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.

Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax.

The Bcl-2 family inhibitors venetoclax and navitoclax demonstrated potent antitumor activity in chronic lymphocytic leukemia patients, notably in reducing marrow load and adenopathy. Subsequent trials with venetoclax have been initiated in non-Hodgkin's lymphoma and multiple myeloma patients. Traditional preclinical models fall short either in faithfully recapitulating disease progression within such compartments or in allowing the direct longitudinal analysis of systemic disease. We show that intravenous inoculation of engineered RS4;11 (acute lymphoblastic leukemia) and Granta 519 (mantle cell lymphoma) bioluminescent reporter cell lines result in tumor engraftment of bone marrow, with additional invasion of the central nervous system in the case of Granta 519. Importantly, apoptosis induction and response of these systemically engrafted tumors to Bcl-2 family inhibitors alone or in combination with standard-of-care agents could be monitored longitudinally with optical imaging, and was more accurately reflective of the observed clinical response.