Biology subjects

Ritter, S.

Publications and source records attributed to Ritter, S..

5 recordsLinked to original sources

bioRxiv2026

Predicting VHH-Fc Developability from Large-Scale IgG Data

The VHH-Fc antibody scaffold is an emerging therapeutic modality. No public large-scale, standardized developability VHH-Fc dataset exists. Filling that gap, we introduce GDPa5, a 160-member VHH-Fc library profiled across 10 biophysical assays on the PROPHET-Ab platform. Cross format models trained on the developability properties of 559 IgGs outperformed intra-format models trained on GDPa5 alone, which is an advantage driven by the larger scale of standardized IgG data rather than by format. The most accurately predicted properties were heparin binding (HAC, Spearman {rho}=0.82), hydrophobicity (HIC, {rho}=0.63), and self-association (AC-SINS, {rho}=0.62), all of which are largely governed by antibody surface properties. Tabular neural networks (TabICLv2, TabPFN v2.5), applied here for the first time to antibody developability prediction, outperformed conventional modeling approaches. Adding experimental HIC and HAC measurements as model inputs improved prediction of the more complex polyreactivity liability (PR-CHO, {Delta}{rho} = +0.10), supporting a tiered assay strategy that extends predictive performance while limiting experimental burden. We demonstrate through this work that IgG-trained models are a practical, data-efficient starting point for VHH-Fc developability prediction.

biophysics↗

bioRxiv2026

Decoding Bispecific Antibody Developability: Design Rules and Predictive Models from a 160-Member Library

Bispecific antibodies deliver functional outcomes that monospecific antibodies cannot, yet emergent self-association, polyreactivity, and aggregation often degrade their developability relative to their parental arms. Whether bispecific developability inherits from the parents or is driven by the format has not been tested at scale. We characterized 160 bispecific antibodies and their 65 parental arms on a uniform knobs-into-holes CrossMab IgG1 scaffold across 10 assays on the PROPHET-Ab high-throughput platform. Bispecific developability separates into three classes of inheritance. Hydrophobicity and surface charge inherit cleanly from the parents (Spearman {rho} {approx} 0.85 to 0.95), so parental-level screening predicts bispecific fate. Self-association and polyreactivity inherit partially ({rho} {approx} 0.60 to 0.88), with mechanistically interpretable emergent outliers driven in part by Fv-Fv charge complementarity and a parental biophysical ceiling on the hydrophobicity (HIC) by surface-charge (HAC) plane. Thermostability is poorly predicted from parental antibodies ({rho} < 0.4), so it requires bispecific-level testing. The class framework yields actionable selection rules: triage hydrophobicity and charge at the parental level, avoid pairing two high-HIC x high-HAC arms, pair opposite-sign Fv charges to suppress self-association but re-validate at the formulation buffer, and measure thermostability on the bispecific itself. This work charts a tractable path from monospecific sequence to bispecific developability prediction. SignificanceBispecific antibodies are a fast-growing therapeutic class, yet the rational design of well-behaving bispecific antibodies from validated monospecific antibody building blocks remains challenging. A key bottleneck is the lack of comprehensive, high-quality public datasets linking parental antibody developability properties to corresponding bispecific antibody developability properties. We address this gap by releasing a dataset comprising 160 bispecific antibodies and the 65 parental monospecific antibodies profiled in 10 developability assays. The data show that bispecific antibody developability is complex. Some properties are easily predictable from the parents, whereas others emerge in the bispecific format or from the bispecific format itself. The factors that govern each property can be identified empirically and used to make practical selection decisions. The mechanistic explanations and predictive models reported here establish a compact set of actionable rules. Together, they define a framework for using computational pipelines to convert monospecific antibodies into bispecific antibodies with drug-like developability properties, enabling faster and more effective generation of high-quality bispecific antibodies for diverse therapeutic applications.

biophysics↗

bioRxiv2026

TOR coordinates plant root growth via brassinosteroid-mediated regulation of the microtubule-associated protein CLASP in Arabidopsis

