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Balance of Anti-CD123 Chimeric Antigen Receptor Binding Affinity and Density for the Targeting of Acute Myeloid Leukemia.

  • Arcangeli S Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano Bicocca, Ospedale San Gerardo/Fondazione MBBM, 20900 Monza, Italy.
  • Rotiroti MC Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano Bicocca, Ospedale San Gerardo/Fondazione MBBM, 20900 Monza, Italy.
  • Bardelli M Istituto di Ricerca in Biomedicina, Università degli Studi della Svizzera Italiana, 6500 Bellinzona, Switzerland.
  • Simonelli L Istituto di Ricerca in Biomedicina, Università degli Studi della Svizzera Italiana, 6500 Bellinzona, Switzerland.
  • Magnani CF Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano Bicocca, Ospedale San Gerardo/Fondazione MBBM, 20900 Monza, Italy.
  • Biondi A Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano Bicocca, Ospedale San Gerardo/Fondazione MBBM, 20900 Monza, Italy. Electronic address: abiondi.unimib@gmail.com.
  • Biagi E Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano Bicocca, Ospedale San Gerardo/Fondazione MBBM, 20900 Monza, Italy. Electronic address: e.biagi@hsgerardo.org.
  • Tettamanti S Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano Bicocca, Ospedale San Gerardo/Fondazione MBBM, 20900 Monza, Italy.
  • Varani L Istituto di Ricerca in Biomedicina, Università degli Studi della Svizzera Italiana, 6500 Bellinzona, Switzerland.
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  • 2017-05-09
Published in:
  • Molecular therapy : the journal of the American Society of Gene Therapy. - 2017
AML
CAR
CD123
affinity
immunotherapy
Binding Sites
Cytotoxicity, Immunologic
Gene Expression
Humans
Immunomodulation
Immunotherapy, Adoptive
Interleukin-3 Receptor alpha Subunit
Leukemia, Myeloid, Acute
Models, Molecular
Molecular Conformation
Protein Binding
Receptors, Antigen, T-Cell
Recombinant Fusion Proteins
Structure-Activity Relationship
T-Lymphocytes
English Chimeric antigen receptor (CAR)-redirected T lymphocytes are a promising immunotherapeutic approach and object of pre-clinical evaluation for the treatment of acute myeloid leukemia (AML). We developed a CAR against CD123, overexpressed on AML blasts and leukemic stem cells. However, potential recognition of low CD123-positive healthy tissues, through the on-target, off-tumor effect, limits safe clinical employment of CAR-redirected T cells. Therefore, we evaluated the effect of context-dependent variables capable of modulating CAR T cell functional profiles, such as CAR binding affinity, CAR expression, and target antigen density. Computational structural biology tools allowed for the design of rational mutations in the anti-CD123 CAR antigen binding domain that altered CAR expression and CAR binding affinity without affecting the overall CAR design. We defined both lytic and activation antigen thresholds, with early cytotoxic activity unaffected by either CAR expression or CAR affinity tuning but later effector functions impaired by low CAR expression. Moreover, the anti-CD123 CAR safety profile was confirmed by lowering CAR binding affinity, corroborating CD123 is a good therapeutic target antigen. Overall, full dissection of these variables offers suitable anti-CD123 CAR design optimization for the treatment of AML.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/120055
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