Engineering Chemical Analogs to Bispecific Antibody Engagers for Cancer Immunotherapy

Cancer cell evasion mechanisms have undermined the promise of off-the-shelf immunotherapy for patients with solid and hematological tumors. Of these evasion mechanisms, most of these tumors can adapt to down-regulate cancer-identifying proteins, called tumor-associated antigens (TAAs), or lack the genetic variability to encode immunogenic proteins. Bispecific antibody (BsAb) molecules are a promising class of immunotherapy that work by binding T cells to the TAA of tumor cells, causing T cell expansion and cytotoxic T cell-mediated death. However, these treatments are based on a unique and sufficient presentation of TAA. We have enhanced BsAb targeting, independent of TAA presentation, by engineering a chemical analog to BsAb molecules (SyTE: synthetic T cell engager antibody) that consists of a T cell-activating antibody with a pyridyl disulfide copolymer that can bind to cancer cells through cell surface thiols. In vitro, SyTE has been shown to bind and kill hematological cancer cells (C1498 cancer model for acute myeloid leukemia). In vivo, SyTE induces a robust antitumor response and prolongs survival of tumor-bearing mice with C1498 acute myeloid leukemia. Like traditional BsAb therapy, we have observed enhanced T cell effector functionality upon SyTE treatment with minimal adverse events. SyTE is a promising cancer immunotherapy that can bind to multiple cancer subtypes without targeting a tumor-associated antigen.