The evolutionarily conserved kinase Target of Rapamycin (TOR) enables eukaryotic organisms to match growth to energy and nutrient availability. In the plant root apical meristem, cell proliferation is dictated by the supply of sucrose from photosynthetic organs, and TOR plays a pivotal role in modulating meristem activity in response to changing energy levels. The progression of cell division requires continual remodeling of microtubule arrays, and the microtubule rescue factor CLIP-Associated Protein (CLASP) is crucial for sustaining cell proliferation. In its absence microtubule arrays lose complexity and cell production plummets. In this report we explore the relationship between TOR signalling and CLASP in the model system Arabidopsis thaliana, and show that TOR, by activating brassinosteroid (BR) signalling, downregulates CLASP expression, leading to increased microtubule dynamics associated with cell cycle progression. We further show that TOR activity enhances the motility of the CLASP-associated retromer subunit sorting nexin 1, which in turn stabilizes the auxin efflux carrier PIN2 at the plasma membrane. Thus, in addition to moderating CLASPs function as a microtubule stabilizer to promote cell division, TOR supports CLASP in sustaining PIN2 levels to control auxin flow, which is a key determinant of the switch from cell division to differentiation. Finally, we found that cell division is suppressed both by continuous chemical inhibition of TOR, which increases CLASP levels, or continuous activation of the brassinosteroid pathway with epi-brassinolide, which decreases CLASP expression. This finding suggests that TOR-mediated oscillations in CLASP levels could be a key for timing cell cycle progression. Significance StatementHow plants translate metabolic energy into physical development requires precise molecular timing. This study reveals that the energy-sensing TOR kinase dictates root growth by tuning the microtubule-stabilizing protein CLASP. We show that TOR activates brassinosteroid signaling to downregulate CLASP, which accelerates microtubule dynamics to drive the cell cycle. Simultaneously, TOR utilizes CLASP to stabilize PIN2 auxin transporters, controlling the switch from cell division to differentiation. Because pushing CLASP levels too high or too low arrests development, our findings suggest a novel metabolic-hormonal pathway by which oscillations in CLASP-dependent cellular architecture set the pace of plant growth.

Cell Biology↗

bioRxiv2023

Ionizing radiation responses are incidental to desiccation responses in the bdelloid rotifer Adineta vaga

BackgroundThe remarkable resistance to ionizing radiation found in anhydrobiotic organisms, such as some bacteria, tardigrades, and bdelloid rotifers has been hypothesized to be incidental to the desiccation resistance. Both stresses produce reactive oxygen species and cause damage to DNA and other macromolecules. However, this hypothesis has only been investigated in a few species. ResultsIn this study, we analyzed the transcriptomic response of the bdelloid rotifer Adineta vaga to desiccation and to low- (X-rays) and high- (Fe) LET radiation to highlight the molecular and genetic mechanisms triggered by both stresses. We identified numerous genes encoding antioxidants, but also chaperones, that are constitutively highly expressed, which may contribute to the protection of proteins against oxidative stress during desiccation and ionizing radiation. We also detected a transcriptomic response common to desiccation and ionizing radiation with the over-expression of genes mainly involved in DNA repair and protein modifications but also genes with unknown functions being bdelloid-specific. A distinct transcriptomic response specific to rehydration was also found, with the over-expression of genes mainly encoding Late Embryogenesis Abundant proteins, specific Heat Shock Proteins, and glucose repressive proteins. ConclusionsThese results suggest that the extreme resistance of bdelloid rotifers to radiation might indeed be a consequence of their capacity to resist complete desiccation. This study paves the way to functional genetic experiments on A. vaga targeting promising candidate proteins playing central roles in radiation and desiccation resistance.

molecular biology↗

bioRxiv2018

Episodic Control as Meta-Reinforcement Learning

Recent research has placed episodic reinforcement learning (RL) alongside model-free and model-based RL on the list of processes centrally involved in human reward-based learning. In the present work, we extend the unified account of model-free and model-based RL developed by Wang et al. (2018) to further integrate episodic learning. In this account, a generic model-free \"meta-learner\" learns to deploy and coordinate among all of these learning algorithms. The meta-learner learns through brief encounters with many novel tasks, so that it learns to learn about new tasks. We show that when equipped with an episodic memory system inspired by theories of reinstatement and gating, the meta-learner learns to use the episodic and model-based learning algorithms observed in humans in a task designed to dissociate among the influences of various learning strategies. We discuss implications and predictions of the model.

neuroscience↗