Biology subjects

Gras, A.

Publications and source records attributed to Gras, A..

3 recordsLinked to original sources

bioRxiv2024

Integrating target capture with whole genome sequencing of recent and natural history collections to explain the phylogeography of wild-growing and cultivated Cannabis

O_LICannabis has provided important and versatile services to humans for millennia. Domestication and subsequent dispersal have resulted in various landraces and cultivars. Unravelling the phylogeography of this genus poses considerable challenges due to its complex history. C_LIO_LIWe relied on a Hyb-Seq approach (combining target capture with shotgun sequencing), with the universal Angiosperms353 enrichment panel, to explore the genetic structure of wild-growing accessions and cultivars by implementing phylogenomic and population genomic workflows on the same Hyb-Seq data. C_LIO_LIOur findings support the treatment of Cannabis as a monotypic genus (C. sativa L.), structured into three main genetic groups--E Asia, Paleotropis, and Boreal--with clear phylogeographic signal despite significant levels of admixture. The E Asia group was sister to the Paleotropis and the Boreal groups. Individuals within the Paleotropis group could be further structured into three subgroups: Iranian Plateau, C & S China and Himalayas, and Indoafrica. Individuals from the Boreal group split into two subgroups: Eurosiberia and W Mongolia and Caucasus and Mediterranean. Hemp and drug-type landraces and cultivars consistently matched their putative geographic origin. C_LIO_LIThese findings enhance our understanding of the genetic patterns in Cannabis and provide a framework for future research into its current and past genetic diversity. C_LI

genomics↗

bioRxiv2021

Lack of blocking activity in anti-CTLA-4 antibodies reduces toxicity, but not anti-tumor efficacy

Anti-CTLA-4 antibodies such as ipilimumab were among the first immune-oncology agents to show significantly improved outcomes for patients. However, existing anti-CTLA-4 therapies fail to induce a response in a majority of patients and can induce severe, immune-related adverse events. It has been assumed that checkpoint inhibition, i.e., blocking the interaction between CTLA-4 and its ligands, is the primary mechanism of action for ipilimumab. In this study we present evidence that checkpoint inhibition is not a primary mechanism of action for efficacy of anti-CTLA-4 antibodies. Instead, the primary mechanism for efficacy is FcR-mediated Treg depletion in the tumor microenvironment. First, we identified a monoclonal antibody (mAb) that binds to CTLA-4 at an epitope that differs from ipilimumabs by only a few amino acids, yet has limited checkpoint inhibitor activity. Surprisingly, the weak checkpoint inhibitor has superior anti-tumor activity compared to ipilimumab in a murine model. The weak checkpoint inhibitor also induces less Treg proliferation and has increased ability to induce in vitro FcR signaling and in vivo depletion of intratumoral Tregs. Further experiments showed that the enhanced FcR activity of the weak checkpoint inhibitor likely contributes to its enhanced anti-tumor activity. Importantly, we also showed that weak checkpoint inhibition was associated with lower toxicity in murine models. Our work suggests that new anti-CTLA-4 drugs should be optimized for Treg depletion rather than checkpoint inhibition.

immunology↗

bioRxiv2020

Capturing and Recreating Diverse Antibody Repertoires as Multivalent Recombinant Polyclonal Antibody Drugs

Plasma-derived polyclonal antibodies are polyvalent drugs used for many important clinical indications that require modulation of multiple drug targets simultaneously, including emerging infectious disease and transplantation. However, plasma-derived drugs suffer many problems, including low potency, impurities, constraints on supply, and batch-to-batch variation. In this study, we demonstrated proofs-of-concept for a technology that uses microfluidics and molecular genomics to capture diverse mammalian antibody repertoires as multivalent recombinant drugs. These "recombinant hyperimmune" drugs comprised thousands to tens of thousands of antibodies and were derived from convalescent human donors, or vaccinated human donors or immunized mice. Here we used our technology to build a highly potent recombinant hyperimmune for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) in less than three months. We also validated a recombinant hyperimmune for Zika virus disease that abrogates antibody-dependent enhancement (ADE) through Fc engineering. For patients with primary immune deficiency (PID), we built high potency polyvalent recombinant hyperimmunes against pathogens that commonly cause serious lung infections. Finally, to address the limitations of rabbit-derived anti-thymocyte globulin (ATG), we generated a recombinant human version and demonstrated in vivo function against graft-versus-host disease (GVHD). Recombinant hyperimmunes are a novel class of drugs that could be used to target a wide variety of other clinical applications, including cancer and autoimmunity.

immunology↗