Biology subjects

Csala, A.

Publications and source records attributed to Csala, A..

4 recordsLinked to original sources

bioRxiv2026

RNA evidence supports clinical stage antibody drug targets in oncology

Background: The selection of efficacious and safe antibody-based oncology targets depends on tumor specificity and normal-tissue expression, and remains challenging. Bulk RNA-seq can identify tumor-enriched surface genes, but may obscure tumor specificity and normal-cell expression patterns that are relevant to the therapeutic window. We evaluated whether single-cell RNA-seq-derived expression features improve retrospective prioritization of clinically pursued antibody targets. Methods: We developed a bulk and single-cell RNA expression-based ranking framework across six solid tumor indications. 4,532 candidate surfaceome targets were scored using tumor Specificity, normal Safety, and blood Sink features derived from bulk RNA-seq, single-cell RNA-seq, or a combined modality. Ranking performance was evaluated against a curated validation set of tumor-associated antibody-based oncology targets using logistic regression, with odds ratios (ORs) reported per one-standard-deviation increase in score. Results: Higher Specificity scores were associated with clinical-stage target selection across all modalities. In cross-indication meta-analysis, single-cell Specificity showed higher ORs than bulk Specificity across clinical phase thresholds, including Phase [≥] 1 (OR 2.56 versus 1.81), Phase [≥] 2 (OR 2.77 versus 1.88), Phase [≥] 3 (OR 3.53 versus 2.04) and Approved targets (OR 3.51 versus 1.74). Combined bulk-and-single-cell Specificity showed intermediate enrichment. Specificity score alone did not consistently show a significant single-cell advantage over bulk in paired indication-level comparisons, except for Phase [≥] 3 targets. After adding normal-cell Safety and blood Sink features, the single-cell general score showed the strongest enrichment across thresholds (Phase [≥] 1 OR 3.61, Phase [≥] 2 OR 4.16, Phase [≥] 3 OR 5.57, and Approved targets OR 4.25). This general score also showed consistently significant single-cell advantage over bulk in paired indication-level comparisons. Safety contributed most strongly in the single-cell modality, increasing meta-analytic ORs by an average of ~36% across thresholds compared to Specificity alone. Performance varied by indication, with breast cancer showing weaker Specificity-based enrichment. Conclusion: Expression-derived ranking features are retrospectively enriched among clinically pursued tumor-associated antibody targets. Single-cell evidence is most informative when tumor Specificity is combined with normal-cell Safety information, supporting its use as an interpretable component of early antibody target prioritization. These findings are in alignment with recent evidence that single-cell RNA-based cell-type specificity supports clinical-stage targets and demonstrate that expression-driven ranking can systematically recover clinically relevant oncology targets.

bioinformatics↗

bioRxiv2026

A Cross-Study Multi-Organ Cell Atlas ofMacaca fascicularis Informed by Human Foundation Model Annotation: A Resource for Translational Target Assessment

Non-human primates (NHPs), particularly Macaca fascicularis (cynomolgus macaque), represent an essential model for preclinical assessment of biologics due to their high genetic and physiological similarity to humans. However, mounting regulatory pressure to reduce NHP use and the lack of a unified, well-annotated single-cell atlas currently limits both target qualification and mechanistic interpretation of toxicity in this species. To address this gap, we assembled and harmonized the largest single-cell transcriptomic atlas of M. fascicularis to date, integrating 30 publicly available studies spanning 57 anatomical regions, 43 organs and 14 physiological systems. We implemented a scalable framework for cross-species cell type annotation by embedding both cynomolgus monkeys and human (Tabula Sapiens V2) datasets into a shared reference space using Universal Cell Embeddings (UCE), enabling consistent harmonization of cell identities. In total, 27 organs were annotated using human reference labels, while the remaining sets retained author-provided annotations or labels transferred from other cynomolgus studies with available annotations. The resulting atlas comprises over 2.5 million cells and demonstrates concordance in cell-type-specific expression patterns between cynomolgus and humans, including tissue-specific markers and targets relevant for biologics development. Through translational use cases, we illustrate how this resource can be applied to assess target expression in tissues affected by concordant human-NHP toxicities, investigate ocular adverse events associated with antibody-drug conjugates (ADCs), and identify species-specific features of immune cell subtypes with known safety implications. By enabling scalable, high-resolution, cross-species comparisons of gene expression across organs, tissues, and cell states, this atlas supports improved target qualification, more mechanistic interpretation of toxicities, and evidence-based decisions on the relevance and design of NHP studies. Collectively, this work provides a unified cross-species single-cell resource for cynomolgus monkey and a modular computational framework that advances new approach methodologies and contributes to the refinement and reduction of NHP use in preclinical research.

