis, and type 1 diabetes.

History

[edit]

Muromonab-CD3 was approved by the U.S. Food and Drug Administration (FDA) in 1986,[5] making it the first monoclonal antibody to be approved anywhere as a drug for humans. In the European Communities, it is the first drug to be approved under the directive 87/22/EWG, a precursor of the European Medicines Agency (EMA) centralised approval system in the European Union. This process included an assessment by the Committee for Proprietary Medicinal Products (CPMP, now CHMP), and a subsequent approval by the national health agencies; in Germany, for example, in 1988 by the Paul Ehrlich Institute in Frankfurt. However, the manufacturer of muromonab-CD3 has voluntarily withdrawn[11] it from the United States market in 2010 due to numerous side-effects, better-tolerated alternatives and declining usage.[12]

Society and culture

[edit]
[edit]

Orthoclone OKT3 was withdrawn from the US market in 2010.[13]

Etymology

[edit]

Muromonab-CD3 was developed before the WHO nomenclature of monoclonal antibodies took effect, and consequently its name does not follow this convention. Instead, it is a contraction from "murine monoclonal antibody targeting CD3".[2]

Research

[edit]

It has also been investigated for use in treating T-cell acute lymphoblastic leukemia.[14]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Muromonab-CD3

View on Grokipedia
from Grokipedia
Muromonab-CD3 is a murine monoclonal immunoglobulin G2a (IgG2a) antibody that specifically targets the CD3 antigen complex on the surface of human T-lymphocytes, acting as a potent to treat and prevent acute rejection in solid organ transplant patients. Marketed under the brand name Orthoclone OKT3 by Janssen-Cilag (formerly Ortho Pharmaceutical), it was the first monoclonal antibody approved for therapeutic use by the U.S. in 1986, revolutionizing therapy for transplants. Initially approved for reversing acute renal allograft rejection, its indications were expanded to include steroid-resistant rejection in heart and liver transplants, as well as off-label uses in preventing and other immune-mediated conditions. The of muromonab-CD3 involves binding to the epsilon chain of the CD3 complex, which inhibits T-cell , promotes rapid internalization of the T-cell receptor complex, and triggers T-cell depletion through mechanisms such as , , and . Administered intravenously at a typical dose of 5 mg daily for 10–14 days in adults (or 2.5 mg in pediatric patients under 30 kg), it has a plasma elimination of approximately 18 hours but induces profound and prolonged lymphopenia, with T-cell counts dropping by over 95% within minutes to hours of the first dose. Clinical trials demonstrated its efficacy in reversing acute rejection episodes in renal, hepatic, cardiac, and transplants, often outperforming conventional therapies like corticosteroids or in refractory cases. Despite its effectiveness, muromonab-CD3 was associated with significant adverse effects, including a severe first-dose (manifesting as fever, chills, nausea, and potentially life-threatening or ), as well as risks of infections, malignancies, and reactivation of latent viruses like due to deep . These safety concerns, combined with the emergence of less immunogenic humanized or chimeric monoclonal antibodies (such as basiliximab and ) offering similar efficacy with improved tolerability, led to its gradual replacement. Production and marketing were discontinued worldwide by 2010–2011, rendering it no longer available for clinical use, though its historical role in transplantation medicine remains notable.

Clinical Applications

Indications

Muromonab-CD3 is indicated for the treatment of acute allograft rejection in renal transplant recipients and steroid-resistant acute allograft rejection in hepatic and cardiac transplant recipients. In renal transplant patients, it is used to reverse episodes of acute rejection that do not respond to high-dose corticosteroids such as . For hepatic and cardiac transplants, the indication specifically targets steroid-resistant acute rejection, where initial therapy has failed to control the rejection process. This targeted use underscores its role as a rescue therapy in transplantation , reserved for cases where standard immunosuppressive regimens prove insufficient. Its application is limited to patients experiencing steroid-resistant rejection, typically confirmed after inadequate response to intravenous pulses (e.g., 500-1000 mg/day for 3 days). Muromonab-CD3 is not recommended for routine prophylaxis against rejection, although a 1996 review highlighted supportive evidence for its prophylactic in renal transplantation when combined with other immunosuppressants, showing reduced rejection incidence compared to triple alone. The drug is suitable for adult and pediatric patients undergoing , with safety and effectiveness established in infants from 1 month of age, and dosing adjustments based on body weight in children to ensure effective T-cell depletion. Off-label and investigational uses of muromonab-CD3 include its limited application in transplantation for reversing (GVHD), particularly in steroid-refractory cases. Early 1990s studies demonstrated response rates of 70-90% in treating acute GVHD, with one phase I/II trial reporting improvement in 7 of 10 patients (70% overall response, including 50% complete responses) using a nonmitogenic anti-CD3 variant, though muromonab-CD3 itself showed comparable efficacy in similar cohorts. These applications remain investigational due to the lack of formal FDA approval for GVHD and concerns over long-term .

