Anti‐tumor activity of an anti‐endoglin monoclonal antibody is enhanced in immunocompetent mice

Abstract

In the present study, we investigated the mechanisms by which anti-endoglin (EDG; CD105) monoclonal antibodies (mAbs) suppress angiogenesis and tumor growth. Antihuman EDG mAb SN6j specifically bound to murine endothelial cells and was internalized into the cells in vitro. SN6j effectively suppressed angiogenesis in mice in the Matrigel plug assay. We found that SN6j is more effective for tumor suppression in immunocompetent mice than in SCID mice. We hypothesized that T cell immunity is important for effective antitumor efficacy of SN6j in vivo. To test this hypothesis, we investigated effects of CpG oligodeoxynucleotides (ODN) and depletion of CD4 1 T cells and/or CD8 1 T cells on antitumor efficacy of SN6j in mice. Systemic (i.v.) administration of a relatively small dose (0.6 lg/g body weight/dose) of SN6j suppressed growth of established s.c. tumors of colon-26 in BALB/c mice and improved survival of the tumor-bearing mice. Addition of CpG ODN to SN6j synergistically enhanced antitumor efficacy of SN6j. In contrast, such enhancing effects of CpG ODN were not detected in SCID mice. Antitumor efficacy of SN6j in BALB/c mice was abrogated when CD41 T cells and/or CD8 1 T cells were depleted; effect of CD8 1 T cell depletion was stronger. Interestingly, CD4-depletion decreased tumor growth while CD8-depletion enhanced tumor growth in the absence of SN6j. SN6j induced apoptosis in human umbilical vein endothelial cells in a dose-dependent manner which indicates an additional mechanism of antiangiogenesis by SN6j. ' 2008 Wiley-Liss, Inc.Key words: endoglin; antiangiogenesis; monoclonal antibody therapy; T cell immunity; synergy Angiogenesis is essential for tumor growth, progression and metastasis and antiangiogenic therapy has become a new promising strategy in the treatment of cancer patients.

The physiological role of endoglin in the cardiovascular system

“…In this regard, there are several reported approaches using experimental animal models (55,117,156,164,165). Among these, the approach of using naked anti-endoglin monoclonal antibodies as a tumor vascular targeting agent is clinically relevant.…”

Src-mediated Post-translational Regulation of Endoglin Stability and Function Is Critical for Angiogenesis

“…Endoglin antibodies have also been previously reported to induce receptor internalization and presumed to become degraded through an unknown mechanism (31,32). As part of our ongoing investigation on the anti-angiogenic properties of TRC105, we tested the functional role of the tyrosine endocytic motif in TRC105-induced endoglin internalization.…”

Tumor neoangiogenesis detection by confocal laser endomicroscopy and anti-CD105 antibody: Pilot study

“…On one hand, this could be related to the tumor grading or staging, as an increase in MVD was demonstrated by using CD105 during progressive stages of colorectal carcinogenesis [21] . On the other hand, reduced endoglin expression could also be caused by a decreased tumor vascularization in endoglin haploinsufficiency cases [22] . There are also differences in reactivity to endothelial cells depending on tumor localization [22][23][24] .…”

“…On the other hand, reduced endoglin expression could also be caused by a decreased tumor vascularization in endoglin haploinsufficiency cases [22] . There are also differences in reactivity to endothelial cells depending on tumor localization [22][23][24] . However, in colorectal cancer, other studies showed that, with cancer progression, endoglin signaling was lost in most of the epithelial cancer cells which became refractory to the TGF-β growth inhibiting properties [25][26][27][28][29] .…”