Intratumoral nanobody–IL-2 fusions that bind the tumor extracellular matrix suppress solid tumor growth in mice
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pgac244.pdf
Description
Published version
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3.03 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Lutz, Emi A
Jailkhani, Noor
Momin, Noor
Huang, Ying
Sheen, Allison
Kang, Byong H
Wittrup, K Dane
Hynes, Richard O
Date Issued
November 2022
Journal
PNAS Nexus
Publisher
Oxford University Press
Citation
Emi A Lutz, Noor Jailkhani, Noor Momin, Ying Huang, Allison Sheen, Byong H Kang, K Dane Wittrup, Richard O Hynes, Intratumoral nanobody–IL-2 fusions that bind the tumor extracellular matrix suppress solid tumor growth in mice, PNAS Nexus, Volume 1, Issue 5, November 2022, pgac244.
Version
Final published version
Abstract
Confining cytokine exposure to the tumors would greatly enhance cancer immunotherapy safety and efficacy. Immunocytokines, cytokines fused to tumor-targeting antibodies, have been developed with this intention, but without significant clinical success to date. A critical limitation is uptake by receptor-expressing cells in the blood, that decreases the dose at the tumor and engenders toxicity. Small-format immunocytokines, constructed with antibody fragments, are hypothesized to improve tumor specificity due to rapid systemic clearance. However, effective design criteria for small-format immunocytokines need further examination. Here, we engineer small interleukin-2 (IL-2) immunocytokines fused to nanobodies with nanomolar to picomolar affinities for the tumor-specific EIIIB domain of fibronectin (also known as EDB). Upon intravenous delivery into immunocompetent mice, such immunocytokines led to similar tumor growth delay as size-matched untargeted IL-2. Intratumoral (i.t.) delivery imparted improved survival dependent on affinity to EIIIB. I.t. administration offers a promising avenue to deliver small-format immunocytokines, given effective affinity for the tumor microenvironment.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution
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DOI of Published Version
10.1093/pnasnexus/pgac244
