Biology subjects

San Miguel, J.

Publications and source records attributed to San Miguel, J..

3 recordsLinked to original sources

bioRxiv2026

Rational engineering of sdAb-based CAR T cells targeting BCMA enhances antitumor efficacy and persistence in Multiple Myeloma

BCMA-directed CAR T therapies have transformed the treatment of relapsed/refractory multiple myeloma (MM), yet durable responses remain limited by insufficient persistence and functional exhaustion. The contribution of antigen-binding domain properties to CAR T cell performance is not fully defined. Here, we report the rational discovery and engineering of BCMA-targeting single-domain antibodies (sdAbs) and their incorporation into second-generation CAR T cells. We generated sdAbs recognizing distinct BCMA epitopes with diverse binding kinetics. Comprehensive biophysical and functional characterization identified sdAb5 as a lead candidate with balanced binding kinetics and a non-overlapping epitope relative to clinically approved constructs. sdAb-based CAR T cells exhibited potent antigen-specific cytotoxicity, minimal tonic signaling, and preserved IL-2 production without excessive inflammatory activation. In xenograft models, sdAb5-based CAR T cells induced durable tumor control, enhanced persistence, and improved responses to tumor rechallenge compared with ide-cel and cilta-cel constructs. Notably, this superior functionality correlated with balanced binding kinetics rather than maximal affinity. Single-cell transcriptomic analyses corroborated these findings, revealing a restrained inflammatory activation in sdAb5-based CAR T cells with preservation of transcriptional plasticity. Collectively, these findings support antigen-binding optimization as a key determinant of CAR T-cell durability and identify sdAb5 as a candidate for next-generation BCMA-directed therapies in MM.

bioengineering↗

bioRxiv2022

gMCStool: automated network-based tool to search for metabolic vulnerabilities in cancer

The development of computational tools for the systematic prediction of metabolic vulnerabilities of cancer cells constitutes a central question in systems biology. Here, we present gMCStool, a freely accessible and online tool that allows us to carry out this task in a simple, efficient and intuitive environment. gMCStool exploits the concept of genetic Minimal Cut Sets (gMCSs), a theoretical approach to synthetic lethality based on genome-scale metabolic networks, including a unique database of thousands of synthetic lethals computed from Human1, the most recent metabolic reconstruction of human cells. Based on RNA-seq data, gMCStool extends and improves our previously developed algorithms to predict, visualize and analyze metabolic essential genes in cancer, demonstrating a superior performance than competing algorithms in both accuracy and computational performance. A detailed illustration of gMCStool is presented for multiple myeloma (MM), an incurable hematological malignancy. gMCStool could identify a synthetic lethal that explains the dependency on CTP Synthase 1 (CTPS1) in a sub-group of MM patients. We provide in vitro experimental evidence that supports this hypothesis, which opens a new research area to treat MM.

systems biology↗

bioRxiv2019

Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma

Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting co-regulated adjacent genes. Among target genes upregulated by this process, we found members of the NOTCH, NFkB, mTOR1 signaling and p53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status, and in addition identified PRDM5 as a novel essential gene for MM. Collectively our data indicates that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.

cancer biology↗