Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade

Dakhel, Sheila; Ongaro, Tiziano; Gouyou, Baptiste; Matasci, Mattia; Villa, Alessandra; Neri, Dario; Cazzamalli, Samuele

doi:10.1101/688507

Cited by 1 publication

(1 citation statement)

References 45 publications

(64 reference statements)

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“…GSK963, a potent inhibitor of RIPK1, 91 was identified as a candidate Intra-Cork molecule to control toxicity associated with high doses of the L19-TNF fusion protein. 92 Transient inhibition of RIPK1 allowed the administration of doses of L19-TNF, which would otherwise be lethal, while the immunocytokine could still accumulate at the tumor site, induce hemorrhagic necrosis, and retain therapeutic activity in preclinical models. Benchmarking with Ibuprofen, a commonly employed premedication for cancer patients undergoing cytokine treatment, did not reduce treatment-related toxicity.…”

Section: ■ Intracellular "Corks"mentioning

confidence: 99%

Cytokine Biopharmaceuticals with “Activity-on-Demand” for Cancer Therapy

Rotta,

Puca,

Cazzamalli

et al. 2024

Bioconjugate Chem.

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Cytokines are small proteins that modulate the activity of the immune system. Because of their potent immunomodulatory properties, some recombinant cytokines have undergone clinical development and have gained marketing authorization for the therapy of certain forms of cancer. Recombinant cytokines are typically administered at ultralow doses, as many of them can cause substantial toxicity even at submilligram quantities. In an attempt to increase the therapeutic index, fusion proteins based on tumor-homing antibodies (also called “immunocytokines”) have been considered, and some products in this class have reached late-stage clinical trials. While antibody-cytokine fusions, which preferentially localize in the neoplastic mass, can activate tumor-resident leukocytes and may be more efficacious than their nontargeted counterparts, such products typically conserve an intact cytokine activity, which may prevent escalation to curative doses. To further improve tolerability, several strategies have been conceived for the development of antibody-cytokine fusions with “activity-on-demand”, acting on tumors but helping spare normal tissues from undesired toxicity. In this article, we have reviewed some of the most promising strategies, outlining their potential as well as possible limitations.

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Section: ■ Intracellular "Corks"mentioning

confidence: 99%