ERIBULIN* ANTIBODY-DRUG CONJUGATE (ADC) PAYLOAD
ERIBULIN*
Eribulin* is a fully synthetic, structurally simplified, macrocyclic ketone analogue of the marine natural product halichondrin B, produced from the marine sponge Halichondria okadai. Eribulin’s anti-tumor activity is mediated by the inhibition of microtubule elongation and mitotic spindle formation, which results in apoptosis. Eribulin mesylate, marketed as Halaven®, is an approved monotherapy in the U.S. for the treatment of metastatic breast cancer patients who previously received at least two chemotherapeutic regimens for metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.
*Any ADC employing eribulin as a payload is investigational and has not been approved by regulatory authorities. For more information on Halaven® (eribulin mesylate), please see www.halaven.com or contact Eisai’s Medical Information toll-free number: 1-888-274-2378.
ADVANTAGES OF ERIBULIN-BASED ADCs**:
- Subnanomolar in vitro anti-mitotic activity
- Additional non-mitotic anti-tumor activity
- Has shown efficacy in vivo and in vitro efficacy in preclinical models
- Well-understood payload toxicity profile
- Payload amenable to multiple linker chemistries
- Drug-to-antibody ratios (DARs) of 4 or greater with very low aggregate levels
- Established payload and ADC manufacturing process
Patent applications are pending for certain ADCs with eribulin as a payload.
ANTI-TUMOR EFFECTS
Eribulin-based ADCs have durable anti-tumor effects in PDX models
ERIBULIN-BASED ADCs**
- Eribulin can be coupled to a variety of linkers using amine-based chemistries for conjugation to monoclonal antibodies for generation of ADCs.
- Eribulin-based ADCs can be readily prepared with drug-to-antibody ratios (DARs) of 4 or greater with excellent retention of desirable biophysical properties, such as low aggregate levels (<1% aggregate).
- Eribulin ADCs have demonstrated durable efficacy both in vitro and in vivo, with very low levels of off-target killing.
- Numerous ADCs to various targets have been prepared and evaluated with the eribulin payload, an example of which is shown below:
TRIPLE NEGATIVE BREAST CANCER
Triple-negative Breast Cancer
BYSTANDER EFFECTS OF ERIBULIN ADC PAYLOAD DEMONSTRATED IN PRECLINICAL MODELS**
ERIBULIN RELEASED VIA ENDOSOMAL PROCESSING OF THE ADC DISPLAYS SUBNANOMOLAR MITOTIC AND NON-MITOTIC EFFECTS ON BOTH THE TUMOR AND TUMOR MICROENVIRONMENT
- The mitotic effects eribulin exhibited as a payload not only include direct cytotoxic effects on receptor-positive cells bound by the ADC, but also on neighboring receptor-negative tumor cells.
- This bystander effect on neighboring receptor-negative tumor cells showed synergistic reduction in growth of heterogeneous patient-derived xenograft (PDX) tumors.
- Furthermore, released eribulin is highly cytotoxic to the stromal cancer-associated fibroblasts that are critical to supporting tumor growth in many cancers.
ERIBULIN ALSO HAS COMPLEX NON-MITOTIC EFFECTS ON THE TUMOR MICROENVIRONMENT
- Eribulin induces vascular remodeling and increases blood perfusion in tumors, thus making a greater percentage of the tumor susceptible and sensitive to subsequently administered therapies.
- Eribulin promotes a mesenchymal-to-epithelial transition (MET) phenotype in tumors, leading to reduced metasticity, reduced immunosuppression and increased drug sensitivity.
**These preclinical models do not imply clinical safety or efficacy.
*Any ADC employing eribulin as a payload is investigational and has not been approved by regulatory authorities. For more information on Halaven® (eribulin mesylate), please see www.halaven.com or contact Eisai’s Medical Information toll-free number: 1-888-274-2378.