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Developing High-Affinity Decoy Receptor Optimized for Multiple Myeloma and Diffuse Large B Cell Lymphoma Treatment [Ribo-seq]

ABSTRACT: This study demonstrates the dichotomous activities of APRIL and BAFF in MM and DLBCL, which can be safely targeted by an engineered fusion protein designed to trap both ligands with ultrahigh binding affinity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206040 | GEO | 2022/06/18

REPOSITORIES: GEO

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Developing High-Affinity Decoy Receptor Optimized for Multiple Myeloma and Diffuse Large B Cell Lymphoma Treatment [RNA-seq]

Project description:This study demonstrates the dichotomous activities of APRIL and BAFF in MM and DLBCL, which can be safely targeted by an engineered fusion protein designed to trap both ligands with ultrahigh binding affinity.

2022-06-18 | GSE206044 | GEO

BAFF and APRIL counterregulate susceptibility to inflammation-induced preterm birth

Project description:Emerging clinical evidence points to a function for B cell activating factor (BAFF) in pregnancy. However, a direct role for BAFF-axis members including BAFF, the closely related a proliferation-inducing ligand (APRIL), and their respective receptors in pregnancy has not been examined. This study demonstrates that loss of BAFF results in decreased inflammatory responsiveness and decreased susceptibility to inflammation-induced preterm birth (PTB). In contrast, loss of APRIL increases inflammatory responsiveness and susceptibility to PTB. Consistent with overlapping receptor utilization by BAFF and APRIL, deletion of BAFF-axis receptors is not sufficient to modify susceptibility to PTB. Critically, therapeutic administration of BAFF/APRIL monoclonal antibodies or recombinant proteins is sufficient to manipulate susceptibility to inflammation-induced PTB. Further, macrophages are identified as the principle BAFF producing immune cells at the maternal-fetal interface and BAFF and APRIL divergently manipulate macrophage gene expression and inflammatory function. Genes linked to labor initiation are upregulated in WT and APRIL deficient macrophages while downregulated in BAFF deficient macrophages and correlate with myeloid gene expression in human placental samples during labor. Thus, BAFF and APRIL play important, but divergent, counterregulatory inflammatory roles in pregnancy and provide new therapeutic targets for mitigating the risk of PTB.

2023-08-03 | GSE202811 | GEO

Developing High-Affinity Decoy Receptor Optimized for Multiple Myeloma and Diffuse Large B Cell Lymphoma Treatment

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-06-18 | GSE206045 | GEO

A BAFF/APRIL axis regulates obesogenic-diet driven weight gain

Project description:Purpose: To define the role of the BAFF/APRIL axis in the regulation of adipose tissue homeostasis through RNAseq. Methods: Primary adipocytes were derived from pre-adipocyte precursors of inguinal white adipose from male C57BL/6 mice aged 6-8 weeks. Adipocytes were treated with rBAFF, rAPRIL, or multiple controls for 24 hours. mRNA profiles were generated for each condition, run in biological duplicates, using Illumina HiSeq2000 with single-end, 50bp reads. Differential gene lists were generated by comparing BAFF and APRIL to controls using unpaired ttests. Results:Following mapping an average of 30million reads across 10 samples to the mm10 mouse genome with annotations from UCSC, differential analysis identified genes involved in adipocyte pathways associated with lipid metabolism, lipolysis, and inflammation. Conclusion: BAFF and APRIL modulate modulate white adipocyte lipid handling.

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Developing High-Affinity Decoy Receptor Optimized for Multiple Myeloma and Diffuse Large B Cell Lymphoma Treatment [Ribo-seq]

Project description:Developing High-Affinity Decoy Receptor Optimized for Multiple Myeloma and Diffuse Large B Cell Lymphoma Treatment [Ribo-seq]

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Developing high-affinity decoy receptors to treat multiple myeloma and diffuse large B cell lymphoma.

Project description:Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an affinity-enhanced mutant sBCMA-Fc fusion molecule (sBCMA-Fc V3) 4- and 500-fold stronger in binding to APRIL and BAFF, respectively. The mutant sBCMA-Fc V3 clone significantly enhanced antitumor activity against both MM and DLBCL. Importantly, we also demonstrated an adequate toxicity profile and on-target mechanism of action in nonhuman primate studies.

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A BAFF/APRIL axis regulates obesogenic-diet driven weight gain

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Gene expression profiles from human splenic Marginal Zone and Naive (Follicular) B cells

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Developing High-Affinity Decoy Receptor Optimized for Multiple Myeloma and Diffuse Large B Cell Lymphoma Treatment

Project description:Developing High-Affinity Decoy Receptor Optimized for Multiple Myeloma and Diffuse Large B Cell Lymphoma Treatment

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Developing High-Affinity Decoy Receptor Optimized for Multiple Myeloma and Diffuse Large B Cell Lymphoma Treatment [RNA-seq]

Project description:Developing High-Affinity Decoy Receptor Optimized for Multiple Myeloma and Diffuse Large B Cell Lymphoma Treatment [RNA-seq]

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