Dr. Wu Ligang of Inoricon Highlights Longevity as Key to Broad Application of mRNA Therapeutics

During the COVID-19 pandemic, mRNA vaccines stood out due to their advantages of broad-spectrum efficacy, high efficiency, rapid development, safety, and flexibility. Taking the mRNA COVID-19 vaccine jointly developed by Pfizer and BioNTech as an example, it took only 63 days from the release of the SARS-CoV-2 genome sequence to the clinical trial of the first vaccine dose, buying precious time for global epidemic control.

As the momentum continues, mRNA R&D in the post-pandemic era has also remained vibrant. In 2024, an RSV mRNA vaccine was approved for market launch, and several other mRNA vaccines achieved significant clinical progress.

Dr. Wu Ligang, who has dedicated nearly three decades to in-depth research in the field of RNA, offers profound insights and reflections on the development of mRNA technology. “It is truly regrettable that China’s independently developed mRNA vaccines were only completed after the end of the COVID-19 pandemic, failing to play their due role during the critical period of epidemic prevention and control.”

 Dr. Wu Ligang, Founder/CEO of InnoCare Pharma

Seizing this opportunity, Dr. Wu Ligang resolved to enter the industry and founded InnoRexon Biopharmaceutical Technology Co., Ltd. (hereinafter referred to as “InnoRexon”) in Shanghai in 2022, focusing on the development of mRNA drugs for tumor immunotherapy, alternative therapies, and metabolic diseases. “Scientists have a responsibility to join or assist the industry in accelerating the R&D of mRNA drugs, so that the technology can benefit more people at an earlier stage. Therefore, even though we missed the first wave of historical opportunities in mRNA drug development, we remain committed to this field.”

Despite the significant technical advantages demonstrated by mRNA vaccines, numerous technical bottlenecks remain to be overcome in their development. Dr. Wu Ligang pointed out, “It should be acknowledged that extensive prior research has successfully unlocked the door to developing mRNA technologies into therapeutics, achieving a major breakthrough from nothing to something. However, for this field to achieve leapfrog development from 1 to 10, and even to 100 and 1,000, further breakthroughs are required in more key foundational technologies.”

According to Dr. Wu Ligang, the most critical technical bottleneck in the current development of mRNA drugs is the insufficient longevity of mRNA. “Compared with DNA, mRNA does not carry the risk of genomic integration; however, its drawback lies in its short half-life, typically lasting only tens of minutes. This results in the rapid disappearance of mRNA after it delivers instructions for protein expression within cells, necessitating repeated administration of high doses. AndImproving the long-acting properties of mRNA is a key bottleneck in the development of mRNA therapeutics. Addressing this challenge would significantly reduce the dosing frequency and dosage of mRNA drugs, lower toxicity and treatment costs, and further enhance patient compliance.“Dr. Wu Ligang explained.”

Long-acting efficacy is key to the widespread application of most drugs. Taking small interfering RNA (siRNA) therapeutics as an example, although siRNA was first discovered in 1998 and garnered significant attention when it won the Nobel Prize in Physiology or Medicine in 2006, multiple siRNA drug candidates subsequently failed in clinical trials. It was not until 2018 that the first siRNA drug, Patisiran, received FDA approval. However, due to drawbacks such as susceptibility to nuclease degradation in vivo and high immunogenicity, which led to poor patient compliance and low sales, the drug was eventually withdrawn from the market. It was only after the second siRNA drug, Givosiran, addressed the challenges of long-acting efficacy and targeted delivery that siRNA therapeutics truly entered a phase of rapid development, becoming a current hotspot in drug discovery.

Currently, InnoCare has established three major technology platforms:ExNeo Nucleic Acid Modification Platform, Nextfold Sequence Optimization Platform, CapHLA Neoantigen Prediction PlatformAmong these, ExNeo nucleic acid modification and Nextfold sequence design are technologies developed to address the technical bottlenecks in mRNA long-acting efficacy. Of the three core technologies, both the Nextfold sequence optimization platform and the CapHLA neoantigen prediction platform extensively leverage advanced AI algorithms.

