Abstract Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily of proteins that play diverse roles in the activation of several intracellular signaling pathways that control cell proliferation, survival, and apoptosis. Activation of the TRAIL pathway has been viewed as an attractive therapeutic approach for the treatment of cancer because of its distinct role in the induction of tumor cell apoptosis. TRAIL can bind as a trimer to membrane-bound or soluble receptors, and only the two closely related cell surface death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) can preferentially trigger the extrinsic pathway of tumor cells, leading to apoptotic cell death. The BCL-2 family member-driven mitochondrial apoptotic pathway can also serve to amplify the extrinsic pathway through further downstream activation of caspases. Given the crosstalk between the extrinsic and intrinsic cell death pathways, several resistance mechanisms have emerged to escape TRAIL-induced apoptosis. These include altered receptor regulation, overexpression of cellular FLICE-like inhibitory protein (cFLIP) that inhibits the proapoptotic activity of the DISC, overexpression of the prosurvival BCL-2 family member proteins, and the inhibitor of apoptosis proteins (IAPs) that directly inhibit caspases. In addition, TRAIL can induce non–cell death signaling pathways (e.g., NF-κB, MAPK, PI3K) to promote tumor cell growth as a potential resistance mechanism. Results of several clinical trials that targeted DR4 and DR5 with first-generation agonistic anti-TRAIL antibodies or human recombinant TRAIL indicated that these agents failed to demonstrate significant improvement in patient progression-free survival compared to standard-of-care therapy. The major contributing factor in this lack of clinical activity is believed to be the suboptimal TRAIL receptor clustering by these agonists. ABBV-621 is a novel, second-generation TRAIL receptor agonist comprising a human IgG1-Fc linked to native single-chain TRAIL-receptor binding domain (scTRAIL-RBD) monomers that are covalently connected by glycosylated linkers, resulting in two sets of trimeric RBDs. ABBV-621 is designed to maximize receptor clustering butdoes not require Fcγ-R-mediated crosslinking for optimal in vivo efficacy, which has been deemed an activity-limiting step for the competitor anti-DR4 and anti-DR5 antibodies in the clinic. In-house studies have demonstrated the requirement for enhanced caspase-8 aggregation into the death-inducing signaling complex (DISC) to induce potent tumor cell death, providing mechanistic insights as to why death receptor agonists originally failed and further distinguishing ABBV-621 from the first-generation agents. ABBV-621 induces dose-dependent apoptotic cell death at sub- to single-digit nanomolar potencies across a large panel (~100) of human hematologic and solid tumor cell lines in vitro. ABBV-621 activity is on-target and mechanism-based as demonstrated by a rapid activation of downstream apoptotic signaling events (cleavage of caspase-8, caspase-3, and PARP). In human tumor xenograft models, ABBV-621 exhibits potent antitumor activity in vivo as a monotherapy and in combination with targeted agents or chemotherapy using xenograft tumors derived from colorectal, lung, leukemia, and lymphoma cell lines. This activity is on-target, mechanism-based, and dose-dependent as indicated by rapid activation of tumor caspase-8 and caspase-3 after a single ascending dose of ABBV-621 in a colorectal carcinoma xenograft model. ABBV-621 exhibits a dose-proportional pharmacokinetic (PK) profile in mice and cynomolgus monkeys, and the projected human half-life is estimated to be ~2 days. PK/pharmacodynamic (PD) assessments estimate that achieving exposure above an efficacious concentration for 4-7 days is sufficient to maintain tumor regressions up to 4-7 weeks. Screens against 95 patient-derived xenograft (PDX) models consisting of 12 different solid tumor types uncovered single-agent activity (regressions) in >50% of all PDXs tested. PDX models can be more reflective of human disease by providing estimation of effects of tumor heterogeneity on ABBV-621 activity. Models that were partially sensitive or completely resistant to treatment were also identified, and collectively these responses are being utilized with associated pre- and post-treatment genomic/proteomic information to further inform potential patient stratification markers. To demonstrate on-target biologic activity in the clinic, proximal and distal target engagement markers will be pursued. In a GLP monkey toxicity study, ABBV-621 was well tolerated with no adverse test item–related findings. The first-in-human (FIH) phase 1/1b study with ABBV-621 will enroll subjects with previously treated advanced solid tumors and hematologic malignancies. The phase 1 objectives will be to establish the safety and tolerability of ABBV-621, as well as to understand the PK properties. Secondary objectives will be to explore target engagement and efficacy biomarkers and to evaluate clinical activity. Citation Format: Susan E. Morgan-Lappe. ABBV-621: A best-in-class TRAIL-receptor agonist fusion protein that enhances optimal clustering for the treatment of solid and hematologic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT01-03. doi:10.1158/1538-7445.AM2017-DDT01-03
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Jan 25, 2018
Amna Abdul Sattar + 2
Open Access
