Ranibizumab bei Makuladegeneration. Angiogenese‐Hemmung gegen Sehverlust

Mohr-Andrä, Marion; Mohr, Klaus

doi:10.1002/pauz.200700239

Cited by 1 publication

(3 citation statements)

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“…Besides reductive cleavage, radical cleavage into two CysS• radicals has been described [40,41]. Cys thiyl radical (CysS•) pairs may be derived from homolytic dissociation of disulfide bonds during photostressing (8)(9)(10)(11)(12) or from oxygen in combination with metal ions [17,19]. A CysS• radical pair can disproportionate into thiol and thioaldehyde or may capture hydrogen atoms from surrounding amino acids [40].…”

Section: General 771mentioning

confidence: 99%

“…Fab fragments are often used therapeutics. LUCENTIS® (ranibizumab) is a Fab fragment that binds to the vascular epidermal growth factor and thus prevents ingression of chroidal capillaries into the retina . Other therapeutic Fabs are directed toward poisons such as Digoxin (Digibind), colchicine, and other compounds such as tricyclic antidepressants .…”

Section: Assessment Of Criticality Of Disulfide‐related Modificationsmentioning

confidence: 99%

“…Therefore, this review on the quality assessment of disulfide and hinge modifications focusses on IgG1, IgG2, and IgG4 antibodies. In case of conserved structure elements, discussed literature information for endogenous standard antibody formats may also by applicable to new format molecules .…”

Section: Introductionmentioning

confidence: 99%

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Assessment of disulfide and hinge modifications in monoclonal antibodies

Moritz

Stracke

2017

Electrophoresis

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During the last years there was a substantial increase in the use of antibodies and related proteins as therapeutics. The emphasis of the pharmaceutical industry is on IgG1, IgG2, and IgG4 antibodies, which are therefore in the focus of this article. In order to ensure appropriate quality control of such biopharmaceuticals, deep understanding of their chemical degradation pathways and the resulting impact on potency, pharmacokinetics, and safety is required. Criticality of modifications may be specific for individual antibodies and has to be assessed for each molecule. However, some modifications of conserved structure elements occur in all or at least most IgGs. In these cases, criticality assessment may be applicable to related molecules or molecule formats. The relatively low dissociation energy of disulfide bonds and the high flexibility of the hinge region frequently lead to modifications and cleavages. Therefore, the hinge region and disulfide bonds require specific consideration during quality assessment of mAbs. In this review, available literature knowledge on underlying chemical reaction pathways of modifications, analytical methods for quantification and criticality are discussed. The hinge region is prone to cleavage and is involved in pathways that lead to thioether bond formation, cysteine racemization, and iso‐Asp (Asp, aspartic acid) formation. Disulfide or sulfhydryl groups were found to be prone to reductive cleavage, trisulfide formation, cysteinylation, glutathionylation, disulfide bridging to further light chains, and disulfide scrambling. With regard to potency, disulfide cleavage, hinge cleavage, disulfide bridging to further light chains, and cysteinylation were found to influence antigen binding and fragment crystallizable (Fc) effector functionalities. Renal clearance of small fragments may be faster, whereas clearance of larger fragments appears to depend on their neonatal Fc receptor (FcRn) functionality, which in turn may be impeded by disulfide bond cleavage. Certain modifications such as disulfide induced aggregation and heterodimers from different antibodies are generally regarded critical with respect to safety. However, the detection of some modifications in endogenous antibodies isolated from human blood and the possibility of in vivo repair mechanisms may reduce some safety concerns.

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