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A first-in-class, humanized antibody targeting alternatively spliced tissue factor: preclinical evaluation in an orthotopic model of pancreatic ductal adenocarcinoma

ABSTRACT: A first-in-class, humanized antibody targeting alternatively spliced tissue factor: preclinical evaluation in an orthotopic model of pancreatic ductal adenocarcinoma

PROVIDER: PRJNA666690 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12749582_1.fastq.gz	Fastqsanger.gz
	SRR12749582_2.fastq.gz	Fastqsanger.gz
	SRR12749583_1.fastq.gz	Fastqsanger.gz
	SRR12749583_2.fastq.gz	Fastqsanger.gz
	SRR12749584_1.fastq.gz	Fastqsanger.gz

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A First-In-Class, Humanized Antibody Targeting Alternatively Spliced Tissue Factor: Preclinical Evaluation in an Orthotopic Model of Pancreatic Ductal Adenocarcinoma.

Project description:In 2021, pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths in the United States. This is largely due to a lack of symptoms and limited treatment options, which extend survival by only a few weeks. There is thus an urgent need to develop new therapies effective against PDAC. Previously, we have shown that the growth of PDAC cells is suppressed when they are co-implanted with RabMab1, a rabbit monoclonal antibody specific for human alternatively spliced tissue factor (asTF). Here, we report on humanization of RabMab1, evaluation of its binding characteristics, and assessment of its in vivo properties. hRabMab1 binds asTF with a KD in the picomolar range; suppresses the migration of high-grade Pt45.P1 cells in Boyden chamber assays; has a long half-life in circulation (~ 5 weeks); and significantly slows the growth of pre-formed orthotopic Pt45.P1 tumors in athymic nude mice when administered intravenously. Immunohistochemical analysis of tumor tissue demonstrates the suppression of i) PDAC cell proliferation, ii) macrophage infiltration, and iii) neovascularization, whereas RNAseq analysis of tumor tissue reveals the suppression of pathways that promote cell division and focal adhesion. This is the first proof-of-concept study whereby a novel biologic targeting asTF has been investigated as a systemically administered single agent, with encouraging results. Given that hRabMab1 has a favorable PK profile and is able to suppress the growth of human PDAC cells in vivo, it comprises a promising candidate for further clinical development.

| S-EPMC8358774 | biostudies-literature

Glycine max Alternatively Spliced Transcript Detecting Microarray (GmASDM).

Project description:Glycine max Alternatively Spliced Transcript Detecting Microarray (GmASDM).

| PRJNA643563 | ENA

A first-in-class, humanized antibody targeting alternatively spliced tissue factor: preclinical evaluation in an orthotopic model of pancreatic ductal adenocarcinoma

Project description:RNA sequencing of 9 samples (3 per group) generated 30 million 150 base long paired end reads revealed differential isoform expression of about 1100 gene transcripts. Hg19 was used as a reference genome for alignment, transcriptome index was created in kallisto using Ensembl cDNA sequences for the reference genome. This index was then used to quantify transcript abundance in raw counts and transcript per million (TPM). We report a suppression in the expression of genes associated with cell cycle regulation (most strongly HBGEF, STN1, ECT2, PLCD3, and RHOC). Suppression of HBGEF and STN1 in hRabMab1 treated tumors was validated by qRT-PCR.

2020-10-01 | GSE158847 | GEO

Mutations primarily alter the inclusion of alternatively spliced exons

Project description:Systematic mutagenesis has revealed that synonymous, non-synonymous and intronic mutations frequently alter the inclusion levels of alternatively spliced exons, suggesting that altered splicing might be a common mechanism by which mutations cause disease. However, most exons expressed in any cell are highly-included in mature mRNAs. Here, by performing deep mutagenesis of highly-included exons and by analysing the association between sequence variation and exon inclusion across the genome, we report that mutations only very rarely alter the inclusion of highly-included exons. This is true for both exonic and intronic mutations as well as for perturbations in trans. Therefore, mutations that affect splicing are not evenly distributed across the genome but are focussed in and around alternatively spliced exons with intermediate inclusion levels. These results provide a resource for prioritising synonymous and other variants as disease-causing mutations.

