Westlake CloudValley Pharma to Initiate IIT for AAV-Based In Vivo CAR-T Therapy

Stock trading depends onGolden Qilin Analyst Report, authoritative, professional, timely, comprehensive, help you explore potential theme opportunities!

(Source: 36Kr)

Text｜Hu Xiangyun

Editor｜Hai Ruo Jing

Recently, the "drug king" Lilly, with a trillion-dollar market value, completed a $2.4 billion (over 16 billion RMB) acquisition, which has once again drawn the pharmaceutical industry's attention back to the cell and gene therapy (CGT) field.

Orna Therapeutics, the acquired company, mainly engages in circular RNA research. Its core drug is an in-vivo CAR-T therapy targeting CD19, which is about to enter the clinical trial stage. Compared with traditional CAR-T therapies that can cost millions per injection, in-vivo CAR-T holds the potential to become a "high-quality yet affordable" cell therapy. Some industry experts believe that if in-vivo CAR-T can eventually become a viable drug and achieve large-scale production, its price could be similar to that of ordinary antibody products, offering a promising solution to the long-standing commercialization challenges faced by traditional CAR-T therapies.

In 2025, four multinational pharmaceutical companies—Bristol-Myers Squibb, AstraZeneca, AbbVie, and Gilead—have successively moved to acquire overseas in vivo CAR-T startups, involving a total amount of nearly 5 billion US dollars. Now, Eli Lilly's entry further injects certainty into the development prospects of this track.

Reflecting on the domestic market in China, according to incomplete statistics from 36Kr, in just the first four months of this year, the financing amount for domestic in vivo CAR-T concept companies in the primary market has approached 2 billion RMB.

“M&A Rather Than BD Indicates That Large Pharmaceutical Companies Already Regard In Vivo CAR-T as the Next-Generation Therapeutic Platform Technology", also pushing the valuation logic of the entire field to shift from single products to platforms," said Ma Lijia, founder of Westlake Genetech.

Ma Lijia, formerly a specially appointed researcher at the School of Life Sciences of Westlake University, moved her lab to Beijing Changping Laboratory earlier this year. With an interdisciplinary background in bioinformatics, molecular biology, and basic medicine, she has long been engaged in systems biology and functional genomics research. After founding Westlake Genetech in 2021, the company has focused on the AI + gene therapy field, independently developing the AI-driven AAV (adeno-associated virus) capsid protein evolution platform AIdit-CAPSID. The company has also developed AAV-TCE001 for in vivo CAR-T applications, as well as AAV variants targeting multiple tissues including the central nervous system, muscles, and retina.

The core of developing in vivo CAR-T products lies in the delivery vector tools targeting T cells, that is, how to stably and efficiently deliver the CAR gene into the human body. Over the past year, the industry has preliminarily formed two mainstream development paths: lentivirus and LNP, with five multinational pharmaceutical companies’ acquisitions revolving around these. Due to the technical difficulty of modifying AAV vectors for T-cell-specific targeting, not many companies have chosen the AAV route.

Ma Lijia admitted that she has been repeatedly asked, "Why did you choose a different path?" However, as the research deepened, "the AAV route has gradually gained industry attention and trust from its previously questioned and non-consensus state, which also brings possibilities for the reallocation of funding and clinical resources."

Notably, in late March this year, Azalea Therapeutics, an in vivo CAR-T company founded by Nobel laureate and co-inventor of CRISPR Jennifer Doudna, collaborated with Justin Eyquem's team from the University of California, San Francisco (UCSF) to publish a study in Nature. The study reported that their self-developed EDV (Envelope Delivery Vehicle)/AAV dual-vector in vivo CAR-T product achieved "90% complete remission" in animal experiments, providing some endorsement for the AAV technology platform. In November last year, Azalea Therapeutics completed an $82 million financing round to advance the development of in vivo CAR-T therapies.

“A 90% remission rate is a very good indicator that supports further in-depth discussion of this technical route within the industry.Ma Lijia explained: "This study addresses a key issue with in vivo CAR-T products: achieving targeted delivery of T cells and site-specific insertion of the CAR sequence into the genome, forming site-specific integrated CAR-T cells in vivo rather than random insertion into the T cell genome."

Ma Lijia believes that in vivo CAR-T with strong targeting capabilities and the ability for site-specific integration "might be the ultimate form of anti-tumor products in this field." This is because it avoids the safety risks associated with random integration and the pain point of unstable expression, allowing in vivo CAR-T to evolve from being effective in the short term to becoming a safe, long-lasting, and industrializable technological pathway.

"The dual-vector technology is very novel. However, from the perspective of drug development, the dual-vector approach involves technical and cost challenges in ensuring that both vectors enter the same cell cooperatively, inevitably leading to a significant increase in dosage. Meanwhile, although AAV has been approved for eight new drugs globally and is a regulatory-accepted technological pathway, EDV, as an entirely new vector that has never been used in human trials, faces uncertainties in future regulatory approval pathways and scalable production," said Ma Lijia.

It is reported that Westlake Genetech's research logic is similar to that of the Doudna/Justin team, but it only uses a single AAV vector and has also achieved "an alleviation rate of over 90% in animal experiments."

Taking AAV-TCE001 as an example: Early research data shows that AAV-TCE001 can efficiently transduce primary T cells, with a significantly higher ability to infect human T cells compared to wild-type AAV, and the generated CAR-T cells can effectively kill B cells. Moreover, with the assistance of AI design, AAV-TCE001 reduced liver accumulation by a hundredfold to a thousandfold in mice and crab-eating macaques, greatly enhancing the safety of in vivo gene therapy.

In February this year, Westlake Genetech, in collaboration with Westlake University, published a study titled "An AAV variant enables human T cell engineering in vivo" in the Chinese top journal Vita. The study introduced an AAV vector capable of highly specific targeting of human T cells. In a humanized mouse model of the autoimmune disease systemic lupus erythematosus (SLE), it achieved in vivo CAR-T cell generation with a single injection and maintained up to 77.5% CAR-T levels six weeks post-injection. In terms of efficacy, it successfully eliminated pathogenic B cells and reversed organ damage such as lupus nephritis.

According to Ma Lijia's revelation,The company plans to launch an IIT (Investigator-Initiated Trial) for in vivo CAR-T within this year."The product characteristics of CAR-T in the body determine its high irreversibility after entering the human body, and since it involves the immune system, the systemic risks are also more complex. Therefore, we tend to advance to clinical trials only after the mechanisms, safety, and dose window design are relatively clear, and we prioritize indications with controllable risks, such as autoimmune diseases."

Overall, in the past year or so, with the publication of various preclinical data and acquisition cases, the in vivo CAR-T field is currently in a stage of co-development through multiple delivery pathways.

"Some investment institutions and multinational pharmaceutical companies will even invest in each platform when evaluating projects. This also proves that the industry is still in its early stages, and there is no clear answer as to which platforms will ultimately succeed. This phase particularly tests the project team's and investors' deep understanding of the field and their ability to interpret data. There will be noise along the way, but regardless of which technical route succeeds first, this exploration around innovative therapies will ultimately translate into safer and more accessible treatment options, benefiting a wide range of patients," Li Jia Ma said with anticipation.