Immunocan Announces Two IND Projects Within Days of Launching Its Full-Length Human Antibody Mouse Platform

HBM Holdings’ proactive strategic shifts this year have drawn significant attention at every step. Notably, its newly established strategic business pillar—its wholly owned subsidiary, Noona Biotech—has secured collaborations within just two months with Moderna, Dragonfly Therapeutics (a rising star in the NK cell field), and Kelun-Biotech (a domestic leader in the ADC space). This also raises the question:Why Is the Fully Human Antibody Animal Platform So Highly In Demand?

An analysis of the current landscape of antibody drug development reveals that fully human antibodies are gradually becoming the mainstream, with animal platforms for generating such antibodies being widely adopted. Data show that as of February 2021, among the more than 100 antibody drugs approved by the U.S. Food and Drug Administration (FDA), 39 were fully human antibodies, nearly 70% of which were developed using transgenic mouse platforms.

Although the construction of fully human antibody animal platforms presents significant technical and resource barriers—with establishing a mouse platform alone taking an average of 5–6 years—numerous well-capitalized companies in China, such as Harbour BioMed, Genmab, and Biocytogen, are actively advancing their efforts in this field.

Notably, just last month, industry rising star Immunocan officially launched its fully human antibody mouse platform built on single-step megabase-level gene replacement technology. Within just over 10 days of the announcement, the company has signed two IND projects. It is understood thatThe platform was constructed in just 18 months, yielding a murine animal platform that harbors fully orthotopically replaced human immunoglobulin variable region coding sequences and cis-regulatory elements.

Immunocan was founded by Dr. Zhou Changyang and Dr. Zhang Jiwei.Dr. Changyang Zhou is currently a Young Principal Investigator at the Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, and serves as the Group Leader of the Gene Editing and Functional Screening Research Group. His work focuses on the development of gene-editing tools and gene-editing therapies. He previously conducted research in Dr. Hui Yang’s laboratory at the Institute of Neuroscience, Chinese Academy of Sciences. Dr. Jiwei Zhang completed his postdoctoral fellowship at The University of Texas MD Anderson Cancer Center and has long been dedicated to the pharmacological study of monomeric drugs for anti-tumor therapy.

What is the current state of research on fully human antibody animal platforms? What are the key challenges? Where do future development directions lie? How has Immunocan emerged as a breakthrough in overcoming technical barriers?To gain insights into these topics, VCBeat New Medicine interviewed Dr. Zhang Jiwei, Founder and CEO of Immunocan, at the 2023 New Year Gathering hosted by the New Drug Founders Club.

VCBeat New Medicine: Immunocan publicly released its fully human antibody mouse platform on December 3. As of now (December 16), has the company engaged in partnership discussions with any enterprises?

Zhang Jiwei:For biotech firms, biopharmaceutical companies, and certain multinational corporations (MNCs), we currently employ two business models: collaborative R&D and platform licensing. Following our official announcement on December 3, 2022, and the subsequent reposting of our article by the New Drug Founders Club’s WeChat official account on December 5, we initiated discussions with several biotech and biopharmaceutical companies. To date, we have signed agreements for two Investigational New Drug (IND) projects. We will continue to accumulate further data to facilitate strategic collaborations.

VCBeat New Medicine: How many companies in the market possess a fully human antibody mouse platform? Which platforms are the most widely used?

Zhang Jiwei:Currently, there are 10 similar companies on the market. Among them, Kymab from the UK (now acquired by Sanofi) and Regeneron from the US are globally recognized as the best platforms in terms of technology and drug discovery efficacy.

VBInsight: Why Do Existing Mouse Platforms on the Market Take an Average of 5–6 Years to Build?

Zhang Jiwei:The mouse platform relies on BAC (bacterial artificial chromosome) vectors for fragment insertion, with a maximum capacity of 300 kb per insert. Given that the total size of the human IgG gene locus is 3.4 Mb, sequential replacement steps are required. This process involves dozens of gene replacement operations in embryonic stem cells, entailing a substantial workload and a high risk of failure.

Both platforms mentioned above adopt this approach. Each replacement step must be performed in embryonic stem cells (ESCs). Since ESCs cannot withstand multiple rounds of genetic replacement, the ESCs are differentiated into mice during the replacement process; subsequent genetic replacement steps are then carried out after re-establishing ESC lines from the fertilized eggs of these mice. The entire process requires more than a dozen steps, with each step taking at least six months. Any failures along the way further prolong the development timeline. Consequently, when Regeneron was building its fully humanized mouse platform, a professor at Harvard Medical School led a team of 20 postdoctoral researchers and spent over six years completing the platform’s construction.

