BioMice’s Target Humanized Mouse Models Enable Preclinical Toxicity Studies to Support IND Approval

BioMice’s Target Humanized Mouse Models Enable Preclinical Toxicity Studies to Support IND Approval

In February 2022, to meet the challenge of NHP shortage, the Food and Drug Administration (FDA) published a new guideline – Nonclinical Considerations for Mitigating Nonhuman Primate Supply Constraints Arising from the COVID-19 Pandemic: Guidance for Industry. To quote, “although the stated preference of ICH S6(R1)8 is for testing the clinical candidate (in the NHP), while the supply of NHPs is disrupted, we strongly encourage the use of appropriate alternative models for assessing DART endpoints (e.g., species-specific surrogates in rodents, genetically modified rodents) when scientifically justified.”

Mouse models could be used as an alternative approach for preclinical drug toxicology studies because of the high degree of genetic similarity between mouse and human, which is only slightly lower than that between NHPs and humans. With advanced gene-editing technologies, Biocytogen has made a series of target humanized mice where the drug-target interactions are similar to that in human and the target biological functions in mice are well maintained. This makes BioMice’s target humanized mice a superior model for drug safety evaluations when the drug-target interactions in NHPs are different than that in human. Therefore, target humanized mice offer an alternative to NHPs not only when NHPs are in short supply, but also when NHPs are not relevant species for some drug evaluations. Additional advantages of mouse models compared to NHPs is their short reproductive cycle and lower cost.

To date, many pharmaceutical companies have received Investigational New Drug (IND) approval with the help of BioMice’s target humanized mice for the repeated-dose (RDT) or development and reproductive toxicity (DART) studies. So far, three drugs’ IND applications were approved by the FDA and eight drugs’ IND applications were approved by NMPA. Among them, two drugs received dual IND approvals from both the FDA and NMPA. Popular humanized mouse models used for drug safety evaluations include humanized immune-checkpoint mouse models such as B-h4-1BB, B-hCCR8, B-hLAG3, B-hCD38 and B-hCD40 mice, humanized cytokine/cytokine receptor mouse models such as B-hIL4/hIL4RA and B-hIL36R mice, and the metabolism-related mouse model B-hGLP1R mice.

To some extent, humanized mouse models can reflect the drug’s adverse effects (AEs), such as hematologic toxicity, hepatic toxicity, and cytokine release syndrome (CRS) seen in patients ([1] Take the partial internal data of B-hCD40 mice as an example:

  • Hematologic toxicity: decreased peripheral lymphocytes, monocytes, and platelets; decreased CD19+ B cells in blood.
  • Hepatic toxicity: elevations in serum liver transaminases and total bilirubin.

Fig 1. B-hCD40 mice of both genders were treated with Selicrelumab (analog, 20 mpk), which showed AE consistent with clinical symptoms on day 14 after treatment.

Increased acute phase proteins and liver damage in response to Selicrelumab (analog) in humanized B-hCD40 mice

Fig 2. (A) Acute phase proteins such as CRP, amyloid A, haptoglobin and IL12p40 are increased in response to Selicrelumab in B-hCD40 mice. (B) Liver pathology demonstrated the increased lymphocyte infiltration compared with PBS treated mice.

Biocytogen has independently developed more than 200 humanized mouse models related to immuno-oncology, inflammatory/autoimmune and metabolic diseases, which can be used for preclinical PK, PD, and toxicology studies.

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[1] Vonderheide RH, Flaherty KT, Khalil M, Stumacher MS, Bajor DL, Hutnick NA, Sullivan P, Mahany JJ, Gallagher M, Kramer A, Green SJ, O’Dwyer PJ, Running KL, Huhn RD, Antonia SJ. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007 Mar 1;25(7):876-83.


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