Isolation and engineering of melanoma-specific antibodies from patients responding to immune checkpoint inhibitors.

• Applicant: Professor Dr. Lukas Flatz
• Subject Area: Dermatology ; Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508470707

Long-term survival of stage IV melanoma patients has improved significantly with the advent of immune checkpoint inhibitors (CI). Mechanistic interpretations and biomarker studies predicting the clinical outcome of CI are currently focusing on cytotoxic T cells Studies investigating the role of B cells and antibodies in melanoma suggest B cells may represent a source of binding specificities that may be converted into next-generation antibody therapeutics. We have previously established a biobank of serial serum, PBMC and tissue samples from more than 100 melanoma patients with all clinical data of this prospective cohort stored in a professional Redcap database. We hypothesize that antibody responses directed against melanoma-associated antigens may complement the anti-cancer action of cytotoxic T lymphocytes. Our preliminary data show that antibodies against the melanoma-associated antigens TYRP1, TYRP2, GP100 and MART-1 were significantly higher in serum of responder patients compared to non-responders, even before the start of CI therapy. In our research project, we aim to generate monoclonal antibodies derived from the unique immune repertoire of melanoma patients who showed complete remission during checkpoint inhibitor treatment. Monoclonal antibodies will be generated after complete sequencing of the variable regions of the heavy and light chain. These antibodies will be tested in an established xenograft mouse model. Lastly the most promising candidates will be further improved by conjugating then with a cytotoxic payload.

• DFG Programme: Research Grants