Abstract Book 2010 - CIMT Annual Meeting
Abstract Book 2010 - CIMT Annual Meeting
Abstract Book 2010 - CIMT Annual Meeting
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064 Hornig | New targets & new leads<br />
Combinatorial approach of a bispecific antibody and costimulatory<br />
antibody fusion proteins for targeted cancer<br />
immunotherapy<br />
Nora Hornig, Philipp Diebolder, Yvonne Eichinger, Roland E. Kontermann & Dafne Müller<br />
Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany<br />
Recombinant bispecific antibodies have shown to<br />
be able to retarget cytotoxic T cells to tumor cells<br />
in a MHC-independent manner, triggering effector<br />
cell activation and consecutive tumor cell killing.<br />
Considering that costimulation is an essential requirement<br />
not only to initiate T cell activation, but<br />
also for the regulation of a proper T cell response,<br />
we propose a combinatorial approach by a recombinant<br />
bispecific antibody and targeted costimulatory<br />
ligands in order to generate a highly efficient<br />
antitumoral immune response. In our model<br />
system we used a bispecific antibody recognizing<br />
the fibroblast activation protein (FAP) on tumor<br />
cells and CD3 on T cells. For targeted costimulation<br />
we generated antibody fusion proteins composed<br />
of a tumor binding antibody moiety and the extracellular<br />
domain of the costimulatory ligands B7.2<br />
and 4-1BBL, respectively. In view of the concomitant<br />
binding requirement of these constructs to the<br />
tumor cell, different antibody moieties, targeting<br />
the antigens FAP and endoglin on the tumor cell,<br />
were used. Costimulatory effects were assayed by<br />
incubating the fusion proteins with the bispecific<br />
antibody on tumor cells in presence of PBMCs and<br />
monitoring IL-2 and IFN-γ release. We showed that<br />
T cell activation induced by the bispecific antibody<br />
was significantly enhanced by targeted costimulation<br />
either with the B7.2 or the 4-1BBL fusion<br />
protein in a concentration-dependent and ligandspecific<br />
manner.<br />
Moreover, further signal enhancement was achie-<br />
ved by the combined application of both costimulatory<br />
fusion proteins, showing a synergistic effect.<br />
Thus, application of recombinant bispecific antibodies<br />
with combinations of tumor directed costimulatory<br />
fusion proteins of B7.2 and 4-1BBL might<br />
be a promising approach for efficient retargeting<br />
and activation of cytotoxic T lymphocytes in cancer<br />
immunotherapy.<br />
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