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The current global COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a public health crisis with more than 168 million cases reported globally and more than 4.5 million deaths at the time of writing. In addition to the direct impact of the disease, the economic impact has been significant as public health measures to contain or reduce the spread have led to country wide lockdowns resulting in near closure of many sectors of the economy. Antibodies are a principal determinant of the humoral immune response to COVID-19 infections and may have the potential to reduce disease and spread of the virus. The development of monoclonal antibodies (mAbs) represents a therapeutic option that can be produced at large quantity and high quality. In the present study, a mAb combination mixture therapy was investigated for its capability to specifically neutralize SARS-CoV-2. We demonstrate that each of the antibodies bind the spike protein and neutralize the virus, preventing it from infecting cells in an in vitro cell-based assay, including multiple viral variants that are currently circulating in the human population. In addition, we investigated the effects of two different mutations in the Fc portion (YTE and LALA) of the antibody on Fc effector function and the ability to alleviate potential antibody-dependent enhancement of disease. These data demonstrate the potential of a combination of two mAbs that target two different epitopes on the SARS-CoV2 spike protein to provide protection against SARS-CoV-2 infection in humans while extending serum half-life and preventing antibody-dependent enhancement of disease.

The current global COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a public health crisis with more than 168 million cases reported globally and more than 4.5 million deaths at the time of writing. In addition to the direct impact of the disease, the economic impact has been significant as public health measures to contain or reduce the spread have led to country wide lockdowns resulting in near closure of many sectors of the economy. Antibodies are a principal determinant of the humoral immune response to COVID-19 infections and may have the potential to reduce disease and spread of the virus. The development of monoclonal antibodies (mAbs) represents a therapeutic option that can be produced at large quantity and high quality. In the present study, a mAb combination mixture therapy was investigated for its capability to specifically neutralize SARS-CoV-2. We demonstrate that each of the antibodies bind the spike protein and neutralize the virus, preventing it from infecting cells in an in vitro cell-based assay, including multiple viral variants that are currently circulating in the human population. In addition, we investigated the effects of two different mutations in the Fc portion (YTE and LALA) of the antibody on Fc effector function and the ability to alleviate potential antibody-dependent enhancement of disease. These data demonstrate the potential of a combination of two mAbs that target two different epitopes on the SARS-CoV2 spike protein to provide protection against SARS-CoV-2 infection in humans while extending serum half-life and preventing antibody-dependent enhancement of disease.

Human monoclonal antibody (mAb) treatments are promising for COVID-19 prevention, post-exposure prophylaxis, or therapy. However, the titer of neutralizing antibodies required for protection against SARS-CoV-2 infection remains poorly characterized. We previously described two potently neutralizing mAbs COV2-2130 and COV2-2381 targeting non-overlapping epitopes on the receptor-binding domain of SARS-CoV-2 spike protein. Here, we engineered the Fc-region of these mAbs with mutations to extend their persistence in humans and reduce interactions with Fc gamma receptors. Passive transfer of individual or combinations of the two antibodies (designated ADM03820) given prophylactically by intravenous or intramuscular route conferred virological protection in a non-human primate (NHP) model of SARS-CoV-2 infection, and ADM03820 potently neutralized SARS-CoV-2 variants of concern in vitro. We defined 6,000 as a protective serum neutralizing antibody titer in NHPs against infection for passively transferred human mAbs that acted by direct viral neutralization, which corresponded to a concentration of 20 microgram/mL of circulating mAb. Competing Interest Statement R.R.C., R.V.H., D.M.S., M.H., B.H., L.C., G.N., M.T.T and K.H. are employees of Ology Bioservices. C.G.G. and N.M.D. are employees of the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense for the United States Department of Defense (JPEO-CBRND). S.A.H. is an employee of Logistics Management Institute (LMI), performing technical contract support for JPEO-CBRND. J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Board of Meissa Vaccines and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from Takeda, IDBiologics and AstraZeneca. Vanderbilt University has applied for patents related to antibodies studied in this paper. M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The laboratory of M.S.D. has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions.

Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.

