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Elimination of large tumors in mice by mRNA-encoded bispecific antibodies

Nature Medicine volume 23, pages 815–817 (2017)Cite this article

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An Erratum to this article was published on 01 October 2017

This article has been updated

Abstract

The potential of bispecific T cell–engaging antibodies is hindered by manufacturing challenges and short serum half-life. We circumvented these limitations by treating mice with in vitro–transcribed pharmacologically optimized, nucleoside-modified mRNA encoding the antibody. We achieved sustained endogenous synthesis of the antibody, which eliminated advanced tumors as effectively as the corresponding purified bispecific antibody. Because manufacturing of pharmaceutical mRNA is fast, this approach could accelerate the clinical development of novel bispecific antibodies.

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Figure 1: In vitro target-dependent lysis of human tumor cell lines by picomolar amounts of in vitro–transcribed mRNA encoding T cell–engager bispecific antibodies.
Figure 2: Sustained plasma level of functional bi-(scFv)2 protein and elimination of advanced xenograft tumors upon treatment of mice with picomolar amounts of bsAb-encoding in vitro–transcribed mRNA.

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  • 20 July 2017

    In the version of this article initially published, in the “Polymer/lipid-based formulation of mRNA” section of the Online Methods, the text incorrectly stated that mRNA was in 190 ml rather than 190 µl of cold DMEM. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We wish to thank the following colleagues: S. Wöll, S. Kühne and M. Erdeljan for immunohistochemistry and data acquisition, N. Brüne for clinical chemistry data, A. Jendretzki, M. LeGall and S. Wessel for construct design and preparation, and K. Schmoldt for performing the in vitro assays. We would also like to acknowledge I. Biermann for supporting the in vivo studies, H. Muramatsu, M. Baiersdörfer, K. Beilstein, S. Fesser and team for IVT mRNA synthesis and characterization and for bioluminescence studies, T. Beissert and team for cell line transduction and K. Reuter for advice on in vivo experiments. Special thanks are given to C. Huber for inspiring discussions.

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Author notes

  1. Bernhard Hebich, Alexandra S Roth and René P Roth: These authors contributed equally to this work.

Authors and Affiliations

  1. BioNTech, Mainz, Germany

    Christiane R Stadler, Hayat Bähr-Mahmud, Leyla Celik, Bernhard Hebich, Alexandra S Roth, René P Roth, Katalin Karikó & Ugur Sahin

  2. Cluster of Individualized Immunointervention (CI3), Mainz, Germany

    Özlem Türeci

  3. Department of Internal Medicine III, Johannes Gutenberg University, Mainz, Germany

    Ugur Sahin

  4. TRON–Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany

    Ugur Sahin

Authors
  1. Christiane R Stadler
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  2. Hayat Bähr-Mahmud
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  7. Katalin Karikó
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  9. Ugur Sahin
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Contributions

C.R.S., H.B.-M., L.C., K.K., Ö.T. and U.S. were engaged in study conception and interpretation and contributed to the critical revision of the manuscript. C.R.S. designed the study and participated in in vivo experiment execution and in general data analysis and interpretation. H.B.-M. was involved in study design, especially of in vitro experiments, and in data analysis and interpretation. L.C. designed, executed and interpreted immunoblot analyses and performed recombinant protein purification. B.H. established, executed and interpreted ELISA assays and performed in vitro experiments. A.S.R. was involved in in vitro assay design, execution and interpretation and produced recombinant proteins as well as RiboMAB supernatants. R.P.R. performed in vivo experiments and supported the design of the studies. Ö.T., C.R.S., H.B.-M., K.K. and U.S. drafted the manuscript. All authors discussed the results, assisted in the preparation of the manuscript and approved the final version.

Corresponding author

Correspondence to Ugur Sahin.

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Competing interests

C.R.S. is Head of Bispecific Antibodies at BioNTech and has ownership interest in patent applications. H.B.-M. is Deputy Head of Bispecific Antibodies at BioNTech and has ownership interest in a patent application. L.C. is a member of Bispecific Antibodies at BioNTech and has ownership interest in a patent application. K.K. is Vice President of BioNTech RNA and has ownership interest in patent applications. Ö.T. has ownership interest in patent applications. U.S. is cofounder of BioNTech and has ownership interest (including patents) in TRON and BioNTech.

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Stadler, C., Bähr-Mahmud, H., Celik, L. et al. Elimination of large tumors in mice by mRNA-encoded bispecific antibodies. Nat Med 23, 815–817 (2017). https://doi.org/10.1038/nm.4356

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