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Immunotherapy using bispecific T cell engager (BiTE®) antibodies: preclinical and clinical experience in acute leukemia
  1. Marion Subklewe1,
  2. Max Topp2,
  3. Christina Krupka1,
  4. Peter Kufer3,
  5. Roman Kischel3,
  6. Thomas Köhnke1,
  7. Patrick Baeuerle3,
  8. Gerhard Zugmaier3,
  9. Stanley Frankel4,
  10. Tapan Maniar5,
  11. Katie Newhall5,
  12. Karsten Spiekermann6,
  13. Gert Riethmueller7,
  14. Dirk Nagorsen8 and
  15. Wolfgang Hiddemann6
  1. Aff1 grid.411095.80000000404772585Department of Internal Medicine IIIKlinikum der Universität München, and Clinical Cooperation Group Immunotherapy at the Helmholtz Institute Munich Germany
  2. Aff2 grid.411760.50000000113787891Medizinische Klinik und Poliklinik IIUniversitätsklinikum Würzburg Germany
  3. Aff3 grid.420023.70000000405384576AMGEN Research (Munich) GmbH Germany
  4. Aff4 Amgen Rockville, Inc. United States
  5. Aff5 grid.417886.40000000106575612Amgen Inc. United States
  6. Aff6 grid.411095.80000000404772585Department of Internal Medicine IIIKlinikum der Universität München, and Clinical Cooperation Group Leukemia at the Helmholtz Institute Munich Germany
  7. Aff7 grid.5252.0000000041936973XInstitute for ImmunologyLudwig-Maximilians-University Germany
  8. Aff8 grid.420023.70000 0004 0538 4576Amgen Inc. Germany

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Meeting abstracts

BiTE® antibodies are novel recombinant single chain Ig domain constructs that leverage the endogenous cytotoxic potential of polyclonal T cells to target malignant cells by utilizing the specific binding properties of variable domains from two different antibodies. Antibody-based immunotherapy represents a promising strategy in cancer. BiTE® antibodies have demonstrated efficacy in hematologic malignancies, both preclinically and clinically.

Two investigational BiTE antibodies are under development targeting leukemia. The most advanced BiTE® antibody, Blinatumomab, directs cytotoxic T cells to CD19-expressing target cells. Blinatumomab has shown anti-leukemia activity in adult relapsed/refractory (r/r) B-precursor ALL. Its efficacy and toxicity was evaluated in a large confirmatory Phase II study. Patients with Ph-negative r/r ALL (N = 189; refractory; 1st relapse

Given the anti-leukemia activity of single-agent Blinatumomab in a difficult-to-treat population with r/r ALL, another BiTE® antibody targeting CD33, AMG 330, was developed for its suitability as immunotherapy in AML. To simulate the natural setting of target and T cells in AML patients, a long-term culture system was developed that supports the growth of primary AML cells ex-vivo for up to 5 weeks. AMG 330 activated and expanded residual autologous T cells within primary AML patient samples and eliminated CD33+ blasts even at very low effector to target ratios. The functional relevance of CD33 expression levels was shown by faster lysis kinetics of CD33BRIGHT versus CD33DIM AML cell lines and primary AML cells in ex-vivo cytotoxicity assays. However, by extending the exposure time to AMG 330, potent anti-leukemic activity was observed in both CD33BRIGHT and CD33DIM cells. AMG 330 treated T cells were shown to up-regulate the activation markers CD25, PD-1, TIM3 and LAG3, which was partially reversible after complete target cell elimination

Clinical experience with Blinatumomab in ALL and ex-vivo activity of AMG 330 in primary AML samples supports further development of BiTE® antibodies for targeted T cell-mediated immunotherapy of patients with malignancies.