Introduction of Utomilumab

Utomilumab is the proposed non-proprietary name for PF-05082566, an investigational immunotherapy and a fully human IgG2 agonist monoclonal antibody (mAb) that binds to the extracellular domain of human 4-1BB/CD137 with high affinity and specificity. It is developed to treat advanced cancers either alone or in combination with other therapies. When utomilumab is injected into a person's bloodstream, it binds to 4-1BB on immune cells and stimulates them. At present, the approval of the monoclonal antibody has not been disclosed in the relevant authoritative drug approval agency, such as the European Medicines Agency and the U.S. Food and Drug Administration (FDA).

Mechanism of Action of Utomilumab

4-1BB/CD137 is an inducible, costimulatory receptor of the tumor necrosis factor (TNF) receptor superfamily expressed on activated immune cells, including effector and regulatory T cells, natural killer (NK) cells, and dendritic cells (DCs). Upon activation, 4-1BB/CD137 signals intracellularly through nuclear factor (NF)-κB and the MAPK cascade, promoting cell proliferation, survival, and cytokine production. Preclinical studies in animal models have demonstrated that agonistic engagement of the immune costimulatory molecule 4-1BB/CD137 leads to enhanced activity of cytotoxic T and NK cells, with effective antitumor responses. In vitro, utomilumab induces NF-κB activation and downstream cytokine production in cell lines and primary lymphocytes. It is capable to block the interaction of 4-1BB/CD137 with 4-1BB ligand (4-1BBL) found mainly on DCs, possibly eliminating reverse signaling through cross-linking 4-1BB/4-1BBL complexes. Furthermore, utomilumab, unlike other CD137 agonist mAbs, is a human IgG2 which requires secondary crosslinking to achieve agonism in vitro. The combination of endogenous ligand blocking and requirement for some degree of cross-linking in situ may enable the delivery of an agonist signal with lower risk of hepatotoxicity. In vivo, utomilumab demonstrated the ability to induce human leukocyte proliferation and to mediate significant antitumor activity, with inhibition of tumor growth in human peripheral blood lymphocyte (PBL)-SCID xenograft models as a single agent.

Fig.1 Mechanism of action of Utomilumab

For research use only. Not intended for any clinical use.