Recently, a breakthrough result was achieved in an IIT clinical study of Leman Biotech’s metabolically enhanced CD19 CAR-T injection, with the first patient achieving complete remission after treatment at a very low dose. The results received widespread attention from medias and investors, and the co-founder of Leman Biotech was interviewed by media “Intellectual Medicine Bureau” to share the specifics of the clinical study and how AI can be incorporated into next-generation solid tumor CAR-T design as the follows.
T-cell Exhaustion poses a significant challenge in tumor immunotherapy. As crucial immune cells, T cells can become exhausted during the battle against tumor cells, leading to a loss of control in monitoring tumors. This exhaustion greatly affects the efficacy of CAR-T therapies, potentially resulting in reduced effectiveness and tumor recurrence. Particularly in solid tumors, limiting the application of CAR-T treatment.
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In May 2021, Professor Li Tang and his team from the Swiss Federal Institute of Technology Lausanne (EPFL) developed the "Meta 10 technology." This innovative approach to tumor immunotherapy focuses on metabolic reprogramming to reactivate terminally exhausted T cells, thus unlocking the significant potential for multiple immunotherapies, including potential treatments for solid tumors.
Building on this breakthrough, Professor Li Tang and Dr. Yugang Guo co-founded Leman Biotech in July 2021. Leman Biotech is an innovative drug discovery company that combines "immune metabolic reprogramming + artificial intelligence." Just six months later, the company secured nearly $11 million USD in funding of angel round and established its research facilities.
Recently, Leman Biotech announced a significant milestone: the successful treatment of the first patient in an investigator-initiated clinical study (IIT) using the metabolism-enhanced CD19 CAR-T injection (Meta10-19). The treatment on the first patient achieved complete remission, allowing the patient to be discharged from the hospital. Notably, the treatment utilized a considerably lower dosage of the novel CAR-T injection compared to conventional therapeutic doses for similar indications.
The success of the first patient holds tremendous significance for Leman Biotech. Dr. Yugang Guo, co-founder of Leman Biotech, participated in an interview with media Intellectual Medicine Bureau to discuss the groundbreaking clinical results. He shed light on the clinical study and highlighted the integration of artificial intelligence in the design of next-generation CAR-T therapies for solid tumors.
Dr. Yugang Guo, currently a researcher in Zhejiang University School of Pharmacy's Hundred Talent Program and CEO of Leman Biotech, obtained his undergraduate and PhD degrees from the University of Science and Technology of China. From 2017 to 2022, he served as a Scientific Collaborator at the Swiss Federal Institute of Technology Lausanne (EPFL). In February 2022, Dr. Yugang Guo returned to China and played a pivotal role in establishing Leman Biotech. Within a year, he assembled a highly skilled and efficient R&D and operations team of 16 individuals, a remarkable achievement considering the company's humble beginnings with just one team member. Notably, 70% of the high-level R&D staff come from prestigious universities, both domestic and international, and possess substantial experience in industrialization.
Q: What is the significance of the successful treatment of the first patient with Meta10-19 CAR T cell therapy?
Dr. Guo: The success of the first patient receiving Meta10-19 CAR T cell therapy holds significant implications for Leman Biotech. Firstly, the clinical trial aimed to assess the safety of the metabolism-enhanced CAR-T platform, and the results demonstrated the excellent safety profile of the Meta10 platform. Throughout the treatment, there were no adverse effects of fever, cytokine storm, or neurotoxicity caused by the therapy.
Moreover, the efficacy of Meta10-19 therapy surpassed expectations. Administering the therapy at a particularly low dose, we did not anticipate such robust effectiveness. The clinical results from the first patient, combined with previous animal studies, further reinforced our understanding of the potential of metabolism-enhanced CAR-T. It confirmed our belief that Meta10-19 exhibits enhanced cell expansion capability and superior tumor-killing activity.
Q: How does Leman Biotech's metabolic reprogramming technology differ from conventional CAR-T technology?
Dr. Guo: Currently, Leman Biotech is the first company globally to apply metabolic reprogramming to CAR-T therapy for tumor immunotherapy, with our core technology being Meta10. The primary distinction from conventional CAR-T therapy lies in the notably superior efficacy we achieve, often resulting in 100% complete cure in animal experiments.
