Tolerance toward tumor antigens, which are shared by normal tissues, have often limited the efficacy of cancer vaccines. However, wild type epitopes can be tweaked to activate cross-reactive T-cell clones, resulting in antitumor activity. The design of these analogs (i.e., heteroclitic peptides) can be difficult and time-consuming since no automated in silico tools are available. Hereby we describe the development of an in silico framework to improve the selection of heteroclitic peptides. The Epitope Discovery and Improvement System (EDIS) was first validated by studying the model antigen SIINFEKL. Based on artificial neural network (ANN) predictions, we selected two mutant analogs that are characterized by an increased MHC-I binding affinity (SIINFAKL) or increased TCR stimulation (SIIWFEKL). Therapeutic vaccination using optimized peptides resulted in enhanced antitumor activity and against B16.OVA melanomas in vivo. The translational potential of the EDIS platform was further demonstrated by studying the melanoma-associated antigen tyrosinase related protein 2 (TRP2). Following therapeutic immunization with the EDIS-derived epitope SVYDFFAWL, a significant reduction in the growth of established B16.F10 tumors was observed, suggesting a break in the tolerance toward the wild type epitope. Finally, we tested a multi vaccine approach, demonstrating that combination of wild type and mutant epitopes targeting both TRP2 and OVA antigens increases the antitumor response. In conclusion, by taking advantage of available prediction servers and molecular dynamics simulations, we generated an innovative platform for studying the initial sequences and selecting lead candidates with improved immunological features. Taken together, EDIS is the first automated algorithm-driven platform to speed up the design of heteroclitic peptides that can be publicly queried online.

Centre for Drug Research at the Division of Pharmaceutical Biosciences Faculty of Pharmacy University of Helsinki Helsinki Finland

Centre for Drug Research at the Division of Pharmaceutical Biosciences Faculty of Pharmacy University of Helsinki Helsinki Finland Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Prague 6 Czech Republic

Department of Molecular Medicine and Medical Biotechnologies University of Naples Federico 2 Naples Italy

Department of Molecular Medicine and Medical Biotechnologies University of Naples Federico 2 Naples Italy CEINGE Biotecnologie Avanzate S C a R L Naples Italy

Department of Pharmacy Center for Drug Research Pharmaceutical Biology Ludwig Maximilians University of Munich Munich Germany

Laboratory of Immunovirotherapy Drug Research Program University of Helsinki Helsinki Finland

Targovax Oy Helsinki Finland

TILT Biotherapeutics Helsinki Finland Cancer Gene Therapy Group Department of Oncology Faculty of Medicine University Helsinki Helsinki Finland

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