Design and In Vitro Evaluation of a Cytotoxic Conjugate Based on the Anti-HER2 Affibody Fused to the Fc Fragment of IgG1

作者：Sochaj Gregorczyk Alicja M; Ludzia Patryk; Kozdrowska Emilia; Jakimowicz Piotr; Sokolowska Wedzina Aleksandra; Otlewski Jacek^*

来源：International Journal of Molecular Sciences, 2017, 18(8): 1688.

DOI：10.3390/ijms18081688

• affibody
• HER2
• Fc fragment of IgG1
• monomethyl auristatin E (MMAE)

In our previous work we demonstrated that a small protein called affibody can be used for a cytotoxic conjugate development. The anti-HER2 affibody was armed with one moiety of a highly potent auristatin E and specifically killed HER2-positive cancer cells with a nanomolar IC50. The aim of this study was to improve the anti-HER2 affibody conjugate by increasing its size and the number of conjugated auristatin molecules. The affibody was fused to the Fc fragment of IgG1 resulting in a dimeric construct with the molecular weight of 68 kDa, referred to as Z(HER2:2891)-Fc, ensuring its prolonged half-life in the blood. Due to the presence of four interchain cysteines, the fusion protein could carry four drug molecules. Notably, the in vitro tests of the improved anti-HER2 conjugate revealed that it exhibits the IC50 of 130 pM for the HER2-positive SK-BR-3 cells and 98 nM for the HER2-negative MDA-MB-231 cells. High efficacy and specificity of the auristatin conjugate based on Z(HER2:2891)-Fc indicate that this construct is suitable for further in vivo evaluation.

• 出版日期2017-8