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

R. N. de Jong, F. J. Beurskens, S. Verploegen, K. Strumane, M. D. van Kampen, M. Voorhorst, W. Horstman, P. J. Engelberts, S. C. Oostindie, Hong-Gang Wang, Albert J. R. Heck, J. Schuurman, P. W. H. I. Parren

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Resumé

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. © 2016 de Jong et al.
OriginalsprogDansk
Artikelnummere1002344
TidsskriftPLoS Biology
Vol/bind14
Udgave nummer1
Antal sider24
ISSN1544-9173
DOI
StatusUdgivet - 2016

Citer dette

de Jong, R. N., Beurskens, F. J., Verploegen, S., Strumane, K., van Kampen, M. D., Voorhorst, M., ... 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, 14(1), [e1002344]. https://doi.org/10.1371/journal.pbio.1002344
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, Hong-Gang ; Heck, Albert J. R. ; Schuurman, J. ; Parren, P. W. H. I. / A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface. I: PLoS Biology. 2016 ; Bind 14, Nr. 1.
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title = "A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface",
abstract = "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. {\circledC} 2016 de Jong et al.",
author = "{de Jong}, {R. N.} and Beurskens, {F. J.} and S. Verploegen and K. Strumane and {van Kampen}, {M. D.} and M. Voorhorst and W. Horstman and Engelberts, {P. J.} and Oostindie, {S. C.} and Hong-Gang Wang and Heck, {Albert J. R.} and J. Schuurman and Parren, {P. W. H. I.}",
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de Jong, RN, Beurskens, FJ, Verploegen, S, Strumane, K, van Kampen, MD, Voorhorst, M, Horstman, W, Engelberts, PJ, Oostindie, SC, Wang, H-G, Heck, AJR, Schuurman, J & Parren, PWHI 2016, 'A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface', PLoS Biology, bind 14, nr. 1, e1002344. https://doi.org/10.1371/journal.pbio.1002344

A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface. / 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, Hong-Gang; Heck, Albert J. R.; Schuurman, J.; Parren, P. W. H. I.

I: PLoS Biology, Bind 14, Nr. 1, e1002344, 2016.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface

AU - de Jong, R. N.

AU - Beurskens, F. J.

AU - Verploegen, S.

AU - Strumane, K.

AU - van Kampen, M. D.

AU - Voorhorst, M.

AU - Horstman, W.

AU - Engelberts, P. J.

AU - Oostindie, S. C.

AU - Wang, Hong-Gang

AU - Heck, Albert J. R.

AU - Schuurman, J.

AU - Parren, P. W. H. I.

PY - 2016

Y1 - 2016

N2 - 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. © 2016 de Jong et al.

AB - 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. © 2016 de Jong et al.

U2 - 10.1371/journal.pbio.1002344

DO - 10.1371/journal.pbio.1002344

M3 - Tidsskriftartikel

C2 - 26736041

VL - 14

JO - P L o S Biology

JF - P L o S Biology

SN - 1544-9173

IS - 1

M1 - e1002344

ER -