Humanized Models

Engineering the immune systems of mice to recreate

the human tumor microenvironment (TME)

Oncodesign Services has a deep experience with the humanization of mice to support the study of antibodies, bispecifics, CAR-Ts and other immuno-modulatory therapies requiring a human immune system.  Our laboratories began using humanized animals in 2002, making us a pioneer in the early days of commercial adoption.  Oncodesign Services continues to adopt the latest approaches to humanization, so as to remain the leading CRO expert offering humanized mouse study services for preclinical pharmacology modeling.

Humanization - timeline of experience

Humanization of rodents (mice, rats) can be approached at two levels:

  • Cellular humanization corresponds to xenograft transplantation of human cells or tissues, either to provide a source of human leucocytes (CD34+ hematopoietic stem cells, PBMC, purified leucocyte sub-populations)
  • Genetic humanization corresponds to mouse gene swap by their human equivalent, either to provide a relevant target to a human-specific therapy, or endogenous support to the generation, maintenance and function of transplanted human cells

There are two main approaches to cellular humanization of mice, each with their own pros and cons: human hematopoïetic stem-cell (hHSC) based models and human PBMC reconstituted models.

Oncodesign Services is agnostic to approach, selecting the right model for the right study. A large variety of mouse recipient models are available (nude mice, scid mice, NOD scid mice, NSG mice, NOG mice, BRGSF mice, NCG mice, immunodeficient rats, etc.) from providers. Depending on the human leucocyte subset of interest, specific models might provide specific advantages – for instance, BRGSF mice permit an improved accumulation of human myeloid cells after HSC transplantation, with the possibility to transiently boost the human dendritic cell compartment.

GET IN TOUCH

Humanization - pros-and-cons approaches

Readouts typical for humanized immuno-oncology studies:

  • Tumor size
  • Survival
  • Cytokine/biomarker expression (by LBA)
  • TIL fractions (by flow/FACS)

Case study #1

In this study, Oncodesign Services tested a BiTe antibody fragment in the B-cell lymphoma line Ramos BCL, humanized with PBMCs in NOG mice. The treatment successfully increased survival, with tumor cell depletion demonstrated by flow/FACS analysis of sampled blood.

Humanization - Ramos Bcell lymphoma in PBMC-humanized NOG mice treat with bispecific antibody

Case study #2

The NIH-OVCAR3 model was injected IP into humanized NOG-mice. The mice were treated with an anti-PD-1 immune checkpoint inhibitor bispecific, with tumor volume estimated from the level of circulating biomarker CA125. The test article successfully suppressed the levels of CA125 and improved survival a little.

Humanization - OVCAR3 in PBMC-humanized NOG mice treated with bispecific