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

Sci Transl Med. 2017 Nov 8;9(415):eaan0401. doi: 10.1126/scitranslmed.aan0401.


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.

MeSH terms

  • Animals
  • Antibodies / metabolism
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use*
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • CTLA-4 Antigen
  • Disease Models, Animal
  • Extracellular Matrix / metabolism*
  • Extracellular Matrix Proteins / metabolism
  • Fibrinolysin / metabolism
  • Genetic Engineering
  • Heparin / metabolism
  • Immunity
  • Immunotherapy*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / therapy*
  • Mice, Inbred C57BL
  • Peptides / pharmacology
  • Peptides / therapeutic use
  • Placenta Growth Factor / chemistry
  • Treatment Outcome


  • Antibodies
  • Antineoplastic Agents
  • CTLA-4 Antigen
  • Extracellular Matrix Proteins
  • Peptides
  • Placenta Growth Factor
  • Heparin
  • Fibrinolysin