Document resource
Background T cell engagers (TCEs) are a promising therapeutic modality that redirects cytotoxic T cells to recognize tumor cells for destruction. By binding both cytotoxic T cells and target antigen-expressing tumor cells, TCEs allow for the activation of bystander T cells and the directed release of cytotoxic proteins, such as perforin and granzymes, thereby leading to antitumor activity. While TCEs are effective in the treatment of hematological malignancies, achieving clinical antitumor activity in solid tumors has been more difficult. Challenges for TCE molecules targeting solid tumors include induction of cytokine release syndrome through peripheral activation of T cells, as well as on-target/off-tumor toxicity. These challenges are due to the systemic activity of these molecules, which could potentially be mitigated by effective masking and selective activation in the tumor microenvironment.Methods Here, we describe the development of a TCE platform to target solid tumors that is designed to overcome the limitations of existing unmasked and prodrug TCEs. Our conditionally activated molecules employ a differentiated approach to masking the anti-CD3 domain that is intended to render INDUCER™ molecules nearly completely inactive until activation in the tumor microenvironment restores their functional activity.Results Our data demonstrate that this masking approach eliminated peripheral cytokine release in vitro and in vivo in mouse models. Furthermore, when coupled with novel and proprietary linker substrates, the mask was efficiently removed in a tumor-selective, protease-dependent manner across a variety of primary human tumor patient samples representing a variety of indications. INDUCER™ molecules that target tumor-associated antigens exhibited potent cytotoxicity and T cell activation in vitro, as well as antitumor efficacy in vivo.Conclusions Together, these data demonstrate the promise of INDUCER™ molecules for the development of effective and better tolerated TCEs for the treatment of solid cancers.Ethics Approval All in vivo mouse work was performed in accordance with current regulations and standards of the U.S. Department of Agriculture and the NIH at Charles River Laboratories or NeoSome Life Sciences with the approval of an Institutional Animal Care and Use Committee. Human tumor samples were purchased from either BioIVT or Discovery Life Sciences from consenting patients.