Clinical-stage biopharmaceutical company Mersana Therapeutics has confirmed that the Phase 1 trial of XMT-2056, an investigational immunosynthen STING-agonist ADC, has been placed on clinical hold by the U.S. Food and Drug Administration (FDA).

XMT-2056 is an investigational ADC composed of HT-19, an antibody directed against the tumor-associated antigen (TAA) human epidermal growth factor receptor 2 (EGFR2; HER2; ErbB2), linked to a payload composed of an agonist for the stimulator of interferon genes protein (STING; transmembrane protein 173; TMEM173), with potential immuno-activating and antineoplastic activities. [1]

Following intravenous administration of XMT-2056, the anti-HER2 antibody moiety targets and binds to HER2 while the STING agonist targets and binds to STING on immune cells in the tumor microenvironment (TME).

Following binding to the intended target XMT-2056 delivers its STING agonist payload into tumor cells and FcγRI (CD64)-expressing myeloid cells. This allows for specific activation of the STING pathway in the TME. In turn, this leads to the production of pro-inflammatory cytokines, including tip 1 interferon (IFNs), enhances the cross-presentation of tumor-associated antigens (TAAs) by dendritic cells (DCs), and induces a cytotoxic T lymphocyte (CTL)-mediated immune response against cancer cells.[1]

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STING, a transmembrane protein that activates immune cells in the TME, plays a key role in the activation of the innate immune system. The conjugation of the anti-HER2 antibody to the STING agonist improves targeted delivery of the STING agonist and increases tumor exposure and enhances the STING-mediated anti-tumor immune responses while limiting systemic toxicity.

Anna Protopapas President and Chief Executive Officer. Photo courtesy Mersana Therapeutics.

Clinical hold
The clinical hold follows Mersana’s voluntarily suspension of the phase 1 clinical trial due to a Grade 5 (fatal) serious adverse event (SAE) that was deemed to be related to XMT-2056. The SAE and its cause remain under investigation.

XMT-2056 is Mersana’s first Immunosynthen STING-agonist ADC product candidate to enter the clinic, and the SAE occurred in the second patient who had been enrolled at the initial dose level in the dose escalation portion of the Phase 1 trial in previously treated patients with HER2+ recurrent or metastatic solid tumors. During the clinical hold, no patients will be enrolled or dosed in the trial.

“In line with our steadfast commitment to patient safety, we have been proactive in our response to this event. With the clinical hold in place, our efforts for XMT-2056 are now focused on undertaking the work required to fully analyze this SAE and consider potential next steps for development,” said Anna Protopapas, President and Chief Executive Officer of Mersana Therapeutics.

“At the same time, we continue to make progress with our UpRi and XMT-1660 clinical trials, which remain unaffected,” she concluded.

Clinical trial
A Study of XMT-2056 in Advanced/Recurrent Solid Tumors That Express HER2 – NCT05514717

[1] Soomer-James J, Damelin M, Malli N. XMT-2056, a HER2-targeted STING agonist antibody-drug conjugate, exhibits ADCC function that synergizes with STING pathway activation and contributes to anti-tumor responses. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4423.

This article was updated following the April 2023 annual meeting of the American Association for Cancer Research (AACR)


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