The primary cause of intracellular mRNA instability is its susceptibility to nuclease-mediated degradation. Therefore, elucidating mRNA degradation mechanisms and developing corresponding mitigation strategies are key to enhancing stability. Dr. Wu and his team have accumulated extensive expertise in the field of mRNA degradation. Based on the biochemical characteristics of mRNA degradation pathways and the involved nucleases, they have designed specific modification strategies that introduce novel chemical groups into mRNA molecules. These modifications prevent recognition and cleavage by these nucleases, thereby improving mRNA stability. Through extensive experimental exploration, InnoRNA has currently mastered an effective method capable of increasing the half-life of mRNA by more than four- to five-fold, achieving sustained in vivo expression.The ExNeo Nucleic Acid Modification Platform is InnoRNA’s core technology and a distinctive feature that sets it apart from other RNA-focused enterprises. This platform technology not only expands the application scenarios for mRNA therapeutics but also holds broad potential for enhancing already developed and applied pipelines. In the well-established field of mRNA infectious disease vaccines, ExNeo nucleic acid modification technology can significantly reduce the required dosage of current mRNA vaccines, thereby providing more cost-effective preventive solutions. In the realm of tumor vaccine therapy, the application of ExNeo technology can reduce dosing frequency and improve therapeutic efficacy. In protein replacement therapies, ExNeo technology demonstrates significant advantages by reducing dosage and lowering dosing frequency, thereby markedly improving patient adherence and delivering a better treatment experience. In frontier applications such as gene replacement therapy and reprogramming therapy, the high efficiency and sustained expression characteristics of ExNeo nucleic acid modification technology are poised to drive transformative advances.

RNA is composed of four nucleobases: A, U, C, and G. Due to the degeneracy of the genetic code, there are an astronomical number of possible mRNA sequence combinations that can encode the same protein. InnoRicon employs AI algorithms combined with experimental validation to comprehensively optimize mRNA codons and higher-order structures. This enhances ribosome binding efficiency, thereby promoting efficient translation and increased protein production. Furthermore, by rationally designing the higher-order structure of mRNA, the company reduces degradation caused by nucleases and mechanical shear forces during manufacturing, further improving stability and ensuring mRNA integrity both intracellularly and throughout industrial production processes.

Accurate identification of tumor neoantigens is critical for the development of neoantigen-based immunotherapeutic agents. Leveraging big data training and AI algorithms based on convolutional neural networks, Inoricon accurately calculates the binding affinity and presentation probability of antigenic peptides to HLA molecules, based on tumor cell mutations and patient HLA typing, thereby screening for neoantigens with high immunogenicity. These neoantigens can efficiently activate T cells, enhancing their ability to recognize and kill tumor cells, thus providing precise targets for personalized cancer immunotherapy and improving the efficacy of immune treatments.

Currently,InnoCare is advancing four pipelines targeting multiple indications, including cervical cancer, tumors prone to recurrence and metastasis, phenylketonuria (PKU), and anemia.

Since mRNA gained prominence during the COVID-19 pandemic, cancer immunotherapy has become one of the primary application areas for mRNA technology. Currently, multiple clinical trials of mRNA-based cancer therapeutic vaccines are underway globally, demonstrating remarkable efficacy in treating patients with pancreatic cancer, melanoma, and lung cancer.

InnoRican has developed a personalized mRNA cancer therapeutic vaccine based on its Nextfold sequence optimization platform and CapHLA neoantigen prediction platform. Employing newly designed linker sequences and a unique method for assembling tumor neoantigens, the candidate has completed preclinical candidate (PCC) molecule selection. According to the company, a single mRNA vector can accommodate the expression of up to 30 neoantigens, with each mRNA molecule optimized via the Nextfold platform to ensure efficient expression and presentation of tumor neoantigens. In an animal study using humanized mice, immunization with this mRNA vaccine significantly increased the number of tumor-infiltrating T cells and effectively elicited neoantigen-specific T-cell immune responses.

“The lethality of tumors lies in their recurrence and metastasis. Theoretically, if these two processes can be effectively prevented, surgical resection alone could achieve a cure. Our R&D efforts are focused on this objective, with the aim of expanding the indications of this drug to cover additional types of tumors.“said Dr. Wu Ligang.”

