Complement dependent cytotoxicity

Another effector function/mode of action of mAbs is the so-called complement-dependent cytotoxicity or complement-mediated cell death . Activation of the complement system can lead to lysis of the antigen-presenting cell, or can induce inflammation reactions aimed at eliminating these cells efficiently. The successive steps of the complement activation can be summarized in a simplified way [9]  

It must be noted that not all mAbs of the IgGl or IgG3 isotypes are capable of activating CDC, most likely because in some cases the density of the antigen may be too low to support the formation of Fc dimers. 

Clearly, one prerequisite for ADCC or CDC is an intact immune system. Hence, unconjugated mAbs are unsuitable for the treatment of immunocompromised patients. In contrast to classical cytotoxic agents, tumor cells will also be attacked in the G0 phase by the antibody-induced ADCC and CDC mechanisms, this being a major advantage of mAbs in antineoplastic therapy. 

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An alternative mechanism is based on non-complement dependent cytotoxicity, e.g., food allergen stimulation of mechanisms of antibody dependent cellular cytotoxicity (ADCC), cytotoxicity of natural killer cells or macrophages. The contribution of ADCC in gastroenteropathy of children induced by cow s milk allergens was demonstrated by Owen et al. (1993). 

It has been proposed that rituximab also functions through the complement-dependent cytotoxicity (CDC) pathway, specifically the classical pathway, which requires... 

Rituximab is a chimeric monoclonal antibody that targets CD20 lymphocytes (see Chapter 55). This depletion takes place through cell-mediated and complement-dependent cytotoxicity and stimulation of cell apoptosis. Depletion of lymphocytes reduces inflammation by decreasing the presentation of antigens to T lymphocytes and inhibiting the secretion of proinflammatory cytokines. Rituximab rapidly depletes peripheral cells although this depletion neither correlates with efficacy nor with toxicity. 

Engineered IgG antibodies have been constructed with altered affinity to human Fey receptors and altered potency in vitro and in animal models [14, 31-33]. Mutations of critical residues in the Fc region (CH2 domain or the hinge region joining CH1 and CH2) have enhanced or decreased antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) [33-37]. In addition, alterations in residues located at the CH2 domain of I gC, i involved in binding with Clq protein, a component of the complement activation cascade, resulted in a significant increase in CDC activity [34, 35]. 

For complement-dependent cytotoxicity, a complex cascade of protein binding and cleavage occurs that culminates in final complement mediated effector functions of phagocytosis, recruitment and activation of leukocytes, and osmotic lysis. It has been reported that Rituximab (anti-CD20) utilizes a complement-dependent mechanism for tumor cell destruction [14], If the desired effect of a therapeutic antibody is complement-dependent activity, the isotype subgroup chosen should be one that binds to complement proteins (IgGl or IgG3). 

CDC Complement-dependent cytotoxicity complement-mediated cell death... 

Goat anti-rabbit IgM was used as the second antibody (step 4), since goat IgG complexed to cell-bound antigen will bind PA efficiently even though fluid-phase goat IgG will not. Even after booster injections, antiline-1 is predominantly IgM while anti-line-10 is IgG. These results agree with the class of complement-dependent cytotoxic antibody determined semiquantitatively. ... 

B-cell receptor bovine semm albumin cerium (IV) ammonium nitrate complement dependent cytotoxicity CDS cytotoxic T-lymphocytes l,8-diazabicyclo[5.4.0]undec-7-ene dendritic cell deoxyribonucleic acid epidermal growth factor enzyme-linked immunosorbent assay endoplasmic reticulum ethyl... 

Go structures Increased dimerization G2 increases complement-dependent cytotoxicity 4.3% Variable Variable Low... 

Antibodies represent a class of flexible molecular adaptors that play a vital role in the adaptive immune systems of vertebrates [1]. First discovered by von Behring and Kitasato in 1890 [2], it was not before 1960 that their basic structure was determined by Porter and Edehnaim [3]. With their inherent diversity and heterogeneity, antibodies mediate humoral and cellular immune responses, and directly execute biochemical mechanisms such as antigen recognition, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) [4]. In most higher mammals, antibodies exist in five distinct classes (IgG, IgA, IgM, IgD, and IgE) that... 

IgM and IgG reactivities by flow cytometry and complement-dependent cytotoxicity (CDC) assays, evaluated using Tn(c) positive LS-C and Tn(c) negative LS-B colon cancer cells. A phase I clinical trial in prostate cancer patients showed that all patients immunized with Tn(c)-MBS-KLH/QS-21 developed high-titer antibody responses against Tn(c), confirming the tmmunogenicity of this Tn(c) vaccine. In addition, the levels of PSA observed in the treated patients either stabilized or dechned, of which the clinical impact and relevance remains to be validated. ... 

Ab, antibody GDC, complement-dependent cytotoxicity DFS, disease-free survival OS, overall survival PSA, prostate-specific anfigen TOP, time-fo-disease progression. 

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