LAUSR

T cell engagers are antibody-based therapeutics that transiently tether T cells via the T cell receptor complex (TCR) to surface antigens on tumor cells. This leads to activation of T cells and redirected lysis of the attached target cell. The therapeutic potential of this modality was demonstrated by blinatumomab, a CD19/CD3-bispecific T cell engager approved for the treatment of adult patients with relapsed/refractory acute lymphoblastic leukemia. Despite success of this T cell-engaging therapy in a hematologic malignancy, clinical studies in solid tumors with other T cell engagers have been less encouraging so far. The TriTAC (Tri-specific T cell Activating Construct) platform was developed to address shortcomings of existing T cell engagers, including short serum half-life, limited tissue penetration, and suboptimal activity. TriTAC constructs are made of a single polypeptide designed to bind to a cancer surface antigen, the CD3 epsilon subunit of the TCR, and to human serum albumin. CD3 is bound by a single-chain variable fragment (scFv) while both tumor targeting and albumin binding are achieved by single domain antibodies. The latter allow TriTACs to be very small, stable, and easily produced and purified. Noncovalent binding to serum albumin has been validated as an effective way to extend the serum half-life of other proteins up to several weeks. Even though TriTACs have three binding domains, their overall size is only ~50 kDa, one third of the size of a monoclonal antibody. This is expected to allow for faster diffusion into human tumor tissues than is possible with antibodies given the high interstitial pressure and dense extracellular matrix in solid tumors. TriTACs can induce T cell to kill tumor cells in vitro at single-digit picomolar to femtomolar concentrations with concomitant induction of inflammatory cytokine release and T cell proliferation. TriTACs can diffuse much faster across an extracellular matrix than antibodies, and eradicate tumors in mouse xenograft models supplemented with human T cells. In nonhuman primates, TriTAC molecules have serum half-lives of approximately 4 days, and appear well tolerated. Citation Format: Holger Wesche, Wade Aaron, Richard J. Austin, Patrick A. Baeuerle, Adrie Jones, Bryan Lemon, Kenneth Sexton, Timothy Yu. TriTACs are novel T cell-engaging therapeutic proteins optimized for the treatment of solid tumors and for long serum half-life [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3814.