Preclinical B cell depletion and safety profile of a brain-shuttled crystallizable fragment-silenced CD20 antibodySchumacher, Pichereau, Bessa
et alClin Transl Med (2025) 15 (3), e70178
Abstract: The blood-brain barrier (BBB) presents a major challenge for the development of monoclonal antibody (mAb)-based therapies for brain disorders. To improve the likelihood of success of such therapies, Roche Brainshuttle technology utilizes a single anti-transferrin receptor 1 (TfR1)-antigen-binding antibody fragment linked to a therapeutic antibody, allowing engagement with TfR1 to transport the therapeutic antibody into the brain via receptor-mediated transcytosis.We compared Fc-silenced and Fc-competent variants of the Brainshuttle and the parental (non-shuttled) type II CD20 mAb, obinutuzumab in in vitro and in vivo (mouse and cynomolgus macaque) models. Endpoints assessed included B cell binding, B cell killing, tolerability, and ability to cross the BBB.The Fc-silenced Brainshuttle construct showed a superior safety profile compared with the Fc-competent construct while maintaining the ability to cross the BBB and to deplete B cells in head-to-head comparisons in human and mouse in vitro and in mouse and cynomolgus macaque in vivo models.Together, our data provide a path forward for the future development of safe and efficacious brain-targeted B-cell-depleting therapies.The BBB hinders mAb-based brain disorder therapies A brain-targeted B-cell-depleting mAb for MS that efficiently crosses the BBB via hTfR1 was developed using Brainshuttle™ technology (1a and 1b) The Brainshuttle™-CD20 mAb was well tolerated (2a and 2b) and displayed B-cell-killing properties (1c), paving the way for future development and clinical translation of TfR1-targetingtherapies for increased brain penetration.© 2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
Respiratory tract lining fluid copper content contributes to pulmonary oxidative stress in patients with systemic sclerosisFrølich, Dove, Friberg
et alWellcome Open Res (2024) 9, 139
Abstract: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs, mostly affecting young and middle-aged women. Significant questions remain as to its pathogenesis, especially the triggers for the associated interstitial lung disease (SSc-ILD). We examined the extent to which SSc and SSc-ILD were related to oxidative stress and altered metal homeostasis at the air-lung interface.In this case-control study, we recruited 20 SSc patients, of which 11 had SSc-ILD. Eighteen healthy individuals were recruited as age-matched healthy controls, for a total of 38 study participants. Low molecular weight antioxidants (ascorbate, urate and glutathione), metal transport and chelation proteins (transferrin and ferritin) and metals (Fe and Cu) concentrations, including a measure of the catalytically active metal pool, were determined in respiratory tract lining fluid (RTLF) collected by bronchoalveolar lavage from the SSc group and compared with healthy controls.In the SSc group, 14 individuals were of female sex (70%) and the median age was 57 years (range 35-75). We observed evidence of oxidative stress in the RTLFs of SSc patients, characterised by increased concentrations of glutathione disulphide (GSSG, P<0.01), dehydroascorbate (DHA, P<0.05) and urate (P<0.01). This was associated with elevated RTLF Fe (P=0.07) and Cu (P<0.001), and evidence of a catalytic metal pool, demonstrated by an enhanced rate of ascorbate oxidation in the recovered lavage fluid (p<0.01). Cu concentrations were significantly associated with the ascorbate depletion rate (r=0.76, P<0.001), and GSSG (r=0.38, P<0.05) and protein carbonyl (r=0.44, P<0.01) concentrations. Whilst these markers were all increased in SSc patients, we found no evidence for an association with SSc-ILD.These data confirm the presence of oxidative stress in the airways of SSc patients and, for the first time, suggest that an underlying defect in metal homeostasis at the air-lung interface may play a role in disease progression.Copyright: © 2025 Frølich A et al.
Are the serum iron parameters related to the severity of obstructive sleep apnea syndrome?Yumrukuz Şenel, Şahin, Çolak
et alSleep Breath (2025) 29 (2), 132
Abstract: To evaluate the correlation and relationship between iron parameters including serum iron level, iron-binding capacity, ferritin, transferrin saturation, and the severity of OSAS in the patients who underwent polysomnography.We retrospectively reviewed 209 patients and divided the patients into two groups; AHI ≥ 30 and AHI < 30. The groups were compared using the Mann-Whitney U and the chi-square test. In addition, Spearman's correlation analysis was performed to analyze the correlation between AHI and iron parameters.The mean age of the patients was 47.9 ± 13.7 (19-89) years. Of the 209 patients, 40.7% (n = 85) were female and 59.3% (n = 124) were male. Iron and transferrin saturation was significantly lower in the patients with AHI ≥ 30 compared to the patients with AHI < 30. In female patients, there wasn't any correlation between AHI and iron, ferritin, transferrin saturation, and iron-binding capacity. But, there was a significant negative correlation between the AHI and iron (r = -0.292, p = 0.001) and transferrin saturation (r = -0.349, p < 0.001) in male patients. Also, the AHI was significantly positively correlated with iron binding capacity (r = 0.307, p = 0.001) in male patients.Our results showed that iron levels were lower in severe OSAS. Suggesting that iron levels decrease as a result of oxidative stress and inflammation seen in OSAS, iron parameters may be a good biomarker in OSAS patients.© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Effects of Darbepoetin Alfa and Ferric Derisomaltose Plus Darbepoetin Alfa in Functional Iron-Deficiency AnemiaSohn, Sul, Kim
et alInt J Mol Sci (2025) 26 (5)
Abstract: Functional iron-deficiency anemia (FIDA) is a side effect of many cancer treatments, occurring when chemotherapy drugs damage bone marrow cells, which are responsible for producing red blood cells, due to the myelosuppressive effects of chemotherapy, or to the cancer itself. This study was performed to compare the effects of darbepoetin alfa alone, or in combination with ferric derisomaltose in cancer patients with FIDA, and to elucidate the mechanism underlying the effects in F36E cells. F36E cells treated with darbepoetin alfa showed increased cell viability. AML and GC cells treated with darbepoetin alfa, ferric derisomaltose, or ferric derisomaltose plus darbepoetin alfa showed no induction of apoptosis. The effects of these drugs on the anticancer efficacy of PTX chemotherapy were examined by analyzing cell viability and induction of apoptosis. Darbepoetin alfa, ferric derisomaltose, and ferric derisomaltose plus darbepoetin alfa showed no significant inhibitory effects on the apoptosis-inducing activity of PTX in GC cell lines. Patients with chemotherapy-induced FIDA in Group I receiving ferric derisomaltose plus darbepoetin alfa showed higher hemoglobin levels, transferrin saturation, and ferritin levels compared to those in Group II, treated with darbepoetin alfa alone. In cancer patients with FIDA, the prognosis of anemia treatment was better in the ferric derisomaltose plus darbepoetin alfa combination group than in the group receiving darbepoetin alfa monotherapy.
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