A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface

Autor: de Jong, Rob N, Beurskens, Frank J, Verploegen, Sandra, Strumane, Kristin, van Kampen, Muriel D, Voorhorst, Marleen, Horstman, Wendy, Engelberts, Patrick J, Oostindie, Simone C, Wang, Guanbo, Heck, Albert J R, Schuurman, Janine, Parren, Paul W H I, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics
Přispěvatelé: Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: PloS Biology [E], 14(1). Public Library of Science
PLoS Biology, Vol 14, Iss 1, p e1002344 (2016)
PLoS Biology
de Jong, R N, Beurskens, F J, Verploegen, S, Strumane, K, van Kampen, M D, Voorhorst, M, Horstman, W, Engelberts, P J, Oostindie, S C, Wang, H-G, Heck, A J R, Schuurman, J & Parren, P W H I 2016, ' A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface ', PLoS Biology, vol. 14, no. 1, e1002344, pp. e1002344 . https://doi.org/10.1371/journal.pbio.1002344
ISSN: 1544-9173
DOI: 10.1371/journal.pbio.1002344
Popis: 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.
Efficient activation of the complement system naturally involves hexamerization of antibodies upon target binding at the cell surface. Screening a library of IgG-Fc mutants reveals how to enhance the effector functions of therapeutic antibodies by maximizing hexamer formation.
Author Summary Immunotherapy is a powerful and rapidly expanding field that makes use of the body’s natural defense mechanisms to eliminate disease entities such as infectious agents or cancer cells. Circulating antibodies bind aberrant structures in a highly target-specific manner and “flag” disease cells for destruction by killing machineries that are present in the bloodstream. We recently showed that activation of one of these immune defense mechanisms, the complement system, is most efficiently initiated by binding of the first complement component C1q to a ring of six antibodies. Since antibody hexamerization occurs naturally only after binding to surface antigens, complement activation and subsequent complement-mediated cell killing is therefore restricted to these antibody-flagged cells. Now, with a mutational screening approach, we identified structural entities in the antibody backbone that potentiate this antigen binding–induced hexamer formation. We identified mutations that enhance the hexamer formation and complement activation by IgG1 antibodies against a wide range of targets on varying cancer cells. Based on our findings, we present a broadly applicable platform for the generation of therapeutic antibodies with enhanced ability to promote hexamerization-induced complement activation and target cell killing only after surface antigen binding.
Databáze: OpenAIRE
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