Demeestere Delphine, Dejonckheere Eline, Steeland Sophie, Hulpiau Paco, Haustraete Jurgen, Devoogdt Nick, Wichert Rielana, Becker-Pauly Christoph, Van Wonterghem Elien, Dewaele Sylviane, Van Imschoot Griet, Aerts Jeroen, Arckens Lutgarde, Saeys Yvan, Libert Claude, Vandenbroucke Roosmarijn E
Inflammation Research Center, VIB, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Mol Ther. 2016 May;24(5):890-902. doi: 10.1038/mt.2016.2. Epub 2016 Jan 18.
A detrimental role for matrix metalloproteinase 8 (MMP8) has been identified in several pathological conditions, e.g., lethal hepatitis and the systemic inflammatory response syndrome. Since matrix MMP8-deficient mice are protected in the above-mentioned diseases, specific MMP8 inhibitors could be of clinical value. However, targeting a specific matrix metalloproteinase remains challenging due to the strong structural homology of matrix metalloproteinases, which form a family of 25 members in mammals. Single-domain antibodies, called nanobodies, offer a range of possibilities toward therapy since they are easy to generate, express, produce, and modify, e.g., by linkage to nanobodies directed against other target molecules. Hence, we generated small MMP8-binding nanobodies, and established a proof-of-principle for developing nanobodies that inhibit matrix metalloproteinase activity. Also, we demonstrated for the first time the possibility of expressing nanobodies systemically by in vivo electroporation of the muscle and its relevance as a potential therapy in inflammatory diseases.
基质金属蛋白酶8（MMP8）在几种病理状况下已被证实具有有害作用，例如致死性肝炎和全身炎症反应综合征。由于基质MMP8基因缺陷型小鼠在上述疾病中受到保护，因此特异性MMP8抑制剂可能具有临床价值。然而，由于基质金属蛋白酶具有很强的结构同源性，在哺乳动物中形成了一个由25个成员组成的家族，因此靶向特定的基质金属蛋白酶仍然具有挑战性。单域抗体，即纳米抗体，由于易于生成、表达、生产和修饰，例如通过与针对其他靶分子的纳米抗体连接，为治疗提供了一系列可能性。因此，我们制备了与MMP8结合的小型纳米抗体，并为开发抑制基质金属蛋白酶活性的纳米抗体建立了原理验证。此外，我们首次证明了通过肌肉体内电穿孔全身表达纳米抗体的可能性及其作为炎症性疾病潜在治疗方法的相关性。
