Rise and Fall of an Anti-MUC1 Specific Antibody

摘要: Background So far, human antibodies with good affinity and specificity for MUC1, a transmembrane protein overexpressed on breast cancers ovarian carcinomas, thus promising target therapy, were very difficult to generate. Results A scFv antibody was isolated from an immune library derived cancer patients immunised MUC1. The anti-MUC1 reacted tumour cells in more than 80% of 228 tissue sections mamma carcinoma samples, while showing low reactivity large panel non-tumour tissues. By mutagenesis phage display, scFvs increased up 500fold 5,7×10−10 M. Half-life serum improved below 1 day 4 weeks correlated the dimerisation tendency individual scFvs. bound T47D MCF-7 mammalian cell lines recloned into scFv-Fc IgG format resulting decrease one binder. variants highest tested mouse xenograft models using OVCAR cells. However, experiments showed no significant growth or increase survival rates. To study reasons failure experiments, ADCC analysed vitro OVCAR3 cells, revealing ADCC, possibly due internalisation, as detected cells. Conclusions Antibody display starting libraries followed by maturation is powerful strategy generate high targets, this case shown creation highly specific subnanomolar small epitope consisting four amino acids. Despite these “best class” binding parameters, therapeutic success prevented biology.