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The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapy

Abstract

Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β7 molecules. The MMG49 epitope, in the N-terminal region of the β7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β7 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β7+ lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.

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Figure 1: The novel MM-specific mAb MMG49 recognizes β7 integrin.
Figure 2: MMG49 specifically reacts with an epitope that is exposed in the activated conformation of integrin β7.
Figure 3: High expression and constitutive activation of integrin β7 in MM cells are responsible for the MM-specific reactivity of MMG49.
Figure 4: MMG49-derived CAR T cells specifically recognize and kill MM cells.
Figure 5: MMG49 CAR T cells exert anti-MM effects without damaging normal hematopoietic cells in vivo.

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Acknowledgements

We thank the Kinki Cord Blood Bank for CB samples and T. Yamane (Osaka City General Hospital) and K. Koh (Osaka General Hospital for West Japan Railway Company) for MM samples. We also thank K. Terasaki, S. Ikeda, Y. Hayami, R. Inada, R. Urakawa, S. Hashiguchi, M. Iwai, and A. Kosugi for technical assistance, and Y. Kanakura (Osaka University), R. Burger (University of Kiel), I. Weissman (Stanford University), T. Kitamura (Tokyo University), and the NIH AIDS Reagents program for providing materials. This work was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas (Analysis and Synthesis of Multidimensional Immune Organ Network) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to J.T.); the Project for Development of Innovative Research on Cancer Therapeutics and Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development AMED (to N.H.); JSPS KAKENHI grant JP26461404 (to N.H.); and Japan Agency for Medical Research and Development–Core Research for Evolutional Science and Technology grant 15652237 (to A.K.).

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N.H. and J.T. designed the experiments; N.H., Y.M., K.H., H.M., Y.N., M. Makita., K.W., M.Y., K.S., S.M., F.F., H.N., J.Nakata., S.N., A.T., Y.Oka., R.U., K.O., Y.B., S.T., N.W., E.M., J.Nishimura., and Y.Oji. performed the experiments; M.Manabe., H.I., Y.A., A.M., T.N., and M.H. collected and analyzed clinical samples; N.H., Y.M., K.H., and J.T. analyzed the data; N.H., Y.M., K.H., K.T., H.S., J.T., and A.K. wrote the manuscript; and all authors reviewed and approved the final version of the manuscript.

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Correspondence to Naoki Hosen.

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N.H., H.S., J.T., and A.K. have applied for a Japanese patent entitled 'Antibody' through the Osaka University Office for University-Industry Collaboration. The other authors declare no competing financial interests.

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Hosen, N., Matsunaga, Y., Hasegawa, K. et al. The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapy. Nat Med 23, 1436–1443 (2017). https://doi.org/10.1038/nm.4431

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