Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events

J Ishihara, K Fukunaga, A Ishihara… - Science translational …, 2017 - science.org
J Ishihara, K Fukunaga, A Ishihara, HM Larsson, L Potin, P Hosseinchi, G Galliverti…
Science translational medicine, 2017science.org
Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies
have reported instances of severe treatment-related adverse events. We sought to explore
local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra-
or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the
checkpoint blockade Abs to an extracellular matrix (ECM)–super-affinity peptide derived
from placenta growth factor–2 (PlGF-2123–144). We show enhanced tissue retention and …
Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)–super-affinity peptide derived from placenta growth factor–2 (PlGF-2123–144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123–144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2123–144–anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2123–144–anti–PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-2123–144–Abs increased tumor-infiltrating activated CD8+ and CD4+ T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade.
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