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BackgroundSAB-185, a novel fully human IgG polyclonal immunoglobulin product, underwent phase 2 evaluation for nonhospitalized adults with mild-moderate coronavirus disease 2019 (COVID-19).MethodsParticipants received intravenous SAB-185 3840 units/kg (low-dose) or placebo, or 10 240 units/kg (high-dose) or placebo. Primary outcome measures were nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA < lower limit of quantification (LLOQ) at study days 3, 7, and 14, time to symptomatic improvement, and safety through day 28.ResultsTwo-hundred thirteen participants received low-dose SAB-185/placebo (n = 107/106) and 215 high-dose SAB-185/placebo (n = 110/105). The proportions with SARS-CoV-2 RNA < LLOQ were higher for SAB-185 versus placebo at days 3 and 7 and similar at day 14, and significantly higher at day 7 for high-dose SAB-185 versus placebo only, relative risk 1.23 (95% confidence interval, 1.01-1.49). At day 3, SARS-CoV-2 RNA levels were lower with low-dose and high-dose SAB-185 versus placebo: differences in medians of -0.78 log10 copies/mL (P = .08) and -0.71 log10 copies/mL (P = .10), respectively. No difference was observed in time to symptom improvement: median 11/10 days (P = .24) for low-dose SAB-185/placebo and 8/10 days (P = .50) for high-dose SAB-185/placebo. Grade ≥3 adverse events occurred in 5%/13% of low-dose SAB-185/placebo and 9%/12% of high-dose SAB-185/placebo.ConclusionsSAB-185 was safe and generally well tolerated and demonstrated modest antiviral activity in predominantly low-risk nonhospitalized adults with COVID-19. Clinical Trials Registration. NCT04518410.

Since SARS-CoV-2 emerged in late 2019, it spread from China to the rest of the world. An initial concern was the potential for vaccine- or antibody-dependent enhancement (ADE) of disease as had been reported with other coronaviruses. To evaluate this, we first developed a ferret model by exposing ferrets to SARS-CoV-2 by either mucosal inoculation (intranasal/oral/ocular) or inhalation using a small particle aerosol. Mucosal inoculation caused a mild fever and weight loss that resolved quickly; inoculation via either route resulted in virus shedding detected in the nares, throat, and rectum for 7–10 days post-infection. To evaluate the potential for ADE, we then inoculated groups of ferrets intravenously with 0.1, 0.5, or 1 mg/kg doses of a human polyclonal anti-SARS-CoV-2 IgG from hyper-immunized transchromosomic bovines (SAB-185). Twelve hours later, ferrets were challenged by mucosal inoculation with SARS-CoV-2. We found no significant differences in fever, weight loss, or viral shedding after infection between the three antibody groups or the controls. Signs of pathology in the lungs were noted in infected ferrets but no differences were found between control and antibody groups. The results of this study indicate that healthy, young adult ferrets of both sexes are a suitable model of mild COVID-19 and that low doses of specific IgG in SAB-185 are unlikely to enhance the disease caused by SARS-CoV-2. [ABSTRACT FROM AUTHOR]

The DiversitabTM system produces target specific high titer fully human polyclonal IgG immunoglobulins from transchromosomic (Tc) bovines shown to be safe and effective against multiple virulent pathogens in animal studies and Phase 1, 2 and 3 human clinical trials. We describe the functional properties of a human monoclonal antibody (mAb), 38C2, identified from this platform, which recognizes recombinant H1 hemagglutinins (HAs) and induces appreciable antibody‐dependent cellular cytotoxicity (ADCC) activity in vitro. Interestingly, 38C2 monoclonal antibody demonstrated no detectable neutralizing activity against H1N1 virus in both hemagglutination inhibition and virus neutralization assays. Nevertheless, this human monoclonal antibody induced appreciable ADCC against cells infected with multiple H1N1 strains. The HA‐binding activity of 38C2 was also demonstrated in flow cytometry using Madin‐Darby canine kidney cells infected with multiple influenza A H1N1 viruses. Through further investigation with the enzyme‐linked immunosorbent assay involving the HA peptide array and 3‐dimensional structural modeling, we demonstrated that 38C2 appears to target a conserved epitope located at the HA1 protomer interface of H1N1 influenza viruses. A novel mode of HA‐binding and in vitro ADCC activity pave the way for further evaluation of 38C2 as a potential therapeutic agent to treat influenza virus infections in humans. [ABSTRACT FROM AUTHOR]

