Biology subjects

Tacke, R.

Publications and source records attributed to Tacke, R..

3 recordsLinked to original sources

bioRxiv2026

Design of full-length agonist and antagonist antibodies for hard targets

Therapeutic antibodies have transformed modern medicine, yet conventional discovery relies on lengthy experimental workflows, offers limited control over how antibodies engage their targets, and struggles to deliver candidates across many important target classes. Despite recent advances in computational protein design, generating full-length antibodies with desired functional activity and favorable developability profiles remains challenging. Here we present an end-to-end computational design pipeline built around Pythia-1, an all-atom generative model that reasons jointly over amino acid sequence and three-dimensional atomic structure under explicit design constraints. We generated candidates in full-length human immunoglobulin G (IgG) format across 22 therapeutic targets spanning receptor ectodomains, cytokines, growth factors, and G protein-coupled receptors (GPCRs), a particularly challenging target class for antibody discovery. Following a single computational design round, experimental screening of at most 48 candidates per target identified antibodies with single-digit nanomolar affinities for soluble proteins and single-digit nanomolar cell-binding EC50 values for GPCRs. The pipeline's ability to target specified epitopes and conformational states enabled the design of antibodies with agonist and antagonist activity. In vitro characterization demonstrated target-specific engagement and potent functional modulation, with single-digit nanomolar inhibitory potency in functional assays for a range of targets, including multiple GPCRs. To our knowledge, this study provides the first demonstration of both GPCR agonism and antagonism by de novo designed full-length IgG antibodies. We incorporated key developability and manufacturability requirements into the initial designs by conditioning generation on human germline frameworks and applying sequence constraints to limit known liabilities. The resulting antibody designs exhibited biophysical profiles comparable to or better than those of clinical-stage therapeutic controls. We provide the complete sequences of all lead candidates to support independent experimental validation and further development. Together, these findings demonstrate that our technology can deliver antibodies with programmable function and key properties expected of lead candidates, opening opportunities for first-in-class therapeutics against hard-to-drug targets.

molecular biology↗

bioRxiv2024

Mature and migratory dendritic cells promote immune infiltration and response to anti-PD-1 checkpoint blockade in metastatic melanoma

Immune checkpoint inhibitors (ICIs) have heralded a remarkable shift in cancer care, significantly extending survival for advanced cancer patients. However, despite their remarkable clinical successes, a substantial majority of patients fail to achieve a lasting response to ICIs. To address this challenge and gain insights into the complex landscape of the tumor microenvironment (TME), we conducted an extensive analysis using single-cell RNA sequencing (scRNA; [~]216K cells across 39 samples) and single-nucleus transposase-accessible chromatin sequencing (snATAC; [~]43K cells from 15 samples) in a metastatic melanoma cohort. This systematic approach delineates 14 distinct cell types and 55 cell subtypes, including the identification of 15 transcriptional hallmarks of malignant cells. Through correlation analysis of cell subtype proportions, we unveiled six distinct clusters associated with varying tumor responses. Particularly intriguing was the identification of the mature DC enriched in immunoregulatory molecules (mregDC) subtype exhibiting correlations with naive T and B cells, forming an anti-tumor program that underscores the importance of multiple immune cell types in mediating anti-tumor immunity. Notably, we found that mregDC abundance represents a good prognostic predictor of progression-free survival (PFS) in the context of ICI treatment, and when combined with the TCF7+/- CD8 T cell ratio, it reliably predicts patient PFS across treatments beyond ICI. We validated our findings using an independent cohort of 274 ICI-treated melanoma samples analyzed using tissue-level expression. We next compared mregDCs and conventional dendritic cell types 1 and 2 (cDC1 and cDC2) using transcriptome signature, differentiation trajectory, interactome, cytokine milieu, and epigenome landscape analyses. This comparative analysis shed light on the unique attributes of mregDCs within the TME. Finally, we investigated cell type/subtype-specific genes, pathways, immune response enrichment, and ligand-receptor interactions closely associated with the proportions of mregDCs within the TME. These molecular and cellular insights, with their critical roles in enhancing the immune response against cancer, offer valuable prospects for predicting the efficacy of ICI regimens, and potentially guiding the selection of rational combinatorial therapies.

cancer biology↗

bioRxiv2021

Zooming into the genomic vicinity of the major locus for vicine and convicine in faba bean (Vicia faba L.)

The versatility of faba bean (Vicia faba L.) seed as valuable protein feed is hampered by its relatively high level of the compounds vicine and convicine (VC), which are antinutritive factors in poultry and further non-ruminant feed. The objective here was to develop the first-ever genetically low-VC winter faba bean. Hence, the low VC allele vc-, that should be the basis of a known, major locus for VC, need verification and molecular identification and be based on appropriately developed DNA-markers; the low VC feature awaited its transfer into the high-performing winter faba bean germplams. Based on bi-parental F2-families and isogenic lines, we thus developed highly useful SNP markers exploiting transcriptomic data. Furthermore, we fine-mapped and, based on synteny to Medicago truncatula and Cicer arietinum, we identified a candidate gene for the VC locus. A novel, genetically low VC winter faba bean population was bred. The path is now well-prepared for further marker-based breeding progress.

genetics↗