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.
Highlights
Antibody-drug conjugates (ADC), which combine the tumor-targeting capacity of monoclonal antibodies with the antitumor activity of cytotoxic agents, received renewed attention in recent years
By carefully selecting tissue factor– specific antibodies that interfere with Tissue factor (TF):factor VIIa (FVIIa)-dependent intracellular signaling, but not with tissue factor procoagulant activity, and that show efficient internalization and lysosomal targeting, we developed an ADC that efficiently kills tumor cells in vivo with only minimal effect on parameters of coagulation
Tissue factor–specific antibodies interfere with TF: FVIIa-mediated intracellular signaling
Summary
Antibody-drug conjugates (ADC), which combine the tumor-targeting capacity of monoclonal antibodies with the antitumor activity of cytotoxic agents, received renewed attention in recent years. Trastuzumab emtansine (T-DM1), an ADC composed of the HER2-specific antibody trastuzumab and the cytotoxic agent DM1, increased progression-free survival in patients that had received prior treatment with unconjugated trastuzumab [1], demonstrating the added value of toxin conjugation to a monoclonal antibody. Expression has been described on tumor cells and the tumor vasculature, and has been associated with poor disease prognosis and increased metastatic properties This, in combination with the known internalizing capacity of tissue factor [4], led us to explore the possibility of using tissue factor as a novel target for an ADC
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