PXD038814

PXD038814 is an original dataset announced via ProteomeXchange.

Title	Demonstration of increased biologically active CXCL12α plasma concentrations after ACKR3 antagonist treatment in humans
Description	CXCL12 is a chemokine that binds to its cognate receptors CXCR4 and ACKR3 (CXCR7). An increase in CXCL12 concentrations has been used as a pharmacodynamic biomarker to assess ACKR3 antagonism in healthy adults. Furthermore, increased CXCL12 concentrations have been observed in various human pathologies. To date, CXCL12 concentrations have typically been quantified using antibody-based assays with overlapping or unclear specificity for the various existing CXCL12 proteoforms. Only the N-terminal full-length CXCL12 proteoform is biologically active and can engage CXCR4 and ACKR3. However, this proteoform could so far not be quantified in healthy adults. Here, we describe a new and validated fit-for-purpose immunoaffinity mass spectrometry (IA-MS) biomarker assay for specific measurement of five CXCL12α proteoforms in human plasma, including the biologically active CXCL12α proteoform. The assay was employed in a Phase 1 clinical study with the ACKR3 antagonist ACT-1004-1239 to quantify CXCL12α proteoforms. At baseline levels, 1.00 nM total CXCL12α and 0.10 nM biologically active CXCL12α was quantified in placebo treated adults. The concentrations of both proteoforms increased up to two-fold in healthy adults following drug administration. At all doses, 10% of CXCL12α was biologically active and the simultaneous increase of all proteoforms suggests that a new equilibrium has been reached 24 h following dosing. Hence, this IA-MS biomarker assay can be used to specifically measure active CXCL12 proteoform concentrations in clinical trials. Specific quantification of active chemokines can support decision making in clinical trial and thus successful drug development.
HostingRepository	PRIDE
AnnounceDate	2024-01-27
AnnouncementXML	Submission_2024-01-27_10:57:52.971.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Peter Blattmann
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-13 22:59:03	ID requested
⏵ 1	2024-01-27 10:57:53	announced

10.1111/CTS.13708;

submitter keyword: Plasma, IA-MS, Biomarker

Peter Blattmann
contact affiliation	Idorsia Pharmaceuticals Ltd, Switzerland
contact email	peter.blattmann@idorsia.com
lab head
Peter Blattmann
contact affiliation	Idorsia Pharmaceuticals Ltd
contact email	peter.blattmann@idorsia.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD038814
     1. Label: PRIDE project
     2. Name: Demonstration of increased biologically active CXCL12α plasma concentrations after ACKR3 antagonist treatment in humans