論文

国際誌
2018年11月

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

Molecular cancer therapeutics
  • Jun Ishihara
  • ,
  • Ako Ishihara
  • ,
  • Lambert Potin
  • ,
  • Peyman Hosseinchi
  • ,
  • Kazuto Fukunaga
  • ,
  • Martina Damo
  • ,
  • Thomas F Gajewski
  • ,
  • Melody A Swartz
  • ,
  • Jeffrey A Hubbell

17
11
開始ページ
2399
終了ページ
2411
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/1535-7163.MCT-18-0091

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.

リンク情報
DOI
https://doi.org/10.1158/1535-7163.MCT-18-0091
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/30097487
ID情報
  • DOI : 10.1158/1535-7163.MCT-18-0091
  • PubMed ID : 30097487

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