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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The Complement-Dependent Cytotoxicity (CDC) pathway comprises of a number of proteins in the blood that can cause cell death after an antibody binds to the cell surface. Usually, this pathway is activated to destroy foreign cells such as bacteria but can also be activated by therapeutic antibodies binding to the surface of tumor cells. In this case the C1 complex binds to these antibodies and protein pores subsequently appear in the cell membrane, ultimately leading to cell death. This process can be triggered by chimeric, humanized, or human antibodies, and those containing an IgG1 Fc region. Once triggered, cell death occurs by several mechanisms, including activation of the membrane attack complex (i.e., Complement-Dependent Cytotoxicity), enhancement of ADCC, or CR3-dependent cellular cytotoxicity.
Treatment of Patients with Rheumatoid Arthritis with Anti-CD4 Monoclonal Antibodies
Published in Thomas F. Kresina, Monoclonal Antibodies, Cytokines, and Arthritis, 2020
Christian Herzog, Wolfgang Müller, Christoph Walker, Werner J. Pichler
Both antibodies VIT4 and MT151 have been characterized biochemically and immunologically (20) and were prepared for in vivo use according to the recommendations published in collaboration with the Gesellschaft für Immunologie (21). Studies by Sattentau et al. (22) suggested that both MAbs detect a similar epitope on the CD4 antigen as they similarly inhibited human immunodeficiency virus (HIV)-induced syncytium formation and showed the same cross-competition pattern between monoclonal antibodies to CD4 (see Ref. 22 and own observations). These in vitro nonmodulating antibodies of the mouse IgG2a isotype induced complement-dependent cytotoxicity in the presence of rabbit but not of human complement.
Adcc in Histocompatibility and Clinical Medicine
Published in Soldano Ferrone, B. G. Solheim, HLA Typing: Methodology and Clinical Aspects, 2019
T. Kovithavongs, J. B. Dossetor
The immunological defense mechanism is conceptually dichotomized into a humoral antibody system and a cell mediated immune system. To certain types of infection, or immunization, the humoral antibody is the predominant mediator of immunity and this is produced by B lymphocytes. The cell mediated mechanisms are characteristic of delayed hypersensitivity, homograft immunity and graft-vs.-host reactions and are carried out by T lymphocytes. The destruction of cells or microorganisms in the former instance is accomplished by a special class of protein, collectively termed “the complement system’’, after interaction has taken place between the antibody and the target, and is known as complement dependent cytotoxicity (CDC). In the latter, T cells are responsible for direct killing of the target cells in contact by a process as yet not entirely understood, known as direct lymphocyte mediated cytotoxicity (LMC), or by releasing factors or lymphokines to facilitate target destruction by other means. In 1965, Müller described another mechanism of target cell killing, now known as antibody dependent cellular cytotoxicity (ADCC), which incorporates humoral antibody and effector cells in mediating cytotoxicity without the participation of complement, and is now well established. To be reviewed here will be the use of this in vitro system in histocompatibility testing, its relevance in organ transplantation, tumor immunity, autoimmune disease, and immunity against microorganisms. Its value as a means of immune complex detection will be examined and finally, an outline of the technical aspect for using this test system in histocompatibility work will be given.
Management of relapsed or refractory large B-cell lymphoma in patients ineligible for CAR-T cell therapy
Published in Expert Review of Hematology, 2022
Salvatore Perrone, Paolo Lopedote, Mario Levis, Alice Di Rocco, Stephen Douglas Smith
The prototype, rituximab, is well known as a chimeric anti-CD20 monoclonal antibody with a long history in DLBCL treatment [99]. Rituximab exerts its effect by at least four mechanisms: 1) The Fc portion of rituximab and the deposited complement is recognized by both FcRs and complement receptors on macrophages, which leads to phagocytosis and ADCC. 2) interaction with natural killer (NK) cells via Fc receptors (FcRs) III, which leads to antibody-dependent cellular cytotoxicity (ADCC). 3) activation of the complement cascade, by complement-dependent cytotoxicity (CDC). 4) The crosslinking of several molecules of rituximab and CD20 in the lipid raft determines activation of a signaling pathway involving Src kinases that mediate direct apoptosis [100]. Newer anti-CD20 drugs have been constructed to enhance ADCC and inducing direct cell death like ofatumumab and obinutuzumab [101]. However, the role of obinutuzumab in LBCL has been disappointing in first line in combination with CHOP [102] or in combination with the more intensive ACVBP [103]. Moreover, in subsequent lines of therapy both obinutuzumab [104] and ofatumumab [105] failed to show more efficacy against the standard rituximab + DHAP. So basically, they have no role in the setting of this review [106].
Rituximab in Myasthenia Gravis - Where do we stand?
Published in Expert Opinion on Biological Therapy, 2021
Zaeem A. Siddiqi, Wasim Khan, Faraz S. Hussain
CD20 is expressed throughout the early pre-B-cell stage and also remains present in mature B-cells. It is absent in stem cells and is lost before the B-cells differentiate into plasma cells. There are several mechanisms by which Rituximab leads to depletion of B-cells after binding to the CD20: (1) Antibody-dependent cellular cytotoxicity: natural killer cells, macrophages and monocytes are recruited through their Fcγ receptors bind to surface CD20, inducing B-cell lysis. (2) Complement-dependent cytotoxicity as a result of complement activation by the B-cell–Rituximab complex and the formation of a membrane attack complex, leading to B-cell lysis. (3) Direct apoptosis of B-cells induced by Rituximab binding. On average, the B-cell depletion in peripheral blood following Rituximab lasts for eight months after which a new ontogeny repopulates the B-cell pool. B-cells do not directly produce antibodies in MG. Rather, after activation and cross-linking of surface immunoglobulins by a specific antigen, B-cells undergo proliferation and differentiation to plasma cells. By depleting B-cell population, Rituximab may benefit MG as plasma cells are not replaced and antibody production decreases. MG is primarily driven by AChR-specific T lymphocytes and a small proportion (up to 2.4%) of these T-cells also co-express CD20 and are depleted by Rituximab [41,42].
Malignant tissues produce divergent antibody glycosylation of relevance for cancer gene therapy effectiveness
Published in mAbs, 2020
Dominik Brücher, Vojtech Franc, Sheena N. Smith, Albert J. R. Heck, Andreas Plückthun
Briefly, fucosylation of the proximal N-acetylglucosamine (GlcNAc) reduces antibody binding to the activating FcγRIIIa receptor on natural killer (NK) cells, a subset of peripheral (5–10%) and splenic monocytes as well as macrophages by steric hindrance, resulting in a reduction of antibody-dependent cell-mediated cytotoxicity (ADCC).4 In contrast, the lack of antibody fucosylation causes increased IgG binding to the low-affinity FcγRIIIb on granulocytes (neutrophils, eosinophils and basophils), which leads to repressed ADCC responses and increased phagocytosis selectively in this cell population.5 Furthermore, terminal galactose or mannose negatively influences the circulating half-life of the antibody, although the importance of this effect is still debated.6 Sialylation of the terminal galactose suppresses antibody-mediated immune responses by: 1) reducing ADCC and antibody-dependent cellular phagocytosis (ADCP) via a decreased affinity to FcγRIIIa; 2) binding to macrophage-presented Siglec-7/9, or by binding to T cell presented Siglec-15; and 3) by impairing complement-dependent cytotoxicity (CDC).7–10 Conversely, antibody sialylation increases the circulating half-life by preventing terminal galactose from binding to the hepatocytic asialoglycoprotein receptor.11 Therefore, depending on the intended biological activity of the antibody, different glycoforms of the antibody may be desired.