Biology subjects

Alcaraz-Serna, A.

Publications and source records attributed to Alcaraz-Serna, A..

3 recordsLinked to original sources

bioRxiv2025

Targeting PD-1+ T-cells with Chimeric Antigen Receptors to reduce the HIV Reservoir

The unique ability of chimeric antigen receptor (CAR) T-cells to infiltrate tissues is revolutionizing our perspectives for tackling severe-refractory and otherwise untreatable diseases. In HIV, CAR-T-cells have been designed to target viral biomarkers, with limited success so far. Here, we investigated the possibility of redirecting CAR-T-cells against a cellular biomarker of the HIV reservoir, PD-1. We designed two second-generation 4-1BB-CARs using the scFv of either a blocking (bPD1-CAR) or a nonblocking (nbPD1-CAR) anti-PD-1 monoclonal antibody. The CAR avidity modulated T-cell sensitivity, trogocytosis, and effector functions, independently of the PD-1 signalling domain. Both anti-PD-1 CAR T-cells could persist for 70 days in HIV-infected humanized mice, correlating with viral protection and a disruption of the lymphoid architecture in the white pulp of the spleen. Altogether, our results open new strategic avenues for reducing the HIV reservoir as we demonstrate the feasibility of depleting specific T-cell subpopulations. SummaryT cells can be redirected against cellular rather than viral-specific biomarkers to reduce the HIV reservoir.

immunology↗

bioRxiv2025

Redirecting TCR specificity in regulatory T cells toward class I HLA antigens mediates tissue-specific homing

Type 1 diabetes (T1D) is marked by the overexpression of class I major histocompatibility complex (MHC) antigens in pancreatic islets, which are targeted by islet-specific CD8+ T cells. Here, we aimed to improve regulatory T cell (Treg) infiltration into pancreatic islets by redirecting their specificity toward class I-restricted islet antigens. We functionally validated two public islet specific HLA-A2 (*02:01) restricted TCRs, one specific for ZnT8186-194 (clone D222D), the second for IGRP265-273 (clone 32) by dual locus (TRAC/CD4) homology-directed editing. Clone D222D was peptide-specific and CD8{beta} dependent while clone 32 exhibited antigen promiscuity and showed CD8 dependency. Engineered CD4to8 TCR Tregs maintained stable phenotypes, suppressed significantly better than their polyclonal counterpart, and showed co-receptor-dependent migration in vivo. This approach demonstrates that TCR specificity, reflected by its functional activity, is crucial for tissue-specific trafficking, paving the way to improve the efficacy of Treg therapies for T1D.

immunology↗

bioRxiv2024

BindCraft: one-shot design of functional protein binders

Protein-protein interactions (PPIs) are at the core of all key biological processes. However, the complexity of the structural features that determine PPIs makes their design challenging. We present BindCraft, an open-source and automated pipeline for de novo protein binder design with experimental success rates of 10-100%. BindCraft leverages the weights of AlphaFold21 to generate binders with nanomolar affinity without the need for high-throughput screening or experimental optimization, even in the absence of known binding sites. We successfully designed binders against a diverse set of challenging targets, including cell-surface receptors, common allergens, de novo designed proteins, and multi-domain nucleases, such as CRISPR-Cas9. We showcase the functional and therapeutic potential of designed binders by reducing IgE binding to birch allergen in patient-derived samples, modulating Cas9 gene editing activity, and reducing the cytotoxicity of a foodborne bacterial enterotoxin. Lastly, we utilize cell surface receptor-specific binders to redirect AAV capsids for targeted gene delivery. This work represents a significant advancement towards a "one design-one binder" approach in computational design, with immense potential in therapeutics, diagnostics, and biotechnology.

bioinformatics↗