Immunology plays a crucial role in development of many diseases. Using a biology-first approach, researchers are freer to study these pathways. Credit: Eisai Inc.
For any biomedical scientist, the acid test is whether their bench research translates to clinical success. Will promising results in models and experiments translate into effective new options to treat diseases and symptoms in people?
When the Japanese pharmaceutical company Eisai realized that its traditional approach to discovery was not fully representing the way disease presents in patients, it decided to change its drug discovery strategy. The company wanted to be sure it could capture the nuances of the systemic conditions that different people might develop. So, in 2022, the company restructured its research efforts to emphasize causal relationships between a proposed target molecule or pathway and a disease phenotype.
In doing so, it dissolved barriers that previously separated its oncology and neurology groups, and encouraged its scientists with diverse backgrounds and expertise to communicate and collaborate. “This situation seems to refresh their scientific insights,” says Takashi Owa, chief discovery officer and president, Deep Human Biology Learning at Eisai Co., Ltd. “Our scientists are freer to allow the science to guide them to novel solutions.”
Eisai calls its approach Deep Human Biology Learning (DHBL), and it aims to benefit from the fact that different diseases often have common roots and causes.
Takashi Owa, chief discovery officer and president, Deep Human Biology Learning at Eisai Co., Ltd. Credit: Eisai Inc.
“We have removed the walls between different therapeutic areas,” says Owa. “Underlying biological pathways and mechanisms are often associated with multiple diseases.”
Collapse of protein homeostasis, for example, is known to lead to an array of different medical problems, from dementia to some types of cancer. It causes misfolded and unfolded proteins to accumulate in cells, which can trigger different disease pathways depending on the protein type, as well as the genetic and environmental factors unique to the patient.
According to Toshimitsu Uenaka, president of Eisai’s Epochal Precision Anti-Cancer Therapeutics (EPAT) division, located in Exton, Pennsylvania, the DHBL approach has so far focused on making clinically relevant disease models.
Toshimitsu Uenaka, president of Eisai’s Epochal Precision Anti-Cancer Therapeutics (EPAT) division Credit: Eisai Inc.
Clinical relevance was a problem under the previous structure. “In oncology, the translatability of our preclinical research was not satisfactory,” Uenaka says. “Unexpected outcomes, both in efficacy and safety, sometimes happened in the clinic.”
Under the new DHBL structure, the company now takes what Uenaka calls reverse translational research: “a bedside-to-bench” approach. “We have focused on clinical biomarker research by using patient specimens in our clinical trials and found several hints about what is happening,” he says. “We will make use of this information in our future drug discovery to advance the development of novel treatments.”
Protein biology for cancer
EPAT, one of Eisai’s discovery centres, specializes in protein biology in two areas: gynaecologic cancers and breast cancers, and the targeting of stroma-rich malignant cancers, including pancreatic cancer, triple-negative breast cancer and scirrhous gastric cancer.
The DHBL approach of looking for common roots and causes should help with cancer research, Owa says. The company is focusing on the early stages of the disease, because early-stage tumours tend to be homogenous, with a limited number of relevant gene mutations. Targeting these genes and associated pathways in early-stage patients could potentially offer a cure or even prevent the cancer taking hold in the first place, he says — a strategy that would be less effective as the disease progresses and diversifies. “To continue to be successful it is critical for us to enrich the project pipeline in the early stage of oncology research and development,” he says.
EPAT’s enrichment focuses on three areas. The first is the identification of new ways to overcome drug resistance in cancer therapy. The company is working with a selective inhibitor it believes can block the key protein-protein interaction between cyclic AMP-response element binding protein-binding protein (CBP) and beta-catenin. This is important for a signalling pathway called Wnt that is closely associated with cancer.
The second is molecular techniques to selectively target and degrade the proteins cancers need to proliferate. Called ‘molecular glue’ and PROTAC (proteolysis-targeting chimera), these methods, Owa says, could be particularly useful against cancers that are often less sensitive to immunotherapies.
The third focus is on antibody-drug conjugates (ADCs), which can be designed to deliver specific anticancer molecules directly to tumour tissue. “ADCs may allow us to deliver an anticancer payload molecule to cancer cells in a selective manner, based on the specificity of the antibody to its cancer-relevant target antigen,” says Owa.
Eisai is working on a novel ADC to deliver anticancer agents to multiple tumour types. Central to that work are methods the company has developed to link the agent to specific antibodies. Called Residue-Specific Conjugation Technology (RESPECT®), the techniques are designed to reduce variability in the manufacturing process, to improve the quality of the therapeutic molecules. With this linkage, the conjugate molecule is more likely to attach the anticancer therapy to the desired impact area of the tumour and release the medicine directly into it, minimizing the impact on surrounding healthy tissue.
“We are now trying to show in clinical trials whether our ADC has antitumour efficacy and whether it can improve the tumour microenvironment,” Uenaka says. Eisai is investigating the conjugation of other anticancer chemicals to antibodies. “And genetics from our data science show which antigens should be targeted, and also which molecules should be degraded,” he adds.
DHBL might be a big change, but Eisai believes it will pay off. Owa sees rapid shifts in the oncology research landscape, as companies bet on the next big thing. “People are starting to ask what the next game changer following cancer immunotherapy will be,” he says. And for Eisai, the logical approach is to follow the biology.
Click here to learn more about Eisai’s new approach to cancer research
This article was created and originally published by Nature Research Custom Media. Here is the original article link: https://www.nature.com/articles/d42473-023-00012-z