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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Catumaxomab consists of one “half” (one heavy chain and one light chain) of an anti-EpCAM antibody and one half of an anti-CD3 antibody, so that each molecule of catumaxomab can bind to both tumor cells (i.e., through EpCAM) and T cells (i.e., through CD3). In addition, like other antibodies, the Fc region can bind to type I, IIa and III Fcγ receptors (FcγRs) on accessory cells (e.g., natural killer cells, dendritic cells, and macrophages) (Figure 7.52). Crucially, all of the immune cells necessary for the mode of action of catumaxomab are present in the peritoneal fluid. Thus, catumaxomab exerts its antitumor effects via processes, including T-cell-mediated lysis, Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC), and phagocytosis via activation of FcγR-positive accessory cells. Its antitumor activity is also assisted by the induction of T-cell-secreted cytokines, such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α. An important aspect is that no additional immune cell activation process is required for effective tumor eradication, so it is a self-supporting antitumor therapy.
Overview of Cell Adhesion Molecules and Their Antagonism
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
There are several methods by which adhesion molecule function might be inhibited (Fig. 3). The most direct strategy involves specific inhibition of the adhesion molecule or its counter-receptor. This has been the method used most widely in both animal models of inflammation as well as in the few human studies using antiadhesion therapy (8,28). Most studies have utilized monoclonal antibodies (mAb) as the therapeutic agent. Monoclonal antibodies possess several desirable characteristics, including exquisite target specificity, availability in large quantities, and the ability to execute various effector functions via their Fc receptors. However, as most mAb produced to date have been generated in mice, there are potential limitations to their therapeutic use for human disease. Because they are foreign, murine mAb will elicit human anti-mouse antibody (HAMA) responses. On repeated administration, these HAMA may not only decrease the serum half-life and thereby the therapeutic utility of the mAb but may also cause potentially serious adverse effects. To circumvent these problems, several methods to reduce the immunogenicity of therapeutic mAb have been developed. Utilizing the techniques of molecular biology, researchers can substitute parts of human antibodies for the murine, yielding chimeric and humanized mAbs (28). The most eagerly awaited development is the ability to produce human mAbs directed against targets such as adhesion receptors.
The Etiopathogenesis of Autoimmunity
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Howard Amital, Yehuda Shoenfeld
Some of the autoimmune disorders are linked to certain functional defects of the immune system as interleukin-2 deficiency, IgA deficiency or with complete hereditary deficiencies of the early components Clq, C2 and C4 in the classical pathway of complement system.22,23 The high concentration of immune complexes detected in the blood of SLE has raised the suspicion that immunoglobulin Fcγ receptors polymorphism might be associated with SLE. Low affinity variants of Fcγ receptors have been shown to be associated with lupus nephritis.23
A perspective toward mass spectrometry-based de novo sequencing of endogenous antibodies
Published in mAbs, 2022
Sebastiaan C. de Graaf, Max Hoek, Sem Tamara, Albert J. R. Heck
Humoral human antibodies are complex proteins produced by B cells.7,19 Most antibody molecules (e.g., IgGs) are made up of four protein chains: two identical light chains and two identical heavy chains, which are interconnected by disulfide bridges (Figure 1). The light- and heavy-chain form two heterodimers, which are connected via disulfide bridges in the hinge region to form the intact antibody. Functionally, the intact antibody can be divided into two antigen-binding domains (also known as Fab or fragment antigen-binding) and a constant domain (also known as Fc or fragment crystallizable)22 (Figure 1a). The Fc is the effector entity of the antibody and can bind to Fc receptors on immune cells7 and mediate immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst, and cytokine release.23 In contrast to the fully conserved sequence and structure of the Fc, the Fab is responsible for the vast diversity in recognized antigens and is thus hypervariable.
Targeting Fc effector function in vaccine design
Published in Expert Opinion on Therapeutic Targets, 2021
Simone I. Richardson, Penny L. Moore
Another limitation that has thwarted progress in this field is nomenclature. The terms ‘non-neutralizing’ or ‘extra-neutralizing’ encourage the perception that only antibodies that do not neutralize can mediate potent Fc effector functions. In fact, as illustrated in this review, the protection afforded by many neutralizing antibodies can be enhanced by Fc receptor binding. Similarly, the concept that the Fab and the Fc are distinct regions and functionally independent is misleading as these two regions clearly influence the function of one another. More attention needs to be given to the role of the antigen in determining Fc effector function, with the realization that biophysical features of the Fc are not enough to explain Fc effector potency. Recent studies that harness both neutralization and Fc effector function are valuable steps toward finally translating decades of insight about Fc effector function in protection from infectious disease – something that has lagged woefully behind the great strides made in the engineering of Fc regions for the treatment of cancer. While it is unlikely to be the sole mechanism of effective vaccines, Fc effector function is clearly a major contributor to protection for several infectious diseases.
ABBV-105, a selective and irreversible inhibitor of Bruton’s tyrosine kinase, is efficacious in multiple preclinical models of inflammation
Published in Modern Rheumatology, 2019
Christian Goess, Christopher M. Harris, Sara Murdock, Richard W. McCarthy, Erik Sampson, Rachel Twomey, Suzanne Mathieu, Regina Mario, Matthew Perham, Eric R. Goedken, Andrew J. Long
BTK plays a role in normal hematopoietic cell development and function but is also implicated in several autoimmune disease pathologies including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). CD19+ peripheral blood B cells from RA patients have increased levels of BTK phosphorylation compared to healthy controls [18]. B cell-restricted overexpression of BTK leads to a lupus-like phenotype characterized by spontaneous germinal center formation, increased plasma cells, and autoantibody production [19]. Activation of Fcγ receptors by immune complex containing autoantibodies leads to subsequent engagement of downstream inflammatory pathways, playing a key role in the pathology of both RA and SLE [20,21]. BTK has a significant role in Fc-mediated phagocytosis and immune complex signaling due to its function in the FcγR signaling pathway and, therefore, provides further evidence that BTK-dependent signaling may be a critical part of disease responses in RA and SLE patients [12,22]. Small molecule inhibition of BTK has demonstrated efficacy in several preclinical models of both RA and SLE, although these molecules carry activity toward other Tec family kinases in addition to BTK [23,24]. Due to both its involvement in various pro-inflammatory pathways and its restriction to the hematopoietic lineage, BTK is an attractive target for pharmacological inhibition in immunological disease [1].