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Surface Proteomics Reveals CD72 as a Target for In Vitro–Evolved Nanobody-Based CAR-T Cells in KMT2A/MLL1-Rearranged B-ALL

  • Nix, Matthew A
  • Mandal, Kamal
  • Geng, Huimin
  • Paranjape, Neha
  • Lin, Yu-Hsiu T
  • Rivera, Jose M
  • Marcoulis, Makeba
  • White, Kristie L
  • Whitman, Jeffrey D
  • Bapat, Sagar P
  • Parker, Kevin R
  • Ramirez, Jonathan
  • Deucher, Anne
  • Phojanokong, Paul
  • Steri, Veronica
  • Fattahi, Faranak
  • Hann, Byron C
  • Satpathy, Ansuman T
  • Manglik, Aashish
  • Stieglitz, Elliot
  • And 1 more
Publication Date
Aug 01, 2021
eScholarship - University of California
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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.

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