Intratumoral nanobody-IL-2 fusions that bind the tumor extracellular matrix suppress solid tumor growth in mice

Emi A Lutz; Noor Jailkhani; Noor Momin; Ying Huang; Allison Sheen; Byong H Kang; K Dane Wittrup; Richard O Hynes

doi:10.1093/pnasnexus/pgac244

Intratumoral nanobody-IL-2 fusions that bind the tumor extracellular matrix suppress solid tumor growth in mice

PNAS Nexus. 2022 Nov 3;1(5):pgac244. doi: 10.1093/pnasnexus/pgac244. eCollection 2022 Nov.

Authors

Emi A Lutz^{1

2}, Noor Jailkhani¹, Noor Momin^{1

2}, Ying Huang¹, Allison Sheen^{1

2}, Byong H Kang^{1

2}, K Dane Wittrup^{1

2

3}, Richard O Hynes^{1

4}

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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.

Keywords: cancer; cytokine; nanobody.

Abstract

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