Humanizing CXCL13 and CXCR5 in mice

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Summary/Abstract Angioimmunoblastic T-cell lymphoma (AITL) has a 47% survival rate over a two-year period despite aggressive cytotoxic therapy, with no significant increase in survival for over two decades. CXCR5 is a chemokine G protein-coupled receptor (GPCR) that is localized on the membrane of AITL cells. We have identified a small molecule compound that antagonizes CXCR5 and shown beneficial effects in AITL-PDX study. We also used phage display technologies and bioinformatics to identify 102 potential antagonists from a library of ~168,000 CXCL13 variants. With a collaborator at Yale (Samuel Katz, MD/PhD), we are also developing a CAR-T by targeting CXCR5. This application intends to make a humanized CXCL13 and CXCR5 strain of C57Bl/6. The ultimate goal is to test the small molecule antagonist and the CXCL13-based biotherapeutic in the context of a tumor microenvironment, which is not possible with PDX mice. The expression of humanized CXCL13 and CXCR5 will be quantitated and compared to vivo levels of normal expression of C57Bl/6. Cells from humanized mice and normal C57Bl/6 mice will be functionally compared in vitro, and the pharmacodynamics of the 18F-antagonist will be determined by in vivo PET studies to more accurately characterize the mouse model. The humanized CXCL13 and CXCR5 mice will not only be available for future AITL studies but also for mouse models of cutaneous T-cell lymphoma, a variety of CXCR5- expressing B-cell lymphomas, cancers of the prostate, colon, lung, and breast, and autoimmune diseases.