Administration and Dosage

Muromonab-CD3 is administered exclusively via intravenous injection to treat acute allograft rejection in renal, cardiac, or hepatic transplant patients. The drug is supplied as a sterile solution in ampules containing 5 mg/5 mL and must be administered immediately after opening, using a low protein-binding filter (0.2 or 0.22 µm) to prevent aggregation. It is administered as a single intravenous bolus injection over less than one minute through a peripheral or central line. The standard dosing regimen for adults is 5 mg administered once daily for 10-14 days, typically for reversal of steroid-resistant rejection in solid organ transplants. In pediatric patients weighing 30 kg or less, the dose is reduced to 2.5 mg daily, while those over 30 kg receive the adult dose of 5 mg daily, also for 10-14 days; doses in children may be adjusted in 2.5 mg increments based on body weight or counts to achieve adequate T-cell depletion. is mandatory to mitigate , particularly with the first 1-2 doses, and includes 8 mg/kg IV administered 1-4 hours prior, followed by acetaminophen 650 mg orally and diphenhydramine 50 mg orally or IV 30-60 minutes before infusion. 100 mg IV may also be given 30 minutes after the initial doses if respiratory symptoms occur. Monitoring during therapy involves daily complete blood counts with differential to assess CD3+ T-cell depletion, targeting fewer than 25 CD3-positive cells/mm³, along with serum muromonab-CD3 levels (≥800 ng/mL via ) to confirm efficacy. Renal and hepatic function tests, , and fluid status should be evaluated daily, with a chest obtained within 24 hours before the first dose to rule out pulmonary congestion; therapy should be adjusted or discontinued if no clinical response is observed after 7 days. Special considerations include temporarily withholding concurrent inhibitors such as cyclosporine during muromonab-CD3 treatment to prevent excessive , resuming them at the lowest effective dose once T-cell counts recover. Administration requires a setting equipped for due to potential severe reactions.

Safety and Tolerability

As muromonab-CD3 was discontinued worldwide by 2010–2011, the following contraindications and adverse effects are based on historical clinical data.

Contraindications

Muromonab-CD3 is contraindicated in patients with known hypersensitivity to the drug or any product of murine origin, including those with a history of anaphylaxis to the agent. It is also absolutely contraindicated in individuals with uncontrolled hypertension, uncompensated congestive heart failure, or evidence of fluid overload, such as a chest X-ray showing infiltrates or more than 3% body weight gain in the preceding week. Additionally, patients with a history of seizures or predisposition to seizures should not receive muromonab-CD3 due to the risk of central nervous system complications. Relative contraindications include , classified as FDA Category C, where potential fetal harm from may occur despite crossing the as an IgG antibody, though use may be considered if benefits outweigh risks. is similarly cautioned against, as the drug may be excreted in , necessitating discontinuation of . Ongoing systemic infections represent a relative barrier, given the heightened risk of exacerbation under . Patients with a history of malignancies face increased risk of progression or new , making administration relatively inadvisable. Prior to administration, screening for anti-mouse antibodies is required in patients with previous exposure to muromonab-CD3 or other murine-derived products; titers of 1:1000 or greater constitute an absolute due to reduced efficacy and heightened adverse reaction potential. Therapy should be avoided in those at risk for fluid overload, including patients with pulmonary conditions that could precipitate . Concomitant administration of live virus vaccines is contraindicated, as the may lead to uncontrolled and reduced efficacy.

