[HTML][HTML] A novel platform for the potentiation of therapeutic antibodies based on antigen-dependent formation of IgG hexamers at the cell surface

RN de Jong, FJ Beurskens, S Verploegen… - PLoS …, 2016 - journals.plos.org
RN de Jong, FJ Beurskens, S Verploegen, K Strumane, MD van Kampen, M Voorhorst…
PLoS biology, 2016journals.plos.org
IgG antibodies can organize into ordered hexamers on cell surfaces after binding their
antigen. These hexamers bind the first component of complement C1 inducing complement-
dependent target cell killing. Here, we translated this natural concept into a novel technology
platform (HexaBody technology) for therapeutic antibody potentiation. We identified
mutations that enhanced hexamer formation and complement activation by IgG1 antibodies
against a range of targets on cells from hematological and solid tumor indications. IgG1 …
IgG antibodies can organize into ordered hexamers on cell surfaces after binding their antigen. These hexamers bind the first component of complement C1 inducing complement-dependent target cell killing. Here, we translated this natural concept into a novel technology platform (HexaBody technology) for therapeutic antibody potentiation. We identified mutations that enhanced hexamer formation and complement activation by IgG1 antibodies against a range of targets on cells from hematological and solid tumor indications. IgG1 backbones with preferred mutations E345K or E430G conveyed a strong ability to induce conditional complement-dependent cytotoxicity (CDC) of cell lines and chronic lymphocytic leukemia (CLL) patient tumor cells, while retaining regular pharmacokinetics and biopharmaceutical developability. Both mutations potently enhanced CDC- and antibody-dependent cellular cytotoxicity (ADCC) of a type II CD20 antibody that was ineffective in complement activation, while retaining its ability to induce apoptosis. The identified IgG1 Fc backbones provide a novel platform for the generation of therapeutics with enhanced effector functions that only become activated upon binding to target cell–expressed antigen.
PLOS