Dosing Begins in Trial of Novel Immunotherapy for Treatment of Advanced Solid Tumors

The first patient has been dosed with the novel therapy, AB248, as a part of the AB248-011 (NCT05653882) phase 1a/1b study of the immunotherapy in combination with pembrolizumab (Keytruda) for adult patients with locally advanced or metastatic solid tumors.¹

The study consists of a dose-escalation and dose-expansion stage to evaluate AB248 along with pembrolizumab for the treatment of patients from multiple treatment landscapes, including melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and squamous cell carcinoma of the head and neck (SCCHN). An intravenous (IV) infusion of AB248 and IV pembrolizumab will be given to patients with NSCLC and SCCHN which will increase based on the patient’s response to the therapy.

“We are delighted to begin clinical evaluation of AB248, our most advanced product candidate,” said Craig Gibbs, PhD, chief executive officer of Asher Bio, in a press release announcing the start of the dose-escalation and expansion portion of the trial. “This is a significant milestone for Asher Bio and our efforts to deliver a new class of therapies that address the limitations of existing immune-based medicines by specifically targeting them to, and activating, only the desired immune cell type, thereby avoiding pleiotropic effects that can both hinder efficacy and drive toxicity.”

The primary outcome of the study is measuring the frequency of dose-limiting toxicities (DLTs), serious adverse events (AEs), treatment-emergent AEs, AEs of special interest, and AEs that lead to dose interruption, discontinuation, and death.

Secondary outcomes researchers are looking at include efficacy measures, such as the objective response rate and duration of response to treatment according to RECIST version 1.1. Investigators are also looking out outcomes solely related to the use of AB248. These include the maximum observed blood concentration, area under the plasma concentration vs time curve, and elimination half-life of AB248.

AB248 is a CD8-targeted interleukin-2 immunotherapy. It is engineered to selectively and potently activate CD8+ T-cells while avoiding natural killer cells that act as a pharmacological sink and contribute to toxicity that are immunosuppressive. Preclinical trials showed that AB248 had an approximate 1,000-fold preference for the activation of CD8+ T cells over natural killer cells and regulatory T-cells.

Pre-clinical data presented at the Society for Immunotherapy in Cancer (SITC) 37th Annual Meeting showed that the murine surrogate for AB248, muAB248, had strong anti-tumor activity without body weight loss and signs of tolerability.² In the mouse tumor infiltrate subset, treatment with muAB248 showed expansion of several CD8+ T cell subsets, with similar results in cynomolgus monkeys.

In the dose-expansion trial for humans, eligible patients include those who have previously treated with a PD-1 treatment and now have advanced or metastatic disease. Patients must be 18 years or older and have adequate organ function and measurable disease per RECIST 1.1. Moreover, they must have an ECOG performance status of 0 or 1 but will be excluded from the trial if they have a diagnosis of immunodeficiency.

The trial will follow the Bayesian Optimal Interval trial design and enroll eligible patients at several dose levels and frequencies of AB248 monotherapy and in combination with pembrolizumab. Once a recommended dose is determined, the study will expand to indication-specific cohorts to evaluate AB248 as a monotherapy and in combination with pembrolizumab.

“I am excited to begin administering AB248 to patients as part of this clinical trial,” said Elizabeth Buchbinder, MD, Dana-Farber Cancer Center, and investigator in the phase 1a/1b clinical trial, in the press release. “Although there has been significant progress made in the treatment of patients with locally advanced and metastatic solid tumors, many patients remain underserved by existing options, particularly once they have failed therapy with immune checkpoint inhibitors. I am encouraged by the preclinical data supporting AB248’s differentiated profile and look forward to working with Asher Bio and fellow clinical investigators to evaluate AB248 in this phase 1a/1b clinical trial.”

^References

^{1. Asher Bio announces dosing of first patient in phase 1a/1b clinical trial of AB248, a cis-targeted IL-2 immunotherapy product candidate, for the treatment of locally advanced or metastatic solid tumors. News release. Asher Bio. January 17, 2023. Accessed January 18, 2023. https://bwnews.pr/3XqEFRU}

^{2. Asher Bio presents new preclinical data at SITC 2022 further supporting advancement of AB248 and AB821 as highly differentiated cis-targeted cancer immunotherapies. News release. Asher Bio. November 10, 2022. Accessed January 18, 2023. https://bwnews.pr/3IZncf3}