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Sortase A‐Generated Highly Potent Anti‐CD20‐MMAE Conjugates for Efficient Elimination of B‐Lineage Lymphomas
Author(s) -
Pan Liqiang,
Zhao Wenbin,
Lai Jun,
Ding Ding,
Zhang Qian,
Yang Xiaoyue,
Huang Minmin,
Jin Shijie,
Xu Yingchun,
Zeng Su,
Chou James J.,
Chen Shuqing
Publication year - 2017
Publication title -
small
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.785
H-Index - 236
eISSN - 1613-6829
pISSN - 1613-6810
DOI - 10.1002/smll.201602267
Subject(s) - cd20 , conjugate , antigen , epitope , chemistry , calicheamicin , sortase , microbiology and biotechnology , antibody drug conjugate , antibody , cancer research , biochemistry , biology , monoclonal antibody , immunology , gene , mathematical analysis , mathematics , bacterial protein
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 mm 3 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.