Dolasynthen

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.

Dolasynthen Advantages

  • Precise Control over DAR: Because ADCs are not one-size-fits-all, the optimal DAR will vary among different targets and antigens. Dolasynthen allows for precise DARs between 2-24, enabling optimization of the DAR for specific antigens and antibodies.
  • Site-Specific Bioconjugation: The site of scaffold bioconjugation to an antibody impacts the overall properties of that ADC. Dolasynthen enables site-specific bioconjugation allowing further ADC optimization.
  • Homogeneous ADC Development: The DAR and antibody bioconjugation is consistent throughout ADCs developed with the Dolasynthen platform allowing for consistent and precise drug delivery to targeted cancer cells, every time.
  • Increased Hydrophilicity: The precise optimization of the hydrophilic moiety on Dolasynthen ADCs allows for increased aqueous solubility and enhanced PK properties.
  • Proprietary DolaLock Payload: Dolasynthen is loaded with our proprietary auristatin chemotherapeutic drug, which is a highly potent anti-tubulin agent selectively toxic to rapidly dividing cells, with the advantages of the DolaLock controlled bystander effect.