Diffractive optic intraocular lens exchange: indications and outcomes.

PURPOSE: To assess indications and outcomes of surgical exchange of diffractive optic multifocal and extended depth-of-focus intraocular lenses (IOLs) in favor of monofocal IOLs. SETTING: Private practice, Los Angeles, California. DESIGN: Retrospective chart review. METHODS: All cases of diffractive optic IOL exchange between June 2007 and October 2020 for diffractive optic dysphotopsia (DOD) (ie, light-induced concentric circles and spider web patterns), poor visual quality, or night vision symptoms were evaluated retrospectively regarding surgical indications, comorbidities, surgical methods, surgical complications, and visual outcomes. Ocular surface disease and ametropia were managed prior to consideration of IOL exchange. RESULTS: The charts of 64 eyes of 46 patients were included. 53/64 (83%) had DOD, 50/64 (78%) experienced reduced quality of vision, and 12/64 (19%) complained of night vision difficulties. 27/64 (42%) of eyes had no ocular comorbidities; 15/64 (23%) of eyes had more than 1 comorbid condition, and 12/64 (19%) were post-laser refractive surgery. Laser posterior capsulotomy had been performed in 15/64 (23%) of eyes. There were a variety of inciting diffractive optic IOLs and various monofocal exchange lenses and fixation techniques were used based on symptoms, comorbidities, and status of the posterior capsule. After IOL exchange, all eyes were relieved of DOD, and all eyes had improved or unchanged corrected distance visual acuity. CONCLUSIONS: Diffractive optic IOLs may induce unsatisfactory visual outcomes. However, in this large series of IOL exchanges, DOD and reduced visual function can be overcome with exchange for a monofocal IOL, despite comorbidities or an open posterior capsule.

In Vivo Reoxidation Kinetics of Free Thiols in Multiple Domains of IgG1 Antibodies in Rats.

While free thiols in monoclonal antibodies (mAbs) have been extensively characterized by in vitro studies to probe its effect on antibody function and stability, their in vivo biotransformation has not been comprehensively studied. In this study, a panel of five recombinant IgG1 mAbs with elevated free thiols in the VH, VL, and CH2 domains were intravenously administered into Wistar rats. In vivo biotransformation of thirty-five free thiol sites in total (7 disulfide pairs in VL, CL, VH, CH1, HH, CH2, CH3 domains across the 5 mAbs) were monitored using a denaturing differential isotopic tagging procedure on immunopurified timepoints followed by LC-MS of tryptic digests. The free thiol levels in two VH domain and one CH2 domain disulfide sites decreased in vivo following first order kinetics. Free thiol levels of the remaining 32 sites were remarkably stable in vivo. Further analytical characterization highlighted a positive association between a free thiol's solvent accessibility and a free thiol's reoxidation propensity. The data and discussion presented here shed valuable insights into the in vivo fate of free thiols in several recombinant IgG1s and its implications for free thiols as a product quality attribute in therapeutic mAb products.

Stress Temperature Studies in Small Scale Hastelloy® Drug Substance Containers Lead to Increased Extent of and Increased Variability in Antibody-Drug Conjugate and Monoclonal Antibody Aggregation: Evidence for Novel Oxidation-Induced Crosslinking in Monoclonal Antibodies.

Health authorities require that suitable stability of the drug substance be shown in relevant materials of construction. ICH Q1A(R2) explicitly states that "stability studies should be conducted on drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution". Stainless steel containers are commonly used for the long-term storage of frozen bulk drug substances (DSs). Hastelloy®-based metal containers are sometimes used due to their higher corrosion resistance and significantly lower iron content to mitigate the potential corrosion-related risks associated with high salt formulations. Despite their benefits, we have found that elevated temperature stability studies in small scale Hastelloy® containers can lead to degradation that is not representative of degradation under typical storage conditions relevant to the manufacturing process. We provide evidence for an oxidation-induced aggregation mechanism that is based on Fenton chemistry with peroxide being supplied by the autoxidation of polysorbate at stress temperatures. Further, variation in the rates of iron leaching between individual small scale containers is shown to be the cause of the variable rates of degradation through strong correlations between leached iron levels and the extents of oxidation and aggregation. The addition of a metal chelator or the removal of polysorbate from the formulation mitigates the oxidation and the non-representative behavior. Extended characterization by LC-MS and 18O labeled peptide mapping shows that a significant portion of the aggregate formed under these conditions is covalently crosslinked and that the predominant covalent species is either a dityrosine or tyrosine-tryptophan crosslink between an Fc peptide and a Fab peptide. This report is the first time either of these two crosslinks have been reported for antibodies with detailed analytical characterization. Because the behavior observed in these studies is not representative of degradation under typical storage conditions relevant to the manufacturing process, this study demonstrates that small scale stress studies in metal containers should be performed with caution and that extended incubation times can lead to non-representative degradation mechanisms.