The HLA-A2 restricted T-cell receptor mimic (TCRm) antibody RL6A has been shown to have antitumor effects in a breast cancer orthotopic xenograft model with MDA-MB-231 cells. Transgenic mice expressing HLA-A2 also take up RL6A into brain across the blood-brain barrier (BBB). The present study evaluates different approaches to obtain a reliable brain tumor model using HLA-A2 transgenic mice, in which pharmacokinetics and antitumor efficacy of RL6A on brain metastasis could be studied. First, available immunocompromised HLA-A2 transgenic strains, such as the HLA-A2 transgenic NSG mouse (Jackson Labs), were utilized and various tumor injection methods were tested. As NSG mice are the most immunocompromised and vulnerable strains, intracardiac injection of brain-seeking human breast cancer cells invariably resulted in tumors of multiple peripheral organs even when using a brain seeking subclone of MDA-MB-231. More targeted approaches (common carotid artery or retrograde external carotid injections) reduced the tumor burden in peripheral organs intracardiac injection, but turned out being too invasive procedures for this brittle mouse strain. Stereotaxic intrastriatal injection in NSG mice resulted in tumor growth at the implantation site within brain, but also in skull bone and dura. Therefore, the NSG background appeared unsuitable for our purpose. We then evaluated intracardiac injections of tumor cells in a Foxn1nu nude mouse strain on a C57BL/6 background, which developed predominantly brain tumors and no tumors in major peripheral organs (lung, liver, kidney). Cross-breeding with C57BL/6 transgenic HLA-A2 mice was initiated and yielded a novel HLA-A2 transgenic nude mouse strain.
Development of a Novel Preclinical Model Based on HLA-A2 Transgenic Mice to Evaluate T-Cell Receptor Mimic Monoclonal Antibodies as Therapeutic Agent against Brain Metastases of Human Breast Cancer
Bickel, Jee Hyun Park, Li Yang, Faleh Alqahtani and Ulrich . 2016
The American Association of Immunologists, Inc