Surface Proteomics Reveals CD72 as a Target for <i>In Vitro</i> –Evolved Nanobody-Based CAR-T Cells in <i>KMT2A/MLL1</i> -Rearranged B-ALL
Matthew A. Nix, Kamal Mandal, Huimin Geng, Neha Paranjape, Yu-Hsiu T. Lin, Jose Rivera, Makeba Marcoulis, Kristie L. White, Jeffrey D. Whitman, Sagar P. Bapat, Kevin R. Parker, Jonathan Ramírez, Anne Deucher, Paul Phojanokong, Veronica Steri, Faranak Fattahi, Byron Hann, Ansuman T. Satpathy, Aashish Manglik, Elliot Stieglitz, Arun P. Wiita
Abstract
Abstract Alternative strategies are needed for patients with B-cell malignancy relapsing after CD19-targeted immunotherapy. Here, cell surface proteomics revealed CD72 as an optimal target for poor-prognosis KMT2A/MLL1-rearranged (MLLr) B-cell acute lymphoblastic leukemia (B-ALL), which we further found to be expressed in other B-cell malignancies. Using a recently described, fully in vitro system, we selected synthetic CD72-specific nanobodies, incorporated them into chimeric antigen receptors (CAR), and demonstrated robust activity against B-cell malignancy models, including CD19 loss. Taking advantage of the role of CD72 in inhibiting B-cell receptor signaling, we found that SHIP1 inhibition increased CD72 surface density. We establish that CD72-nanobody CAR-T cells are a promising therapy for MLLr B-ALL. Significance: Patients with MLLr B-ALL have poor prognoses despite recent immunotherapy advances. Here, surface proteomics identifies CD72 as being enriched on MLLr B-ALL but also widely expressed across B-cell cancers. We show that a recently described, fully in vitro nanobody platform generates binders highly active in CAR-T cells and demonstrate its broad applicability for immunotherapy development. This article is highlighted in the In This Issue feature, p. 1861