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Clinical Studies In Oncology
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Jan Schmielau, Wolff Schmiegel
The classic complement cascade could be initiated by binding of the Clq-subunit to the CH2-domain of aggregated IgG molecules or to the CH3-domain of a single IgM-molecule. Cell lysis in complement-mediated cytotoxicity (CDC) occurs as a consequence of formation of the membrane attack complex which consists of a tetramolecular C5b, C6, C7, C8-complex and up to twelve C9 molecules that assemble a membrane perforating tube (Müller-Eberhard, 1988). Cellular cytotoxicity utilizes a C9-related protein, perforin, which is cytotoxic by itself, and is supplemented by secreted enzymes and lymphokines like the tumor necrosis factor α (TNF-α) and interferon y (IFN-γ). Among murine antibodies the mAb of the IgM and IgG3-class are most effective in mediating cytotoxicity in conjugation with human complement followed by IgG2a and IgG2b (Herlyn et al., 1985).
Complement system network in cell physiology and in human diseases
Published in International Reviews of Immunology, 2021
Roberta Romano, Giuliana Giardino, Emilia Cirillo, Rosaria Prencipe, Claudio Pignata
Another major clinical disorder related to abnormalities of the regulatory network of the complement cascade is the Paroxysmal Nocturnal Hemoglobinuria. Paroxysmal Nocturnal Hemoglobinuria is a rare hematopoietic stem cell disease due to the clonal expansion of hematopoietic stem cells carrying a somatic mutation in the gene phosphatidylinositol glycan anchor biosynthesis, class A (PIG-A) located on X chromosome. This gene encodes for an enzyme involved in the biosynthesis of phosphatidylinositol glycan that serves as anchor for membrane proteins such as Decay Accelerating Factor and CD59, whose physiological function is to inhibit complement system activation. DAF inhibits C3 convertase while CD59 competes with the C9 for the binding to the C5b-C8 complex thus interfering with Membrane Attack Complex formation. When their regulatory effect on complement system is impaired, complement mediated lysis of cells occurs leading to profound intravascular hemolysis and hemoglobinuria, hallmarks of the disease. Patients affected with Paroxysmal Nocturnal Hemoglobinuria show moderate to severe anemia and are prone to thromboembolic events usually affecting hepatic or cerebral veins and representing the main cause of morbidity and mortality associated with the disease [56]. Intravascular hemolysis releases free hemoglobin, which causes typical symptoms like dysphagia and abdominal pain, due to smooth muscles dystonia consequent to nitric oxide (NO) depletion.
Connecting the sequence dots: shedding light on the genesis of antibodies reported to be designed in silico
Published in mAbs, 2019
Maximiliano Vásquez, Eric Krauland, Laura Walker, Dane Wittrup, Tillman Gerngross
As in the influenza example, the similarity is remarkable, with 89% and 90% identity, for VH and VL, respectively. This is obtained without any gaps in the alignment, and thus all CDR lengths are identical between ZAb_FLEP and EDE1 C8. Considering conservative substitutions, as before, yields similarities of 95% and 98%, respectively, for VH and VL. Within the CDRs of the VH, there is a single V to A non-conservative substitution (as defined by BLAST default settings). There are only three conservative substitutions in VL CDRs; in fact, one in each CDR, all involving S/T exchanges. The non-conservative substitutions in the context of the known EDE1 C8 complex with Zika protein27 are depicted in Figure 5. Once again, given the remarkable sequence similarity, it is important to emphasize the prior publication of the EDE1 C8 sequences, in the context of both dengue and Zika (Figure S2).27,30