Background Depletion of undesired immune cells has shown to be a promising approach to treat cancer. B cell depleting antibodies such as Rituximab are often used to treat patients with lymphoma and has shown improved patients’ survival. Cell depletion can be triggered by antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). ADCP and ADCC activities are mediated by Fcγ receptors (FcgR) expressed on immune cells such as natural killer (NK) and macrophages. Translatable assessment of cell depleting agents in preclinical models requires the presence of functional immune cells and expression of functional FcγR receptors. Importantly, expression pattern of FcγR in mouse and human are distinct and therefore add to the complexity of investigating depleting antibodies in preclinical models. Herein, we described two preclinical humanized models for assessment of cell depleting agents.
Methods BRGSF is a highly immunodeficient mouse featuring reduced murine myeloid cells. Upon CD34+ HSC-engraftment, BRGSF-HIS mice display major human hematopoietic cell subsets, such as B, T, NK, dendritic cells (cDC and pDC) and monocytes/macrophages.
Results Human FcγRs are expressed on human immune cells developed in BRGSF-HIS mice. We previously reported that a CD47-TAA bispecific antibody induces ADCP in peritoneal and bone marrow-derived macrophages. It has also been described that an anti-VISTA induced monocytes/macrophages and cDC depletion, as well as cytokine release in BRGSF-HIS mice. In vivo, a single administration of Rituximab, an anti-CD20 mAb (hIgG1), induced B cell depletion in blood and spleen, without altering the absolute number of T and NK cells. While this data suggest that BRGSF-HIS mice enable assessment of depleting agents, the contribution of murine stroma cells present in the model might be misinterpreted. Alternatively, assessment of depleting agents can be performed in FcγR humanized (hFcγR) mice. In this model, an injection of mouse anti-CD20 mAb (hIgG1) intravenously induced B cell depletion in blood and liver, which was sustained 7 days post-treatment. B cell depletion was dependent on Fc effector function, as no activity in mouse anti-CD20 (hIgG1) Fc null mAb was observed.
Conclusions Antibody-mediated depletion of immune cells is achieved in the two humanized models described here, confirming their value to assess efficacy of depleting agents. Although the fully functional immune system and the expression of humanized FcγR in the stroma is an advantage of hFcγR model, assessment of mouse biology is a drawback. Alternatively, BRGSF-HIS mice, could be used to assess depleting agents in the presence of human immune cells.
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