All about ADCs

Eisai’s antibody-drug conjugate shows target selectivity and antitumor effects

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TOKYO—Late September saw the 8th Annual World ADC meeting take place, held this year in San Diego. One of the presenters was Eisai Co. Ltd.’s research subsidiary, Morphotek Inc., which shared preclinical data regarding MORAb-202, Eisai’s first antibody-drug conjugate (ADC) developed by Morphotek.
MORAb-202 was featured in an oral presentation at the meeting, as well as three poster presentations. The World ADC oral presentation consisted of data from nonclinical studies of MORAb-202. It has been shown to display high target selectivity for FRA-positive cancer cells and strong anticancer activity, as well as a long half-life in blood and a long-lasting antitumor effect after only a single dose. In mice with triple-negative breast cancer cells who had received 5 mg/kg of MORAb-202, researchers saw a 60-day tumor regression effect and complete response in four out of the eight mice. MORAb-202 also demonstrated a bystander effect, showing antitumor activity on FRA-negative cancer cells around the FRA-positive cancer cells.
Nicholas Nicolaides, president and CEO of Morphotek, said in a press release that “Based on the preclinical data to be presented, we are excited to begin transitioning MORAb-202 into the clinical development stage later this year.”
MORAb-202 is an ADC consisting of farletuzumab and eribulin. Farletuzumab is an investigational anti-folate receptor alpha (FRA) antibody. FRA expression is seen in a variety of cancers—such as endometrial, non-small cell lung, triple-negative breast, gastric and ovarian cancer—but for the most part is not found in normal tissue. The humanized, IgG1 monoclonal antibody is being evaluated in Phase 2 clinical trials in Japan, the United States and Europe for recurrent platinum-sensitive ovarian cancer with a low CA125 level.
Eribulin, an anticancer agent developed in-house by Eisai, is part of the halichondrin class of microtubule dynamics inhibitors. Its mechanism of action is thought to be the inhibition of the growth phase of microtubule dynamics, which prevents cell division, and recent studies show it is also associated with increased vascular perfusion and permeability in tumor cores. As noted in a World ADC press release, “in preclinical studies of human breast cancer, eribulin demonstrated complex effects on the tumor biology of surviving cancer cells, including increases in vascular perfusion resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype, promoting the epithelial phenotype, opposing the mesenchymal phenotype. Eribulin has also been shown to decrease the migration and invasiveness of human breast cancer cells.”
The two components are combined with an enzyme cleavable linker. Once MORAb-202 enters target cancer cells, the linker is enzymatically cleaved, which separates eribulin from the antibody—which in turn is believed to generate a therapeutic effect on cancer cells and their surrounding cancer microenvironment. While most ADCs are known to present with high aggregation levels, given hydrophobic payloads, eribulin is water-soluble, and as such, aggregation is under 1 percent.
In older eribulin-related news, Morphotek announced in April of this year that it had launched its Antibody Drug Conjugate Services business based on its proprietary REsidue-SPEcific Conjugation Technology (RESPECT) and eribulin-linker toxin platforms. As noted in a Morphotek press release, “RESPECT is a site-specific conjugation technology that targets select amino acid residues as a way of producing investigational homogeneous ADCs with defined drug-to-antibody ratios. The platform allows for site-specific conjugation of a single cytotoxic payload or two payloads with different mechanisms of action. The platform employs eribulin as one of the cytotoxic payloads along with a proprietary high-throughput screening system that can evaluate multiple ADC products simultaneously for client-desired biophysical properties and target-specific binding. As part of our services, the eribulin-linker payload is offered as an option to develop investigational ADCs using traditional bioconjugation for companies interested in developing next-generation formats of their own antibodies.”

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