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Targeted single domain antibodies with catalytic activity (T-CAN)

AsparaginaseLeukaemiaSingle-domain antibodiesTargeted therapy

Introduction

The present invention finds application in the medical field and in particular for the treatment of tumors and, more specifically, for the treatment of Acute Lymphoblastic Leukaemia (ALL). Specifically, the present invention discloses targeted single domain antibodies with catalytic activity for the treatment of tumors

Technical features

The asparagynolytic activity is typical of a class of amidohydrolases, namely Asparaginases (EC 3.5.1.1), found in bacteria, fungi and plants. Asparaginases are of great clinical interest since they are capable of inhibiting tumor growth by removing the asparagine and, to a lesser extent, the glutamine supply needed for cancer cells proliferation.

The present invention is based on the finding that a camelid single domain antibody (sdAb) can be engineered for providing it with asparaginolytic activity; the obtained sdASNase molecule proved to be unexpectedly active and stable and could be targeted onto cancer cells by an antibody.

The asparaginic activity was transferred to a totally original scaffold, a nanobody with dimensions that facilitate the passage of the blood brain barrier. In addition, another molecule can be combined with this molecule to further facilitate targeting. This fusion generates a new Antibody-Drug Conjugate (ADC), which we have defined Targeted Catalytic Nanobody (T-CAN), capable of carrying the catalytic activity and targeting itself specifically on the target cell.


Possible Applications

  • Treatment of leukaemias and lymphoma dependent on exogenous asparagine supply;
  • Potential access to the brain;
  • Potential effectiveness on solid tumors dependent on exogenous asparagine supply;

Advantages

  • Reduced size and, in turn, improved tissue permeability;
  • Modular assembly: versability;
  • High therapeutic specificity;
  • Reduced off-target cytotoxicity;
  • Improved stability;
  • Reduced side effects;
  • Improved efficacy.