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Open AccessArticle

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

1
University Clinic for Internal Medicine IV, Hematology/Oncology, Medical Faculty of Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
2
Institute of Pharmacy, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
3
University Hospital Halle (Saale), Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Simona Collina
Molecules 2019, 24(16), 2865; https://doi.org/10.3390/molecules24162865
Received: 26 June 2019 / Revised: 2 August 2019 / Accepted: 3 August 2019 / Published: 7 August 2019
(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)
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. View Full-Text
Keywords: anti-angiogenic therapy; VEGF; ANGPT2; Ang-2; bispecific antibody; CrossMab; bevacizumab; vanucizumab; colorectal cancer anti-angiogenic therapy; VEGF; ANGPT2; Ang-2; bispecific antibody; CrossMab; bevacizumab; vanucizumab; colorectal cancer
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Mueller, T.; Freystein, J.; Lucas, H.; Schmoll, H.-J. Efficacy of a Bispecific Antibody Co-Targeting VEGFA and Ang-2 in Combination with Chemotherapy in a Chemoresistant Colorectal Carcinoma Xenograft Model. Molecules 2019, 24, 2865.

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