Introduction
Ublituximab is a novel glycoengineered monoclonal antibody targeting CD20-expressing B-cells. Approved by the FDA in December 2022, it represents an important advancement in the treatment of relapsing forms of multiple sclerosis. This anti-CD20 monoclonal antibody is engineered for enhanced antibody-dependent cellular cytotoxicity (ADCC) through glycoengineering technology.
Mechanism of Action
Ublituximab binds specifically to the CD20 antigen expressed on the surface of pre-B and mature B lymphocytes. The binding results in B-cell lysis through three primary mechanisms: 1. Antibody-dependent cellular cytotoxicity (ADCC) 2. Complement-dependent cytotoxicity (CDC) 3. Direct induction of apoptosis
The glycoengineering process reduces fucose content in the Fc region, significantly enhancing binding to FcγRIIIa receptors on natural killer cells and macrophages, thereby potentiating ADCC activity compared to earlier anti-CD20 therapies.
Indications
- Treatment of relapsing forms of multiple sclerosis (RMS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults
Dosage and Administration
Initial dosing regimen:- Infusion 1: 150 mg intravenous infusion over at least 4 hours
- Infusion 2 (2 weeks later): 450 mg intravenous infusion over at least 4 hours
- 450 mg intravenous infusion over at least 1 hour every 24 weeks
- Methylprednisolone 100 mg IV (or equivalent) approximately 30 minutes prior to each infusion
- Antihistamine (e.g., diphenhydramine) approximately 30-60 minutes prior to each infusion
- Antipyretic (e.g., acetaminophen) approximately 30-60 minutes prior to each infusion
- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: Not studied; use with caution
- Elderly: No specific dosage adjustment recommended
Pharmacokinetics
Absorption: Administered intravenously; complete bioavailability Distribution: Volume of distribution approximately 3.1-4.0 L; targets CD20-positive B-cells Metabolism: Degraded via proteolytic enzymes throughout the body; no hepatic cytochrome P450 involvement Elimination: Half-life approximately 16-18 days; clearance primarily through target-mediated drug disposition and nonspecific proteolytic degradation Time to maximum concentration: Immediately post-infusion Steady-state: Achieved by approximately 24 weeks with every-24-week dosingContraindications
- Active hepatitis B virus infection
- Known hypersensitivity to ublituximab or any component of the formulation
- Active, untreated tuberculosis
Warnings and Precautions
Infusion-related reactions: Occur in approximately 47% of patients; may include fever, headache, nausea, throat irritation, erythema, and hypotension Infections: Increased risk of serious bacterial, viral, and fungal infections Hepatotoxicity: Monitor liver function tests; cases of drug-induced liver injury reported Progressive multifocal leukoencephalopathy (PML): Although not reported with ublituximab, PML has occurred with other anti-CD20 antibodies Immunization: Live vaccines should not be administered during treatment Fetal risk: May cause fetal harm based on animal data; advise effective contraception Tumor lysis syndrome: Rare cases reported in patients with hematologic malignanciesDrug Interactions
Live vaccines: Contraindicated during treatment Immunosuppressants: May enhance immunosuppressive effects B-cell depleting therapies: Avoid concomitant use CYP substrates: Ublituximab does not affect CYP enzymes; no expected interactions with CYP substrate medicationsAdverse Effects
Very common (≥10%):- Infusion-related reactions (47%)
- Upper respiratory tract infections (30%)
- Headache (20%)
- Arthralgia (11%)
- Lower respiratory tract infections
- Herpes infections
- Rash
- Fatigue
- Nausea
- Pyrexia
- Back pain
- Hypertension
- Serious infections (2.5%)
- Hepatitis B reactivation
- Infusion-related severe reactions
- Autoimmune disorders
Monitoring Parameters
Prior to initiation:- Hepatitis B virus screening
- Quantitative immunoglobulins
- CBC with differential
- Liver function tests
- Tuberculosis screening
- Monitor for infusion reactions during and for at least 1 hour post-infusion
- CBC with differential before each infusion
- Liver function tests periodically
- Signs and symptoms of infection
- Immunoglobulin levels (if recurrent infections occur)
- Annual tuberculosis screening in high-risk patients
- Monitor for signs of PML (cognitive changes, motor weakness, vision changes)
- Pregnancy testing in women of childbearing potential
Patient Education
- Report any signs of infection (fever, cough, sore throat) immediately
- Understand the risk of infusion reactions and report any symptoms during or after treatment
- Avoid live vaccines during treatment and discuss vaccination timing with healthcare provider
- Use effective contraception during treatment and for 6 months after last dose
- Inform all healthcare providers about ublituximab treatment before any procedures
- Regular monitoring is essential for safety
- Report any new neurological symptoms promptly
- Maintain all scheduled infusion appointments for optimal efficacy
References
1. FDA Prescribing Information: Ublituximab-xiiy (Briumvi). December 2022. 2. Fox E, Lovett-Racke AE, Gormley M, et al. A phase 2b study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing multiple sclerosis. Mult Scler. 2021;27(3):420-429. 3. Steinman L, Fox E, Hartung HP, et al. Ublituximab versus teriflunomide in relapsing multiple sclerosis. N Engl J Med. 2022;387(8):704-714. 4. National Multiple Sclerosis Society. FDA Approves Briumvi (ublituximab-xiiy) for Relapsing MS. 2022. 5. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688. 6. ClinicalTrials.gov: ULTIMATE I and II Phase 3 Trials (NCT03277261; NCT03277248)