Enhanced antitumor effect of anti‐tissue factor antibody‐conjugated epirubicin‐incorporating micelles in xenograft models

Abstract

For the creation of a successful antibody–drug conjugate (ADC), both scientific and clinical evidence has indicated that highly toxic anticancer agents (ACA) should be conjugated to a monoclonal antibody (mAb) to administer a reasonable amount of ADC to patients without compromising the affinity of the mAb. For ordinary ACA, the conjugation of a mAb to ACA-loaded micellar nanoparticles is clinically applicable. Tissue factor (TF) is often overexpressed in various cancer cells and tumor vascular endothelium. Accordingly, anti-TF-NC-6300, consisting of epirubicin-incorporating micelles (NC-6300) conjugated with the F(ab')2 of anti-TF mAb was developed. The in vitro and in vivo efficacy and pharmacokinetics of anti-TF-NC-6300 were compared to NC-6300 using two human pancreatic cancer cell lines, BxPC3 (high TF expression) and SUIT2 (low TF expression), and a gastric cancer cell line, 44As3 (high TF expression). The intracellular uptake of epirubicin was faster and greater in BxPC3 cells treated with anti-TF-NC-6300, compared with NC-6300. Anti-TF-NC-6300 showed a superior antitumor activity in BxPC3 and 44As3 xenografts, compared with NC-6300, while the activities of both micelles were similar in the SUIT2 xenograft. A higher tumor accumulation of anti-TF-NC-6300 compared to NC-6300 was seen, regardless of the TF expression levels. However, anti-TF-NC-6300 appeared to be localized to the tumor cells with high TF expression. These results indicated that the enhanced antitumor effect of anti-TF-NC6300 may be independent of the tumor accumulation but may depend on the selective intratumor localization and the preferential internalization of anti-TF-NC-6300 into high TF tumor cells.

Utility of epirubicin‐incorporating micelles tagged with anti‐tissue factor antibody clone with no anticoagulant effect

“…In the present study, anti‐TF1859‐NC‐6300 showed superior antitumor activity to NC‐6300 in the TF‐high expressing human pancreatic cancer model. This is similar to our previous report concerning anti‐TF1849‐NC‐6300 . Anti‐TF1849‐NC‐6300 was distributed throughout all of the tumor tissues and was efficiently internalized into tumor cells; it showed potent antitumor activity in TF‐high expressing cancer cells, indicating that the conjugation of anti‐TF mAb to micelles offered that advantage.…”

“…In addition, overexpression of TF on tumor cells is closely related to poor patient prognosis in various cancers . We previously developed an anti‐TF antibody (clone 1849) conjugated with NC‐6300 (anti‐TF1849‐NC‐6300) and showed that it had superior antitumor activity when compared with NC‐6300 alone …”

FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy

“…As a result, EPI has less side effects compared with DOX at doses producing equivalent antitumor effects [35]. EPI therefore has been nanosized to various formulations such as micelles [36], liposomes [37], nanoparticles [38,39], and, most interesting for us, water-soluble conjugates to improve its therapeutic index. In general, polymer-EPI conjugates were produced via polymeranalogous reaction in which EPI is attached to polymer through active ester [27] or in the presence of coupling agents [25,28].…”

Development of polymeric micelles for targeting intractable cancers

“…These immunomicelles were conjugated with antibodies targeting osteopontin, epidermal growth factor receptor, human epidermal growth factor receptor‐2, and others. Recently, we reported immunomicelles conjugated with anti‐tissue factor (TF) antibody fragments . Tissue factor is known as a primary initiator of blood coagulation, and plays an important role in tumor proliferation, invasion, and metastasis .…”

“…Importantly, these properties, which might critically affect the performance as a drug carrier, can be optimized by fine‐tuning chemical structures and compositions of the micelle‐forming block copolymers . In addition, installation of functional molecules such as environment‐responsive cleavable linkages and targetable ligands on the block copolymers allows construction of polymeric micelles with smart functionalities . Owing to the above‐mentioned prominent advantages beyond other drug vehicles, several micellar formulations of anticancer drugs are currently under evaluation in preclinical and clinical studies .…”