The genetic organization of the idn genes that encode the pathway for L-idonate catabolism was characterized. The monocistronic idnK gene is transcribed divergently from the idnDOTR genes, which were shown to form an operon. The 215-bp regulatory region between the idnK and idnD genes contains promoters in opposite orientation with transcription start sites that mapped to positions -26 and -29 with respect to the start codons. The regulatory region also contains a single putative IdnR/GntR binding site centered between the two promoters, a CRP binding site upstream of idnD, and an UP element upstream of idnK. The genes of the L-idonate pathway were shown to be under catabolite repression control. Analysis of idnD- and idnK-lacZ fusions in a nonpolar idnD mutant that is unable to interconvert L-idonate and 5-ketogluconate indicated that either compound could induce the pathway. The L-idonate pathway was first characterized as a subsidiary pathway for D-gluconate catabolism (GntII), which is induced by D-gluconate in a GntI (primary gluconate system) mutant. Here we showed that the idnK and idnD operons are induced by D-gluconate in a GntI system mutant, presumably by endogenous formation of 5-ketogluconate from D-gluconate. Thus, the regulation of the GntII system is appropriate for this pathway, which is primarily involved in L-idonate catabolism; the GntII system can be induced by D-gluconate under conditions that block the GntI system.

Research has been conducted on the genomic expression patterns of cells that grow on minimal glucose medium in Escherichia coli. The effect of growth conditions on the physiological state of the cells is discussed.

Experiments were performed to investigate the physiological dynamics of metabolic pathways in the GntII system genes of Escherichia coli through a biochemical analysis of the pathway enzyme gluconate and its accompanying intermediates and growth experiments involving mutants with lesions in particular sites in the pathway. DNA sequence analysis and nuclear magnetic resonance studies were performed on the mutants. Findings suggested that the GntII system genes encoded a pathway for catabolism of L-idonate in which D-gluconate was an intermediate.

Single-copy gnt::lacZ fusion and Northern hybridization analysis were utilized to characterize the expression of the Escherichia coli gntT gene and determine the biochemical function of its protein product. Northern hybridization analysis of the Escherichia coli gntT gene indicated the presence of properties that were characteristic of integral membrane transport proteins. Furthermore, gntT gene expression was enhanced during the logarithmic phase indicating the role of GntT in promoting microbial growth.

The article offers information on the technical aspects of therapeutic protein production. It looks into the Chinese Hamster Ovary (CHO) cell biology that manages the production of therapeutic recombinant proteins in order to address the demand for it. The authors highlight the significance of a systems-biology discovery approach in widening the interpretation of CHO cellular and molecular biology toward the identification of gene targets and cellular signaling pathways. Apart from this, they also stress the value of formulating enhanced cell culture media formulations in optimizing therapeutic protein production from CHO cells.

Examines the genomic expression patterns of Escherichia coli cell growing in minimal and rich media. Comparison of growth rate between the two media; Role of the RpoS regulation in cellular growth; Impact of the medium quality on growth rate; Effect of environmental stresses on gene expression; Function of the genes in coregulation.

