Abstract
By enabling the simultaneous engagement of two distinct targets, bispecific antibodies broaden the potential utility of antibody-based therapies. However, bispecific-antibody design and production remain challenging, owing to the need to incorporate two distinct heavy and light chain pairs while maintaining natural nonimmunogenic antibody architecture. Here we present a bispecific-antibody production strategy that relies on co-culture of two bacterial strains, each expressing a half-antibody. Using this approach, we produce 28 unique bispecific antibodies. A bispecific antibody against the receptor tyrosine kinases MET and EGFR binds both targets monovalently, inhibits their signaling, and suppresses MET and EGFR-driven cell and tumor growth. Our strategy allows rapid generation of bispecific antibodies from any two existing antibodies and yields milligram to gram quantities of bispecific antibodies sufficient for a wide range of discovery and preclinical applications.
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Acknowledgements
We thank members of the Antibody Engineering, Protein Chemistry, Pharmacokinetics and Pharmacodynamics, Biochemical Pharmacology and Translational Oncology departments at Genentech for technical support and/or advice and stimulating discussions. In particular we would like to thank H. Xiang, E. Mai, J. Young, D. Delarosa, B. Wilson, and K. Billeci for help in assessing the pharmacokinetics of antibodies. We would also like to thank P.J. Carter and D. Vandlen for useful discussions and comments on the manuscript.
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Conception and design: C.S., M.M., D.G.Y. and J.M.S.; development of methodology: C.S., D.G.Y. and J.M.S.; acquisition of data: C.S., A.H., Z.Z., N.-Y.Y., J.P., D.E., W.S. and J.M.S.; analysis and interpretation of data: C.S., M.M., D.R., D.G.Y. and J.M.S.; writing, review and/or revision of the manuscript: C.S., M.M., D.R., D.G.Y. and J.M.S.
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All of the authors are employees of Genentech.
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Spiess, C., Merchant, M., Huang, A. et al. Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing two distinct half-antibodies. Nat Biotechnol 31, 753–758 (2013). https://doi.org/10.1038/nbt.2621
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DOI: https://doi.org/10.1038/nbt.2621
