TLR9-mediated activation of dendritic cells by CD32 targeting for the generation of highly immunostimulatory vaccines

Human Vaccines & Immunotherapeutics
J A Sepulveda-ToepferGeert C Mudde

Abstract

The rational for designing dendritic cell (DC)-targeted immunotherapies is their central role in orchestrating immunity. Most studies addressing antigen-targeting to DCs for eliciting T cell responses have employed ex-vivo matured DCs derived from monocytes or myeloid DCs isolated from peripheral blood. More recently, also plasmacytoid DCs (pDCs) emerged as attractive targets that can be readily isolated and activated ex vivo. pDCs are known as key effectors of innate and adaptive immunity due to their exquisite ability to produce large amounts of type-1 interferons upon signaling via TLR7 or TLR9 intracellular receptor for viral RNA or bacterial DNA, respectively. In this study, we describe and characterize the immune modulating and targeting module of a composite human specific vaccine platform for active immunotherapy. This module, called warhead (WH), is composed of a single-chain variable fragment (scFv) and CpG-C type oligonucleotides (ODNs) that are covalently coupled. The scFv mediates specific binding to FcγRII/CD32 on APCs and internalization of the ODNs which stimulate TLR9-expressing B cells and pDCs. Furthermore, the scFv in the WH is extended with a five-time heptad repeat (EVSALEK) alpha helix which allows for a ...Continue Reading

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Methods Mentioned

BETA
ELISA
biolayer interferometry
gel filtration
protein assay
flow cytometry
FCS
biosensors

Software Mentioned

ForteBio
Magellan
Graphpad Prism
Graphpad
Excel
Data Analysis

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