Adverse Effects

Muromonab-CD3 is associated with a range of adverse effects, primarily stemming from its potent immunosuppressive action and murine origin. These effects can be acute, occurring shortly after infusion, or delayed, manifesting over weeks to years. Common manifestations include symptoms of , while serious risks involve cardiovascular instability, infections, and neurological complications. The most frequent adverse reaction is , typically occurring within hours of the first dose and affecting approximately 77% of patients with fever and 43% with . Additional symptoms in more than 10% of cases during the initial 48 hours include dyspnea (21%), or (19%), (11%), (14%), and (13%). These flu-like effects, such as myalgias and , generally peak early and diminish with subsequent doses, though they can be severe in up to 77% of overall treatments. Cardiovascular and pulmonary complications represent significant risks, particularly in patients with fluid overload. occurs in 2-5% of cases overall and up to 13% in severe instances, often accompanied by dyspnea or wheezing (13-16%). affects 12-25% of patients, while is reported in 19-64%, with rare but fatal outcomes including or . arises in 9-14% of recipients. Immunosuppression-related effects heighten susceptibility to infections, including bacterial, viral (such as ), and opportunistic pathogens like , with rates varying by study, pathogen, and patient population (e.g., CMV in ~19% of renal transplant recipients). Post-treatment lymphoproliferative disorders and malignancies, often EBV-associated, are rare (<1% overall) but elevated at 9% in certain cohorts compared to 1% without muromonab-CD3 exposure. Neurological adverse effects impact 5-10% of patients, manifesting as (13%), (up to 7%), , or seizures. These can include (6%), (6%), or more severe presentations like in vulnerable populations. Other notable effects include the development of human anti-mouse antibodies () in 44-89% of patients, which can lead to and reduced efficacy after 7-10 days of therapy. or may occur in sensitized individuals, alongside reactions like or . Long-term consequences involve potential prolonged T-cell dysfunction, contributing to sustained and increased post-transplant complications such as persistent infections or graft issues.

Pharmacological Profile

Mechanism of Action

Muromonab-CD3, a murine of the IgG2a isotype, specifically targets the ε chain of the CD3 complex on the surface of mature human T-lymphocytes, a key component of the (TCR) complex essential for recognition and T-cell activation. This binding inhibits TCR-mediated , thereby blocking T-cell effector functions critical for immune responses such as graft rejection. The antibody's specificity is limited to CD3-expressing cells, sparing other immune components like B-cells and natural killer (NK) cells. Initial binding and subsequent cross-linking of CD3 molecules on the T-cell surface trigger paradoxical activation of these cells, leading to proliferation and massive release of pro-inflammatory , including tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), interferon-γ (IFN-γ), and IL-6, typically within 1-4 hours of administration. This release contributes to the acute first-dose but also primes T-cells for elimination. The IgG2a isotype facilitates engagement, amplifying these early effects. Following activation, muromonab-CD3 induces profound depletion of CD3+ T-cells through several complementary mechanisms: (ADCC), where Fc receptors on macrophages and NK cells recognize the antibody-coated T-cells and trigger their ; (CDC), involving activation of the complement cascade; and direct of activated T-cells via internalization and modulation of the CD3-TCR complex. These processes result in a rapid reversal of circulating CD3+ T-cell counts, with depletion beginning within minutes to hours, becoming profound within 1-2 days, and reaching a around days 2-7. By eliminating effector T-cells, muromonab-CD3 achieves potent , effectively halting acute allograft rejection in organ transplant recipients while preserving broader immune surveillance against non-T-cell-mediated threats.

Pharmacokinetics

Muromonab-CD3 is administered intravenously, resulting in 100% and an immediate following . Following administration, muromonab-CD3 rapidly binds to circulating T-cells expressing the , leading to quick distribution primarily within the intravascular space. Its large molecular size as an IgG2a (approximately 150 ) limits extravascular penetration, with a reported of about 6.5 L. The metabolism of muromonab-CD3 involves proteolytic degradation primarily by the , particularly after binding to target T-cells, without involvement of hepatic enzymes. Elimination follows a of approximately 18 hours in clinical use for rejection treatment (or up to 36 hours for prophylactic use), reflecting both clearance through T-cell binding and general IgG . Formation of human anti-murine antibodies (HAMA) during repeat courses can accelerate clearance, potentially reducing in subsequent treatments. Pharmacokinetic parameters can vary with dosing; higher doses tend to prolong the by saturating target sites. Serum levels of muromonab-CD3 are not routinely monitored in ; instead, therapeutic is assessed through peripheral T-cell counts, targeting near-complete depletion of CD3-positive cells.

