Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance
Menée in vitro et in vivo sur des modèles de cancer HER2+, cette étude évalue, par rapport au trastuzumab et au pertuzumab, l'activité antitumorale d'un anticorps tripartite ciblant trois sous-domaines du récepteur HER2
Human epidermal growth factor receptor 2 (HER2) plays an important role in the development and maintenance of the malignant phenotype of several human cancers. As such, it is a frequently pursued therapeutic target and two antibodies targeting HER2 have been clinically approved trastuzumab and, pertuzumab. It has been suggested that optimal inhibition of HER2 is achieved when utilizing two or more antibodies targeting non-overlapping epitopes. Superior clinical activity of trastuzumab plus pertuzumab combination in metastatic breast cancer supports this hypothesis. Since trastuzumab and pertuzumab were not co-developed, there may be potential for further optimizing HER2 targeting. The study herein evaluated functional activity of anti-HER2 antibody combinations identifying optimal epitope combinations that provide efficacious HER2 inhibition. High affinity antibodies to all four extracellular domains on HER2 were identified and tested for ability to inhibit growth of different HER2 dependent tumor cell lines. An antibody mixture targeting three HER2 subdomains proved to be superior to trastuzumab, pertuzumab, or a combination in vitro and to trastuzumab in two in vivo models. Specifically, the tripartite antibody mixture induced efficient HER2 internalization and degradation demonstrating increased sensitivity in cell lines with HER2 amplification and high EGFR levels. When compared with individual and clinically approved mAbs, the synergistic tripartite antibody targeting HER2 subdomains I, II, and IV demonstrates superior anti-cancer activity.
http://mct.aacrjournals.org/content/early/2015/01/22/1535-7163.MCT-14-0697.abstract 2015