Antibody-Based Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
B cells are a fundamental component of the body’s immune system. However, like most cells in the body, B cells can become cancerous leading to such diseases as non-Hodgkin’s lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL). Targeting B-cell surface antigens that are highly expressed in B-cell malignancies with monoclonal antibodies is an ideal treatment strategy as both the B cells and antibodies can come into immediate contact in the bloodstream, and the antibodies can be designed to be highly specific for the individual surface antigens. Antibodies have been developed for several surface antigens including the “cluster of differentiation” or “CD” glycoproteins, found primarily on the surface of B cells (Figure 7.10). Examples include CD20 (targeted by ofatumumab and rituximab) and CD52 (targeted by alemtuzumab). B-lymphocyte surface antigens have also been targeted by Antibody-Drug Conjugates (ADCs) such as ibritumomab tiuxetan and tositumomab (i.e., CD20), brentuximab vedotin (i.e., CD30), and gemtuzumab ozogamicin (i.e., CD33) (see Section 7.3). As discussed above, interaction of the naked antibodies described in this section with their corresponding antigens can lead to cell death through both the ADCC and CDC effects, and also a direct apoptotic effect.
Physiology
Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams in Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
The human gut harbours >100 trillion microbes – the gut microbiota. Most reside in the colon. Gut microbiota are essential for the development of gut mucosal immunity. Microbiota-driven immune response can prevent the development of inappropriate inflammation, which allows the microbiota to survive in the inflammatory free environment. Host-microbial symbiosis is essential for gut homeostasis. If a pathogen penetrates physical barriers, then the innate immune system provides immediate non-specific response mediated by T lymphocytes and the humoral immune system provides a slower, antigen specific response mediated by antibodies produced by B lymphocytes. The function of T cells and B cells is to recognise specific ‘non-self’ antigens, during a process known as antigen presentation. The cells generate specific responses that are tailored to eliminate specific pathogens or pathogen-infected cells. B cells respond to pathogens by producing large quantities of antibodies which neutralise foreign objects, i.e. bacteria and viruses. In response to pathogens, some T cells, called T helper cells, produce cytokines that direct the immune response, whilst other T cells, called cytotoxic T cells, produce toxic granules which induce the death of pathogen-infected cells. Following activation, B cells and T cells leave a lasting legacy of the antigens they have encountered in the form of memory cells.
The immune and lymphatic systems, infection and sepsis
Peate Ian, Dutton Helen in Acute Nursing Care, 2020
Lymphocytes are the cells of the lymphatic system. Produced in the bone marrow, they form part of the cell-mediated response to antigens. As their name suggests, they spend most of their life cycle, which is about 2–4 years, within the lymphoid tissues. There are different types and sizes of lymphocytes, T cells and B cells. T cells are produced in the bone marrow, but are matured (or become immunocompetent) within the thymus. B cells are also produced in the bone marrow, but remain there to mature and become immunocompetent (see Figure 12.2). The T and B cells are exposed to antigens, normally in the lymphoid tissue, where they differentiate and mature. Within the T and B cell population, there are a range of cells with differing functions. B cells mediate the humoral or antibody response and T cells mediate the cellular immune response.
Idelalisib induces apoptosis in the lymphoid tissues and impairs lung function in mice
Published in Journal of Chemotherapy, 2020
Junu A. George, Zainab Alshebli, Asma Alneyadi, Noura Al Mukhaini, Suhail Al-Salam, Manjusha Sudhadevi, Abdul-Kader Souid, Ahmed R. Alsuwaidi
Several pre-clinical studies have evaluated the effects of PI3Kδ inhibition on B and T-cell development and immune responses to various pathogens.3,22,23 In this study, idelalisib treatment negatively affected the immune system. The pronounced involution of thymus and reduction of splenic weight (Fig 1b and d) indicated disruption of the immune system, which was also reported in previous studies. Mature CD4+ and CD8+ T-cell differentiation and cytokine production are tightly regulated by p110δ.24,25 Studies using knockout mice demonstrated that p110δ deficiency had a higher influence on B cells than T cells.26 Similarly, this study demonstrated the reduction in the number of B cells after idelalisib treatment. However, the cytotoxicity of idelalisib against B cell subsets is unknown. B cells play a very important role as antigen-presenting cells. Healthy B cells are essential to provide necessary co-stimulatory signals to promote T cell sustenance and multiplication.27 These functions are expected to be altered as a consequence of PI3K p110δ inhibitor use.
HERC6 is upregulated in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and promotes the disease progression
Published in Autoimmunity, 2022
Ling Cao, Hui Zhang, Jin Bai, Tingting Wu, Yingjuan Wang, Ning Wang, Caihong Huang
SLE is a chronic autoimmune disease characterized by the formation of autoantibodies against nuclear components, presenting a variety of clinical manifestations and immune phenomena [29]. Despite recent advances in treating the disease, treatment options remain limited and often untargeted [30]. SLE is associated with abnormal innate and adaptive immunity reactions, but little is known about the underlying pathogenesis of the disease [16]. Defective clearance of apoptotic substances in the innate immune response is thought to lead to a loss of self-tolerance and ultimately to B cells producing autoantibodies and exhibiting abnormal activation and expression. In turn, anti-nuclear antibodies (ANA) and anti-DNA antibodies (anti-DNA) are produced [31]. In addition, B cells play a crucial role in the formation of immune complexes containing their own antigens, which are deposited in various tissues. The intervention of Fc receptors and the activation of complement cascades contribute to inflammation [15,32]. The object of this study is PBMCs, and the main components are immune-related cells. Compared with specific types of immune cells, PBMCs have the characteristics of simple acquisition, and some physical and chemical parameters of PBMCs can be used as indicators of SLE diagnosis or treatment, which is more feasible in clinic.
SPLICELECT™: an adaptable cell surface display technology based on alternative splicing allowing the qualitative and quantitative prediction of secreted product at a single-cell level
Published in mAbs, 2020
Christel Aebischer-Gumy, Pierre Moretti, Romain Ollier, Christelle Ries Fecourt, François Rousseau, Martin Bertschinger
Interestingly, the human immune system provides an additional and elegant way to link cell surface display and secretion. B cells are the antibody producers in the human immune system. Each B cell expresses a single antibody specifically binding a single antigen. In resting B cells (memory cells), the antibody is predominantly membrane-bound. Upon recognition of its antigen, a B cell will proliferate into plasma cells expressing a huge amount of secreted antibody.44 The only difference between the two antibody isoforms is a C-terminal extension of the membrane-bound version with a transmembrane region.45 The controlled transition between the two isoforms of antibody (membrane-bound and secreted) is achieved by alternative splicing.45,46 Splicing describes the precise excision of the introns of the mRNA, accomplished by a protein complex called spliceosome that is able to recognize consensus sequences: the 5ʹ splice donor (5ʹ SD) and 3ʹ splice acceptor (3’SA) sites at the intron/exon borders and the branch point and the poly pyrimidines (poly(Y)) tract in the intron. The efficiency of the splicing depends largely on the different consensus sequences, but also on so-called splicing enhancer and repressor sequences present in both introns and exons. Alternative splicing describes the mechanisms by which a single pre-mRNA is matured into different mRNA, a process that is usually highly regulated by interaction of many different factors.47–58
Related Knowledge Centers
- Adaptive Immune System
- Antibody
- Antigen Presentation
- Humoral Immunity
- Memory B Cell
- White Blood Cell
- Lymphocyte
- Cytokine
- B-Cell Receptor
- Antigen-Presenting Cell