bifunctional TGF-beta antagonist/IL-15 protein complex HCW9218

A heterodimeric, bifunctional fusion protein composed of the ectodomains of the transforming growth factor (TGF) beta (TGF-beta; TGFb) receptor II (TGFbRII;TGFBR2) fused to a human immunostimulatory cytokine interleukin-15 (IL-15)/ IL-15 receptor alpha complex, with potential immunostimulatory and antineoplastic activities. Upon administration of the bifunctional TGF-beta antagonist/IL-15 protein complex HCW9218, the TGFbRII moiety specifically and selectively targets, binds to and neutralizes TGF-beta, an immunosuppressive cytokine secreted by tumors. This prevents TGF-beta from binding to TGF receptors and prevents TGFb-mediated signaling. This abrogates TGFb-mediated immunosuppression in the tumor microenvironment (TME), enhances immune cell infiltration and anti-tumor immunity in the TME, and promotes a cytotoxic T-lymphocyte (CTL)-mediated immune response against tumor cells leading to tumor cell death. This may lead to a reduction in TGFb-dependent proliferation of cancer cells. The IL-15 moiety stimulates the proliferation and cytotoxic activity of natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) and memory T cells locally in the TME, which further induces an anti-tumor immune response, and increases tumor cell killing. In addition, by stimulating the immune system and NK cell activation, HCW9218 may eliminate chemotherapy-induced senescent cells in tumors and normal tissues, may reduce senescence-associated secretory phenotype (SASP) factor activity, and may reduce therapy-induced senescence (TIS)-mediated proinflammatory side effects in normal tissues. TGFb, overproduced in many types of cancer, plays a key role in immunosuppression in the TME, enhances tumor cell proliferation, and promotes cancer progression. IL-15 regulates CD8+ T and NK cell development, activation and proliferation.