Research Project
9254009
Project summary Therapeutic strategies that seek to stimulate adaptive immunity for the treatment of cancer have recently shown convincing clinical efficacy. Immune checkpoint inhibitors (CPIs), for example, reactivate a patient?s own T cells to eliminate tumors by blocking interactions that cause tumor infiltrating lymphocytes (TILs) to become exhausted. CPIs have demonstrated remarkable success against metastatic melanoma and non-small cell lung cancer, and are in testing for the treatment of numerous other tumor types, either alone or in combination. Infiltration of the tumor by CD8+ cytotoxic T cells appears to be a requisite for CPI treatment to be effective. Accordingly, CD8 has been identified as a potential predictive biomarker for response to CPI therapy, at least in melanoma. The current standard for assessment of this biomarker entails biopsy of primary and metastatic tumor foci, followed by immunohistochemical characterization. Limitations of biopsy include its invasiveness, the difficulty of accessing tumors at many anatomical locations, and sampling bias related to the heterogeneous distribution of markers both within and between tumor foci, increasing the likelihood of false negative results. There is an urgent need for non-invasive imaging techniques that allow visualization of biomarker distribution on the entire surface of primary and metastatic tumor foci at diverse anatomical locations. 121 Bio is uniquely positioned to develop such a non-invasive imaging approach. Our platform exploits the advantages of single domain antibodies (sdAbs), combined with site-specific conjugation for controlled and reproducible installation of a radio-isotopic label for positron emission tomography (PET) imaging. Due to their small size, the resulting imaging agents show high tissue uptake and rapid blood clearance. This design allows high PET tumor-to-background ratios, even at low levels of antigen abundance and within 2 to 4 hours of injection, enabling same day imaging at high resolution. Mouse proof of concept experiments using radiolabelled sdAbs against specific immune markers have were successful at visualizing immune cells within lymphoid structure and tumors by PET imaging. 121Bio has assembled a highly qualified scientific team with broad experience in protein engineering, antibody discovery and development, tumor immunology and nuclear medicine. To complement internal capabilities, we have gained access to outside facilities and have recruited a panel of expert tumor immunology and PET imaging consultants. We have generated a series of mouse and human CD8-reactive sdAbs, and propose here to: a) further characterize their ability to detect tumor-infiltrating CD8 T cells in mouse models, and b) select and characterize the lead candidate for development toward use in humans. This anti-CD8 imaging agent offers the potential to be the first non-invasive imaging agent to be used in selection and management of patients underdoing CPI cancer immunotherapy.
