Abstract 4559: Herceptin trimers linked by EDC could boost direct tumor cell death and overcome resistance to trastuzumab treatment via programmed tumor cell necrosis

Abstract

Abstract The human epidermal growth factor receptor 2 (Her2) is overexpressed in multiple types of tumors, including breast tumors and osteosarcoma. Tumor-targeted antibody therapy is one of the safest therapeutics available, but it is often ineffective in treating primary and acquired antibody-resistant tumor cells via indirect tumor cell death and inducing direct tumor cell death. This study reveals that Herceptin conjugates, if generated via the crosslinker EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodimide hydrochloride), is capable of causing Her2 positive tumor cell death. Using an HPLC system, two peaks with estimated molecular weights of antibody dimers and trimers were isolated. The Herceptin dimer and trimer separated by HPLC, especially the trimer, induces significant levels of necrotic tumor cell death. Unlike SMCC conjugated Herceptin, this study indicates that the EDC-conjugated Herceptin overcomes the acquired resistance. The Herceptin trimer is more effective than the dimer in enhancing Herceptin-resistant tumor cell death. Surprisingly different from the known cell death mechanism often resulting from antibody treatment, the Herceptin trimer causes effective and direct tumor cell death via a novel cell death mechanism: programmed cell necrosis. Inhibition of RIP, a critical regulator of programmed necrotic cell death, reversed the Herceptin trimer-induced cell death. In summary, the Herceptin conjugate especially trimer linked by EDC could overcome Her2 positive breast cancer or osteosarcoma cells as well as the resistant cell lines via program cell necrosis cell death. This conjugate has great potential for overcoming the tumor cell resistance to the Herceptin treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4559. doi:10.1158/1538-7445.AM2011-4559