Sortase A‐Generated Highly Potent Anti‐CD20‐MMAE Conjugates for Efficient Elimination of B‐Lineage Lymphomas. Issue 6 (22nd November 2016)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Small. Volume 13:Issue 6(2017)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2016-11-22
• Subjects: antibody–drug conjugates -- B‐lineage lymphomas -- CD20 -- drug delivery -- site‐specific conjugation; Nanotechnology -- Periodicals; Nanoparticles -- Periodicals; Microtechnology -- Periodicals; 620.5
• DOI: 10.1002/smll.201602267
• Languages: English
• ISSNs: 1613-6810

Abstract

Abstract : 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. Abstract : Efficient elimination of B‐lineage lymphomas by Sortase A‐generated ofatumumab (OFA)‐modified monomethyl auristatin E (MMAE) conjugates. Sortase A‐mediated transpeptidation has been used to specifically conjugate triple glycine‐MMAE, a highly toxic antimitotic agent, to OFA equipped with a short C‐terminal LPETG tag at heavy chain, which generates ADCs that show extremely strong potency in killing CD20 positive cancer cells.