Abbv-621 Is a Novel and Potent TRAIL Receptor Agonist Fusion Protein That Induces Apoptosis Alone and in Combination with Navitoclax and Venetoclax in Hematological Tumors

Cell death can be initiated through activation of the extrinsic and intrinsic apoptotic signaling pathways. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, preferentially triggers the extrinsic apoptotic pathway by binding as a trimer to two closely related cell surface death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5). When these receptors undergo trimerization, it leads to the formation of the death-inducing signaling complex (DISC) to recruit and activate downstream caspases that ultimately leads to apoptotic cell death. Since TRAIL was found to induce apoptosis, several TRAIL receptor agonists have been developed for the treatment of cancer. ABBV-621 is a novel, second generation TRAIL receptor agonist that is currently being tested in Phase 1 clinical trials. It is an engineered fusion protein consisting as an IgG₁-Fc linked to a single chain trimer of TRAIL subunits resulting in a total of six death receptor binding sites per molecule in order to maximize receptor clustering. ABBV-621 exhibited potent single agent activity in acute myeloid lymphoma (AML) and diffuse large B-cell lymphoma (DLBCL) cell lines following 24hrs treatment. This activity was rapid and mechanism-based since activation of downstream apoptotic signaling events (caspase activation, mitochondrial depolarization, phosphatidylserine exposure) were observed as early as 1 hour following the addition of ABBV-621, and cell death could be completely blocked with the pan caspase inhibitor z-VAD-FMK . In vivo, ABBV-621 demonstrated robust single agent anti-tumor activity in pre-clinical models of AML and DLBCL.

The intrinsic apoptotic pathway is regulated by the BCL-2 protein family which controls the release of cytochrome c from the mitochondria resulting in the activation of downstream caspases. Because the two apoptotic pathways are linked, the intrinsic pathway can influence cell death mediated through the extrinsic pathway. The elevated expression of the anti-apoptotic proteins, BCL-2 and BCL-X_L, can inhibit the activation of the intrinsic apoptotic pathway and enable resistance to anti-cancer therapeutics, including TRAIL. Venetoclax (ABT-199), a BCL-2 selective inhibitor, and navitoclax (ABT-263) a BCL-2/BCL-X_L selective inhibitor, were tested in combination with ABBV-621 in a number of hematologic tumor cell lines in vitro and in vivo . The anti-tumor activity of ABBV-621 in combination with venetoclax or navitoclax exceeded that of either agent tested alone in pre-clinical and AML and DLBCL xenograft models.

Collectively, these data highlight that targeting the extrinsic apoptosis signaling pathway with either ABBV-621 alone or in combination with venetoclax/navitoclax to harness the intrinsic apoptosis signaling pathway has potential therapeutic benefit in hematologic malignancies.

Disclosures:

All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.