Hantaviruses are rodent-borne viruses that cause severe disease in infected humans. In the New World, major hantaviruses include Andes virus (ANDV) and Sin Nombre virus (SNV) causing hantavirus pulmonary syndrome. In the Old World, major hantaviruses include Hantaan virus (HTNV) and Puumala virus (PUUV) causing hemorrhagic fever with renal syndrome. Here, we produced a pan-hantavirus therapeutic (SAB-163) comprised of fully human immunoglobulin purified from the plasma of transchromosomic bovines (TcB) vaccinated with hantavirus DNA plasmids coding for the major glycoproteins of ANDV, SNV, HTNV, and PUUV. SAB-163 has potent neutralizing antibodies (PRNT50 > 200,000) against the four targeted hantavirus and cross-neutralization against several other heterotypic hantaviruses. At a dosage of 10 mg/kg, SAB-163 is bioavailable in Syrian hamsters out to 70 days post-treatment with a half-life of 10-15 days. At this same dosage, SAB-163 administered 1 day before, or 5 days after exposure, protected all hamsters from lethal disease caused by ANDV. At a higher dose, partial but significant protection was achieved as late as day 6. SAB-163 also protected hamsters in the HTNV, PUUV, and SNV infection models when administered 1 day before or up to 3 days after challenge. This pan-hantavirus therapeutic is attractive because it is fully human, multi-targeted, safe, stable at 4°C, and effective in animal models. SAB-163 was evaluated for safety in GLP human tissue binding studies and a GLP rabbit toxicity study at 365 and 730 mg/kg and is investigational new drug enabled for phase 1 clinical trial(s)., Importance: This candidate polyclonal human IgG product was produced using synthetic gene-based vaccines and transgenic cows. Having now gone through cGMP production, GLP safety testing, and efficacy testing in animals, SAB-163 is the world's most advanced anti-hantavirus antibody-based medical countermeasure, aside from convalescent human plasma. Importantly, SAB-163 targets the most prevalent hantaviruses on four continents., Competing Interests: P.C., E.J.S., and J.W.H. are inventors on patents or patents pending related to technology used to develop proof-of-concept antibody-based products described in the paper (i.e., lipid nanoparticles, Tc bovine, and DNA vaccines).

Background: To address the need for novel COVID-19 therapies, we evaluated the fully-human polyclonal antibody product SAB-185 in a phase 3 clinical trial., Methods: Non-hospitalized high-risk adults within 7 days of COVID-19 symptom onset were randomized 1:1 to open-label SAB-185 3,840 units/kg or casirivimab/imdevimab 1200 mg. Non-inferiority comparison was undertaken for the pre-Omicron population (casirivimab/imdevimab expected to be fully active) and superiority comparison for the Omicron population (casirivimab/imdevimab not expected to be active). Primary outcomes were the composite of all-cause hospitalizations/deaths and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28. Secondary outcomes included time to sustained symptom improvement and resolution., Results: Enrollment was terminated early due to low hospitalization/death rates upon Omicron emergence. 733 adults were randomized, 255 included in pre-Omicron and 392 in Omicron analysis populations. Hospitalizations/deaths occurred in 6 (5.0%) and 3 (2.2%) of pre-Omicron SAB-185 and casirivimab/imdevimab arms, respectively (absolute difference [95% CI] 2.7% [-2.3%, 8.6%]), inconclusive for non-inferiority; and 5 (2.5%) versus 3 (1.5%) (absolute difference 1.0% [-2.3%, 4.5%]) for Omicron. Risk ratios for grade ≥3 TEAEs were 0.94 [0.52, 1.71] (pre-Omicron) and 1.71 [0.96, 3.07] (Omicron). Time to symptom improvement and resolution were shorter for SAB-185, median 11 vs 14 (pre-Omicron) and 11 vs 13 days (Omicron) (symptom improvement), and 16 vs 24 days and 18 vs >25 days (symptom resolution), p<0.05 for symptom resolution for Omicron only., Conclusions: SAB-185 had an acceptable safety profile with faster symptom resolution in the Omicron population. Additional studies are needed to characterize its efficacy for COVID-19., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)