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 – 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.
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, tumor-directed 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 objective is to assess the safety and tolerability of ATOR-1017 at therapeutic doses. The first patient was dosed in December 2019. As of data cut-off January 18, 2022, a total of 22 patients with varying advanced solid malignancies had been included. 4 patients (18.2%) remained on treatment, 1 (4.5%) of whom had confirmed stable disease for a period of 4 months.
The results from the evaluation of doses up to and including 600 mg, presented in a poster presentation at the 2022 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 to moderate and transient. No dose-limiting toxicity have been reported and thus the maximum tolerated dose (MTD) of ATOR-1017 has not been reached. The results further demonstrate that ATOR-1017 exhibits a favorable pharmacokinetic profile. Activation of T cells in the circulation was observed across therapeutic dose levels of ATOR-1017 demonstrating biological activity and proof of mechanism. Stable disease was achieved as best objective response in 10 (45%) of patients, with the longest treatment duration being 16 months. Dose escalation continues at 900 mg dose level.
On September 30, 2022, Alligator announced that the study has completed enrollment, with data showing that for doses up to 900 mg there were no significant safety concerns with durable stable disease as the best tumor response. Two patients remain on the study benefitting from ATOR-1017 treatment.
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.