Mendelsohn Brian A, Barnscher Stuart D, Snyder Josh T, An Zili, Dodd Jennifer M, Dugal-Tessier Julien
Agensys Inc. an affiliate of Astellas Pharma Inc., 1800 Stewart Street, Santa Monica, California 90404, United States.
Bioconjug Chem. 2017 Feb 15;28(2):371-381. doi: 10.1021/acs.bioconjchem.6b00530. Epub 2017 Jan 6.
Antibody drug conjugates offer a targeted cancer treatment for the delivery of potent cytotoxic drugs. Derivatives of the natural product dolastatin 10 containing pyridines and other basic amines were examined with the objective of determining if a more hydrophilic auristatin derivative would be potent enough for use as part of an ADC. This may be advantageous if a less hydrophobic drug makes a better ADC. A pyridine derivative, monomethyl auristatin PYE, showed the greatest potency when tested in vivo. While only a modest tumor growth inhibition was observed when the HCC1954 human breast cancer xenografts were treated with"non-cleavable" linker ADCs, tumor regression was seen when treated with an enzymatically degradable "cleavable" linker ADC when conjugated to trastuzumab. Based on these studies, monomethyl auristatin PYE shows promise for use as an ADC payload.
抗体药物偶联物为强效细胞毒性药物的递送提供了一种靶向癌症治疗方法。对含有吡啶和其他碱性胺类的天然产物多拉司他汀10的衍生物进行了研究，目的是确定一种更具亲水性的奥瑞他汀衍生物是否有足够的效力用作抗体药物偶联物（ADC）的一部分。如果疏水性较低的药物能制成更好的ADC，这可能会具有优势。一种吡啶衍生物，单甲基奥瑞他汀PYE，在体内测试时显示出最大的效力。在用“不可裂解”连接子ADC处理HCC1954人乳腺癌异种移植瘤时，仅观察到适度的肿瘤生长抑制，而当与曲妥珠单抗偶联并用可酶促降解的“可裂解”连接子ADC处理时，则出现了肿瘤消退。基于这些研究，单甲基奥瑞他汀PYE有望用作ADC的有效载荷。
