An antibody-drug conjugate that targets tissue factor exhibits potent therapeutic activity against a broad range of solid tumors.

Abstract

Tissue factor (TF) is aberrantly expressed in solid cancers and is thought to contribute to disease progression through its procoagulant activity and its capacity to induce intracellular signaling in complex with factor VIIa (FVIIa). To explore the possibility of using tissue factor as a target for an antibody-drug conjugate (ADC), a panel of human tissue factor-specific antibodies (TF HuMab) was generated. Three tissue factor HuMab, that induced efficient inhibition of TF:FVIIa-dependent intracellular signaling, antibody-dependent cell-mediated cytotoxicity, and rapid target internalization, but had minimal impact on tissue factor procoagulant activity in vitro, were conjugated with the cytotoxic agents monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). Tissue factor-specific ADCs showed potent cytotoxicity in vitro and in vivo, which was dependent on tissue factor expression. TF-011-MMAE (HuMax-TF-ADC) was the most potent ADC, and the dominant mechanism of action in vivo was auristatin-mediated tumor cell killing. Importantly, TF-011-MMAE showed excellent antitumor activity in patient-derived xenograft (PDX) models with variable levels of tissue factor expression, derived from seven different solid cancers. Complete tumor regression was observed in all PDX models, including models that showed tissue factor expression in only 25% to 50% of the tumor cells. In conclusion, TF-011-MMAE is a promising novel antitumor agent with potent activity in xenograft models that represent the heterogeneity of human tumors, including heterogeneous target expression.

• Authors: Esther C W Breij, Bart E C G de Goeij, Sandra Verploegen, Danita H Schuurhuis, Ali Amirkhosravi, John Francis, Vibeke Breinholt Miller, Mischa Houtkamp, Wim K Bleeker, David Satijn, Paul W H I Parren
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 4 Pg. 1214-26 (Feb 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24371232 (Publication Type: Journal Article)
• Copyright: ©2013 AACR.

Chemical References

• Aminobenzoates
• Antibodies, Monoclonal
• Antineoplastic Agents
• Immunoconjugates
• Oligopeptides
• auristatin
• Thromboplastin
• monomethyl auristatin E

Topics

• Aminobenzoates (therapeutic use)
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Cells, Cultured
• HCT116 Cells
• HEK293 Cells
• Humans
• Immunoconjugates (therapeutic use)
• Mice
• Mice, Nude
• Molecular Targeted Therapy
• Neoplasms (drug therapy)
• Oligopeptides (therapeutic use)
• Thromboplastin (antagonists & inhibitors, immunology)
• Xenograft Model Antitumor Assays