Anti‐endoglin monoclonal antibodies are effective for suppressing metastasis and the primary tumors by targeting tumor vasculature

Abstract

Anti-metastatic activity of an antitumor agent is exceedingly important because metastasis is the primary cause of death for most solid cancer patients. In this report, we show that 3 anti-endoglin (ENG) monoclonal antibodies (mAbs) SN6a, SN6j and SN6k which define individually distinct epitopes of ENG of tumor vasculature are capable of suppressing tumor metastases in the multiple metastasis models. The metastasis models were generated by i.v., s.c. (into flank) or mammary gland fat pad injection of 4T1 murine mammary carcinoma cells and splenic injection of two types of colon26 murine colorectal carcinoma cells. Individual mAbs were injected i.v. via the tail vein of mice. SN6a and SN6j effectively suppressed the formation of metastatic colonies of 4T1 in the lung in all of the three 4T1 metastatic models. In addition, these mAbs were effective for suppressing the primary tumors of 4T1 in the skin and mammary fat pad. These mAbs effectively suppressed microvessel density and angiogenesis in tumors as measured by the Matrigel plug assay in mice. No significant side effects of the administered mAbs were detected. Furthermore, SN6a and SN6j extended survival of the tumor-bearing mice. SN6j, SN6k and their immunoconjugates with deglycosylated ricin A-chain were all effective for suppressing hepatic metastasis of colon26. The findings in the present study are clinically relevant in view of the ongoing clinical trial of a humanized (chimerized) form of SN6j.

Neovascularization evaluated by CD105 correlates well with prognostic factors in breast cancers

“…These effects are potentially inhibited by a dual blockade of the TGF-β and CD105 pathways (35). Moreover, the anti-CD105 antibody as a single agent as well as CD105 as a target for an oral DNA vaccine have also been reported to be effective agents for suppressing or preventing tumor progression and prolonging survival in in vitro models (36)(37)(38).…”

Beyond VEGF: The NOTCH and ALK1 Signaling Pathways as Tumor Angiogenesis Targets

“…SN6j has an antiproliferative effect on human endothelial cells in vitro (She et al, 2004) and decreased tumor growth in several mouse tumor models (Tsujie et al, 2006;Uneda et al, 2009). SN6j also www.intechopen.com inhibited lung and liver metastases in metastatic cancer models (Uneda et al, 2009).…”

“…SN6j has an antiproliferative effect on human endothelial cells in vitro (She et al, 2004) and decreased tumor growth in several mouse tumor models (Tsujie et al, 2006;Uneda et al, 2009). SN6j also www.intechopen.com inhibited lung and liver metastases in metastatic cancer models (Uneda et al, 2009). The anti-tumor mechanism of action of SN6j is thought to derive from its anti-angiogenic properties, as SN6j significantly decreased the vascularization of a matrigel plug assay (Tsujie et al, 2006).…”

Tumor angiogenesis as prognostic and predictive marker for chemotherapy dose-intensification efficacy in high-risk breast cancer patients within the WSG AM-01 trial

“…Targeting of TGF-β signaling leads to depression of angiogenesis (among others through endoglin) and can reverse a stem cell phenotype to a more-differentiated luminal phenotype [41] These effects can be potentially inhibited by dual blockade of TGF-beta and endoglin pathways [42]. Moreover, anti-endoglin antibodies as single agents as well as CD 105 as target for oral DNA vaccine have also been reported as effective in suppressing or preventing tumor progression and prolonging survival in in-vitro models [43,44]..…”