While T cells can successfully eliminate a few tumor cells consecutively, the task becomes challenging and burdensome when faced with hundreds or thousands of tumor cells. In such scenarios, T cells exhaust and become incompetent, losing control over tumor growth.
Essentially, our anti-T-cell exhaustion strategy manifests in two aspects. Firstly, through metabolic reprogramming, T cells enhance oxidative phosphorylation metabolism, enabling continuous proliferation. Secondly, they not only sustain a proliferative state but also maintain superior killing activity. Thus, T cells subjected to metabolic reprogramming using our technology can overcome exhaustion.
Based on our validation, Meta10 technology seamlessly complements various existing tumor immunotherapies, particularly T-cell-based therapies. Therefore, this technology has immense potential to serve as a platform that significantly enhances the efficacy of therapeutic approaches like CAR-T, TCR-T, TILs, and immune checkpoint antibodies.
Q: The dosage for the first patient was only 5% compared to commercially available conventional CD19 CAR-T. Have you measured the impact of this reduced dose on manufacturing cycle time and therapy cost?
Dr. Guo: While we haven't conducted detailed calculations on the manufacturing cycle yet, it's important to note that any changes to the process would require subsequent manufacturing protocol optimization. However, I can mention that Meta 10 CAR T cell culture time has been significantly reduced, now requiring only 2 to 3 days instead of the conventional 14 days. Regarding manufacturing cost, we have made preliminary estimates, and we expect to control it within 100,000 CNY. This suggests that the future price of our Cell therapy may not exceed 300,000 CNY, making it highly promising for potential medical insurance reimbursement in China and worldwide.
Q: How does the company plan to proceed with Meta10-19 in the future?
Dr. Guo: Our future plans for Meta10-19 do not involve commercializing it independently, as we recognize our strengths and focus. Additionally, CD19 was chosen because it has been extensively studied, and there are already several drugs available on the market. Our intention is to license out this drug, and we are currently in discussions with companies that have an interest in CAR-T development for hematological tumors.
Q: Besides hematology, what other areas does the company plan to prioritize in the future? Could you provide information about the current pipeline?
Dr. Guo: Moving forward, Leman Biotech's strategic goal is to leverage our core technology, Meta 10, to develop innovative approaches for solid tumors. This will be our primary focus in the future.
At present, the company has three major pipelines: the biomolecule pipeline, the metabolism-enhanced CAR-T pipeline, and the AI super factor pipeline. The biomolecule pipeline is progressing well and has already entered the CMC stage.
Regarding the cell therapy pipeline, it is divided into three parts. Firstly, we are personally involved in the metabolism-enhanced CAR-T pipeline to validate the feasibility of the concept, including safety and efficacy evaluations. Secondly, we are collaborating with leading companies in the TCR-T and TILs pipeline to incorporate our Meta 10 technology into their cell therapy products. This collaboration aims to expedite the development of cell therapies for solid tumors. Lastly, in the AI pipeline, we are utilizing high-precision computational chemistry and state-of-the-art artificial intelligence algorithms to optimize super factors, and we have made significant progress in this area.
Our ultimate objective is to develop therapies for solid tumors, aligning with our focus on leveraging Meta 10 technology to address this significant medical challenge.
AI is significant for next-generation platforms
Q: Leman Biotech is an AI+metabolic reprogramming company, what are the practical applications of AI in CAR-T therapy or tumor immunity?
Dr. Guo: Initially, I was skeptical about the practical applications of AI in immunology research. However, through our deep collaboration with XtalPi, my perception has completely changed. The development of the AI superkine pipeline has yielded remarkable results and convinced me of the tremendous potential of AI.
XtalPi also applies AI algorithms to antibody design, with different optimization targets compared to other market companies. Utilizing AI to develop a novel antibody that specifically recognizes mutant antigens on tumor cell surfaces while differentiating them from wild-type antigens on normal cell surfaces. The team is currently working on optimizing antibody sequences and binding epitopes using AI, which can be applied to solid tumor CAR-T therapies.
The practical applications of AI algorithms extend beyond antibodies. They can optimize individual components of CAR-T therapies to enhance efficacy and specificity. Moreover, AI algorithms have the capacity to learn the effects of combinations between individual components, guiding the design of new and more effective CAR-T combinations. Similar applications can be extended to other tumor immunotherapies.
