Humanized mice and in vivo therapeutic production? This is not science fiction

Trastuzumab is a common treatment for various HER2-positive cancers.  It is an antibody that specifically binds to HER2, a problematic protein over-expressed on cancer cells that signals for nonstop cell growth and division. By binding HER2, trastuzumab blocks signaling and tags cancer cells for the immune system to attack.  Trastuzumab treatment is highly effective and boosts long-term survival rates but is logistically burdensome for patients. The treatment involves antibody infusions every 1-3 weeks, with each infusion lasting 30-90 minutes, usually for a full year.

Antibody therapies like trastuzumab are used to treat myriad cancers, autoimmune disorders, and infectious diseases. These therapies can be life-changing and lifesaving. But treatment regimens often require frequent infusions for the drugs to maintain their therapeutic benefit. The obstacle of appointment logistics limits both the accessibility and effectiveness of these therapies.

Engineered plasma cells (ePCs) present an appealing solution to this challenge by turning the body into a drug factory. Plasma cells are the immune system’s antibody production specialists. They have a long lifespan (a half-life of 11-200 years) and continuously produce massive quantities of antibodies (up to 10,000 per second!).  Each plasma cell produces a unique and specific antibody, that generally targets abnormal or foreign proteins. Most people don’t produce therapeutic antibodies on their own. However, scientists can engineer plasma cells that produce these antibodies and engraft them into a patient, potentially eliminating the need for burdensome infusion appointments. The engineered plasma cells could provide the patient a constant supply of their medicine.

Dr. Richard James at the Seattle Children’s Research Institute’s Center for Immunity and Immunotherapy and colleagues at the University of Washington and Fred Hutch Cancer Center are investigating engineered plasma cell therapies. Dr. James explained, “Engineered plasma cells offer a promising platform for long-term therapeutic antibody delivery, but existing preclinical models lack the human immune components necessary to study their in vivo biology, persistence, and function.” So ePCs are great in theory but there is no way to test if they’re also great in practice. 

Scientists rely on model systems to evaluate the biology and establish the effectiveness of potential therapies before conducting trials in human subjects. These models span from cells to organoid tissues to living animals. Not all models are created equal, and using a physiologically relevant model is essential for capturing results that are applicable to how a therapy functions in humans.

Plasma cells require signals from and interactions with other components of the human immune system to produce antibodies. Without a system that contains these components, there’s no way to know how human ePCs may behave when given to a human. Researchers investigating human ePCs face a conundrum: they need an non-human animal model that contains a human immune system.

In a recent study published in Molecular Therapy Advances, Dr. James and colleagues addressed this challenge by developing a humanized mouse model, harboring components of a human immune system. This involved engrafting human hematopoietic stem cells into NSG mice, an immunodeficient mouse strain. Over time, the stem cells differentiated into various human immune cells. By 10 to 12 weeks after stem cell transplant, the mice had all the human immune components necessary for plasma cell function, including cells like T cells and cytokine signaling molecules like B-cell activating factor (BAFF), IL-6, and IL-21.

To test the viability of the humanized mice as a model for ePC biology, the team administered ePCs expressing a luminescent reporter gene into the humanized NSG mice and control NSG counterparts. They measured radiance to detect the presence and localization of ePCs for 100 days following transplant. The results were promising – they found that that ePCs engrafted efficiently and durably in the humanized mice. The ePCs were abundant, and they distributed throughout the body, including to lymphoid tissues like the spleen. They also secreted human antibodies. 

Now equipped with a suitable model, the researchers tested whether the ePCs could produce therapeutic antibodies in practice. They engineered plasma cells that express AMMO1, an antibody known to bind to Epstein Barr Virus (EBV) and block it from infecting cells. They infused these cells into the humanized NSG mice and found that the mice did durably express the AMMO1 antibody, but at levels too low to prevent EBV infection.

The team tried again, this time generating ePCs with an antibody that binds to the spike protein of the SARS-CoV-2 virus. The ePCs successfully engrafted in the humanized mice and robustly produced the antibody for up to nine weeks. Blood serum from these mice, which contained high levels of the antibody, potently bound the spike protein and blocked SARS-CoV-2 from infecting cells.

These experiments establish that ePCs can successfully engraft and produce antibodies at therapeutic levels. The variability in success from the different ePC constructs highlights the need to learn more about ePC biology and optimize their function. But now an animal model exists to do just that.

Dr. James commented, “These findings prompt important questions about the specific human immune signals that support ePC survival and localization, and how this model might be adapted to evaluate ePC therapies for autoimmune disease, infection, or cancer in the presence of functional human immune responses.”  Perhaps one day it will be standard for people to receive antibody therapies continuously, not with endless infusions, but instead produced within themselves.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Andrew McGuire, David Rawlings, and Richard James contributed to this research.

The spotlighted research was funded by the National Institutes of Health, Seattle Children’s Research Institute Program for Cell and Gene Therapy, the Children’s Guild Association Endowed Chair in Pediatric Immunology, the Hansen Investigator in Pediatric Innovation Endowment, and Be Biopharma.

Hill TF, Helmers AE, Cheng RY-H, Singh S, Homad LJ, Narvekar P, Asher GD, Camp ND, Suchland ER, Ott AR, Hale M, Thouvenel CD, Stoffers CM, Lachkar S, McGuire AT, Rawlings DJ, James RG. 2026. Humanized mice enable in vivo evaluation of engineered plasma cell biology and therapeutic function. Molecular Therapy Advances. doi: 10.1016/j.omta.2026.201666