Betting on in vivo CAR-T with AAV, "Westlake YunGu BioPharma" is about to launch an IIT study.

Text | Hu Xiangyun

Editor | Hai Ruojing

Recently, Eli Lilly, the "king of medicine" with a trillion - dollar market value, completed an acquisition worth $2.4 billion (over 16 billion RMB), which has redirected the pharmaceutical industry's attention back to the field of cell and gene therapy (CGT).

The acquired company, Orna Therapeutics, is mainly engaged in circular RNA research. Its core drug is an in - vivo CAR - T targeting CD19, which is about to enter the clinical trial stage. Compared with traditional CAR - T treatments that can cost millions of yuan per injection, in - vivo CAR - T is a cell therapy with the potential to be both effective and affordable. Some industry insiders believe that if in - vivo CAR - T can be developed into a drug in the future and mass - produced, its price could be similar to that of ordinary antibody products, which is expected to solve the long - standing commercialization problems of traditional CAR - T.

In 2025, four multinational pharmaceutical companies, Bristol Myers Squibb, AstraZeneca, AbbVie, and Gilead, successively acquired overseas in - vivo CAR - T startups, with a total transaction value of nearly $5 billion. Now, Eli Lilly's entry further injects certainty into the development prospects of this track.

Reflecting on the domestic market, according to an incomplete statistics by 36Kr, in the first four months of this year alone, domestic in - vivo CAR - T concept companies raised nearly 2 billion RMB in the primary market.

"Mergers and acquisitions rather than BD indicate that large pharmaceutical companies have regarded in - vivo CAR - T as the next - generation treatment platform technology, which also promotes the valuation logic of the entire field to shift from single - product to platform - based," said Ma Lijia, the founder of Westlake YunGu BioTech.

Ma Lijia was formerly a distinguished researcher at the School of Life Sciences of Westlake University. She moved her laboratory to Beijing Changping Laboratory at the beginning of this year. With a cross - disciplinary background in bioinformatics, molecular biology, and basic medicine, she has long been engaged in research on systems biology and functional genomics. After founding Westlake YunGu BioTech in 2021, the company has focused on the field of AI + gene therapy. It has self - developed an AI - driven AAV (adeno - associated virus) capsid protein evolution platform, AIdit - CAPSID, and has developed AAV - TCE001 for in - vivo CAR - T, as well as AAV variants targeting multiple tissues such as the central nervous system, muscles, and retinas.

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. In the past year or so, two mainstream development paths, lentivirus and LNP, have initially formed in the industry, and the acquisitions of five multinational pharmaceutical companies have also revolved around these. Due to the technical difficulties in 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 choose a different route?" However, as research deepens, "the AAV route has gradually gained industry attention and trust from a state of being questioned and non - consensus, which also brings the possibility of reallocating funds and clinical resources."

Notably, in late March this year, Azalea Therapeutics, an in - vivo CAR - T company founded by Nobel laureate and CRISPR co - inventor Jennifer Doudna, in collaboration with the Justin Eyquem team from the University of California, San Francisco (UCSF), published a study in Nature, stating that their self - developed EDV (enveloped delivery vehicle)/AAV dual - vector in - vivo CAR - T product achieved a "90% complete remission" in animal experiments, which to some extent endorses the AAV technical route. In November last year, Azalea Therapeutics completed an $82 million financing to promote the development of in - vivo CAR - T therapy.

"A 90% remission rate is a very good indicator that can support the industry to continue in - depth discussions on this technical route." Ma Lijia explained, "This study solves a key problem of in - vivo CAR - T products: achieving targeted delivery of T cells in the body and site - specific insertion of the CAR sequence into the genome to form in - vivo site - specific integrated CAR - T cells, rather than randomly inserting into the T - cell genome."

Ma Lijia believes that in - vivo CAR - T with strong targeting and site - specific integration "may be the ultimate form of anti - tumor products in this track." Because it avoids the safety risks of random integration and the pain points of unstable expression, it can upgrade in - vivo CAR - T from short - term effectiveness to a safe, long - acting, and industrializable technical route.

"The dual - vector technology is very novel. However, from the perspective of drug development, the dual - vector approach involves the technical and cost issues of how to make two vectors enter the same cell synergistically, which inevitably leads to a significant increase in dosage. At the same time, although AAV has had 8 new drugs approved globally and is a regulatory - recognized technical path, EDV, as a brand - new vector that has never been used in human trials, has uncertainties in future regulatory approval paths and large - scale production," Ma Lijia said.

It is reported that Westlake YunGu BioTech has a similar research logic to the Doudna/Justin team but uses only a single AAV vector and has also achieved a "remission rate of over 90% in animal experiments."

Taking the aforementioned AAV - TCE001 as an example: Early research data shows that AAV - TCE001 can efficiently transduce primary T cells, and its ability to infect human T cells is significantly better than that of wild - type AAV. The generated CAR - T cells can efficiently kill B cells. In addition, with the assistance of AI design, AAV - TCE001 has reduced liver accumulation by a hundred to a thousand times in mice and crab - eating macaques, greatly improving the safety of in - vivo gene therapy.

In February this year, Westlake YunGu BioTech, in collaboration with Westlake University, published a study titled An AAV variant enables human T cell engineering in vivo in the new domestic top - tier journal Vita. It introduced an AAV vector that can highly specifically target human T cells. In a humanized mouse model of systemic lupus erythematosus (SLE), an autoimmune disease, it achieved the generation of in - vivo CAR - T cells with a single injection, and the CAR - T level remained at a maximum of 77.5% six weeks after injection. In terms of efficacy, it can successfully clear pathogenic B cells and reverse organ damage such as lupus nephritis.

Ma Lijia also revealed that the company plans to initiate an IIT (Investigator - Initiated Trial) for in - vivo CAR - T this year. "The product characteristics of in - vivo CAR - T determine that it has a relatively high irreversibility after entering the human body, and due to its involvement with the immune system, the systemic risks are also more complex. Therefore, we prefer to advance clinical trials after the mechanism, safety, and dosage window design are relatively clear, and we will give priority to indications with controllable risks, such as autoimmune diseases."

Overall, in the past year or so, with the release of various pre - clinical data and merger and acquisition cases, the in - vivo CAR - T field is currently in a stage where multiple delivery paths are developing together.

"Some investment institutions and multinational pharmaceutical companies even invest in each platform when evaluating projects, which also proves that the industry is still in its early stage of development. There is no clear answer as to which platform will ultimately succeed. This stage greatly tests the in - depth understanding and data interpretation ability of the project operation team and investors in this field. There will also be some noise during the process. However, no matter which technical route is the first to succeed, this exploration of innovative therapies will ultimately translate into safer and more accessible treatment options, benefiting a large number of patients," Ma Lijia expects.