Efficacy of a Bispecific Antibody Co-Targeting VEGFA and Ang-2 in Combination with Chemotherapy in a Chemoresistant Colorectal Carcinoma Xenograft Model.

Thomas Mueller,Hans-Joachim Schmoll,Henrike Lucas,Juana Freystein

doi:10.3390/molecules24162865

Thomas Mueller, Hans-Joachim Schmoll + Show 2 more

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https://doi.org/10.3390/molecules24162865

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Abstract

Vascular endothelial growth factor (VEGF) inhibition by the addition of bevacizumab to the chemotherapy regimen of metastatic colorectal cancer leads to an improved outcome. However, anti-angiogenic tumor therapy targeting a single factor may be limited by complementary mechanisms. Angiopoietin-2 (Ang-2, ANGPT2) is another important factor that cooperates with VEGF to drive tumor angiogenesis. It was shown that high Ang-2 levels are associated with a poor clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Therefore, combined inhibition of VEGF and Ang-2 was supposed to improve anti-angiogenic therapy. Here, we evaluated the efficacy of a bispecific antibody (CrossMab) co-targeting VEGF and Ang-2 in combination with chemotherapy in a chemoresistant colorectal carcinoma model. Antitumor activity was evaluated in athymic nude mice bearing subcutaneous DLD1 xenograft tumors and treated with anti-VEGF (B20), anti-Ang-2 (LC06) and anti-VEGF/Ang-2 (CrossMab) antibodies. Chemotherapy consisted of 5-FU and irinotecan. Resected tumors were analyzed immunohistochemically. First, an impact of targeting each single factor but also a clear advantage of co-targeting both factors could be demonstrated. Accordingly, tumor tissue showed strong staining for VEGF and Ang-2. Chemotherapy alone was less effective. Efficient tumor growth inhibition could be achieved by treatment with anti-VEGF/chemotherapy, single CrossMab and CrossMab/chemotherapy, which resulted in 3 out of 10, 6 out of 10 and 10 out of 10 complete responses, respectively, during seven weeks. Complete retarded tumors were characterized by massive intratumoral necrosis surrounded by layers of vital tumor cells and connective tissue with CD31-positive vessels at the periphery. In some cases, a distinct feature known as vessel co-option could be observed. In conclusion, the data from this model clearly support the strategy of co-targeting VEGF and Ang-2 and further demonstrate the beneficial impact of co-treatment with chemotherapy. The clear superiority of the CrossMab-containing regimen compared to clinical standard anti-VEGF/chemotherapy warrants further analyses in other models.

Highlights

Tumor angiogenesis is a hallmark of cancer [1] and targeting angiogenesis represents an attractive therapeutic approach to treat cancer [2,3]
Impact of Vascular endothelial growth factor (VEGF) and Ang-2 single Targeting Compared to Co-targeting in the Colorectal Carcinoma Model
A first preliminary study using three mice per group was performed to analyze the impact of single targeting VEGF and Ang-2 using specific antibodies compared to co-targeting mediated by the bispecific CrossMab in the DLD1 colorectal carcinoma xenograft model (Figure 1)

Summary

Introduction

Tumor angiogenesis is a hallmark of cancer [1] and targeting angiogenesis represents an attractive therapeutic approach to treat cancer [2,3]. Molecules 2019, 24, 2865 molecule in this context and plays a major role for angiogenesis, vascular permeability and tumor progression. The monoclonal antibody bevacizumab, which binds VEGFA, is one among several other angiogenesis inhibitors that are clinically approved. The addition of bevacizumab to chemotherapy has been shown to prolong patient survival in various cancers including colorectal cancer compared with chemotherapy alone [4]. Intrinsic or developing resistance is frequently observed. This is due to the presence of overlapping and compensatory alternative angiogenic pathways providing escape mechanisms that limit the potential of VEGF-targeted therapies [5,6]

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