Effects of the surface polarity of nanomaterials on their interaction with complement protein gC1q

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness among older adults in the Western world. While therapies exist for patients with exudative AMD, there are currently no approved therapies for non-exudative AMD and its advanced form of geographic atrophy (GA). The discovery of genetic variants in complement protein loci with increased susceptibility to AMD has led to the investigation of the role of complement inhibition in AMD with a focus on GA. Here, we review completed and ongoing clinical trials evaluating the safety and efficacy of these studies. Overall, complement inhibition in GA has yielded mixed results. The inhibition of complement factor D has failed pivotal phase 3 trials. Studies of C3 and C5 inhibition meeting their primary endpoint are limited by high rates of discontinuation and withdrawal in the treatment arm and higher risks of conversion to exudative AMD. Studies evaluating other complement members (CFB, CFH, CFI and inhibitors of membrane attack complex—CD59) are ongoing and could offer other viable strategies.

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Halting targeted and collateral damage to red blood cells by the complement system

Seminars in Immunopathology ◽

10.1007/s00281-021-00859-8 ◽

2021 ◽

Author(s):

M. Jalink ◽

E. C. W. de Boer ◽

D. Evers ◽

M. Q. Havinga ◽

J. M. I. Vos ◽

...

Keyword(s):

Red Blood Cells ◽

Complement System ◽

Blood Cells ◽

Defense Mechanism ◽

Standard Of Care ◽

Complement Protein ◽

Complement Inhibition ◽

Complement Inhibitors ◽

The Complement System ◽

Patient Burden

AbstractThe complement system is an important defense mechanism against pathogens; however, in certain pathologies, the system also attacks human cells, such as red blood cells (RBCs). In paroxysmal nocturnal hemoglobinuria (PNH), RBCs lack certain complement regulators which sensitize them to complement-mediated lysis, while in autoimmune hemolytic anemia (AIHA), antibodies against RBCs may initiate complement-mediated hemolysis. In recent years, complement inhibition has improved treatment prospects for these patients, with eculizumab now the standard of care for PNH patients. Current complement inhibitors are however not sufficient for all patients, and they come with high costs, patient burden, and increased infection risk. This review gives an overview of the underlying pathophysiology of complement-mediated hemolysis in PNH and AIHA, the role of therapeutic complement inhibition nowadays, and the high number of complement inhibitors currently under investigation, as for almost every complement protein, an inhibitor is being developed. The focus lies with novel therapeutics that inhibit complement activity specifically in the pathway that causes pathology or those that reduce costs or patient burden through novel administration routes.

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Distinct primary translation products from human liver mRNA give rise to secreted and cell-associated forms of complement protein C2.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)90976-2 ◽

1984 ◽

Vol 259 (16) ◽

pp. 10380-10385 ◽

Cited By ~ 1

Author(s):

D H Perlmutter ◽

F S Cole ◽

G Goldberger ◽

H R Colten

Keyword(s):

Human Liver ◽

Complement Protein

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Safety and effectiveness of eculizumab in Japanese patients with generalized myasthenia gravis: interim analysis of post-marketing surveillance

Therapeutic Advances in Neurological Disorders ◽

10.1177/17562864211001995 ◽

2021 ◽

Vol 14 ◽

pp. 175628642110019

Author(s):

Hiroyuki Murai ◽

Shigeaki Suzuki ◽

Miki Hasebe ◽

Yuji Fukamizu ◽

Ema Rodrigues ◽

...

Keyword(s):