Q: Leman Biotech and XtalPi have an in-depth collaboration. Can you highlight some aspects of this collaboration?
Dr. Guo: Our collaboration with Xtalpi primarily focuses on the development of the AI superkine pipeline. This pipeline draws inspiration from the work of Professor Christopher Garcia's group at Stanford University, particularly their structure-based optimization of IL-10 sequence published in Science.
Professor Christopher's work on IL-10 involved wet laboratory experiments, limited in their ability to modify a few specific sites. We contemplated whether we could employ high-precision computational chemistry and AI algorithms to systematically modify and optimize IL-10 instead of relying solely on wet lab experiments. This led us to collaborate with XtalPi to advance this pipeline.
Initially, with limited available data, we performed the first round of corrections and calculations, which only slightly outperformed Stanford's Super 10 after initial screening. We provided the feedback, to the computational team for further iteration.
In the second iteration, we obtained several thousand mutants with significant improvements in affinity. Subsequently, 20 mutants were selected for analysis and testing, and among them, several candidates exhibited hundreds or even thousands of times higher affinity compared to Stanford's Super 10. The iterative process was remarkably fast, taking less than a month. The experimental validation process is ongoing.
Through this collaboration, my perception of AI has undergone a significant transformation. I now recognize its great potential and efficiency, which are difficult to achieve through conventional wet experiments alone.
Q: Since Meta10-19 developed from laboratory experiments, what is the role of AI in the company's strategy?
Dr. Guo: Indeed development of Meta10-19, an improved CAR-T therapy based on preclinical results originating from lab experiments. However, AI plays a crucial role in our company's strategy. By combining AI technology with our autonomous metabolic enhancement platform, we aim to build the second generation of the Meta 10 platform at Leman Biotech.
There are two primary reasons for incorporating AI into our strategy. Firstly, the existing Meta10 has some limitations, and we strive to enhance its therapeutic potential through AI-driven optimizations. Secondly, once our research or clinical results are officially announced, we anticipate a significant interest from other companies. To maintain our technological advantage, we aim to develop a second-generation product that surpasses the first, thereby raising the technological bar for our company. The highlight of our second-generation product at Leman Biotech is its optimized metabolic regulator, which poses a significant challenge.
Q: Cell therapy has been controversial recently, with big pharma turning to it, biotech laying off staff, and concerns about its expensive and narrow applications. What are Dr. Guo's thoughts on this?
Dr. Guo: This is an excellent question. Personally, I believe the main reason for the controversy surrounding cell therapy is the lack of truly innovative technologies and new drugs in big pharma and some biotech companies. As a result, they resort to conventional targets like CD19 CAR-T. However, in the long term, companies realize that making new breakthroughs in this field may be challenging in the short term. Consequently, some companies voluntarily adjust their strategies and withdraw their pipeline.
Once new breakthroughs in technology and theory emerge, the big pharmaceutical companies will likely return to explore truly innovative technologies. Our Meta 10 technology, which regulates end-depleted T cells, holds substantial potential as a breakthrough point for the next generation of tumor immunotherapy. If we succeed in our endeavors, it is possible that related companies will re-enter this field.
Q: What kind of development plan does the company have for the next 1-3 years?
Dr. Guo: In the immediate future, our plan is to select 1-2 metabolism-enhanced CAR-T therapies for solid tumors to enter clinical trials. We will proceed after completing a certain number of investigator-initiated clinical trials. Over the next 1-3 years, we will continue advancing the clinical development of three pipelines: macromolecules, cell therapy, and AI superkines.
Once significant progress is achieved, we intend to initiate global multi-center clinical studies in Europe or US. However, this is a costly process, so we will confirm the results repeatedly in China before embarking on global multi-center trials.
The core technologies, including the Meta 10 metabolism-enhancing platform, have been initially developed. The company's AI research and development are being conducted in collaboration with XtalPi, an industry leader. For other corresponding standardized R&D activities, we rely on experienced CDMO (Contract Development and Manufacturing Organization) or CRO (Contract Research Organization) companies that can standardize and expedite the preclinical and clinical phases of our projects. Our future focus will be on applying the core platform technology to different T-cell therapies and various large molecule drugs.
