인간 면역 시스템이 이식된 마우스 모델

바이오사이토젠의 고도화 면역 결핍 마우스인 B-NDG 마우스는 인간 PBMC와 hHSC (CD34+ hematopoietic stem cells)를 이식하기에 좋은 도구입니다. 이 인간화 면역 세포가 이식된 모델들은 인간 면역 세포에서 면역항암제의 효과를 검증하기 위한 강력한 도구이며, CDX 와 PDX 모델에서의 효능 평가를 위해서도 유용합니다.

Case 1: 인간 PBMC가 이식된 B-NDG 마우스에서 단일 클론 항체와 이중특이성 항체의 항종양 연구 CDX 모델



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

Case 2 : 인간 CD34+가 이식된 B-NDG 마우스에서의 항종양 연구 CDX 모델

B-NDG mice engrafted with CD34+ HSC cells were used forin 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 4: B-NDG 마우스에 인간 PBMC가 이식된 GvHD (이식편대숙주질환) 모델

B-NDG 마우스에 인간 PBMC가 이식된 GvHD (이식편대숙주질환) 모델

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.

암이 이식된 B-NDG 마우스에서 GvHD를 더욱 악화시키는 면역관문 억제제.

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.

B-NDG 마우스에서 GvHD 모델의 약리학적 유효성: corticosteroid 약물로 GvHD가 감소함.

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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.

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Case 5: B-NDG에서 인간 PBMC 매개 항암 효능 평가 모델 개발.

PBMC 가 이식된 RKO/B-NDG 마우스 모델에서 면역관문 억제제의 항암 활성 증강 효과가 관찰됨

 

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.

PBMC RKO/B-NDG 마우스 모델의 혈액에서 CD8의 농도와 CD8/Treg 비율을 면역관문억제제가 유의미하게 증가시킴.

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.

RKO-bearing B-NDG의 GvHD 효과

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


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