ADCs are not one-size-fits-all. The Dolasynthen platform enables an iterative approach to develop the right ADC for a given indication through customization and optimization. Dolasynthen utilizes a synthetic scaffold for precise control of DAR (from 2-24) and site-specific antibody bioconjugation. The platform is also able to homogeneously generate ADCs with precisely defined DARs for consistent drug delivery to cancer cells. The Dolasynthen scaffold has been precisely balanced to provide optimal water solubility, charge balance, linker stability and DAR. Dolasynthen retains the favorable properties of Dolaflexin, including our proprietary DolaLock technology for a controlled bystander effect, with even better physicochemical and pharmacokinetic properties.
Illustrated by our preclinical data, optimized Dolasynthen ADCs exhibit a broad therapeutic index as a cancer therapy. These data demonstrate the ability of the Dolasynthen platform to generate and identify the optimal ADC for a given target and antibody, and the significant potential for clinical application. Our second clinical candidate, XMT-1592, is a Dolasynthen ADC-targeting NaPi2b expressing tumors. We initiated a Phase 1 dose escalation trial of XMT-1592 in patients with tumors expressing NaPi2b in May 2020.
XMT-1660 is a first-in-class Dolasynthen ADC targeting B7-H4. B7-H4 is expressed in high unmet need tumors including breast, endometrial and ovarian. B7-H4 is expressed on both tumor cells and immunosuppressive tumor-associated macrophages (TAMs). This provides the potential for both a direct, cytotoxic antitumor effect as well as for additional payload delivery to the tumor microenvironment that can further contribute to immunogenic cell death, dendritic cell activation, and stimulation of an immune response consistent with the features of the Company’s unique DolaLock payload. In preclinical studies, XMT-1660 demonstrated robust in vivo activity against multiple triple-negative breast cancer models, as well as an ER+/HER2- breast cancer model, all of which express B7-H4. XMT-1660 is in IND-enabling studies and is expected to enter a Phase I dose escalation clinical study in early 2022.