The currently available anti-CD20 mAb therapies for use in multiple sclerosis—rituximab, ocrelizumab, ofatumumab, and ublituximab—have led to significant improvements in disease outcomes through robust efficacy on clinical manifestations and MRI lesion activity, and are a cornerstone of highly effective disease-modifying treatment. |
Adaptations of how these medications are used to reduce adverse effects are under investigation. |
CNS-penetrant therapies are still needed to more effectively address the compartmentalized inflammation that is thought to play an important role in disability progression. |
1 Introduction
2 Search Strategy
3 Role of B Cells in Multiple Sclerosis (MS) Pathogenesis
4 Molecular and Pharmacological Attributes of Anti-CD20 Monoclonal Antibodies
Rituximab [16] | Ocrelizumab [18] | Ofatumumab [32] | Ublituximab [74] | |
---|---|---|---|---|
CD20 target epitope | Binds to amino acid residues 168-175 on large extracellular loop | Binds to amino acid residues 165–180 on large extracellular loop | Binds to discontinuous sequences of the small (residues 74–80) and large extracellular loops (residues 145–161) | Binds to residues 168–171 and 158–159 on large extracellular loop |
Degree of humanization | Chimeric murine/human IgG1κ anti-CD20 mAb | Recombinant humanized glycosylated IgG1VκI anti-CD20 mAb | Fully human IgG1κ anti-CD20 mAb | Chimeric IgG1κ anti-CD20 mAb with glycoengineered Fc segment that enhances affinity for FCγRIIIa receptors |
Effector mechanism | CDC > ADCC apoptosis + | ADCC > CDC apoptosis ++ | CDC = ADCC apoptosis ++ | ADCC > CDC |
Route of administration | IV infusion | IV infusion | SC injection | IV infusion |
Dosing schedule | Initial dose 1000 mg Second dose 1000 mg at week 2 Subsequent dosing 1000 mg Q6 months | Initial dose 300 mg over ≥ 2.5 h Second dose 300 mg over ≥ 2.5 h at week 2 Subsequent dosing 600 mg over ≥ 3.5 h or over ≥ 2 h if no prior infusion reaction Q6 months | Initial dose 20 mg Second dose 20 mg at weeks 1 and 2 Subsequent dosing 20 mg Q4 weeks starting at week 4 | Initial dose 150 mg over 4 h Second dose 450 mg over 1 h at week 2 Subsequent dosing 450 mg over 1 h at week 24 |
Terminal half-life | 22 days | 33 days | 16 days | 22 days |
Immunogenicity | Most | Less | Least | Less |
4.1 Rituximab
4.2 Ocrelizumab
4.3 Ofatumumab
4.4 Ublituximab
5 Clinical Trials
5.1 Rituximab
5.2 Ocrelizumab
5.3 Ofatumumab
5.4 Ublituximab
5.5 Relative Efficacy
6 Immunogenicity of Anti-CD20 Monoclonal Antibodies
7 Mechanism of Action and Adverse Events
7.1 Rituximab
7.2 Ocrelizumab
7.3 Ofatumumab
7.4 Ublituximab
7.5 Progressive Multifocal Leukoencephalopathy
7.6 Immune-Mediated Colitis
7.7 COVID-19
7.8 Tuberculosis
8 Vaccine Response
9 Pregnancy and Family Planning Considerations
10 Pre-Treatment Testing and Safety Monitoring
Contraindications | Active hepatitis B infectiona |
History of life-threatening infusion reaction to medicationb | |
Recommended pretreatment testinga | Complete blood count with differential |
Comprehensive metabolic panel | |
Quantiferon/tuberculosis screen | |
Hepatitis panel | |
Varicella zoster virus IgG (to ensure immunity) | |
Quantitative Ig levels | |
Urine or serum beta human chorionic gonadotropin (where appropriate) | |
Brain MRI | |
All necessary vaccinations > 4 weeks prior to first dose | |
Recommended monitoring schedulea | Complete blood count with differential (every 6 months) |
Comprehensive metabolic panel (every 6 months) | |
CD19 count (every 6 months) | |
Quantitative Ig levels (every 6 months) | |
Monitor for recurrent or serious infection | |
Monitor for malignancy/ensure all age-appropriate cancer screening up to date | |
Pregnancy and family planning | Recommend contraception during treatment and for 6 months aftera |