PXD047339

PXD047339 is an original dataset announced via ProteomeXchange.

Title	A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors
Description	Interleukin-12 (IL12) is a pro-inflammatory cytokine with potent anti-cancer activity. Attempts to develop recombinant IL12 as a biopharmaceutical have been hampered by severe toxicity, observed already at daily dose of 500 ng/kg. The antibody-based delivery of IL12 significantly increases the therapeutic index of the cytokine but does not completely prevent side effects associated with peak concentrations of the product in blood upon intravenous administration. Here we describe an innovative technology, named “Intra-CORK”, engineered to mask systemic IL12 activity without impacting anti-tumor efficacy. Our strategy relies on the transient inhibition of the intracellular signaling of IL12 by a kinetically-matched pre-administration of Ruxolitinib, a commercially available JAK2 inhibitor. When treating tumor-bearing mice with the L19-IL12 fusion protein, targeting alternatively-spliced fibronectin, we achieved a long residence time of the cytokine within the tumor with rapid clearance from circulation. The short half-life of Ruxolitinib substantially increased the tolerability profile of L19-IL12 while preserving anti-tumor activity. Our technology relies on judiciously-chosen inhibitors matching circulatory half-lives of biopharmaceuticals and may be broadly applied to other antibody-cytokine fusion products in clinical trials
HostingRepository	PRIDE
AnnounceDate	2024-01-25
AnnouncementXML	Submission_2024-01-25_03:00:03.850.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Domenico Ravazza
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-28 08:21:35	ID requested
⏵ 1	2024-01-25 03:00:04	announced

Dataset with its publication pending

submitter keyword: Tumor targeting,Mouse, Liver, Tumor, jak2 inhibitors

Ettore Gilardoni
contact affiliation	Philochem AG
contact email	ettore.gilardoni@philochem.ch
lab head
Domenico Ravazza
contact affiliation	Philochem AG
contact email	domenico.ravazza@philochem.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047339
     1. Label: PRIDE project
     2. Name: A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors