3D Medicines Announces Global First Exosome-Based In Vitro Diagnostic Kit for Ovarian Cancer Receives NMPA Approval

According to data from the "2022 National Cancer Report" released by the National Cancer Center, there were 60,000 new cases of ovarian cancer and 40,000 deaths in China in 2020. Ovarian cancer is characterized by late-stage diagnosis, high recurrence rates, and low five-year survival rates, with its mortality rate ranking first among malignant tumors of the female reproductive system.^[1]The “Healthy China 2030” Planning Outline sets forth the requirement to “increase the overall cancer survival rate by 15% by 2030.”

The five-year survival rate for ovarian cancer is 40.5%. Due to the lack of effective detection methods, the five-year survival rate for ovarian cancer has increased by only 0.4 percentage points over the past decade, significantly lower than the 14.4-percentage-point increase observed in cervical cancer.^[2,3]. Early diagnosis of ovarian cancer is of great significance, with the 5-year survival rate approaching 90% for patients diagnosed at an early stage. However, early diagnosis of ovarian cancer has long been a challenge for clinicians. Since CA125 was discovered in the 1980s and widely adopted in clinical diagnostics, no superior diagnostic product has surpassed the detection performance of CA125 over the past four decades. Although transvaginal ultrasound and serum tumor markers such as CA125 and HE4 are widely used in clinical practice, these conventional methods have limitations, including low sensitivity for the early diagnosis of ovarian cancer.^[4]. In particular, serum CA125 has a sensitivity of only 43.5–65.7% in early-stage ovarian cancer.^[5], it is also elevated to varying degrees in other benign gynecological conditions and non-malignant tumors, which can easily lead to false positives and fails to meet the clinical need for precise early diagnosis of ovarian cancer.

Therefore, in the field of ovarian cancer, the “three 70%s” have long plagued clinicians and patients: approximately 70% of patients are diagnosed at an advanced stage; although the response rate to first-line treatment with surgery combined with platinum-based chemotherapy can exceed 80%, 70% of ovarian cancer patients experience recurrence within two to three years after initial treatment; and 70% of patients have a survival time of no more than five years.^[6]。

The human exosome CA125, HE4, and C5a detection kit (trade name: MiSiYou™), developed by Shanghai 3D Medicines Biomedical Technology Co., Ltd. (abbreviated as “3D Medicines Diagnostics”), is based on breakthroughs in the clinical application of exosome technology and has become renowned for its superior detection performance.The world's first exosome technology-based in vitro diagnostic product for ovarian cancer to complete multicenter clinical trials and receive regulatory approval^[7]。

The advent of MiSiYou™ is poised to become a powerful tool for the early diagnosis of ovarian cancer. By facilitating earlier clinical diagnosis, it aims to ultimately improve the 5-year survival rate for ovarian cancer patients, bringing significant benefit to those affected by the disease.

Exosomes are extracellular vesicles with a diameter of 30–150 nm. During their formation, various cellular contents, including proteins, lipids, and nucleic acids, are selectively packaged into exosomes and released via active processes into multiple body fluids such as blood and urine. By mediating intercellular communication, exosomes play a crucial role in human physiological and pathological processes.

In 2013, the Nobel Prize in Physiology or Medicine was awarded to three scientists—James E. Rothman, Randy W. Schekman, and Thomas C. Südhof—for their research on the regulatory mechanisms of cellular vesicle transport, thereby propelling exosome-related research to a new peak. Currently, nearly 5,000 exosome-related studies are published worldwide each year, primarily focusing on the regulatory mechanisms of exosomes in physiological and pathological processes, their role as diagnostic biomarkers for diseases, and the exploration of using exosomes secreted by cells in vitro for disease treatment and as drug delivery vehicles.

Given the immense potential value of exosomes in disease diagnosis and therapy, a significant number of biotechnology entrepreneurs and capital investors have entered this field. Clinical trials led by biotechnology companies are currently underway across the three primary application areas: disease diagnosis, disease treatment, and drug delivery.

Although exosomes were first discovered in the 1990s to play a significant role in tumor development and metastasis, nearly 30 years have passed since then. However, similar to the challenges encountered by other disruptive biotechnologies—such as mRNA vaccines, CAR-T cell therapy, and antibody-drug conjugates (ADCs)—during their pre-approval “uncharted territory” exploration phase, exosome technology still faces numerous hurdles in its translation into clinical applications. For instance, in the development of diagnostic biomarkers, challenges remain in discovering novel biomarkers and ensuring that the stability of exosome isolation and purification meets the regulatory requirements for in vitro diagnostic registration. In therapeutic applications, issues regarding production yield, purity, uniformity, and batch-to-batch consistency still require breakthroughs. For drug delivery purposes, technologies related to drug encapsulation, in vivo delivery efficiency, and metabolic stability are still in the early stages of development. Due to these technical difficulties, although many clinical trials involving exosome-based disease diagnosis, treatment, and drug delivery are underway, very few have successfully completed clinical trials and achieved the expected outcomes.

Misiyou^™The core advantage of this technology lies in leveraging the rich information contained within exosomes—small vesicles released by cells—demonstrating significant value in early disease diagnosis.^[8]。

Specifically, using exosomal proteins as biomarkers offers significant advantages: only 1% of target proteins identifiable as potential biomarkers in plasma/serum are detectable, whereas this proportion reaches as high as 75% in exosomes.^[9,10]This significantly reduces interference from high-abundance proteins during the discovery and application of novel biomarkers. Meanwhile, as exosomal contents are protected by a phospholipid bilayer membrane, they exhibit high stability, which further minimizes biomarker degradation. Additionally, biomarkers can be enriched via exosomes, thereby ensuring the high sensitivity and specificity of exosome-based biomarkers as diagnostic products.

Additionally, 3D Medicines Diagnostics’ independently developedNegative Pressure Nanoultrafiltration Combined with Reverse Hydrophobic Aggregation and Sedimentation TechnologyExosome isolation and extraction, compared to traditional exosome isolation and preparation techniques, offersHigh Stability and Ease of OperationThese advantages overcome the bottlenecks in the clinical application of exosome technology, enabling it to truly serve clinical practice and patients.

In addition to using exosomal proteins as biomarkers for disease diagnosis, another major innovation of Misiyou™ is its multi-target biomarker panel analysis based on exosomal proteins.

Preliminary studies, through exosome mass spectrometry and data mining analysis based on clinical cohorts, have not only demonstrated that exosome-derived CA125 and HE4 can significantly improve the accuracy of differentiating between benign and malignant ovarian tumors, but also innovatively identified a novel biomarker, C5a (the core complement system protein C5a). Furthermore, previous research has shown that aberrant C5a expression is closely associated with the onset and progression of ovarian cancer.^[11]。

During the subsequent development of biomarkers, given that exosome-derived biomarkers are generally present at lower levels than blood-derived ones, MiSiYou™ has, for the first time, combined a highly efficient exosome extraction method with a highly sensitive chemiluminescent immunoassay.Exosomes were isolated from peripheral blood, and the concentrations of CA125, HE4, and C5a within these exosomes were measured. An OCS score was calculated through cohort training and validated in independent, multicenter clinical cohorts, ultimately achieving superior clinical diagnostic performance compared to traditional single-marker approaches.ThisThe use of biomarker panels, rather than traditional single-protein indicators, as biomarkers is also a future trend in biomarker development.

After years of breakthroughs in exosome technology and biomarker research, overcoming a series of technical challenges—including efficient and stable isolation and preparation of exosomes, discovery, screening, and training of multi-biomarker panels, and ensuring the stability of multi-parameter exosome detection in clinical samples—Professor Zhou Qi from Chongqing University Cancer Hospital led the initiation of a multicenter clinical registry study in 2019. In collaboration with Professor Lin Zhongqiu from Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Professor Zhu Jianqing from the Cancer Hospital, University of Chinese Academy of Sciences; and Professor Han Liping from the First Affiliated Hospital of Zhengzhou University, this study prospectively enrolled approximately 1,500 female patients with adnexal masses. Using pathological diagnosis as the gold standard, the study analyzed MiSiYou.^TMPerformance in Diagnosing Ovarian Cancer.

Results show:Misiyou^TMThe overall sensitivity for ovarian cancer detection was 95.5%, with a specificity of 90.2% in the differential diagnosis between epithelial ovarian cancer and benign adnexal masses; notably, the sensitivity reached 89.7% in patients with stage I ovarian cancer., significantly superior to traditional serum CA125 (27.8-64.3%)^[5]. Meanwhile, in CA125-negative ovarian cancer patients, it demonstrated a sensitivity of 72.7% and a specificity of 98.4%, reducing the risk of missed diagnosis and misdiagnosis of ovarian cancer. For high-grade serous ovarian cancer, which accounts for the largest proportion and has the highest degree of malignancy among epithelial ovarian cancers, Misyou^TMThe diagnostic sensitivity reached 98.3%. Moreover, unlike the ROMA index (a calculated combination based on serum CA125 and HE4), whose sensitivity is significantly affected by menopausal status, MisYou^TMIt demonstrates excellent sensitivity in both premenopausal and postmenopausal women, at 94.3% and 96.2%, respectively, which significantly improves the diagnostic rate of ovarian cancer in premenopausal women. Furthermore, among women under the age of 45, MisYou^TMThe sensitivity for diagnosing ovarian cancer also reached 92.7%, suggesting that MiSiYou^TMSuperior Performance in Women of Childbearing Age at High Risk for Early-Stage Ovarian Cancer

These data indicate:Misoyou^TMIt can serve as an excellent hematological biomarker for the diagnosis of ovarian cancer, facilitating early detection. Furthermore, research data suggest that it also demonstrates significant potential in differentiating between benign and malignant adnexal masses and in screening asymptomatic high-risk populations for ovarian cancer.

Given their inherent biological characteristics and close association with the pathogenesis and progression of diseases, exosomes have emerged as one of the most cutting-edge technological avenues in current international scientific research and industrial development. Exosomes have already been validated for application in diagnostic research for tumors, immune system disorders, and infectious diseases. In the future, diagnostic kits can be developed at scale targeting disease-specific biomarkers.

Meanwhile, exosomes are widely present in various body fluids and can cross the blood-brain barrier, making them suitable for the early diagnosis of Alzheimer’s disease and other challenging neurological disorders. They hold broad prospects for application in the diagnosis, therapeutic efficacy assessment, and recurrence prediction of various complex diseases. The approval of MiSiYou™ also reflects, from another perspective, the National Medical Products Administration’s embrace and support for innovative technologies.

It is foreseeable that in the near future, as exosome technology continues to mature, more innovative medical products developed based on this technology will be submitted for regulatory approval and enter clinical trials. The application of exosome technology is expected to expand from exosome-based diagnostics to innovative technologies and products such as cell-secreted exosome therapies and exosome-based drug delivery systems.

After eight years of research and development, 3D Medicines Diagnosis has overcome a series of world-class technical challenges in the field of exosome technology, established a “bench to bedside” product translation pathway, and successfully launched the world’s first exosome-based in vitro diagnostic product for ovarian cancer: MiSiYou.^TMIts market launch will also accelerate the rapid translation of exosome technology across major disease areas, yielding a series of innovative diagnostic and other medical application products that address the diagnostic and therapeutic challenges of many complex and refractory diseases. Meanwhile, ThinkMed Diagnostics’ successful exploration in the “no-man’s land” of medical innovation will further strengthen China’s pharmaceutical innovation ecosystem, helping to generate more innovative achievements.

*For the intended use and performance specifications of the product, please refer to the product instructions.

[1] National Health Commission of the People's Republic of China, "Guidelines for the Diagnosis and Treatment of Ovarian Cancer (2022 Edition)"

[2] 2021 Statistical Data from the National Cancer Center

[3] Transcript of the Regular Press Conference Held by the National Health Commission on June 8, 2018, National Health Commission of the People's Republic of China,

June 8, 2018, http://www.nhc.gov.cn/wjw/xwdt/201806/d5a307f70cb84538847e18af2de1f715.shtml

[4] Zou Yupeng, Li Li. Tumor Prevention and Treatment Research, 2017;44(9):631-635

[5]  Biochim Biophys Acta Rev Cancer. 2021 Apr;1875(2):188503.

[6] Three 70%s Plague Clinicians and Ovarian Cancer Patients, Guangming Online, May 13, 2022,

https://m.gmw.cn/baijia/2022-05/13/35726645.html

[7] Shanghai-based company’s globally first in vitro diagnostic product for ovarian cancer approved for market launch, People's Daily Client Shanghai Channel, January 23, 2024,

https://wap.peopleapp.com/article/7323614/7160111

[8] Expert Consensus on the Research, Translation, and Clinical Application of Exosomes, Journal of Translational Medicine, Vol. 7, No. 6, December 2018

[9] Bleijerveld, O.B., Zhang, Y.N., et al, PROTEOMICS-Clinical Applications,7(7-8), 2013; pp.490-503.

[10]  Boukouris, Stephanie and S. Mathivanan.  Clinical applications. 2015; 9 34 :358-67.

[11] Merle NS, Noe R, Halbwachs-Mecarelli L, Front Immunol. 2015;6:257