Historical Development

Discovery and Approval

Muromonab-CD3, marketed under the trade name Orthoclone OKT3, was developed in 1979 by Ortho Pharmaceutical Corporation, a subsidiary of , utilizing the pioneered by Georges Köhler and in 1975 for producing monoclonal antibodies. This murine IgG2a antibody was the first to specifically target the CD3 complex on human T cells, enabling precise modulation of T-cell function. Preclinical studies in the early 1980s using animal models, including mice and nonhuman , demonstrated its capacity for T-cell depletion and prolongation of allograft survival, with key experiments showing reversal of rejection in approximately 80% of renal transplant models. These findings established the foundation for its immunosuppressive potential in preventing organ rejection. Clinical development progressed rapidly, with Phase I and II trials initiated between 1981 and 1985 in patients undergoing to assess and in reversing acute rejection episodes. In a pivotal multicenter conducted from 1984 to 1985 involving 123 patients with acute cadaveric renal allograft rejection, muromonab-CD3 administered at 5 mg daily for 14 days achieved a 94% reversal rate, significantly outperforming the 75% rate observed with conventional high-dose (p=0.009). This superior , coupled with improved one-year graft survival (62% versus 45%), supported its advancement to regulatory review. The U.S. Food and Drug Administration granted approval for muromonab-CD3 on June 19, 1986, marking it as the first therapeutic monoclonal antibody for treating acute, steroid-resistant rejection in renal transplant recipients. It received approval in several European countries in 1986. In 1993, the FDA expanded indications to include acute rejection in liver and heart transplants, further solidifying its role in solid organ transplantation. As a groundbreaking immunosuppressant, muromonab-CD3 revolutionized transplant medicine, with over 200,000 patients treated worldwide by 2000.

Discontinuation

On January 4, 2010, Janssen-Cilag, the successor to Ortho Biotech and the manufacturer of muromonab-CD3 (marketed as Orthoclone OKT3), announced the voluntary worldwide discontinuation of production, with the drug withdrawn from the market that year and marketing ending in the on July 30, 2011. The primary reasons for discontinuation included declining clinical use attributable to the drug's high adverse effect profile, such as and increased risk of infections, alongside the emergence of safer alternatives like basiliximab (an interleukin-2 ) and (a polyclonal preparation). A 2006 Cochrane review further highlighted that while muromonab-CD3 demonstrated superior efficacy to corticosteroids in reversing acute rejection, it carried greater risks of adverse effects, contributing to reduced adoption. Market factors also played a key role; as a complex biologic , muromonab-CD3 faced no generic competition, but annual sales had fallen to unviable levels by the late due to these clinical shifts. The transition was managed without immediate supply shortages, as existing stockpiles supported continued use until 2011, while transplant guidelines evolved to favor newer induction agents; the KDIGO clinical practice guideline, published in 2010, recommended interleukin-2 receptor antagonists as first-line therapy for most transplant recipients, further diminishing reliance on muromonab-CD3. The discontinuation accelerated a broader shift in transplant protocols toward maintenance regimens centered on inhibitors (e.g., ) combined with interleukin-2 receptor blockers, while underscoring the need for less immunogenic antibodies and informing the development of humanized monoclonal antibodies with improved tolerability profiles.

Regulatory and

Muromonab-CD3, marketed as Orthoclone OKT3, was voluntarily discontinued by its manufacturer, Ortho Biotech Products, L.P., in in due to declining demand and the availability of alternative therapies with improved safety profiles. The U.S. (FDA) lists it as a discontinued biological product with no active commercial availability. Post-withdrawal, the FDA continues to monitor adverse events associated with any residual use via its MedWatch reporting system. In the , muromonab-CD3 received marketing authorization but was subsequently withdrawn around for similar commercial and clinical reasons. It is no longer available through standard channels in EMA member states. Globally, muromonab-CD3 became unavailable in most countries following its worldwide discontinuation in , with no ongoing production or marketing by the original manufacturer or any generics. As of 2025, it is absent from active pharmaceutical markets. No generic or versions were pursued due to the drug's discontinuation and the shift toward newer immunosuppressive agents.

Etymology

The (INN) for muromonab-CD3 follows an early convention predating standardized , with "muromonab" derived from the stem "muro-" indicating its murine (mouse-derived) origin and "-monab" signifying a , particularly one of the immunoglobulin class. The appended descriptor "-CD3" specifies the target as the 3 (CD3) , a defining on the surface of mature T lymphocytes essential for T-cell signaling. The trade name Orthoclone OKT3 originates from its development by Ortho Pharmaceutical Corporation in collaboration with researcher Patrick Kung, where "OK" reflects "Ortho Kung" and "T3" denotes the T-cell-specific CD3 target; it was marketed as Orthoclone OKT3 Sterile Solution for intravenous administration. This naming was established under World Health Organization (WHO) guidelines in the , reflecting the drug's status as the first INN assigned to a and distinguishing its fully murine composition from later humanized variants bearing suffixes like "-umab." As such, muromonab-CD3 established an influential precedent for systematic biotech nomenclature in pharmaceutical development.