VCBeat New Medicine: How Did Immunocan Complete Its Launch in 18 Months?

Zhang Jiwei:Immunocan leverages its proprietary MASIRT^®Technology: Using linear artificial chromosomes for delivery increases the upper limit of gene loading per instance and reduces the number of loading cycles.Through MASIRT^®Each technical replacement requires only 3–6 months, and can accommodate gene fragments ranging from 1 MB to 5 MB in size.Human IgG genes are located on three chromosomes: IgH, IgK, and Igλ, with sizes of 1 Mb, 1.6 Mb, and 0.8 Mb, respectively. We first performed sequential in situ replacements in three individual mice. Following the replacements, these mice were crossbred, and subsequent screening yielded a homozygous fully humanized mouse platform. The entire process took 18 months.Meanwhile, because we manipulate zygotes directly and do not rely on the pluripotency of embryonic stem cells, we can achieve cross-species replacement of ultra-large DNA fragments in multiple species.

VBInsight: Did you also encounter the issue of low loading efficiency during the development of the mouse platform?

Zhang Jiwei:We first performed in situ replacement of the heavy chain (H chain), followed by replacement of the light chains, specifically the kappa (κ) and lambda (λ) chains. During the initial phase of heavy chain replacement, we encountered low vector efficiency; due to the large size of the replacement fragment, the positive rate was particularly low, at only 1%–2%. Subsequently, our R&D team continuously refined the technology, increasing the positive rate to approximately 5% during light chain replacement. This has also accumulated relevant experience for the future development of a fully human antibody rabbit platform, and we believe that the establishment of this rabbit platform will proceed more smoothly.

VBInsight: How much has the efficiency issue of fully human antibody animal platforms been resolved in recent years, and how is the technical stability?

Zhang Jiwei:In 1994, scientists realized that by replacing mouse gene sequences with human counterparts and then immunizing the animals to generate human-sequence antibodies, there would be no need for subsequent humanization of mouse antibodies. However, gene-editing technologies available today were not yet developed at that time. Using conventional transgenic techniques, only very small DNA fragments—less than one-tenth of what is achievable now—could be replaced. Although desired antibodies could still be identified, the success rate was extremely low, requiring substantial workload. With continuous advancements in biotechnology, Kymab and Regeneron began building their fully human antibody animal platforms around 2006 and largely completed them by approximately 2012, progressing at a similar pace. These fully human antibody animal platforms quickly gained industry attention and recognition, prompting many other companies to enter the field, which led to some improvements in efficiency. Nevertheless, most approaches still relied on random insertion via transgenesis, enabling the identification of some antibodies but offering limited stability.

VBInsight: Leveraging Existing Animal Platforms, How Does Immunocan Plan to Conduct Platform Validation?

Zhang Jiwei:In the early stages, we focused on platform validation, primarily targeting well-known targets that are already on the market or about to be launched. This approach allows for comprehensive, multi-dimensional head-to-head data comparisons to establish the superiority of our platform. Preliminary data have met our expectations, robustly confirming the capability of our fully human mouse platform to generate high-quality antibodies and providing solid reference data for our partners.

VCBeat New Medicine: How Do Investors Evaluate the Value of Fully Human Antibody Mouse Platform Projects?

Zhang Jiwei:First, Immunocan’s fully human antibody animal platform holds complete intellectual property rights. Second, our technology enables ultra-large fragment gene replacement across multiple species. Currently, there is no global platform for fully human rabbits that achieves complete in situ replacement; however, this is realized through Immunocan’s MASIRT.^®With this technology, we can rapidly establish other animal platforms. Therefore, investors are not only bullish on our mouse platform but also on our subsequent fully humanized rabbit and alpaca mouse platforms. Although we are not currently raising funds and the market is experiencing a capital winter, we have still received significant unsolicited interest from investors.

VBInsight: The biopharmaceutical industry currently has higher requirements for drug quality. In this context, how do you assess the market potential of fully human antibody animal platforms?

Zhang Jiwei:China has introduced relevant policies requiring that new drugs must demonstrate superiority over already marketed drugs in head-to-head comparisons before they can be approved for market entry. Under these circumstances, biotech companies can no longer secure financing merely by developing “me-too” or “me-better” drugs; instead, they must provide robust head-to-head comparative data. Compounded by the current capital winter and the high costs associated with pipeline advancement, stakeholders are exercising greater rigor in selecting sources for antibody sequence discovery.

