Overview of Monoclonal Antibodies Targeting B Cells

B cells are a type of adaptive immune cells that mature in the bone marrow and differentiate into antibody-producing plasma cells or memory cells with immune memory when they encounter a specific antigen. B cells not only participate in the humoral immune response but also have the functions of phagocytosis and antigen presentation. The development and function of B cells are regulated by a variety of cytokines and receptors. B cells play an important pathogenic role in many autoimmune diseases and are therefore therapeutic targets. Abnormalities in B cells have been linked to some autoimmune diseases and cancers. Therefore, studying the role and function of B cells is of great significance for understanding the mechanisms of the immune system and developing new therapeutic strategies.

Monoclonal antibodies against B cells are an effective means of immunotherapy. They can induce apoptosis of B cells, inhibit the activation of B cells or block the signal transduction of B cells by binding to specific molecules or factors on the surface of B cells. Currently, a variety of monoclonal antibodies against B cells have been used clinically or are under development, such as monoclonal antibodies against targets such as CD20, CD19, BAFF, CD22, CD37, CD40, and CD52. These targets play different roles in the development, maturation and function of B cells, so the monoclonal antibodies against them also have different mechanisms and effects.

Table 1. monoclonal antibodies for B cell targets

Monoclonal Antibodies Targeting CD20

The cluster of differentiation 20 (CD20) is a molecule expressed on the surface of B cells and plasma cells, also known as B-lymphocyte antigen CD20. CD20 is involved in the development, activation and signal transduction of B cells, especially related to the regulation of calcium ion channels. CD20 is highly expressed in B-cell malignancies and autoimmune diseases, but lower in normal tissues, making it an important therapeutic target.

Monoclonal antibodies against CD20 are an effective means of immunotherapy. They can induce apoptosis, antibody-dependent cell-mediated cytotoxicity, or complement-dependent cytotoxicity of B cells by binding to CD20, thereby eliminating pathological B cells. Currently, a variety of monoclonal antibodies against CD20 have been used clinically or are under development, such as rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ublituximab. These monoclonal antibodies are mainly used to treat various types of B-cell lymphoma, leukemia and B-cell-mediated autoimmune diseases. Among them, rituximab is the first monoclonal antibody against CD20 approved for marketing, which was launched in the United States in 1997 for the treatment of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma . Later, rituximab was approved for the treatment of other types of lymphoma, leukemia and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. The combined use of rituximab and chemical drugs can significantly improve the survival rate and quality of life of patients.

Among these anti-CD20 monoclonal antibodies, obinutuzumab is a type II monoclonal antibody against CD20, which can eliminate pathological B cells by inducing B cell apoptosis and antibody-dependent cell-mediated cytotoxicity. Obinutuzumab is used in combination with chemotherapy drugs for the treatment of untreated chronic lymphocytic leukemia (CLL) and relapsed or refractory follicular lymphoma (FL). Obilimomab was approved by the U.S. Food and Drug Administration (FDA) in 2013 for the treatment of untreated CLL in combination with chloramide. Compared with chloramide, obilimomab can significantly improve the progression-free survival and overall survival of patients. In 2017, obilimomab was approved in combination with bendamustine for the treatment of relapsed or refractory FL. Compared with bendamustine, obilimomab can significantly improve the progression-free survival of patients.

Fig.1 Putative mechanisms of action of Obinutuzumab. (Kensei, 2016)

Monoclonal Antibodies Targeting CD19

The cluster of differentiation 19 (CD19) is a molecule expressed on the surface of B cells and plasma cells, also known as B-lymphocyte antigen CD19. CD19 is a part of the B cell receptor complex, which is involved in the development, activation and signal transduction of B cells, especially related to the synergy between B cell receptor (BCR) and CD21. CD19 is highly expressed in B-cell malignancies and autoimmune diseases, but lower in normal tissues, making it an important therapeutic target.

Fig.2 CD19 molecular structure. (Wang, 2019)

Monoclonal antibodies against CD19 can induce apoptosis of B cells, antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity by binding to CD19, thereby eliminating pathological B cells. Currently, a variety of monoclonal antibodies against CD19 have been used clinically or are under development, such as blinatumomab, inotuzumab ozogamicin, MEDI-551, and MOR208. These monoclonal antibodies are mainly used to treat various types of leukemia, lymphoma and B cell-mediated autoimmune diseases. Among them, blinatumomab is the first monoclonal antibody against CD19 approved for marketing, which was launched in the United States in 2014 for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL). Blinatumomab binds both CD19 and CD3, allowing T cells to approach and kill leukemia cells. In 2017, inezolizumab was also approved for the treatment of relapsed or refractory ALL. Inotuzumab ozogamicin is a CD19 monoclonal antibody combined with calicheamicin toxin, which can deliver the toxin into the interior of leukemia cells and induce their apoptosis by binding to CD19.

