Human Immune System Engrafted Mouse Model

Biocytogen’s severely immune-deficient B-NDG mice are good host for engraftment of human PBMC and CD34+ hematopoietic stem cells (hHSC). These human immune cell engraftment models are powerful tools for examining effect of immuno-oncology agents on human immune cells and assessing efficacy of such test agents on CDX and PDX tumor growth.

Case 1: Anti-CDX tumor efficacy study by monoclonal and bispecific antibodies in human PBMC engrafted B-NDG mice

 

Efficacy study of monoclonal and bispecific antibodies in human PBMC engrafted B-NDG mice of Raji-Luc B lymphoma model.

Case 2: Anti-CDX tumor efficacy study in human CD34+ engrafted B-NDG mice

B-NDG mice engrafted with CD34+ HSC cells were used for in vivo efficacy assessment. Mice were treated with anti-human PD-1 antibody Pembrolizumab or anti-CD20 antibody Rituximab after Raji-Luc cell implantation. Dramatic tumor growth inhibition by both Pembrolizumab and Rituximab was observed.

Case 3: Anti-PDX tumor efficacy study by anti-human PD-1 antibody in human CD34+ engrafted B-NDG mice

Efficacy evaluation of the human PD-1 antibody Pembrolizumab in CD34+ HSC engrafted B-NDG mice implanted with hPD-L1 positive lung PDX.

Case 4: Establishing human PBMC engrafted GvHD model in B-NDG mice

Establishment of human PBMC engrafted GvHD model in B-NDG mice

Figure 1. Establishment of human PBMC engrafted GvHD model in B-NDG mice.

B-NDG mice (female, 8-week old, n=5) were engrafted with 10 million human PBMC from two donors (D1, D2) on day 0. PBMC from donor 2 demonstrated more robust GvHD than those from donor 1.  GvHD were scored according to Table 1.


Checkpoint inhibitors aggravated GvHD in tumor-bearing B-NDG mice

Figure 2. Checkpoint inhibitors aggravated GvHD in RKO tumor-bearing B-NDG mice.

B-NDG mice (female, 8-week old, n=5) bearing RKO tumor (5 million, 50% Matrigel, inoculated subcutaneously on day 4) were engrafted with 10 million human PBMC from two donors (D1, D2) on day 0. Treatment by 125 ug per mouse pembrolizumab and ipilimumab, BIW, i.p. started on day 14. Checkpoint inhibition resulted in earlier onset and more severe GvHD, with more prominent effects with PBMC from donor 2, which had more robust GvHD than PBMC from donor 1. GvHD scores are shown in top panels and body weight (BW) changes in low panels. GvHD was scored according to Table 1.


Pharmacological validation of GvHD model in B-NDG mice: Reduction of GvHD by corticosteroid drug

Figure 3. Pharmacological validation of GvHD model in B-NDG mice: alleviation of GvHD by corticosteroid drug.

B-NDG mice (female, 8-week old, n=7-8) were engrafted with 20 million human PBMC (iv) on day 0. Drug treatment (i.m., qdx4) started on day 7. Robust GvHD developed in the absence of treatment. Corticosteroid drug dose-dependently controlled the disease. High dose (1 mg/kg) of the drug GvHD resulted in delayed onset and reduced severity of symptoms while low dose (0.1 mg/kg) of the drug led to intermediated effect. GvHD was scored according to Table 1.


Case 5: Model development of human PBMC-mediated anti-tumor efficacy in B-NDG mice

Checkpoint inhibitors showed encouraging anti-tumor activity in PBMC engrafted RKO/B-NDG model

 

Figure 1. Checkpoint inhibitors showed encouraging anti-tumor activity in PBMC engrafted RKO/B-NDG model.

B-NDG mice (female, 8-week old, n=4-5) were engrafted with 10 million  human PBMC (iv) and 5 M RKO cells (in 50% Matrigel, inoculated subcutaneously) according to Panel A. Tumor volume (B-D) and body weight (E) were monitored over time. Percent of human CD45 cells in total human and mouse CD45 cells in terminal bleeds were indicated (C, D). Data were expressed as mean +/- SEM. TGI: tumor growth inhibition. Pembro/ipi: pembrolizumab/ipilimumab.


Checkpoint inhibitors increased CD8 content and CD8/Treg ratio significantly in blood in PBMC RKO/B-NDG model; Dichotomy of responders vs non-responders observed in tumor & blood

Figure 2. Checkpoint inhibitors increased CD8 content and CD8/Treg ratio significantly in blood in PBMC RKO/B-NDG model.

Flow cytometry analysis of terminal blood (A,B) and tumor (C, D) samples were performed. A dichotomy of responders vs non-responders to checkpoint inhibition was observed in tumor and blood. Blue circles: poor (<1%) human PBMC engraftment; green and magenta circles: responders and non-responders in Figure 2C, respectively.


GvHD of RKO-bearing B-NDG mice

Figure 3. GvHD and body weight (BW) of RKO-bearing B-NDG mice. GvHD were scored according to Table 1.


Back to top