Development of a Revolutionary Imaging Method for Visualization of Drug Release and Drug Distribution from Antibody-Drug Conjugates (ADCs) in Cancer Tissue
Enabling Precise Design of ADCs-Next Generation Cancer Therapeutics
National Cancer Center
- Using Imaging Mass Spectrometry (IMS), Japan's National Cancer Center (NCC; President: Hitoshi Nakagama, Chuo-ku, Tokyo) has established the world's first method for the visualization of drug release and drug distribution from antibody-drug conjugates (ADCs)*1 in cancer tissue.
- ADCs consist of an antibody to which an anticancer drug or other molecule is attached. The ability of antibodies to bond to cancer cells that display a specific molecule is used to carry the drug directly to the cancer cell, where the drug is released and exhibits an antitumor effect.
- Together with immune checkpoint inhibitors, ADCs are a next generation of cancer therapeutics currently under intense research and development, though mainly in the U.S. They are expected to become a mainstream treatment for cancer.
- The development of a method that allows observation of the release and distribution of drugs in cancer tissue, without the need to label the drug with radioisotopes, could be a revolutionary advancement in ADC drug design.
This study was conducted jointly by a research team consisting of members from the Division of Developmental Therapeutics (Director: Yasuhiro Matsumura) of NCC's Exploratory Oncology Research & Clinical Trial Center (NCC-EPOC; Director: Atsushi Ochiai), RIKEN, and Shimadzu Corporation.
These findings were published in Scientific Reports (http://www.nature.com/srep/) on April 21.
ADCs are a new type of cancer therapeutic designed to attack cancer cells and avoid effects on normal cells by using an antibody that targets only cancer cells, and delivering the drug attached to the antibody directly into cancer cells (Fig. 1). Particularly in the U.S., clinical development has already been pursued for over 50 ADCs.
Since an ADC that was created by attaching an anticancer agent to trastuzumab (trastuzumab emtansine, T-DM1) showed efficacy in the treatment in patients with HER2 positive advanced and recurrent breast cancers that had become resistant to trastuzumab alone, expectations are also growing that ADCs will provide a new means of overcoming the issue of anticancer drug resistance.
However, so far we have had no way of evaluating accurately the two mechanisms required for ADCs to exhibit an antitumor effect. These are for the ADC to reach cancer cells, and for the drug to be released into cancer cells. This inability has probably limited the achievement of optimal ADC drug design.
Fig. 1: ADC Structure
1. ADC binds to antigen.
2. ADC and antigen are taken into the cell.
3. ADC is broken down inside endosomes and lysosomes, releasing the drug.
4. The cell is damaged.
The technique developed by this research team is able to identify clearly by IMS the drug released from an ADC. This technique allows qualitative and semiquantitative analysis of where and how much of a released drug is distributed (Fig. 2). Because this technique does not label the drug with a radioisotope, it is superior to conventional methods in providing a more accurate representation of drug distribution in cancer cells, and also in being simpler and cheaper than conventional methods.
The relationship between cancer and blood coagulation has been known for many years. NCC-EPOC's Division of Developmental Therapeutics (DDT) focused on the extravascular activation of blood coagulation caused by expression of the clotting initiator tissue factor (TF) at the surface of cancer cells, or in and around tumor vessels, and developed an antibody to TF. Then, NCC-EPOC's DDT created an ADC consisting of this antibody and a drug called MMAE attached by a linker created by RIKEN (anti-TF antibody-MMAE conjugate). This ADC was administered intravenously to tumor-bearing mice. IMS*2 was used to confirm the ADC was carried to the cancer tissue and that MMAE was released selectively into the clump of cancer cells inside the cancer tissue (Fig. 3).
Conventional methods of observing the internal kinetics of ADC have required the linked drug be labeled with a radioisotope, which is a costly and time-consuming process. Conventional methods are also unable to discern between drug before and after release from the ADC, unable to evaluate whether the ADC has actually reached the cancer cells, and unable to determine whether the drug has been released in the cancer cells.
Fig. 2: Intratumoral MMAE Distribution Visualized by Imaging Mass Spectrometry
MMAE was applied to a IMS slide glass and analyzed by IMS. Imaged results showed a dose-dependent increase in the number of dots.
Fig. 3: Intratumoral Distribution of MMAE Delivered by an ADC as Evaluated by Imaging Mass Spectrometry
MMAE is only detected by IMS after it is released from the ADC, and is not detected while linked to the antibody as an ADC.
ADC research and development activities are expected to increase even further. The method developed in this study for evaluation of intratumoral distribution is a very simple but accurate means of determining optimal conditions for the delivery of ADCs to cancer tissue and attached drugs to cancer cells. This method promises to become an essential technique in the precise design of ADCs.
[Journal Name: Scientific Reports]
|Title:||Imaging mass spectrometry for the precise design of antibody-drug conjugates|
|Authors:||Yuki Fujiwara, Masaru Furuta, Shino Manabe, Yoshikatsu Koga, Masahiro Yasunaga, Yasuhiro Matsumura|
*1 Antibody-drug conjugate: ADC
ADCs consist of an antibody to which an anticancer drug or other molecule is attached. The ability of antibodies to bind to cancer cells that display a specific molecule is used to carry the drug directly to the cancer cell, where the drug is released and exhibits its antitumor effect.
*2 Imaging mass spectrometer: IMS
A molecular imaging device consisting of a combination of an optical microscope and mass spectrometer. This instrument was developed by Shimadzu Corporation with the support of the Japan Science and Technology Agency's program for Development of Systems and Technology for Advanced Measurement and Analysis. Conventional mass spectrometry is used to analyze for target molecules after living tissue has been broken and separated, so it cannot be used to evaluate where molecules are located in a living sample. IMS is able to perform mass spectrometric analysis of target areas and target molecules present within those target areas without the need to break down the living tissue. Previous imaging mass spectrometry instruments have had a resolution of just 100 to 200 μm, while Shimadzu's imaging mass spectrometer can perform high resolution imaging able to identify targets on a cellular level at a maximum resolution of 5 μm. With this resolution, Shimadzu's imaging mass spectrometer is expected to be able show to the distributions of intracellular drugs that could not be shown previously.
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