An Anti-CD276 Antibody–Drug Conjugate Kills Tumor Cells and Vasculature

The use of antibody–drug conjugates (ADC) has emerged as a potential therapeutic strategy to improve the efficacy of monoclonal antibodies in cancer therapy. The ADCs in clinical use target the tumor cells, and their efficacy is thereby limited by tumor cell heterogeneity and genomic instability that can promote acquired resistance. To overcome these challenges, Seaman and colleagues sought to develop an ADC targeting both tumor cells and the tumor vasculature. The cell-surface tumor endothelial cell marker CD276 was investigated as a therapeutic target, as it may distinguish pathologic angiogenesis from physiologic angiogenesis and is frequently overexpressed on tumor cells. CD276 was expressed on the angiogenic and nonangiogenic tumor vasculature, and despite broad expression of CD276 on multiple tumor types, it was not required for tumor cell growth. Treating tumor xenografts with anti-CD276 linked to the antimitotic drug monomethyl auristatin E (MMAE) resulted in tumor regression followed by relapse, and tumor cells expressing low levels of CD276 were more resistant to treatment. Although anti-CD276–MMAE effectively targeted tumor cells, the tumor endothelium was unaffected. Endothelial cells were found to be more sensitive to DNA-damaging pyrrolobenzodiazepine (PBD) dimers than MMAE. Thus, anti-CD276 was conjugated to PBD, and the ADC selectively targeted both CD276⁺ tumor cells and tumor endothelial cells, resulting in tumor regression in mouse xenografts with CD276⁺ tumor cells and tumor vessels. Further, anti-CD276–PBD was well tolerated and had broad antitumor and antimetastatic activity in lung, breast, and colon cancer xenografts. In addition to developing an anti-CD276–PBD ADC that induces tumor regression, this study demonstrates that dual targeting of tumor cells and tumor vasculature may be an effective therapeutic strategy in many solid tumor types.

Seaman S, Zhu Z, Saha S, Zhang XM, Yang MY, Hilton MB, et al. Eradication of tumors through simultaneous ablation of CD276/B7-H3-positive tumor cells and tumor vasculature. Cancer Cell 2017;31:501–15.e8.

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