Research and Future Directions

Historical Studies

Early clinical trials of muromonab-CD3 (OKT3) began in the early , focusing on its potential to treat acute rejection in transplant recipients. A Phase I trial conducted in 1981 involving 10 patients with transplants demonstrated complete T-cell depletion following administration, establishing the drug's immunosuppressive potency through rapid modulation of the on T lymphocytes. This initial study laid the groundwork for subsequent evaluations, highlighting OKT3's ability to achieve 100% T-cell clearance in peripheral blood without immediate graft loss. Building on these findings, a multicenter in 1984 enrolled 123 patients experiencing acute rejection of cadaveric renal allografts and compared OKT3 to standard therapies, showing rejection reversal in 94% of the OKT3 group versus 75% in the control arm. The pivotal study supporting the 1986 FDA approval for renal involved a of 123 patients, where a 5 mg daily dose of OKT3 demonstrated superior efficacy in reversing steroid-resistant rejection compared to conventional immunosuppressive regimens. This trial, conducted by the Ortho Multicenter Transplant Study Group, reported significant improvements in graft function preservation, with OKT3 enabling 94% complete reversal at 14 days. In the 1990s, indications expanded to liver and heart transplants. Key publications from the Ortho Multicenter Transplant Study Group, including a report in the Journal of Medicine in 1985, provided foundational evidence of OKT3's role in enhancing short-term outcomes across organ types. Comparative analyses further contextualized OKT3's profile; a 1996 meta-analysis of prophylactic use in renal, liver, and cardiac transplants found similar efficacy to in preventing rejection but noted higher risks of with OKT3, including fever and . Long-term follow-up data from the 2000s, drawn from observational cohorts of renal transplant recipients treated with OKT3, indicated 1-year graft survival rates exceeding 90%, attributable to reduced acute rejection incidence. However, these studies revealed limitations, such as high dropout rates due to severe side effects like first-dose reactions, and underrepresentation of pediatric patients and diverse ethnic populations, which constrained generalizability.

Emerging Therapies

Following the discontinuation of muromonab-CD3, research has shifted toward humanized anti-CD3 monoclonal antibodies that achieve T-cell modulation with reduced risk of severe side effects. Otelixizumab, developed by GlaxoSmithKline and Tolerx, underwent Phase III trials in the 2010s for new-onset , demonstrating effective partial T-cell modulation and preservation of regulatory T cells without causing full T-cell depletion, though it did not meet its primary endpoint for beta-cell function preservation. Similarly, teplizumab, a humanized anti-CD3 , received FDA approval in November 2022 for delaying the progression from stage 2 to stage 3 in adults and children aged 8 years and older, based on trials showing a median delay of over two years in disease onset through targeted T-cell exhaustion and regulatory responses. In , CD3 bispecific antibodies have emerged as successors inspired by muromonab-CD3's T-cell engagement principle, redirecting cytotoxic T cells to tumor antigens without broad depletion. , a CD19/CD3 bispecific T-cell engager, was approved by the FDA in December 2014 for relapsed or refractory Philadelphia chromosome-negative B-cell precursor (ALL), achieving complete remission rates of approximately 40% in pivotal trials by inducing T-cell-mediated of CD19-positive leukemic cells. These agents are also being explored in combination with CAR-T cell therapies to enhance tumor targeting and overcome resistance; for instance, CD3 bispecifics like anti-CD79b/CD3 have shown synergistic cytotoxicity with CD19 CAR-T cells in preclinical models, amplifying T-cell activation at the tumor site. For transplantation, low-dose anti-CD3 monoclonal antibodies are under investigation for inducing while minimizing . Foralumab, a fully anti-CD3 administered as a , has entered 2020s trials to promote regulatory T-cell expansion and mucosal tolerance in autoimmune conditions, with preclinical data indicating reduced compared to intravenous routes. Phase II studies of low-dose anti-CD3 therapies in transplant recipients have reported improved graft tolerance through selective pathogenic T-cell depletion and preservation of regulatory subsets. Key challenges from muromonab-CD3, such as high and off-target effects, have been addressed through humanization techniques that replace murine components with human frameworks, lowering anti-drug antibody formation rates to below 10% in clinical settings. Targeted delivery methods, including bispecific formats and mucosal administration, further limit systemic exposure and storms by focusing activity on disease sites. As of 2025, no efforts are underway to revive muromonab-CD3 directly, but numerous CD3-targeting agents, primarily bispecifics and humanized monoclonals, remain in clinical pipelines for , , and transplantation, reflecting sustained interest per data.

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