2020-06-29 | GSE151942 | GEO

Mutations primarily alter the inclusion of alternatively spliced exons

Project description:Mutations primarily alter the inclusion of alternatively spliced exons

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An alternatively spliced p62 isoform promotes breast cancer chemoresistance

Project description:An alternatively spliced p62 isoform promotes breast cancer chemoresistance

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Gene expression profiling of Capan-1 and Pt45P1 cells treated or not with alternatively spliced tissue factor (asTF)

Project description:The effects of alternatively spliced tissue factor (asTF) were measured by gene expression profiling of Capan-1 and Pt45P1 cells.

2013-04-10 | GSE45928 | GEO

Gene expression profiling of Capan-1 and Pt45P1 cells treated or not with alternatively spliced tissue factor (asTF)

Project description:The effects of alternatively spliced tissue factor (asTF) were measured by gene expression profiling of Capan-1 and Pt45P1 cells. 4 samples: Capan-1 cells +/- asTF, Pt45P1 cells +/- asTF.

2013-04-10 | E-GEOD-45928 | biostudies-arrayexpress

Validation of alternatively spliced protein isoforms in human mesenchymal stem cells

Project description:Alternative splicing of mRNA diversifies the function of human proteins, with tissue- and cell-specific protein isoforms being the most difficult to validate. While transcriptomic experiments enable the detection of many alternatively spliced transcripts, it is not known if these transcripts have protein-coding potential. We recently published the PG Nexus pipeline, which facilitates high confidence validation of exons and exon-exon junctions of spliced transcripts by integrating transcriptomics and proteomics data. Using the PG Nexus, we analyzed undifferentiated human mesenchymal stem cells and compared the number of protein isoforms validated using different protein sequence database, including public online databases and RNA-seq derived databases. With significant overlaps with other databases, we identified 8,011 exons and 3,824 splice junctions with the Ensembl database. Both exonic and junction peptides were important for protein isoform validation. The Ensembl database consistently outperformed the other data sources, but predicted open reading frames from RNA-seq derived transcripts were comparable, with only 6 less splice junctions validated. Using proteotypic and isoform-specific peptides, we validated 462 protein isoforms. This number increases to 1,083 if multiple proteotypic peptides per protein are included. Multiplexing proteotypic peptides in SRM assays or similar experiments will increase the confidence and coverage of protein isoform validation experiments.

2015-05-20 | PXD001449 | Pride

Analysis of alternatively spliced transcripts in leaf, root, panicle and seed of rice with a long oligomer microarray

Project description:RNA splicing is a molecular mechanism to increase protein diversities acquired through the evolution while the underlieing driving forces for the phenomenon are unknown especially in terms of gene expression. Rice alternatively spliced transcript detecting microarray (ASDM) was designed and applied to differentiate the transcriptome of 4 representative organs of Oryza sativa L. cv. Ilmi including leaves, roots, panicles at 1 cm stage and young seeds at 20 days after pollination. The comparison of the data between the microarray and RNA-seq shows a ‘bell shape distribution’ and a strong co-lineation for highly expressed genes. The transcripts are classified according to the degree of organ enrichment using coefficient value (CV, the ratio of standard deviation to the mean values); highly variable (CVI), variable (CVII), and constitutive (CVIII) groups. The genes of highly variable group show the characteristics of the organs. The index of the portion of loci with alternatively spliced transcripts in a group (IAS) is designated for these CV groups and showed the higher value in the constitutive group. In addition, within a locus, a transcript with longer cds tends to be higher expressed and the spliced_intron is the most commonly found type of alternative splicing for the extended cds. Thus, constitutively expressed genes might be under evolutionary pressure toward alternative splicing that might have a longer cds. These data show that less resource consuming and better designed microarray might be a niche technology to test the transcriptome analysis including alternatively spliced transcripts in plants.

2017-01-01 | GSE87536 | GEO

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