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GEMMs with Human Gene Targets
Optimizing Translational Relevance
GEMMs with human gene targets represent a key evolution in preclinical research. These models combine the sophistication of genetically engineered mice with the ability to express specific human proteins that serve as drug targets. Specifically, they are tumor transplants derived from original GEMMs, but engrafted into mice that have been genetically modified to «humanize» certain proteins or genetic loci. This enables drugs targeting human proteins, such as monoclonal antibodies or CAR-T cell therapies, to effectively interact with their targets in a mouse model.
Bridging Mouse Biology and Human Therapeutics
The fundamental objective of these models is to create an in vivo environment where therapies targeting human proteins can be evaluated in a relevant and precise manner. By expressing human targets in the mouse, the species-specificity barrier that often limits the translatability of preclinical models is overcome. This is especially critical for the development of biological drugs that require specific recognition of human proteins for their function.
Development of Targeted and Cellular Therapies
Evaluating Human Target-Directed Therapies
They enable testing the efficacy and safety of monoclonal antibodies, small molecule drugs, and other therapies that act on specific human proteins.
Myeloma and Lymphoma Research
They provide advanced platforms for studying responses to new therapies in these hematological cancers.
Autologous/Allogeneic Transplantation Studies
They are valuable tools for investigating the efficacy of transplantation strategies and the interaction between transplanted cells and the tumor microenvironment.
Research with Genome-Edited Stem Cells
They facilitate the study of therapies based on genomic editing of stem cells, allowing evaluation of their integration and function in a tumor context.
Available Humanizations (Targets for Myeloma and Lymphoma)
BCMA + CD3ε + CRBN (Myeloma)
Mice expressing BCMA (B-cell maturation antigen), a key target for myeloma therapies like CAR-T. The addition of CD3ε (a component of the TCR complex) and CRBN (Cereblon, a target of IMiDs) allows for a comprehensive evaluation of therapies acting on these pathways.
GPRC5D (Myeloma – endogenous or neutral H11 locus)
Expression of GPRC5D, another emerging target in multiple myeloma. This can be achieved through its endogenous expression or by inserting it into the neutral H11 locus, which allows for controlled expression without affecting important adjacent genes.
CD38 (inserted in H11 locus – Myeloma)
Expression of CD38, a cell surface protein widely used as a target in myeloma therapies, inserted into the H11 locus for stable expression.
CD19 & CD20 + CD3ε/CRBN (Lymphoma)
For lymphoma, CD19 and CD20 targets are expressed, which are fundamental for B-cell therapies. The inclusion of CD3ε and/or CRBN allows for the evaluation of combined or bimodal therapies.
CRBN + FcγR (Myeloma and Lymphoma)
Expression of CRBN and FcγR (Fc gamma receptors). CRBN is the target for IMiDs (such as lenalidomide), while FcγRs are crucial for the activity of monoclonal antibodies that mediate antibody-dependent cell-mediated cytotoxicity (ADCC). This humanization is relevant for studying combination therapies in both myeloma and lymphoma.
