The activation-induced costimulatory molecule 4-1BB (CD137; TNFRS9), a surface glycoprotein that belongs to the tumor necrosis factor receptor family (TNFRSF9), is an important regulator of immune responses. Targeting 4-1BB or its natural ligand 4-1BB ligand, known as 4-1BBL, has important implications in many clinical conditions, including cancer. Ongoing research shows that 4-1BB-mediated anti-cancer effects are based on its ability to induce activation of cytotoxic T lymphocytes (CTL), and among others, high amounts of IFN-γ.[1]

Based on available data, 4-1BB is a compelling target for cancer immunotherapy and new formats of 4-1BB agonist moieties are being developed, showing great promise for achieving potent immune activation while avoiding limiting immune-related adverse events.

ASCOSupportive data from the ongoing Phase I clinical trial with the 4-1BB drug candidate ATOR-1017 being developed by Alligator Bioscience, as a tumor-directed therapy for metastatic cancer, shows positive results.

In a preclinical, experimental model of colorectal cancer (MC38) ATOR-1017 triggered potent anti-tumor effects. The investigational agent has also shown a dose-dependent inhibitory effect on tumor growth and improves survival.

The preclinical data demonstrate that ATOR-1017 stimulates both natural killer (NK), immune cells that specifically target tumor cells trying to evade the immune system’s response, and T-cells, both of which contribute to effective immune-mediated killing of tumor cells.

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NK cells also strengthen cell-death signaling from the immune system’s tumor-specific T cells. Hence, stimulatory antibodies against 4-1BB strengthen the ability of both NK and T cells to attack tumor cells.

Preclinical data further support the positioning of the 4-1BB antibody ATOR-1017 as best-in-class with the potential to minimize side effects while also triggering powerful immune responses.

A very favorable safety profile
Data presented in a poster presentation at the 2021 ASCO Annual Meeting, validate the therapeutic potential of ATOR-1017, demonstrating a very favorable safety profile combined with clear signs of proof of mechanism, as activation of T-cells in the circulation was observed across active dose levels of ATOR-1017.

“ATOR-1017 is the first of the second generation monospecific 4-1BB antibodies to report proof of mechanism by showing an increase in the number of activated T-cells in the circulation. Safety data show that ATOR-1017 is safe and well tolerable at doses up to 200 mg and no dose-limiting toxicity has occurred,” said Søren Bregenholt, Chief Executive Officer of Alligator Bioscience.

“We are encouraged by these data validating the potential of ATOR-1017. and we are now focused on completing the study and determining the dose for the subsequent Phase II program,” Bregenholt added.

ATOR-1017 is distinct from other 4-1BB antibodies, partly because of its unique binding profile, but also because its immunostimulating function is dependent on cross-linking to Fc-gamma receptors in immune cells. This localizes the immunostimulation to the tumor region where both 4-1BB and Fc-gamma receptors are expressed at high levels

Clinical trial
The Phase I study with ATOR-1017 is a dose-escalation study in patients with advanced solid cancer (NCT04144842). The primary endpoint of the study is to investigate the safety and tolerability of ATOR-1017 and to determine the recommended dose for subsequent Phase II studies.

The first patient was dosed in December 2019. As of data cut-off March 31, 2021, a total of 13 patients with varying advanced solid malignancies had been included. 4 patients (31%) remained on treatment, 3 (23%) of whom had confirmed stable disease for a period of 3.5-12.5 months.

The results from the evaluation of doses up to and including 200 mg demonstrate that ATOR-1017 has an encouraging safety profile as the drug-related adverse events in the study have generally been mild and transient. No dose-limiting toxicity or severe immune-related adverse events have been reported. The results further demonstrate that ATOR-1017 exhibits a favorable pharmacokinetic profile with linear elimination and no accumulation. Activation of T-cells in the circulation was observed across therapeutic dose levels of ATOR-1017 demonstrating biological activity and proof of mechanism.

Clinical trial
ATOR-1017 First-in-human Study – NCT04144842

[1] Vinay DS, Kwon BS. 4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy. BMB Rep. 2014 Mar;47(3):122-9. doi: 10.5483/bmbrep.2014.47.3.283. PMID: 24499671; PMCID: PMC4163883.
[2] Ullenhag GJ, Yachnin J, Carneiro A, Elison E, Carlsson M, Russell CA, Smith KE. A first-in-human, multicenter, open-label, phase 1 study of ATOR-1017, a 4-1BB antibody, in patients with advanced solid malignancies. Abstract: 2646; Presented at: American Society of Clinical Oncology (ASCO), held June 4 – 8, 2021.J Clin Oncol 39, 2021 (suppl 15; abstr 2646)

Featured image: Scientist at work in a laboratory. Photo courtesy: © 2016 – 2021 Fotolia/Adobe. Used with permission.

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