Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2.

As immunological selection for escape mutants continues to give rise to future SARS-CoV-2 variants, novel universal therapeutic strategies against ACE2-dependent viruses are needed. Here we present an IgM-based decavalent ACE2 decoy that has variant-agnostic efficacy. In immuno-, pseudovirus, and live virus assays, IgM ACE2 decoy had potency comparable or superior to leading SARS-CoV-2 IgG-based mAb therapeutics evaluated in the clinic, which were variant-sensitive in their potency. We found that increased ACE2 valency translated into increased apparent affinity for spike protein and superior potency in biological assays when decavalent IgM ACE2 was compared to tetravalent, bivalent, and monovalent ACE2 decoys. Furthermore, a single intranasal dose of IgM ACE2 decoy at 1 mg/kg conferred therapeutic benefit against SARS-CoV-2 Delta variant infection in a hamster model. Taken together, this engineered IgM ACE2 decoy represents a SARS-CoV-2 variant-agnostic therapeutic that leverages avidity to drive enhanced target binding, viral neutralization, and in vivo respiratory protection against SARS-CoV-2.

Engineering a pure and stable heterodimeric IgA for the development of multispecific therapeutics.

ABBREVIATIONS: CE-SDS: capillary electrophoresis sodium dodecyl sulfate; DSC: differential scanning calorimetry; FACS: fluorescence-activated cell sorting; FSA: full-sized antibody; Her2: human epidermal growth factor receptor 2; MFI: mean fluorescent intensity; OAA: one-armed antibody; PBS: phosphate-buffered saline; PDB: Protein Data Bank; SEC: size-exclusion chromatography; prepSEC (preparative SEC); RMSD: root-mean-square deviation; RU: resonance units; SPR: surface plasmon resonance; TAA: tumor-associated antigen; WT: wild-type.

Hydrogel Gate Graphene Field-Effect Transistors as Multiplexed Biosensors.

Nanoscale field-effect transistors (FETs) represent a unique platform for real time, label-free transduction of biochemical signals with unprecedented sensitivity and spatiotemporal resolution, yet their translation toward practical biomedical applications remains challenging. Herein, we demonstrate the potential to overcome several key limitations of traditional FET sensors by exploiting bioactive hydrogels as the gate material. Spatially defined photopolymerization is utilized to achieve selective patterning of polyethylene glycol on top of individual graphene FET devices, through which multiple biospecific receptors can be independently encapsulated into the hydrogel gate. The hydrogel-mediated integration of penicillinase was demonstrated to effectively catalyze enzymatic reaction in the confined microenvironment, enabling real time, label-free detection of penicillin down to 0.2 mM. Multiplexed functionalization with penicillinase and acetylcholinesterase has been demonstrated to achieve highly specific sensing. In addition, the microenvironment created by the hydrogel gate has been shown to significantly reduce the nonspecific binding of nontarget molecules to graphene channels as well as preserve the encapsulated enzyme activity for at least one week, in comparison to free enzymes showing significant signal loss within one day. This general approach presents a new biointegration strategy and facilitates multiplex detection of bioanalytes on the same platform, which could underwrite new advances in healthcare research.

Vibrotactile Force Perception - Absolute and Differential Thresholds and External Influences.

Three experiments were carried out to determine absolute and differential thresholds for vibrotactile forces and external influences in the frequency range of 5 to 1,000 Hz at the tip of the index finger. Differential thresholds were obtained for reference stimuli of 0.5, 0.25 N, and near the individual threshold. Frequency, temperature, age, fingertip size, and contact force were investigated as parameters in a full-factorial design. Experiments were conducted with at least 27 subjects and a 1up-2down staircase procedure with 3IFC paradigm. We find absolute thresholds ranging from 1.7 to 19 mN with the lowest threshold at 320 Hz. Weber fractions from 18 to 41 dB are found near the absolute threshold. For larger references, they range from 4.9 to 23 dB. ANOVA finds frequency as significant medium effect for both absolute and differential thresholds. Results imply impact of age on the absolute threshold, but no effect of motor skill, temperature, fingertip size, and contact force. Differential thresholds are affected by frequency only, which is attributed to saturation effects of the Pacinian channel. Fingertip size and motor skill are not able to explain effects on thresholds and the interpersonal variance. Results of this work are intended as requirement source for the design of task-specific haptic interfaces.