ATOR-1017: Stimulation of both T and NK cells induces potent killing of tumor cells

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 crosslinking 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 – totally in line with the treatment strategy for Alligator’s drug candidates.
The objective is to achieve an effective tumor-targeting immune response with minimum side effects.

1. ATOR-1017 binds to the target molecule 4-1BB on the surface of T cells.
2. The immune activating function is dependent on binding to Fc-gamma receptor on macrophages.
3. The beneficial T cells are activated to kill tumor cells.

Project

ATOR-1017 activates 4-1BB receptors, which increases the immune system’s ability to discover and kill tumor cells. This makes 4-1BB a highly interesting target for cancer immunotherapy. ATOR-1017 has a unique profile, including boosting the immunostimulatory effect in environments with high levels of immune cells, which occurs specifically in tumors. This creates an opportunity for potent, tumordirected immunostimulation that can increase the effect and reduce side effects for the patient.

ATOR-1017 is being evaluated in a dose escalation study in patients with advanced solid cancer (NCT04144842). The study is taking place at three medical centers in Sweden, and the primary endpoint is to assess the safety and tolerability of ATOR-1017 and determine a 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, presented in a poster presentation at the 2021 ASCO Annual Meeting, 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.

Large volumes of preclinical data have been presented showing that ATOR-1017 stimulates both natural killer (NK) and T cells, both of which contribute to an effective immune-mediated killing of tumor cells. NK cells are immune cells that respond specifically to tumor cells that are trying to evade the immune system’s response. NK cells also strengthen cell-death signaling from the immune system’s tumor-specific T cells. Stimulatory antibodies targeting 4-1BB therefore strengthen the ability of both NK and T cells to attack tumor cells.

In June 2020, the United States Patent and Trademark Office (USPTO) issued U.S. Patent No. US 10,689,454 which covers compositions of matter directed to ATOR-1017. This is the first granted US patent related to ATOR-1017 and its earliest expiry year is 2037.