bioinformatics↗

bioRxiv2023

Gonadal androgens are associated with decreased type I interferon production by pDCs and increased IgG titres to BNT162b2 following co-vaccination with live attenuated influenza vaccine in adolescents

mRNA vaccine technologies introduced following the SARS-CoV-2 pandemic have highlighted the need to better understand the interaction of adjuvants and the early innate immune response. Interferon type I (IFN-I) is an integral part of this early innate response and can prime several components of the adaptive immune response. Females are widely reported to respond better than males to seasonal tri- and quad-valent influenza vaccines. Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production and female pDCs produce more IFN-I than male pDCs since the upstream receptor TLR7 is encoded by the X-chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains putative androgen response elements and androgens have been reported to suppress pDC IFN-I in-vitro. Unexpectedly, therefore, we recently observed that male adolescents mount stronger antibody responses to the Pfizer BNT162b2 mRNA vaccine than female adolescents after controlling for natural SARS-CoV-2 infection. We here examined pDC behaviour in this cohort to determine the impact of IFN-I on anti-Spike and anti-receptor-binding domain titres to BNT162b2. Through LASSO modelling we determined that serum free testosterone was associated with reduced pDC IFN-I but, contrary to the well-described immunosuppressive role for androgens, the more potent androgen dihydrotestosterone was associated with increased IgG titres to BNT162b2. Also unexpectedly, we observed that co-vaccination with live-attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together these data support a model where systemic IFN-I increased vaccine-mediated immune responses, but for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently vaccine-driven immunity. Author SummaryType I interferons (IFN-I) are potent antiviral proteins which play a central role in activating the immune response and driving inflammation. IFN-I is predominantly produced by plasmacytoid dendritic cells (pDCs) and female pDCs produce more IFN-I than male pDCs. Consequently, females typically generate stronger antibody responses to vaccines such as seasonal influenza vaccines. In addition, females typically suffer more serious adverse events from vaccines. However, we recently reported in a study of adolescents that males generate stronger antibody responses to the SARS-CoV-2 mRNA vaccine BNT162b2 than females. Here we examine the IFN-I response of pDCs in adolescents co-/vaccinated with BNT162b2 and live-attenuated influenza vaccine (LAIV). We find that male sex hormones reduce pDC IFN-I but are associated with increased BNT162b2 antibody titres. We also observe that LAIV boosts BNT162b2 antibody titres through possible bystander activation of immune cells. These findings are consistent with a reportedly higher incidence of adverse events among males associated with this vaccine. Together these data suggest that IFN-I production typically enhances vaccine-specific immune responses but for new mRNA vaccines such as BNT162b2, that are modified to reduce innate immunogenicity, localised dampening of the IFN-I response in vaccinated tissue by male sex hormones may further delay the clearance of the vaccine, increasing vaccine antigen exposure and allowing time for a stronger antibody response.

immunology↗

bioRxiv2019

Low Replication Capacity Virus Is Preferentially Transmitted In Mother-To-Child-Transmission But Not In Adult-To-Adult-Transmission Of HIV-1

Previous studies of the transmitted/founder virus compared to viral quasispecies in the donor have yielded conflicting results. In heterosexual adult-to-adult transmission (ATAT), the viral replicative capacity (VRC) of transmitted virus is reportedly either similar to, or somewhat higher than, that of donor virus, whilst transmitted virus in mother-to-child transmission (MTCT) has a significantly lower VRC than that of maternal virus. These discrepancies may be explained by the different methodologies used in these studies, or they may reflect true differences in the transmission bottleneck. To resolve this question, we here use the same methodology to compare transmitted versus donor virus in MTCT and ATAT. We show that, in a South African mother-child cohort, infant virus samples obtained at 1-2 days after birth had VRC significantly lower than in the mothers (p=0.0003). By contrast, in Zambian ATAT transmission pairs, VRC of transmitted virus was similar to or somewhat higher than donor virus (p=ns). The VRC of virus transmitted to the recipient, compared to that in the donor, was significantly lower in MTCT versus heterosexual ATAT (p=0.01). These studies demonstrate that fundamental differences exist between the viruses transmitted via the MTCT and ATAT bottlenecks that are not explained by methodological factors. This result is of importance since transmission of low replicative capacity virus results in low immune activation and a small viral reservoir, and therefore the preferential transmission of low fitness viruses in MTCT might be expected to increase cure potential in in utero infected infants and children.\n\nIMPORTANCEUnderstanding the factors determining which viruses are preferentially transmitted in HIV infection is critical to the development of new, effective strategies to prevent transmission. Despite this, much remains unknown in this respect, both with regard to adult-to-adult transmission (ATAT) but especially with respect to mother-to-child transmission (MTCT). The finding here that fundamental differences exist in the genetic bottleneck of HIV transmission between heterosexual ATAT and MTCT is an important initial step to help define the viral mechanisms contributing to transmission in each case. In addition, we show that viruses of low viral replicative capacity are preferentially transmitted in MTCT. This suggests the possibility that a window of opportunity exists following in utero infection in which early anti-viral intervention not only reduces the size and diversity of the viral reservoir, but additionally maintains a reservoir comprising low viral replicative capacity HIV. Low replicative capacity of transmitted virus has previously been shown to result in low immune activation and low proviral DNA load in central memory cells, factors likely to be directly relevant to increasing cure potential in HIV-infected infants and children.

immunology↗