Comparative evaluation of bolus and fractionated administration modalities for two antibody-cytokine fusions in immunocompetent tumor-bearing mice.

Abstract

Antibody-cytokine fusion proteins are being considered as biopharmaceuticals for cancer immunotherapy. Tumor-homing cytokine fusions typically display an improved therapeutic activity compared to the corresponding unmodified cytokine products, but toxicity profiles at equivalent doses are similar, since side effects are mainly driven by the cytokine concentration in blood. In order to explore avenues to harness the therapeutic potential of antibody-cytokine fusions while decreasing potential toxicity, we compared bolus and fractionated administration modalities for two tumor-targeting antibody-cytokine fusion proteins based on human interleukin-2 (IL2) and murine tumor necrosis factor (TNF) (i.e., L19-hIL2 and L19-mTNF) in two murine immunocompetent mouse models of cancer (F9 and C51). A comparative quantitative biodistribution analysis with radio-labeled protein preparations revealed that a fractionated administration of L19-hIL2 could deliver comparable product doses to the tumor with decreased product concentration in blood and normal organs, compared to bolus injection. By contrast, L19-mTNF (a product that causes a selective vascular shutdown in the tumor) accumulated most efficiently after bolus injection. Fractionated schedules allowed the safe administration of a cumulative dose of L19-mTNF, which was 2.5-times higher than the lethal dose for bolus injection. Dose fractionation led to a prolonged tumor growth inhibition for F9 teratocarcinomas, but not for C51 colorectal tumors, which responded best to bolus injection. Thus, dose fractionation may have different outcomes for the same antibody-cytokine product in different biological contexts.

• Authors: Emanuele Puca, Roberto De Luca, Frauke Seehusen, Josep Maria Monné Rodriguez, Dario Neri
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 317 Pg. 282-290 (01 10 2020) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 31790729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Antibodies
• Cytokines
• Recombinant Fusion Proteins

Topics

• Animals
• Antibodies
• Cytokines
• Immunotherapy
• Mice
• Neoplasms (drug therapy)
• Recombinant Fusion Proteins
• Tissue Distribution