ATOR-1015: Tumor-localizing bispecific CTLA-4 antibody with dual immunostimulatory function

ATOR-1015 binds to two different immunomodulatory receptors – the CTLA-4 inhibitory receptor, and an OX40 costimulatory receptor. In preclinical studies, the biospecificity has been shown to cause a significant increase in the immunostimulatory effect and is expected be achieved mainly in environments where both of the target molecules are expressed at high levels, such as in a tumor. This means that ATOR-1015 may have potent immunostimulatory effects in the tumor environment, but not in the rest of the body, with the goal of reducing the side effects while maintaining efficacy.

1. ATOR-1015 binds to CTLA-4 and OX40 on the regulatory T cells, the cells which restrain the immune system.
2. The macrophages are activated to kill Tregs, removing the inhibitory effect of Tregs on the beneficial T cells.
3. The effector T cells (light green) are multiplied in number and are activated to kill the tumor cells.

Project status

The ongoing dose escalation study in patients with metastatic cancer is planned to comprise up to 53 patients. The principal investigator is Dr Jeffrey Yachnin from the Department of Oncology at Karolinska University Hospital in Stockholm. The primary endpoint of the study is to investigate the safety and tolerability of ATOR-1015 and to determine the recommended dose for subsequent Phase II studies.

The study commenced in March 2019 with a titration phase using a single patient per dose level. This phase was then followed by the standard 3+3-design, where a cohort of at least three patients per dose level are treated before escalating to a higher dose. The study progresses well and currently, patients are given doses of 750 mg, approximately 12.5 mg/kg, every two weeks. The results presented at AACR (AACR oral presentation) and ASCO (ASCO 2020 Poster) evaluation of doses up and including 600 mg (about 10 mg/kg) which show that ATOR-1015 is well tolerated. To date, 21 patients with varying cancer types (colon cancer, eye melanoma, pancreatic cancer, ovarian cancer, gallbladder cancer, gastric cancer, and melanoma) have been evaluated in terms of safety. 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 positive tolerability profile of ATOR-1015 has led to the frontloading of a Phase Ib study for demonstration of single-agent activity. This allows for an efficacy readout as early as H2 2021 in malignant melanoma. This could significantly increase the value of the concept and will be followed by a Phase II combination study with anti-PD-1.

For further information, refer to https://www.clinicaltrials.gov/ct2/show/NCT03782467?term=1015&rank=1.