Immunocompromised Human Serum Albumin/Human Neonatal Fc Receptor Mouse Model: A New Xenograft Model for Efficacy Studies of Immunotherapies
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The authors also showed that these mice can successfully grow human tumors when inoculated with human cancer cell lines.9 The model was developed to study the anti-tumor efficacy and pharmacodynamic profile of a bispecific light T-cell engager (anti-EGFR nanobody x anti-CD3 scFv; LiTE) antibody genetically fused to HSA variants engineered with either null, wild type or high binding (HB) human FcRn affinity. The results of this study, published in 2021 in Communications Biology, reveal that HSA/hFcRn/Rag1-/- mice subcutaneously inoculated with the human HT-29 colorectal cancer cell line are susceptible to tumor growth, similarly to C57BL/6 Rag1-/- animals (Figure 2A). Moreover, the authors found that mice injected with HSA–LiTE-HB fusion display greater tumor growth retardation compared to those treated with cetuximab (a commercial anti-EGFR antibody) or the other LiTE fusions (Figure 2B), suggesting that the HSA/hFcRn/Rag1-/- model allows accurate anti-tumor investigations of an anti-EGFR x anti-CD3 bispecific HSA fusion in tumors nonresponsive to standard anti-EGFR monoclonal therapies. Finally, analysis of serum levels showed that the albumin fusion Albu-LiTE-HB has an increased half-life compared to LiTE (Figure 2C).9
Figure 2 │ Tumor growth characterization and inhibition in AlbuMus RAG1 KO mice. A) HT-29 cells were inoculated subcutaneously in AlbuMus RAG1 KO or C57BL6 RAG1 KO mice to follow tumor growth. B) HT-29 cells mixed with human PBMCs were inoculated subcutaneously in AlbuMus RAG1 KO mice, and animals were injected with cetuximab, LiTE or Albu-LiTE-HB. Time points where the Albu-Lite-HB tumor group is comparably smaller are marked *p < 0.01, #p < 0.05. C) Blood samples were drawn at 9 time points and detection in serum was performed by sandwich ELISA. The highest concentration was seen in the 4-hour sample and set as T0. ****p < 0.0001, ***p = 0.001. Adapted from Mandrup et al., Communications Biology, 2021. |
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Importantly, human peripheral blood mononuclear cells (PBMCs) need to be co-injected with the tumor cell line and tested compound, thus providing an unusual distribution and infiltration of immune cells in the tumor micro environment. This specific point was discussed by Kenneth A. Howard during the Q&A session of his talk at genOway’s first Bespoke Event. These data show that the HSA/hFcRn/Rag1-/- model represents a valid tool for xenograft studies, and to assess the therapeutic efficacy and pharmacokinetics of drugs in primary immunodeficiency diseases, immuno-oncology and infectious diseases.
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