Advances in Humanized Models for Antibody Development

Humanized monoclonal antibodies, derived from fully human sequences or engineered to resemble human antibodies, have addressed critical challenges of immunogenicity seen with earlier antibody therapies.

THX Mice: First Mouse Model With Complete, Functional Human Immune System 

Researchers developed humanized TruHuX (THX) mice by grafting genetically myeloablated immunodeficient pups with human hematopoietic stem cells, followed by hormonal conditioning with 17β-estradiol to promote immune differentiation. 

Key features of THX mice include: 

• Development of human-like lymphoid structures, including lymph nodes and Peyer’s patches. 

• Functional human T and B cells capable of class-switch recombination, somatic hypermutation, and memory cell formation. 

• Neutralizing antibody responses to vaccines such as the Pfizer-BioNTech COVID-19 mRNA vaccine. 

These mice serve as an advanced platform for studying human immune responses, paving the way for the discovery of novel vaccines and therapeutics.¹

Humanized Mouse Models in Immuno-Oncology

Immuno-oncology has seen remarkable progress, yet understanding the complex interactions between human tumors and the immune system remains a challenge. Humanized mice co-engrafted with human tumors and immune cells offer a preclinical model to address these gaps. 

Applications in Immuno-Oncology: 

• Checkpoint Inhibitors and CAR-T Therapy: Humanized mice enable evaluation of immunotherapeutics, including their efficacy and mechanisms of action. 

• Biomarker Identification: These models help identify predictive biomarkers, improving patient stratification and therapy outcomes. 

• Patient-Derived Xenografts (PDX): Mice engrafted with matched patient tumors and immune cells offer insights into personalized therapeutic strategies. 

While these models have limitations, such as incomplete HLA compatibility and restricted development of innate immune cells, next-generation humanized platforms are addressing these gaps, further accelerating cancer immunotherapy research.²

Humanized Mice in HIV Research 

Despite advances in antiretroviral therapy, HIV-1 remains a chronic and incurable infection due to the persistence of viral reservoirs. To overcome the challenges in understanding HIV pathogenesis and developing new treatments, humanized mouse (Hu-mouse) models have emerged as a critical tool in HIV research. Hu-mice are immunodeficient mice engrafted with human immune cells or tissues. These models closely replicate human HIV infection, including immune response dynamics and disease progression. 

Key Advancements in Hu-Mouse Models for HIV: 

• Background Strains and Reconstitution: Variations in mouse strains and methods of immune cell reconstitution improve model fidelity, enabling more accurate studies of HIV infection mechanisms. 

• Engraftment Techniques: Use of human hematopoietic stem cells or tissue grafts allows tailored modeling of specific aspects of HIV pathogenesis. 

• Emerging Areas of Research: Hu-mice are now being used to explore HIV-mucosal infections, microbiota interactions, and HIV-TB co-infections, expanding the scope of HIV-related studies.³

Fully Human Antibodies: Revolutionizing Therapeutics 

Fully human antibodies have become a cornerstone in modern medicine, offering improved safety and efficacy in treating a wide range of diseases. Unlike traditional monoclonal antibodies derived from animal models, fully human antibodies are designed to minimize immunogenicity and adverse immune reactions, making them ideal for long-term therapies. Their development has been propelled by advanced technologies, including phage display, transgenic animal platforms, and humanized mouse models. These innovations not only enhance therapeutic capabilities but also enable deeper insights into human immune mechanisms.

Our High-throughput Fully Human Antibody Discovery Platform integrates Cyagen’s HUGO-Ab™ mice with Biointron’s AbDrop™ microdroplet-based single B cell screening. This powerful combination accelerates the discovery and development of fully human antibodies, reducing the time from target identification to therapeutic candidate to just three months. Learn more about the service here.

References:

1.  Chupp, D. P., Rivera, C. E., Zhou, Y., Xu, Y., Ramsey, P. S., Xu, Z., Zan, H., & Casali, P. (2024). A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses. Nature Immunology, 25(8), 1489-1506. https://doi.org/10.1038/s41590-024-01880-3

2. Chuprin, J., Buettner, H., Seedhom, M. O., Greiner, D. L., Keck, J. G., Ishikawa, F., Shultz, L. D., & Brehm, M. A. (2023). Humanized mouse models for immuno-oncology research. Nature Reviews Clinical Oncology, 20(3), 192-206. https://doi.org/10.1038/s41571-022-00721-2

3. Gillgrass, A., Wessels, J. M., Yang, J. X., & Kaushic, C. (2021). Advances in Humanized Mouse Models to Improve Understanding of HIV-1 Pathogenesis and Immune Responses. Frontiers in Immunology, 11, 617516. https://doi.org/10.3389/fimmu.2020.617516