The candidate mRNA vaccine targeting cervical cancer and its precancerous lesions represents a potential best-in-class pipeline, with preclinical candidate (PCC) molecule development already completed. Dr. Wu Ligang stated, “The animal study results are highly promising. This nucleic acid molecule is currently the shortest known sequence internationally for a bivalent therapeutic mRNA vaccine against HPV16/HPV18-related cervical cancer. Preclinical data demonstrate that excellent antitumor efficacy can be achieved even at extremely low doses.”

In addition, InnoRNA is advancing two alternative therapy pipelines for phenylketonuria and anemia. “Beyond our R&D efforts in oncology, we are also committed to developing alternative therapies that leverage mRNA technology to enable endogenous synthesis of deficient metabolic enzymes or cytokines within patients. We have already completed the development of PCC molecules. Furthermore, we have established R&D pipelines targeting autoimmune diseases and fatty liver disease. Our mRNA therapies, developed based on the globally leading ExNeo nucleic acid modification platform for extended half-life, have demonstrated significantly superior efficacy data compared to competitors. We plan to engage in collaborative development or pipeline licensing agreements with overseas pharmaceutical companies. Cooperation with international industry leaders will accelerate research and regulatory approval processes, ensuring that patients worldwide can benefit from these treatments as early as possible,” stated Dr. Wu Ligang.

For growing Chinese biotech companies, collaborative development or licensing-out of pipelines to overseas enterprises has become an important strategic choice; meanwhile, as Chinese biotechs continue to achieve new breakthroughs, they have become highly sought-after partners and acquisition targets for overseas companies.

In 2024, InnoRegen stood out in the “Star Starting Point” program and claimed the top spot.The “Star Starting Point” program, jointly launched in 2022 by Novo Nordisk China R&D Center and ATLATL Innovation Center, aims to support high-potential, high-quality innovative projects. It is a key initiative by Novo Nordisk to strengthen collaboration with local innovation forces in China.

“One of the reasons semaglutide has become a global blockbuster drug is the technological improvements made to its long-acting formulation. At InnoCare Pharma, we also prioritize long-acting formulations as a key focus of our R&D efforts and have achieved critical breakthroughs in this area, which bolsters our confidence in pursuing deep collaborations with major pharmaceutical companies in the future,” said Dr. Wu Ligang.

It is undeniable that the innovative drug industry remains in the grip of a winter, and the mRNA sector faces numerous challenges. Whether it is the post-pandemic industry downturn or difficulties in advancing pipelines, these issues have become mounting “burdens” weighing on all entrepreneurs in the mRNA industry.

For Dr. Wu Ligang, who has dedicated many years to the RNA field, his scientific career has been marked by outstanding achievements: he has undertaken numerous research projects funded by the Ministry of Science and Technology, the National Natural Science Foundation of China, and the Shanghai Municipal Government; published more than 50 research papers in prestigious international journals; and holds over ten invention patents related to RNA technologies. Nevertheless, he resolutely transitioned into the industry after the so-called “dividend period” of technological development came to an end. His motivation extends beyond bringing advanced technologies to Chinese patients as early as possible; it is also driven by his fervent commitment to China’s scientific and technological innovation. “If scientists were to give up in the face of substantial challenges, the gap between us and overseas enterprises would continue to widen, and we would never become a leading force in international drug innovation.”

To accelerate the catch-up with overseas R&D progress, InnoRecon will increase its investments in talent acquisition, pipeline development, and technological innovation. Currently, Dr. Lin Yijun serves as Chief Scientific Officer, Dr. Zhang Ying as Chief Technology Officer, and Li Shengbin as Executive Deputy General Manager. With a ratio of employees holding master’s or doctoral degrees exceeding 70%, the company will continue to strengthen its talent team.

In terms of pipeline R&D and technological innovation, Inorecon will expedite the advancement of multiple candidate pipelines into clinical stages and continue to develop long-acting mRNA technology and targeting technologies to expand its pipeline of new candidates. Regarding funding, Inorecon secured tens of millions of yuan in angel-round investment from renowned investment firms shortly after its establishment and has built a 1,000-square-meter R&D facility. Currently, Inorecon has initiated a new round of financing.

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