Unlocking HER2-Targeted Therapy: XMT-1522's Potential in Low-Expressing Tumors and Synergy with Trastuzumab Regimens

Antibody-drug conjugates (ADCs) have shown efficacy in treating HER2-enriched breast cancer and Hodgkin's lymphoma, yet existing technologies have limitations in broadening patient reach and target scope. Ado-trastuzumab emtansine, known as T-DM1, is an ADC with 3-4 cytotoxic agents per antibody, recently sanctioned for HER2 IHC 3+ or amplified breast cancer. Studies indicate that T-DM1 is more beneficial for patients with HER2 mRNA levels above the median, highlighting the necessity for more potent anti-HER2 ADCs to optimize benefits for high HER2-expressing patients and to extend therapy to those with low HER2 expression (HER2 IHC 1+/2+).

XMT-1522 is an innovative anti-HER2 ADC that employs a novel human anti-HER2 antibody designed for enhanced cytotoxic payload delivery. It does not compete with trastuzumab or pertuzumab for HER2 binding. The conjugation of approximately 15 proprietary auristatin molecules to each antibody is facilitated by Fleximer, a biodegradable hydrophilic polymer. XMT-1522 exhibits nanomolar potency against cultured tumor cells with as few as 10,000 HER2 receptors per cell, typically outperforming T-DM1 by 1-3 logs across a range of 25 tumor cell lines.

In mouse xenograft studies, XMT-1522 demonstrates favorable pharmacokinetics and achieves complete tumor regressions at doses that are well tolerated. In a high HER2-expressing gastric cancer model, a single 1 mg/kg dose of XMT-1522 is sufficient for complete regressions, whereas 10 mg/kg of T-DM1 is necessary for comparable effects. Furthermore, the combination of XMT-1522 with trastuzumab and pertuzumab leads to tumor regressions where the individual treatments result in stasis.

In low HER2-expressing breast and gastric cancer models, XMT-1522 achieves complete regressions with single doses of 1 mg/kg or 0.67 mg/kg, respectively, while T-DM1 shows no activity at doses of 10 mg/kg or higher. XMT-1522 also displays good stability in non-human primates with a half-life of approximately 5 days in plasma and minimal exposure to free payload. Notably, despite its high potency in low HER2 tumor models, XMT-1522 does not exhibit related toxicity in critical HER2-expressing tissues such as the heart and lungs.

The preclinical findings support the evaluation of XMT-1522 as a standalone treatment for tumors with low HER2 expression, where current HER2-targeted therapies are not suitable. Additionally, the combination of XMT-1522 with trastuzumab and/or pertuzumab could potentially enhance cytotoxic payload delivery while maintaining the capability for complete HER2 signaling inhibition, which may be essential for improving outcomes in HER2-driven tumors.

Reference: Bergstrom DA, Bodyak N, Yurkovetskiy A, et al. A novel, highly potent HER2-targeted antibody-drug conjugate (ADC) for the treatment of low HER2-expressing tumors and combination with trastuzumab-based regimens in HER2-driven tumors. Cancer Res 2015;75(15 Suppl):Abstract nr LB-231. doi:10.1158/1538-7445.AM2015-LB-231.