Apr 30, 2020

An engineered 4-1BBL fusion protein with ''activity-on-demand''

BioRxiv : the Preprint Server for Biology
J. C. MockDario Neri

Abstract

Engineered cytokines are gaining importance for cancer therapy but those products are often limited by toxicity, especially at early time points after intravenous administration. 4-1BB is a member of the tumor necrosis factor receptor superfamily, which has been considered as a target for therapeutic strategies with agonistic antibodies or using its cognate cytokine ligand, 4-1BBL. Here we describe the engineering of an antibody fusion protein (termed F8-4-1BBL), which does not exhibit cytokine activity in solution but regains biological activity upon antigen binding. F8-4-1BBL bound specifically to its cognate antigen, the alternatively-spliced EDA domain of fibronectin, and selectively localized to tumors in vivo, as evidenced by quantitative biodistribution experiments. The product promoted a potent anti-tumor activity in various mouse models of cancer, without apparent toxicity at the doses used. F8-4-1BBL represents a prototype for antibody-cytokine fusion proteins, which conditionally display ''activity-on-demand'' properties at the site of disease upon antigen binding and reduce toxicity to normal tissues.

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Mentioned in this Paper

Positioning Attribute
YARS2 gene
Right Bundle Branch Block
Reverse Transcriptase Polymerase Chain Reaction
Salmonidae
Acanthamoeba sp. Nich
Species
Analysis
Centroid protein, Xenopus
Pemetrexed

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