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Group for Innovative Cancer TreatmenDivision of Developmental Therapeutics
Masahiro Yasunaga, Yoshikatsu Koga, Shinji Saijo, Shingo Hanaoka, Hikaru Iwafuji, Ryo Tsumura, Hiroki Takashima, Hirobumi Fuchigami, Takahiro Anzai, Takashi Aiba, Daigo Arita, Takanori Noguchi, Yohei Tsuruta, Madoka Nakayama, Mamiko Shimada, Masahisa Kudo
Infrastructure for the mAb development
We have established an infrastructure for antibody development including antigen production, animal immunization, hybridoma production, antibody expansion and purification, SPR characterization, and ELISA development. Simultaneously, we have found various cell surface molecules specific to colorectal cancer and succeeded in developing mAbs against the one of those molecules.
Cancer Stromal Targeting Therapy
In spite of recent success of antibody drug conjugate (ADC) therapy in patients with hypervascular and special tumors recognized by a particular mAb, there are several issues to be solved for ADC counted as universal therapy for any types of cancer. Especially most human solid tumors possess abundant stroma that hinders the distribution of ADC. To overcome these drawbacks, we developed a unique strategy that the cancer-stromal targeting (CAST) therapy by cytotoxic immunoconjugate bound to the collagen 4, tissue factor (TF), or fibrin network in the tumor stroma from which the payload released gradually and distributed throughout the tumor, resulting in the arrest of tumor growth due to induced damage to tumor cells and tumor vessels. We successfully developed a mAb (102-10 clone) that reacted only with human fibrin, not with human fibrinogen and cross-reacted with mouse fibrin but not with mouse fibrinogen. The specificity of our 102-10 differs from existing anti-fibrin mAbs. Namely, 102-10 reacts only with fibrin clot, but not with fibrinogen, soluble fibrin, or D-dimer. The anti-fibrin antibody therefore did not make immune complex in the blood stream and circulated in the blood for a long time. We then prepared the antibody drug conjugate (ADC) that is MMAE conjugated anti-fibrin mAb. The ADC may selectively extravasate from leaky tumor vessels, bind to the fibrin network in the stroma and create a scaffold from which effective sustained release of the free MMAE occur. This free MMAE may easily reach the cancer cells by diffusion through the stroma barrier. Another benefit is that MMAE released from the ADC may also attack the vascular endothelial cells.
DDS in Cancer Chemotherapy
Tumor-targeted delivery of therapeutic agents is a longstanding pharmacological goal to improve the treatment selectivity and therapeutic index. Most scientists have sought to use 'active' receptor-mediated tumor-targeting systems. However, the 'passive' targeting afforded by the “Enhanced Permeability and Retention (EPR) effect” provides a versatile and non-saturable approach for tumor-selective delivery. Polymeric micelles are ideally suited to exploit the EPR effect, and have been used for the delivery of a range of anticancer drugs in preclinical and clinical studies.
In this year, we reported that anti-TF mAb conjugated micelle incorporating epirubicin exerted a potent antitumor effect in a human pancreatic cancer model, especially TF-high-expressing tumors.
Noninvasive Diagnostic Test for Colorectal Cancer
Regarding colorectal cancer (CRC), we investigated the applicability of the fecal miRNA test (FmiRT) to fecal samples used for previous fecal occult blood test (FOBT) stored under various conditions.