Improving Efficacy and Safety of Agonistic Anti-CD40 Antibody Through Extracellular Matrix Affinity

Mol Cancer Ther. 2018 Nov;17(11):2399-2411. doi: 10.1158/1535-7163.MCT-18-0091. Epub 2018 Aug 10.


CD40 is an immune costimulatory receptor expressed by antigen-presenting cells. Agonistic anti-CD40 antibodies have demonstrated considerable antitumor effects yet can also elicit serious treatment-related adverse events, such as liver toxicity, including in man. We engineered a variant that binds extracellular matrix through a super-affinity peptide derived from placenta growth factor-2 (PlGF-2123-144) to enhance anti-CD40's effects when administered locally. Peritumoral injection of PlGF-2123-144-anti-CD40 antibody showed prolonged tissue retention at the injection site and substantially decreased systemic exposure, resulting in decreased liver toxicity. In four mouse tumor models, PlGF-2123-144-anti-CD40 antibody demonstrated enhanced antitumor efficacy compared with its unmodified form and correlated with activated dendritic cells, B cells, and T cells in the tumor and in the tumor-draining lymph node. Moreover, in a genetically engineered BrafV600E βCatSTA melanoma model that does not respond to checkpoint inhibitors, PlGF-2123-144-anti-CD40 antibody treatment enhanced T-cell infiltration into the tumors and slowed tumor growth. Together, these results demonstrate the marked therapeutic advantages of engineering matrix-binding domains onto agonistic anti-CD40 antibody as a therapeutic given by tumori-regional injection for cancer immunotherapy.Implications: Extracellular matrix-binding peptide conjugation to agonistic anti-CD40 antibody enhances antitumor efficacy and reduces treatment-related adverse events. Mol Cancer Ther; 17(11); 2399-411. ©2018 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / adverse effects*
  • Antibodies, Monoclonal / therapeutic use
  • Antibody Affinity*
  • B-Lymphocytes / immunology
  • CD40 Antigens / agonists*
  • CD40 Antigens / immunology
  • Cell Line, Tumor
  • Cross-Priming / immunology
  • Dendritic Cells / immunology
  • Extracellular Matrix / metabolism*
  • Humans
  • Immunity
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Mice, Inbred C57BL
  • Mice, Nude
  • Peptides / chemistry
  • Placenta Growth Factor / metabolism
  • T-Lymphocytes / immunology
  • beta Catenin / metabolism


  • Antibodies, Monoclonal
  • CD40 Antigens
  • Peptides
  • beta Catenin
  • Placenta Growth Factor