Mersana Therapeutics Presents Preclinical Data Highlighting Potential of XMT-2056 and XMT-1660 in Three Posters at Virtual 2021 AACR Annual Meeting - Seite 2

• In the MX-1 triple-negative breast model, XMT-1660 showed complete, durable regressions of tumors at a DolaLock payload dose of 0.15 mg/kg. In contrast, the DAR-2 and DAR-12 ADCs required twice the payload dose for comparable efficacy. XMT-1660 also showed superior efficacy at matched payload doses in the TNBC patient-derived xenograft model HBCx-24, and in the ER+/HER2- breast cancer PDX model HBCx-19 versus comparators.
• Pharmacokinetics of XMT-1660 as well as the Dolasynthen DAR-2 and Dolaflexin DAR-12 comparator ADCs were evaluated in tumor-bearing mice and all were shown to be highly stable in vivo. Pharmacokinetics and tolerability of XMT-1660 and the Dolasynthen DAR-2 ADC were evaluated in non-human primates at equivalent payload doses. The PK and tolerability profiles were comparable and both ADCs exhibited high stability. These results, together with the superior efficacy of XMT-1660, support the selection of XMT-1660 for further development and for clinical study for the treatment of B7-H4-expressing tumors, such as breast, endometrial and ovarian.

Poster Title: XMT-2056, a well-tolerated, Immunosynthen-based STING-agonist antibody-drug conjugate which induces anti-tumor immune activity
Poster Number: 1738
Session Category: Immunology
Session Title: Immunomodulatory Agents and Interventions

These data suggest that XMT-2056, an Immunosynthen STING-agonist ADC, can overcome the limitations of the current therapeutic approaches, enabling tumor-targeted delivery of a STING agonist with improved efficacy and tolerability over a free IV STING agonist. Anti-tumor activity of Immunosynthen STING-agonist ADCs involves targeted activation of the STING pathway in both tumor-resident immune cells and tumor cells, delivering a one-two punch with the potential to increase the therapeutic index.

• In vitro studies show that XMT-2056 has potent STING activity with >100-fold improvement in activity in comparison to the free STING-agonist payload.
• XMT-2056 shows excellent in vivo efficacy even after a single IV dose, while having minimal effect on systemic cytokines. A single, low dose administration of XMT-2056 led to sustained tumor regressions in mice in comparison to the IV STING agonist which showed modest activity even at a dose approximately 100 times higher than that of the ADC. In contrast, when comparing the effect on systemic cytokine levels, the IV STING agonist had significantly higher levels compared to the STING-agonist ADC, which supports the hypothesis that a STING-agonist ADC can target STING activation to the tumor microenvironment, leading to improved anti-tumor activity and a significantly greater therapeutic index.
• In vitro and in vivo studies demonstrate that STING agonist ADCs are able to activate the STING pathway in both tumor-resident immune cells and tumor cells, offering a potential advantage over other innate immune activating pathways.
• To evaluate the safety profile, XMT-2056 was administered intravenously to non-human primates (NHP) in single and repeat-dose studies at multiple dose levels. XMT-2056 shows favorable pharmacokinetics in NHPs and is well tolerated at a dose level >10-fold higher than required for sustained tumor regression in mice models. Together these data support the clinical development of XMT-2056.

Poster Title: Tumor cell-intrinsic STING pathway activation leads to robust induction of Type III Interferons and contributes to the anti-tumor activity elicited by STING agonism