dalutrafusp alfa

A bifunctional fusion protein composed of a humanized aglycosylated immunoglobulin G1 kappa (IgG1k) antibody directed against the ectoenzyme 5'-ecto-nucleotidase (cluster of differentiation 73; CD73; 5'-NT; ecto-5'-nucleotidase; NT5E), fused to the extracellular domain of human transforming growth factor beta (TGFbeta) receptor type II (TGFbetaRII), with potential immunomodulating and antineoplastic activities. Upon administration, dalutrafusp alfa targets and binds to both CD73 expressed on tumor cells and TGFbeta in the tumor microenvironment (TME). The binding of dalutrafusp alfa to CD73 prevents CD73-mediated conversion of extracellular adenosine monophosphate (AMP) to adenosine and the adenosine-mediated suppression of lymphocyte activity and trafficking. This increases the activity of cytotoxic T lymphocytes (CTLs), activates macrophages and reduces the activity of both myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes (Tregs). By abrogating the inhibitory effect on the immune system and enhancing the CTL-mediated immune response against cancer cells, tumor cell growth is decreased. The binding of dalutrafusp alfa to TGFbeta neutralizes TGFbeta and prevents TGFbeta-mediated signaling. This abrogates TGFbeta-mediated immunosuppression in the TME, enhances immune cell infiltration and anti-tumor immunity in the TME, and promotes the CTL-mediated immune response against tumor cells leading to tumor cell death. CD73, a plasma membrane protein belonging to the 5'-nucleotidase (NTase) family, is upregulated on a number of cancer cell types and catalyzes the conversion of extracellular nucleotides, such as AMP, to membrane-permeable nucleosides, such as adenosine; it plays a key role in adenosine-mediated immunosuppression within the TME. TGFbeta, overproduced in many types of cancer, plays a key role in immunosuppression in the TME, enhances tumor cell proliferation, and promotes cancer progression.