Understanding Rituximab and the Need for Alternatives
Rituximab is a chimeric anti-CD20 monoclonal antibody that has become a cornerstone therapy for a range of conditions, including B-cell non-Hodgkin lymphomas (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), and multiple sclerosis (MS) [1.2.3]. It works by targeting the CD20 protein on the surface of B-cells, leading to their depletion through several immune-mediated mechanisms [1.2.3]. The success of rituximab is undeniable, with its addition to CHOP chemotherapy for diffuse large B-cell lymphoma (DLBCL), for instance, significantly improving 10-year overall survival rates [1.2.3].
However, the need for alternatives arises from several factors. Some patients may have a disease that is refractory to, or relapses after, rituximab treatment [1.6.4]. Others may experience significant side effects, such as infusion-related reactions, which can occur in a high percentage of patients during the first dose [1.2.3]. Furthermore, long-term use can lead to complications like hypogammaglobulinemia (low antibody levels), increasing infection risk [1.2.3]. The development of resistance and the desire for more effective or convenient treatment options have driven the development of a diverse landscape of alternatives.
Next-Generation Anti-CD20 Monoclonal Antibodies
To improve upon the original, researchers have developed second and third-generation anti-CD20 antibodies, which are humanized or fully human and may be engineered for enhanced effects [1.5.1].
Ofatumumab (Kesimpta, Arzerra)
Ofatumumab is a fully human, second-generation anti-CD20 monoclonal antibody [1.5.1]. It binds to a different part of the CD20 molecule than rituximab and is particularly effective at inducing complement-dependent cytotoxicity (CDC), a key mechanism for killing target cells [1.6.2, 1.6.3]. While preclinical models showed enhanced activity compared to rituximab, clinical trial results in lymphoma have been mixed, with one study in follicular lymphoma failing to show superiority over rituximab [1.6.2, 1.6.4]. However, ofatumumab has found a solid place in treating relapsing MS, offered as a relatively low-dose subcutaneous injection that patients can administer themselves [1.6.1].
Ocrelizumab (Ocrevus)
Ocrelizumab is a humanized anti-CD20 antibody approved for both relapsing and primary progressive forms of MS [1.4.4]. Unlike rituximab, which is used off-label for MS in many regions, ocrelizumab was specifically studied and approved for this indication [1.7.1, 1.8.1]. Observational studies suggest that ocrelizumab may be more effective than rituximab at reducing MS relapses, although disability progression outcomes appeared similar [1.4.2, 1.7.3]. One real-world data analysis also found that rituximab-treated patients had significantly higher rates of all-cause and infection-related hospitalizations compared to those treated with ocrelizumab [1.7.4].
Ublituximab (Briumvi)
Ublituximab is another anti-CD20 antibody approved for MS [1.8.1]. It has been glyco-engineered to enhance its ability to cause antibody-dependent cellular cytotoxicity (ADCC) [1.8.3]. This modification allows it to be effective at lower doses and administered via a one-hour infusion, which is significantly shorter than many other infused monoclonal antibodies [1.8.2, 1.8.1].
Obinutuzumab (Gazyva)
Obinutuzumab is a third-generation, humanized, and glycoengineered anti-CD20 antibody [1.5.1]. It was designed to produce greater ADCC and direct cell death compared to rituximab, while having less reliance on CDC [1.2.3, 1.6.3]. In clinical trials for follicular lymphoma (GALLIUM trial), obinutuzumab-based chemotherapy demonstrated superior progression-free survival compared to rituximab-based chemotherapy [1.13.2]. This makes it a preferred option in certain first-line settings for follicular lymphoma, although it may come with a higher incidence of some adverse events [1.5.1, 1.13.2].
Bispecific Antibodies: A Novel Approach
A newer class of drugs, bispecific T-cell engagers (BiTEs), represents a different immunotherapeutic strategy. Instead of just targeting the cancer cell, they act as a bridge, binding to both the cancer cell and a T-cell (a key immune killer cell) to facilitate targeted destruction.
- Mosunetuzumab (Lunsumio): This bispecific antibody binds to CD20 on malignant B-cells and CD3 on the surface of T-cells [1.9.1]. This action redirects the patient's own T-cells to engage and eliminate the lymphoma cells. It is approved for adult patients with relapsed or refractory follicular lymphoma after two or more prior lines of therapy [1.9.1, 1.9.2].
- Epcoritamab (Epkinly): Working similarly to mosunetuzumab, epcoritamab also binds to CD3 on T-cells and CD20 on B-cells to induce T-cell-mediated killing of the lymphoma cells [1.10.1, 1.10.3]. It is also being investigated in combination with rituximab [1.10.4].
Alternatives with Different Mechanisms
For some conditions, the best alternative to rituximab may not be another anti-CD20 antibody at all.