IntroductionIdiopathic pulmonary fibrosis (IPF) is a lung disease of unknown cause characterised by progressive scarring, with limited effective treatment and a median survival of only 2–3 years. Our aim was to identify potential occupational and environmental exposures associated with IPF in Australia.MethodsCases were recruited by the Australian IPF registry. Population-based controls were recruited by random digit dialling, frequency matched on age, sex and state. Participants completed a questionnaire on demographics, smoking, family history, environmental and occupational exposures. Occupational exposure assessment was undertaken with the Finnish Job Exposure Matrix and Australian asbestos JEM. Multivariable logistic regression was used to describe associations with IPF as ORs and 95% CIs, adjusted for age, sex, state and smoking.ResultsWe recruited 503 cases (mean±SD age 71±9 years, 69% male) and 902 controls (71±8 years, 69% male). Ever smoking tobacco was associated with increased risk of IPF: OR 2.20 (95% CI 1.74 to 2.79), but ever using marijuana with reduced risk after adjusting for tobacco: 0.51 (0.33 to 0.78). A family history of pulmonary fibrosis was associated with 12.6-fold (6.52 to 24.2) increased risk of IPF. Occupational exposures to secondhand smoke (OR 2.1; 1.2 to 3.7), respirable dust (OR 1.38; 1.04 to 1.82) and asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF. However occupational exposures to other specific organic, mineral or metal dusts were not associated with IPF.ConclusionThe burden of IPF could be reduced by intensified tobacco control, occupational dust control measures and elimination of asbestos at work.

Benthic foraminiferal assemblages are useful tools for paleoenvironmental studies but rely on the calibration of live populations to modern environmental conditions to allow interpretation of this proxy downcore. In regions such as the region offshore of Thwaites Glacier, where relatively warm Circumpolar Deep Water is driving melt at the glacier margin, it is especially important to have calibrated tracers of different environmental settings. However, Thwaites Glacier is difficult to access, and therefore there is a paucity of data on foraminiferal populations. In sediment samples with in situ bottom-water data collected during the austral summer of 2019, we find two live foraminiferal populations, which we refer to as the Epistominella cf. exigua population and the Miliammina arenacea population, which appear to be controlled by oceanographic and sea ice conditions. Furthermore, we examined the total foraminiferal assemblage (i.e., living plus dead) and found that the presence of Circumpolar Deep Water apparently influences the calcite compensation depth. We also find signals of retreat of the Thwaites Glacier Tongue from the low proportion of live foraminifera in the total assemblages closest to the ice margin. The combined live and dead foraminiferal assemblages, along with their environmental conditions and calcite preservation potential, provide a critical tool for reconstructing paleoenvironmental changes in ice-proximal settings.

The rowmotion operator acting on the set of order ideals of a finite poset has been the focus of a significant amount of recent research. One of the major goals has been to exhibit homomesies: statistics that have the same average along every orbit of the action. We systematize a technique for proving that various statistics of interest are homomesic by writing these statistics as linear combinations of \"toggleability statistics\" (originally introduced by Striker) plus a constant. We show that this technique recaptures most of the known homomesies for the posets on which rowmotion has been most studied. We also show that the technique continues to work in modified contexts. For instance, this technique also yields homomesies for the piecewise-linear and birational extensions of rowmotion; furthermore, we introduce a \\(q\\)-analogue of rowmotion and show that the technique yields homomesies for \"\\(q\\)-rowmotion\" as well.

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs , but also revealed how quickly viral escape can curtail effective options . With the emergence of the SARS-CoV-2 Omicron variant in late 2021, many clinically used antibody drug products lost potency, including Evusheld and its constituent, cilgavimab . Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies with a known clinical profile to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign COV2-2130 to rescue in vivo efficacy against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the contemporaneously dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and many variants of concern that subsequently emerged, and provides protection against the strains tested, WA1/2020, BA.1.1, and BA.5. Deep mutational scanning of tens of thousands pseudovirus variants reveals 2130-1-0114-112 improves broad potency without incurring additional escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Because our approach is computationally driven, not requiring experimental iterations or pre-existing binding data, it could enable rapid response strategies to address escape variants or pre-emptively mitigate escape vulnerabilities.