Profiling the Biophysical Developability Properties of Common IgG1 Fc Effector Silencing Variants.

Therapeutic antibodies represent the most significant modality in biologics, with around 150 approved drugs on the market. In addition to specific target binding mediated by the variable fragments (Fvs) of the heavy and light chains, antibodies possess effector functions through binding of the constant region (Fc) to Fcγ receptors (FcγR), which allow immune cells to attack and kill target cells using a variety of mechanisms. However, for some applications, including T-cell-engaging bispecifics, this effector function is typically undesired.

Structure-based engineering of a novel CD3ε-targeting antibody for reduced polyreactivity.

Bispecific antibodies continue to represent a growth area for antibody therapeutics, with roughly a third of molecules in clinical development being T-cell engagers that use an anti-CD3 binding arm. CD3 antibodies possessing cross-reactivity with cynomolgus monkey typically recognize a highly electronegative linear epitope at the extreme N-terminus of CD3 epsilon (CD3ε). Such antibodies have high isoelectric points and display problematic polyreactivity (correlated with poor pharmacokinetics for monospecific antibodies).

Antibody-mediated protection against symptomatic COVID-19 can be achieved at low serum neutralizing titers.

Multiple studies of vaccinated and convalescent cohorts have demonstrated that serum neutralizing antibody (nAb) titers correlate with protection against coronavirus disease 2019 (COVID-19). However, the induction of multiple layers of immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure has complicated the establishment of nAbs as a mechanistic correlate of protection (CoP) and hindered the definition of a protective nAb threshold. Here, we show that a half-life-extended monoclonal antibody (adintrevimab) provides about 50% protection against symptomatic COVID-19 in SARS-CoV-2-naïve adults at serum nAb titers on the order of 1:30.

Biophysical properties of the clinical-stage antibody landscape.

Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of "developability.

Peptide-mediated reduction of silver ions on engineered biological scaffolds.

Herein we report the spontaneous reduction of silver ions into nanostructures by yeast surface-displayed glutamic acid (E(6)) and aspartic acid (D(6)) peptides. Light spectroscopy and electron microscopy reveal that silver ions are photoreduced in the presence of the polycarboxylic acid-containing peptides and ambient light, with an increase in reduction capability of E(6) expressing yeast over D(6) yeast. The importance of tethering peptides to a biological scaffold was inferred by observing the reduced particle forming capacity of soluble peptides with respect to corresponding yeast-displayed peptides.

Peptide tags for enhanced cellular and protein adhesion to single-crystalline sapphire.

In order to facilitate a novel means for coupling proteins to metal oxides, peptides were identified from a dodecamer peptide yeast surface display library that bound a model metal oxide material, the C, A, and R crystalline faces of synthetic sapphire (alpha-Al(2)O(3)). Seven rounds of screening yielded peptides enriched in basic amino acids compared to the naive library. While the C-face had a high background of endogenous yeast cell binding, the A- and R faces displayed clear peptide-mediated cell adhesion.

Probing the interface between biomolecules and inorganic materials using yeast surface display and genetic engineering.

Although promising for biomimetic materials applications, polypeptides binding inorganic material surfaces and the mechanism of their function have been difficult to characterize. This paper reports sequence-activity relationships of peptides interfacing with semiconductor CdS, and presents methodologies broadly applicable to studying peptide-solid surface interactions. We first employed yeast surface display with a human repertoire antibody library and identified rarely-occurring scFv fragments as CdS-binding polypeptides.

Design criteria for engineering inorganic material-specific peptides.

Development of a fundamental understanding of how peptides specifically interact with inorganic material surfaces is crucial to furthering many applications in the field of nanobiotechnology. Herein, we report systematic study of peptide sequence-activity relationships for binding to II-VI semiconductors (CdS, CdSe, ZnS, ZnSe) and Au using a yeast surface display system, and we define criteria for tuning peptide affinity and specificity for these material surfaces. First, homohexapeptides of the 20 naturally occurring amino acids were engineered, expressed on yeast surface, and assayed for the ability to bind each material surface in order to define functional groups sufficient for binding.