Tumor stroma-targeted antibody-drug conjugate triggers localized anticancer drug release

J Clin Invest. 2018 Jul 2;128(7):2927-2943. doi: 10.1172/JCI120481. Epub 2018 Jun 4.

Abstract

Although nonmalignant stromal cells facilitate tumor growth and can occupy up to 90% of a solid tumor mass, better strategies to exploit these cells for improved cancer therapy are needed. Here, we describe a potent MMAE-linked antibody-drug conjugate (ADC) targeting tumor endothelial marker 8 (TEM8, also known as ANTXR1), a highly conserved transmembrane receptor broadly overexpressed on cancer-associated fibroblasts, endothelium, and pericytes. Anti-TEM8 ADC elicited potent anticancer activity through an unexpected killing mechanism we term DAaRTS (drug activation and release through stroma), whereby the tumor microenvironment localizes active drug at the tumor site. Following capture of ADC prodrug from the circulation, tumor-associated stromal cells release active MMAE free drug, killing nearby proliferating tumor cells in a target-independent manner. In preclinical studies, ADC treatment was well tolerated and induced regression and often eradication of multiple solid tumor types, blocked metastatic growth, and prolonged overall survival. By exploiting TEM8+ tumor stroma for targeted drug activation, these studies reveal a drug delivery strategy with potential to augment therapies against multiple cancer types.

Keywords: Angiogenesis; Cancer; Therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor / antagonists & inhibitors
  • Biomarkers, Tumor / deficiency
  • Biomarkers, Tumor / genetics
  • Brentuximab Vedotin
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Mice, SCID
  • Microfilament Proteins
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Peptide / antagonists & inhibitors
  • Receptors, Peptide / deficiency
  • Receptors, Peptide / genetics
  • Stromal Cells / drug effects
  • Tumor Microenvironment / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • ANTXR1 protein, human
  • Antineoplastic Agents
  • Antxr1 protein, mouse
  • Biomarkers, Tumor
  • Immunoconjugates
  • Microfilament Proteins
  • Neoplasm Proteins
  • Receptors, Cell Surface
  • Receptors, Peptide
  • Brentuximab Vedotin