In other words,It is essential to identify the highest-quality candidate molecules right from the outset.. Previously, antibody drugs were developed by immunizing wild-type mice followed by humanization engineering. This approach tends to induce anti-drug antibodies (ADA), which is a major cause of compromised therapeutic efficacy of antibody drugs. Therefore, an increasing number of pipeline developers seek to conduct immunogenicity risk assessment during the early discovery phase of antibody drug development to mitigate R&D risks.The fully human antibody animal platform is currently the most advantageous platform for antibody discovery, with relatively lower subsequent development risks.. Amid the trend toward greater rationality in national industrial promotion and more prudent investment attitudes, the industry will attract increased attention.

VBInsight: From what dimensions do you think the quality of a mouse platform can currently be evaluated?

Zhang Jiwei:There are three key criteria.First, replacement of the complete IgG gene sequence is the basis for providing more diverse amino acid sequences. Second, in situ replacement is an important condition for stable inheritance in mice. Third, whether the mice exhibit immune responses comparable to those of wild-type mice.The most fundamental criterion for evaluating the quality of a mouse platform is its ability to achieve complete gene replacement. Currently, most platforms on the market offer only incomplete replacement. The more complete the replacement, the greater the diversity of humanized antibodies that can be generated, which serves as a critical benchmark for assessment.

Additionally, it is important to determine whether orthotopic replacement is employed. Orthotopic replacement ensures stable inheritance; however, most platforms currently available on the market still adopt a random insertion strategy, which involves randomly inserting human sequences into mouse chromosomes and then knocking out the corresponding mouse genes. This approach exhibits poor genetic stability.

The immune response in mice is also critical. Immunocan’s ImmuMab mouse exhibits immune cell characteristics comparable to those of wild-type mice and demonstrates immune responsiveness on par with wild-type counterparts. It is capable of generating antibodies with high serum titers and a high proportion of positive antibodies, thereby facilitating the development of high-quality candidate antibody molecules.

VBInsight: Why Are Researchers Turning to Rabbit and Alpaca Mouse Platforms After the Mouse Platform?

Zhang Jiwei:For certain diagnostic antibodies or sequences such as CAR-NK and CAR-T, drug discovery using fully human mouse platforms is entirely feasible. However, for targets with high affinity and low sensitivity, the rabbit platform plays a critical role. For antibody-drug conjugates (ADCs) and bispecific antibodies, alpaca-mouse platforms or common light chain platforms are required.

The advantages of the fully human antibody rabbit platform are unmatched by mice. First, the rabbit spleen is ten times larger than that of mice, offering significantly greater antibody diversity. Second, rabbit antibodies exhibit excellent specificity, with affinity constants in the 10^-12approximately, whereas mice can only reach 10^-9. Furthermore, rabbits possess a natural advantage: their antibodies can recognize both murine and human targets. Therefore, during subsequent drug validation of antibody sequences discovered via the rabbit platform—particularly in pharmacological studies conducted in mice—there is no need to generate humanized target knock-in mouse models. Pharmacological evaluation can be performed directly, significantly reducing the time and workload required for downstream development.

Arterial New Medicine: Will There Be Any New Challenges in Building an Alpaca-Mouse Platform?

Zhang Jiwei:Currently, the animal platform for nanobody development primarily relies on alpacas; however, this approach is costly. The price of a single alpaca exceeds RMB 30,000, with daily feeding expenses ranging from RMB 60 to 100. Furthermore, each round of aggregated immunization requires at least 10 mg of protein antigen, resulting in substantial demand and posing a significant cost challenge.

VCBeat New Medicine: How to Control the Cost of the Alpaca Mouse Platform? How Long Does It Take to Build This Platform?

Zhang Jiwei:Immunocan’s alpaca-mouse platform is highly cost-controllable. During the initial development of its fully humanized mouse platform, heavy-chain replacement was a time-consuming process, through which the company accumulated substantial expertise; consequently, the current engineering efficiency is significantly higher. In collaboration with partners that provide alpaca cells, Immunocan loads the alpaca heavy chain onto linear artificial chromosomes for large-fragment gene replacement, thereby substituting the variable region sequences of the mouse antibody heavy chains with alpaca-derived sequences. This approach enables rapid platform establishment, with the alpaca-mouse platform expected to be available by July or August 2023. Upon successful development, this platform will essentially replace the role of alpacas in nanobody R&D, substantially accelerating the progress of nanobody-based drug development.

Artery New Medicine: What do you think will be the future development direction of fully human antibody animal platforms?

Zhang Jiwei:The future is likely to see a trend toward multi-platform integration, including fully humanized mouse platforms, alpaca-mouse hybrid platforms, and fully human antibody rabbit platforms. Different customized platforms are required for the discovery of drugs intended for different applications.In addition to having completed the development of its fully human antibody mouse platform, Immunocan is currently building an alpaca-mouse platform and a fully human antibody rabbit platform.