Sortase A-Generated Highly Potent Anti-CD20-MMAE Conjugates for Efficient Elimination of B-Lineage Lymphomas

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• 作者：Liqiang Pan ; Wenbin Zhao ; Jun Lai ; Ding Ding ; Qian Zhang ; Xiaoyue Yang ; Minmin Huang ; Shijie Jin ; Yingchun Xu ; Su Zeng ; James J. Chou and Shuqing Chen
• 刊名：Small
• 出版年：2017
• 出版时间：February 10, 2017
• 年：2017
• 卷：13
• 期：6
• 全文大小：4364K
• ISSN：1613-6829

文摘

Antibody–drug conjugate (ADC) targeting antigens expressed on the surface of tumor cells are an effective approach for delivering drugs into the cells via antigen-mediated endocytosis. One of the well-known tumor antigens, the CD20 of B-lymphocyte, has long been suggested to be noninternalizing epitope, and is thus not considered a desirable target for ADCs. Here, sortase A (srtA)-mediated transpeptidation is used to specifically conjugate triple glycine-modified monomethyl auristatin E (MMAE), a highly toxic antimitotic agent, to anti-CD20 ofatumumab (OFA) equipped with a short C-terminal LPETG (5 amino acids) tag at heavy chain (HL), which generates ADCs that show extremely strong potency in killing CD20 positive cancer cells. One of the srtA-generated ADCs with a cleavable dipeptide linker (valine-citrulline, vc), OFA-HL-vcMMAE, shows IC50 values ranging from 5 pg mL⁻¹ to 4.1 ng mL⁻¹ against CD20+ lymphoma cells. Confocal laser scanning microscopy confirms that OFA-HL-vcMMAE internalization by Ramos cells is significantly improved compared to OFA alone, consistent with the high antitumor activity of the new ADC. OFA-HL-vcMMAE, at 5 mg kg⁻¹ dose, is able to eliminate tumors with mean volume ≈400 mm³ while no obvious drug-related toxicity is observed. The results show that srtA-generated OFA-MMAE conjugate system provides a viable strategy for targeting CD20+ B lineage lymphomas.