Lutz, Jailkhani, and Momin et al. developed a nanobody–interleukin-2 (IL-2) fusion immunocytokine with picomolar affinity to target the tumor-specific EIIIB domain of fibronectin. Despite the high affinity, intravenous administration of EIIIB-specific nanobody–IL-2 fusions resulted in a modest impact on tumor growth and cellular biodistribution compared to untargeted IL-2, suggesting the dominance of a systemic sink of cells binding IL-2. However, intratumoral administration of the nanobody–IL-2 fusion to B16F10 tumors markedly reduced tumor growth, enabled a high B16F10 cure rate, and produced prolonged immunological memory, with reduced IL-2 dose and frequency.
Contributed by Shishir Pant
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.
Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biological Engineering, Massachusetts Institute o
Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (2) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (3) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (4) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (5) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (6) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (7) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (8) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