Myasthenia Gravis ◽

Interim Analysis ◽

Japanese Patients ◽

Phase Iii ◽

High Dose ◽

Complement Protein ◽

Double Blind ◽

Post Marketing Surveillance ◽

Post Marketing ◽

History Of

Background: Eculizumab, a humanized monoclonal antibody targeted to terminal complement protein C5, is approved in Japan for treatment of patients with anti-acetylcholine receptor antibody-positive (AChR+) generalized myasthenia gravis (gMG) whose symptoms are difficult to control with high-dose intravenous immunoglobulin (IVIg) therapy or plasmapheresis. Methods: This interim analysis of mandatory post-marketing surveillance in Japan assessed the safety and effectiveness of eculizumab at 26 weeks after treatment initiation in patients with AChR+ gMG. Results: Data were available for 40 adult patients in Japan [62.5% (25/40) female; mean age at eculizumab initiation, 51.0 years]. Fifteen patients had a history of thymoma. Six patients were excluded from the effectiveness analysis set due to participation in the open-label extension part of the phase III, randomized, double-blind, placebo-controlled REGAIN study [ClinicalTrials.gov identifier: NCT02301624]. After 26 weeks’ follow up, 32 patients (80%) were continuing eculizumab treatment. Adverse drug reactions were reported by seven patients [most frequently headache ( n = 3)]. One death was reported during eculizumab treatment (relationship unclear as determined by the treating physician) and there was one death 45 days after the last dose (considered unrelated). No meningococcal infections were reported. Mean (standard deviation) changes from baseline in Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores were −3.7 (2.61) ( n = 27) and −5.6 (3.50) ( n = 26), respectively, at 12 weeks, and −4.3 (2.72) ( n = 26) and −5.6 (4.02) ( n = 24), respectively, at 26 weeks. Improvements in MG-ADL and QMG scores were generally similar in patients with/without a history of thymoma. Frequency of IVIg use decreased following eculizumab initiation. Conclusion: In a real-world setting, eculizumab was effective and well tolerated for the treatment of AChR+ gMG in adult Japanese patients whose disease was refractory to IVIg or plasmapheresis. These findings are consistent with the efficacy and safety results from the global phase III REGAIN study of eculizumab.

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Categorization of surface polarity from a crystallographic approach

Computational Materials Science ◽

10.1016/j.commatsci.2015.11.042 ◽

2016 ◽

Vol 113 ◽

pp. 221-230 ◽

Cited By ~ 23

Author(s):

Yoyo Hinuma ◽

Yu Kumagai ◽

Fumiyasu Oba ◽

Isao Tanaka

Keyword(s):

Surface Polarity

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Atypical Protein Kinase C Is Involved in the Evolutionarily Conserved Par Protein Complex and Plays a Critical Role in Establishing Epithelia-Specific Junctional Structures

The Journal of Cell Biology ◽

10.1083/jcb.152.6.1183 ◽

2001 ◽

Vol 152 (6) ◽

pp. 1183-1196 ◽

Cited By ~ 292

Author(s):

Atsushi Suzuki ◽

Tomoyuki Yamanaka ◽

Tomonori Hirose ◽

Naoyuki Manabe ◽

Keiko Mizuno ◽

...

Keyword(s):

Epithelial Cells ◽

Cell Polarity ◽

Protein Complex ◽

Mdck Cells ◽

Critical Role ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Surface Polarity ◽

C Elegans ◽

Evolutionarily Conserved

We have previously shown that during early Caenorhabditis elegans embryogenesis PKC-3, a C. elegans atypical PKC (aPKC), plays critical roles in the establishment of cell polarity required for subsequent asymmetric cleavage by interacting with PAR-3 [Tabuse, Y., Y. Izumi, F. Piano, K.J. Kemphues, J. Miwa, and S. Ohno. 1998. Development (Camb.). 125:3607–3614]. Together with the fact that aPKC and a mammalian PAR-3 homologue, aPKC-specific interacting protein (ASIP), colocalize at the tight junctions of polarized epithelial cells (Izumi, Y., H. Hirose, Y. Tamai, S.-I. Hirai, Y. Nagashima, T. Fujimoto, Y. Tabuse, K.J. Kemphues, and S. Ohno. 1998. J. Cell Biol. 143:95–106), this suggests a ubiquitous role for aPKC in establishing cell polarity in multicellular organisms. Here, we show that the overexpression of a dominant-negative mutant of aPKC (aPKCkn) in MDCK II cells causes mislocalization of ASIP/PAR-3. Immunocytochemical analyses, as well as measurements of paracellular diffusion of ions or nonionic solutes, demonstrate that the biogenesis of the tight junction structure itself is severely affected in aPKCkn-expressing cells. Furthermore, these cells show increased interdomain diffusion of fluorescent lipid and disruption of the polarized distribution of Na+,K+-ATPase, suggesting that epithelial cell surface polarity is severely impaired in these cells. On the other hand, we also found that aPKC associates not only with ASIP/PAR-3, but also with a mammalian homologue of C. elegans PAR-6 (mPAR-6), and thereby mediates the formation of an aPKC-ASIP/PAR-3–PAR-6 ternary complex that localizes to the apical junctional region of MDCK cells. These results indicate that aPKC is involved in the evolutionarily conserved PAR protein complex, and plays critical roles in the development of the junctional structures and apico-basal polarization of mammalian epithelial cells.

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