Monoclonal antibodies against CD19 can be used in combination with other treatments. For example, a monoclonal antibody against CD19 combined with an immune checkpoint inhibitor can boost the immune system's attack on B cells. For example, MEDI-551 is a monoclonal antibody against CD19, which can induce apoptosis and antibody-dependent cell-mediated cytotoxicity of B cells by binding to CD19. MEDI-551, in combination with the PD-1 inhibitor durvalumab, is in clinical trials for the treatment of relapsed or refractory non-Hodgkin's lymphoma (NHL). As another example, monoclonal antibodies against CD19 combined with radioactive isotopes can enhance the killing effect on B cells. ibritumomab tiuxetan is a CD19 monoclonal antibody combined with the radioactive isotope yttrium-90, which can deliver the radioactive isotope to the interior of leukemia cells or lymphoma cells and induce their apoptosis by binding to CD19. ibritumomab tiuxetan has been approved by the FDA for the treatment of relapsed or refractory B-cell NHL.

Common adverse reactions of monoclonal antibodies against CD19 include infusion-related reactions, infection, low platelets, low white blood cells, anemia, nervous system damage, abnormal liver function, etc. Monoclonal antibodies against CD19 may also cause serious adverse reactions, such as recurrence of hepatitis B virus, multiple leukoencephalopathy, and lung injury.

Monoclonal Antibodies Targeting BAFF

B-cell activating factor of the TNF family (BAFF) is a molecule expressed on a variety of cell types, also known as B-cell activating factor, B-lymphocyte stimulator, or tumor necrosis factor superfamily member 13b. BAFF is an important B cell survival factor, which regulates the development, activation and differentiation of B cells by binding to its receptors BCMA, TACI and BAFF-R. BAFF is overexpressed in autoimmune diseases, leading to abnormal proliferation of B cells and production of autoantibodies, thereby damaging normal tissues and organs.

Monoclonal antibodies against BAFF are effective to bind to BAFF and block its interaction with receptors, thereby reducing the number and function of pathological B cells. There is already a monoclonal antibody against BAFF in clinical use, belimumab, which is a fully humanized anti-BAFF monoclonal antibody, was approved by the FDA in 2011 for the treatment of active, autoantibody-positive systems Lupus erythematosus (SLE). Belimumab can significantly improve the response rate and progression-free survival of SLE patients compared with standard treatment. In addition, there are several other monoclonal antibodies against BAFF or its receptors in clinical trials, such as tabalumab against BAFF-R, brutacapab against TACI, atacicept against BCMA and TACI, etc. These monoclonal antibodies are mainly used to treat SLE and other B cell-mediated autoimmune diseases, such as rheumatoid arthritis, primary Sjogren's syndrome.

Monoclonal antibodies against BAFF can also be used in combination with other treatments. First, monoclonal antibodies against BAFF combined with other immunosuppressants can improve the remission rate and survival of patients. For example, belimumab combined with standard therapy (including corticosteroids, hydroxychloroquine, azathioprine, etc.) can be used to treat active, autoantibody-positive SLE. And compared with standard treatment, combination therapy can significantly improve the remission rate and progression-free survival of SLE patients. Second, the combination of brutacapab and metothidone is currently in clinical trials for the treatment of primary Sjögren's syndrome. Monoclonal antibodies against BAFF can be used in combination with other targeted drugs to enhance the killing effect on B cells. For example, belimumab in combination with rituximab is in clinical trials for the treatment of relapsed or refractory NHL. Third, monoclonal antibodies against BAFF can be used in combination with other novel drugs to explore new therapeutic strategies. For example, belimumab is in clinical trials in combination with BRII-196 and BRII-198, two monoclonal antibodies against the novel coronavirus SARS-CoV-2, for the treatment of mild or moderate COVID-19.

Conclusion

B cells are the pathogenic cells of a variety of malignant tumors, and monoclonal antibodies targeting B cell surface antigens are an effective means of immunotherapy. Among them, monoclonal antibodies targeting CD20 have become the standard treatment for many B-cell tumors, significantly improving the survival rate and quality of life of patients. However, the therapeutic effect of these monoclonal antibodies is limited by factors such as drug resistance of tumor cells, decreased responsiveness to retreatment, and adverse drug reactions. In order to overcome these limitations, a new generation of monoclonal antibodies targeting CD20 is being developed, which have advantages such as higher affinity, stronger effector functions, and better pharmacokinetics, which may enhance the efficacy of monoclonal antibody therapy.

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