Selective apoptotic killing of malignant hemopoietic cells by anti body-targeted delivery of an amphipathic peptide
Selective apoptotic killing of malignant hemopoietic cells by anti body-targeted delivery of an amphipathic peptide
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DOI：
10.1158/0008-5472.can-04-2594
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发表时间：
2005-03-15
期刊：
影响因子：
11.2
通讯作者：
Wickremasinghe, RG
中科院分区：
文献类型：
--
作者：
Marks, AJ;Cooper, MS;Wickremasinghe, RG
如果通过合适的靶向机制内化，α-螺旋两亲性肽D-（KLAKLAK）（2）对真核细胞是有毒的。我们已经通过与识别谱系特异性细胞表面分子的单克隆抗体结合将该肽靶向恶性造血细胞。抗-CD 19/肽缀合物有效地杀死3/3 B淋巴系。然而，抗CD 33/肽缀合物仅对三种CD 33阳性髓性白血病系之一具有细胞毒性。对敏感品系的IC 50在低纳摩尔范围内。缀合物具有高度选择性，并且不杀死不表达抗体部分的适当细胞表面同源物的细胞。抗-CD 19/肽缀合物有效地杀死慢性淋巴细胞白血病患者的细胞，但抗-CD 33/肽试剂对新鲜的急性髓性白血病细胞的有效性较低。因此，我们建议，两亲性肽可能是有价值的靶向治疗药物的治疗血液系统恶性肿瘤的一个子集。
The alpha-helical amphipathic peptide D-(KLAKLAK)(2) is toxic to eukaryotic cells if internalized by a suitable targeting mechanism. We have targeted this peptide to malignant hemopoietic cells via conjugation to monoclonal antibodies, which recognize lineage-specific cell surface molecules. An anti-CD19/peptide conjugate efficiently killed 3/3 B lymphoid lines. However, an anti-CD33/peptide conjugate was cytotoxic to only one of three CD33-positive myeloid leukemia lines. The IC50 towards susceptible lines were in the low nanomolar range. Conjugates were highly selective and did not kill cells that did not express the appropriate cell surface cognate of the antibody moiety. Anti-CD19/ peptide conjugates efficiently killed cells from patients with chronic lymphocytic leukemia but anti-CD33/peptide reagents were less effective against fresh acute myeloid leukemia cells. We therefore suggest that amphipathic peptides may be of value as targeted therapeutic agents for the treatment of a subset of hematologic malignancies.