The Active Conformation of Integrin β₇ May Be a Multiple Myeloma Target

Many cancer-specific cell surface proteins have been identified that have the potential to be therapeutically targeted by monoclonal antibodies (mAb) or adoptive transfer of chimeric antigen receptor (CAR)–expressing T cells. However, the transcriptomic and proteomic analyses used to identify previous targets would likely miss cancer-specific antigen epitopes formed by post-translational events or conformational changes. In order to identify the potentially missed cancer-specific antigens, Hosen and colleagues performed a mAb screen to uncover therapeutic targets in multiple myeloma (MM). Screening more than 10,000 mAb clones found that MMG49 bound specifically to MM cells, but not normal peripheral blood mononuclear cells. MMG49 was found to bind to the N-terminal region of integrin β₇ and specifically recognized the extended active conformation without specificity for the inactive bent conformation. These findings suggest that the active conformation of integrin β₇ may be a therapeutic target in MM, and, accordingly, integrin β₇ was highly expressed and constitutively active in MM cells. Based on these findings, an MMG49-based CAR was designed with the single-chain variable fragment from MMG49 linked to the CD28 and CD3-ζ signaling domains. T lymphocytes were transduced with the MMG49 CAR and expanded in vitro, and, when cocultured with cells expressing MMG49, these CAR T cells secreted the cytokines IFNγ and IL2 and exhibited cytotoxic activity, completely eliminating the MM cells. MMG49 CAR T cells also had activity against primary MM cells. In a xenograft model of MM, MMG49 CAR T cells reduced the tumor burden without toxicity to normal hematopoietic cells. In addition to suggesting that the active conformation of integrin β₇ may be an effective therapeutic target in MM, these findings illustrate the possibility for CAR T-cell targeting of conformation-specific targets.

Hosen N, Matsunaga Y, Hasegawa K, Matsuno H, Nakamura Y, Makita M, et al. The activated conformation of integrin β₇ is a novel multiple myeloma–specific target for CAR T cell therapy. Nat Med 2017 Nov 6 [Epub ahead of print].

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