Glioblastoma is an aggressive brain tumour found in adults, and the therapeutic approaches available have not significantly increased patient survival. Recently, we discovered that ELTD1, an angiogenic biomarker, is highly expressed in human gliomas. Polyclonal anti-ELTD1 treatments were effective in glioma pre-clinical models, however, pAb binding is potentially promiscuous. Therefore, the aim of this study was to determine the effects of an optimized monoclonal anti-ELTD1 treatment in G55 xenograft glioma models. MRI was used to assess the effects of the treatments on animal survival, tumour volumes, perfusion rates and binding specificity.Immunohistochemistry and histology were conducted to confirm and characterize microvessel density and Notch1 levels, and to locate the molecular probes. RNAsequencing was used to analyse the effects of the mAb treatment. Our monoclonal anti-ELTD1 treatment significantly increased animal survival, reduced tumour volumes, normalized the vasculature and showed higher binding specificity within the | 1739 ZALLES Et AL.
Monoclonal antibodies have yet considerably modified the field of clinical oncology. The growing knowledge of key cellular pathways in tumor induction and progression, targeted therapies represent an increasing proportion of new drugs entering clinical trials. Some molecules such as trastuzumab, rituximab, alemtuzumab, cetuximab are now widely used in clinical practice. These antibodies are now tested in different indications alone or in combination with standard chemotherapy. They are also developed for the treatment of inflammatory diseases (rituximab). Numerous others antibodies are currently in pre-clinical and clinical development phases for several malignancies including renal carcinoma, melanoma, lymphomas, leukaemia, breast, ovarian and colorectal cancer. An alternative approach is to conjugate the monoclonal antibody to a toxin, a cytotoxic agent, or a radioisotope. In other cases these antibodies aim to modify the tumour microenvironment through inhibition of angiogenesis or enhancing host immune response against cancer. If the molecule targeted by the antibodies is clearly identified, most often the precise mechanism of action of these immunoglobulins is not fully understood. They can have direct effects in inducing apoptosis or programmed cell death. They can block growth factor receptors, efficiently arresting proliferation of tumor cells. Indirect effects include recruiting cells that exert cytotoxicity, such as monocytes and macrophages (ADCC). Monoclonal antibodies also bind complement, leading to toxicity known as complement dependent cytotoxicity (CDC). The side effects associated with these new treatments were in part foreseeable depending on the affected cell or function. But new or surprising side effects emerged from clinical studies. We present an overview of the monoclonal antibodies used in clinical oncology or currently in development phases. We particularly focus on recent development including new indications, clinical trial results and specific side effects of monoclonal antibodies used in the treatment of cancer.
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