Compositions and methods for preventing or reversing T-cell depletion through ectonucleotidase inhibition and antibody-mediated target cytosis

摘要

When combined with conventional therapies (eg, targeted therapy, chemotherapy and angiogenesis inhibitors, etc.), immunotherapy targeting checkpoint molecules has shown potential for treatment of solid or liquid tumors. However, apoptosis regulatory T cells (Treg) induced by these therapies are often further inhibited in the tumor microenvironment (TME) through increased production of ectonucleotidase, adenosine, which is tightly controlled by CD39 and CD73. . A new checkpoint molecule, CD39/ENTPD1, is highly expressed and activated in the tumor vasculature, penetrates immune cells, and promotes tumor growth. Deletion or blockade of CD39 enhances anti-tumor activity by increasing the anti-tumor immune response and inhibiting tumor angiogenesis. The present invention is the development of anti-CD39 antibodies that mediate CD39 downregulation in immune cells such as T-cells with T-cell depletion markers, and demonstrated the development of these antibodies in blocking tumor growth while minimizing side effects in preclinical models. It is based at least in part on usability.