Principal Research Scientist / Laboratory Head
Is cancer a genetic disease?
It is well known that cancers usually acquire resistance of drugs including anticancer agents and molecular targeting agents. This means that any cancers can change their phenotype, indicating that they change their genes diversely.
We could say that cancer is not a genetic disease but the disease with gene diversity. Therefore, it should be noted that attacking cancer cells themselves is more important than molecular targeting.
Monoclonal antibody (mAb) therapeutics based on ADCC and CDC or Antibody drug conjugate (ADC) are reasonable way to kill cancers because mAbs can selectively accumulate in cancer tissue by means of the EPR effect and have ability of active targeting. Recent advance of ADC as an active targeting is promising but this ADC strategy should be confined to highly toxic anticancer agents but not to ordinary ACA such as taxane, adriamycin and others because only less than three ACA molecules should be conjugated to the mAb, otherwise the affinity of the mAb is diminished if too many molecules of ACA are attached to the mAb. According to this principle, unrealistic amount of ADC should be administered if the mAbs are conjugated with an ordinary ACA. Therefore, for an ordinary ACA, nanoparticles should be considered as a DDS tool.
To date we have developed several cancer related monoclonal antibodies including anti-TF mAb. In collaboration with Nanocarrier Inc., we have succeeded in developing an anti-TF mAb-conjugated epirubicin (EPI) incorporating micelles. In in vitro using TF expressing pancreatic cancer BxPC3, free EPI showed the most potent cytocidal effect and the anti-TF-NC6300 clearly showed stronger cytocidal effect than NC-6300. Free Epi showed the fastest internalization into cytoplasm followed by nucleus. But this is the in vitro system. In vivo, free Epi should be cleared rapidly from blood stream. Between the anti-TF-NC-6300 and NC-6300, the anti-TF-NC-6300 was internalized sooner and more efficiently into cytoplasm.
Compared to free epirubicin and NC-6300, the anti-TF NC-6300 exerted the most potent anti-tumor activity in mice bearing BxPC3 xenografts. This was confirmed in a stomach cancer xenograft model as well. The GMP products will be prepared soon.
|Matsumura, Yasuhiro||Laboratory Head／Principal Research Scientist|
|Yasunaga, Masahiro||Deputy Principal Research Scientist|
|Koga, Nobukatsu||Senior Research Scientist|
|Takashima, Hiroki||Research Scientist|