ABBV-184: A Novel Survivin-specific TCR/CD3 Bispecific T-cell Engager is Active against Both Solid Tumor and Hematologic Malignancies

◥ CD3 bispecific T-cell engagers (TCE), comprised of a tumor-targeting domain linked to a CD3 binding domain, function by bridging target-positive tumors and CD3-expressing effector T cells enabling redirected T cell-mediated killing of tumor cells. Although the majority of CD3 bispecific molecules in clinical development incorporate tumor-targeting antibody-based binding domains, many tumor-associated antigens derive from intracellular proteins and are not accessible to targeting via antibody. Intracellular proteins processed into short peptide fragments and presented on the cell surface by MHC proteins are recognized by T-cell receptors (TCR) on the surface of T cells. Here we describe the generation and preclinical evaluation of ABBV-184, a novel TCR/anti-CD3 bispecific composed of a highly selective soluble TCR that binds a peptide derived from the oncogene survivin (BIRC5) bound to the class I MHC allele human leukocyte antigen (HLA)-A*02:01 expressed on tumor cells, linked to a specific binder to the CD3 receptor on T cells. ABBV-184 drives an optimal distance between T cell and target cell thereby enabling sensitive recognition of low-density peptide/MHC targets. Consistent with the expression profile of survivin across a broad range of both hematologic and solid tumors, treatment of acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC) cell lines with ABBV-184 results in T-cell activation, proliferation, and potent redirected cytotoxicity of HLA-A2-positive target cell lines, both in vitro and in vivo, including patient-derived AML samples. These results indicate that ABBV-184 is an attractive clinical candidate for the treatment of patients with AML and NSCLC. ABBV-184 scTCR Anti-CD3 Knob-in-hole Fc A B T cell Tumor cell Tumor with low immune infiltration T cell Tumor cell ABBV-184 Tumor with ABBV-184 treatment T cells in tumor indicated with arrows Increased T cell frequency in treated tumor ABBV-184 drives lymphocyte infiltration into established tumors in humanized CD34+ NSG mice (B) compared to vehicle control (A). Created with BioRender.com

Automated summary

CD3 bispecific T-cell engagers (TCE) are effective in redirecting T cell-mediated killing of tumor cells by bridging target-positive tumors and CD3-expressing effector T cells. ABBV-184, a novel TCR/anti-CD3 bispecific, demonstrates sensitive recognition of low-density peptide/MHC targets and shows potential as a treatment for AML and NSCLC.