- For Rheumatoid Arthritis: If a patient does not respond adequately to rituximab (which itself is often used after other biologics like TNF inhibitors fail), other classes of medication are available. These include Janus kinase (JAK) inhibitors like upadacitinib (Rinvoq), which are oral small molecules that disrupt inflammatory signaling pathways inside the cell [1.2.3]. Other options include TNF alfa inhibitors (Humira), IL-6 inhibitors (tocilizumab), and various other disease-modifying antirheumatic drugs (DMARDs) [1.2.1, 1.13.1].
- For Non-Hodgkin's Lymphoma: For relapsed or refractory disease, treatment options extend far beyond monoclonal antibodies. Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary treatment where a patient's own T-cells are genetically engineered to target their cancer. Approved CAR T-cell therapies include Yescarta, Kymriah, and Breyanzi [1.3.3]. Other options include PI3K inhibitors, other chemotherapy combinations, and hematopoietic stem cell transplantation [1.3.1, 1.3.3].
Comparison of Rituximab Alternatives
| Medication (Brand Name) | Class | Mechanism of Action | Key Approved Indications | Administration |
|---|---|---|---|---|
| Rituximab (Rituxan) | Chimeric Monoclonal Antibody | Targets CD20, depletes B-cells via CDC and ADCC [1.2.3] | NHL, CLL, RA, Pemphigus Vulgaris [1.2.3, 1.12.1] | Intravenous (IV) Infusion [1.3.3] |
| Ofatumumab (Kesimpta) | Human Monoclonal Antibody | Targets CD20, potent CDC [1.6.2, 1.5.1] | Relapsing MS, CLL [1.5.1, 1.4.1] | Subcutaneous (SC) Injection (for MS) [1.6.1] |
| Ocrelizumab (Ocrevus) | Humanized Monoclonal Antibody | Targets CD20, potent ADCC [1.8.3, 1.8.4] | Relapsing & Primary Progressive MS [1.7.1] | IV Infusion [1.7.2] |
| Ublituximab (Briumvi) | Chimeric Monoclonal Antibody | Glyco-engineered to enhance ADCC [1.8.3] | Relapsing forms of MS [1.8.1] | IV Infusion (1 hour) [1.8.1] |
| Obinutuzumab (Gazyva) | Humanized Monoclonal Antibody | Glyco-engineered to enhance ADCC & direct cell death [1.5.1] | CLL, Follicular Lymphoma [1.5.1] | IV Infusion [1.3.3] |
| Mosunetuzumab (Lunsumio) | Bispecific Antibody | Engages T-cells (via CD3) to kill CD20+ B-cells [1.9.1] | Relapsed/Refractory Follicular Lymphoma [1.9.1] | IV Infusion [1.9.1] |
| Upadacitinib (Rinvoq) | JAK Inhibitor | Inhibits JAK1, disrupting intracellular cytokine signaling [1.2.3] | RA, Psoriatic Arthritis, Ulcerative Colitis [1.2.3] | Oral Tablet [1.2.3] |
The Role of Biosimilars
Beyond novel drugs, another important category of alternatives is rituximab biosimilars. A biosimilar is a biologic medication that is highly similar to an original, FDA-approved biologic and has no clinically meaningful differences in terms of safety and effectiveness [1.12.1]. Several rituximab biosimilars are approved, including Truxima (rituximab-abbs), Ruxience (rituximab-pvvr), and Riabni (rituximab-arrx) [1.12.1, 1.12.3].
The primary advantage of biosimilars is cost. They can be significantly less expensive than the originator product, leading to substantial healthcare savings [1.11.2]. For example, one study in the Netherlands showed that the adoption of rituximab biosimilars led to a 43% reduction in annual costs without compromising survival outcomes [1.11.2]. In the U.S., Ruxience is noted to be about 24% less expensive than its reference product [1.12.3]. This makes biosimilars a crucial alternative for improving access to treatment.
Conclusion
The question 'What is an alternative to rituximab?' now has a multifaceted answer. The choice depends entirely on the specific disease being treated, the patient's treatment history, the desired mechanism of action, and considerations of safety, convenience, and cost. For some, a next-generation anti-CD20 antibody like ocrelizumab for MS or obinutuzumab for lymphoma may offer improved efficacy [1.4.2, 1.13.2]. For others with highly refractory lymphoma, novel approaches like bispecific antibodies or CAR T-cell therapy are changing the standard of care [1.3.3, 1.9.2]. Finally, the availability of cost-effective biosimilars ensures that the benefits of rituximab-like therapy can reach more patients [1.11.2]. The therapeutic landscape continues to evolve, offering a more personalized and effective array of options beyond the original breakthrough drug.
