Abstract LB-234: Development of HER2 targeted HSP90 inhibitors delivery system

Abstract

Abstract Heat shock protein 90 (HSP90) plays a crucial role in the survival and growth of cancer cells by improvement of the stability and activity of many signaling proteins such as Akt, Raf-1 and HER2/neu. HSP90 inhibitors (HSP90i) such as geldamanycin (GM), AUY922 and STA-9090 have been developed for inhibition of multiple signaling pathways that are initiated by HSP90. Although geldanamycin derivatives (GM) which is the first class of HSP90 inhibitors were disappointing in the initial clinical trials, these studies have shown promise in patients with HER2 positive cancers. To improve anticancer efficacy of HSP90i, HER2 targeted HSP90i delivery system (HER2-HBD) was constructed because of difficulty in chemical modification of HSP90i. HER2-HBD consist of HER2 scFv and HSP90i binding domain, was expressed from 293 cells. This system could incorporate HSP90i into recombinant antibody fusion protein based on biological binding affinity. HER2-HBD and HSP90i was spontaneously formed HER2-HBD/HSP90i complex. HER2-HBD/HSP90i complex specifically delivered HSP90i into HER2 positive cancer cell and reduced cancer cell growth in vitro and in vivo test. HER2-HBD recombinant system based on biological affinity between HSP90i and HBD was not required chemical reaction to conjugate antibody and drug. This system might be useful targeted delivery systems for HSP90i without tailored conjugation method to develop antibody-drug conjugate (ADC) and also applied to develop targeted delivery systems for biological inhibitor drugs. Citation Format: Kwangsuk Lim, Yudong Hong, Young-Wook Won. Development of HER2 targeted HSP90 inhibitors delivery system [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-234.