Abstract LB535: A novel IL12-based immunocytokine targeting fibroblast activation protein (FAP) for the treatment of cancer

Abstract

Abstract Immunocytokines, which consist of the fusion of cytokines to tumor targeting antibodies, represent a novel class of biopharmaceuticals that have great potential for cancer treatment. The use of these products improves the efficacy of the delivered drug by reducing related side effects and significantly enhances the therapeutic index of the payload. Over the past years, nuclear medicine studies have validated the Fibroblast Activation Protein (FAP) as a pantumoral antigen, with more than 28 different cancer types successfully imaged in patients. Since FAP is mostly undetectable in healthy organs, it has been considered as an attractive target for both imaging and therapeutic applications. For this reason, here we describe the generation of a novel fully human monoclonal antibody targeting FAP. The antibody was isolated from a synthetic antibody phage display library and its tumor recognition properties were validated by immunofluorescence performed on a commercial tissue microarray as well as on freshly frozen colon cancer biopsies from human patients. An ex vivo biodistribution analysis in mice confirmed the ability of anti-FAP in IgG1 format to selectively localize to solid tumors while sparing healthy organs. Furthermore, Pharmacokinetics (PK) studies in Cynomolgus Monkey showed no sink effects at early time points and a slow clearance from bloodstream as expected for IgG1 antibodies. Encouraged by these results, an antibody cytokine fusion (mIL12-FAP) based on the novel anti-FAP antibody was generated and characterized in vitro and in vivo, showing activation of the immune system both in immunocompetent and immunodeficient mouse models bearing FAP-positive tumors. mIL12-FAP exhibited strong anticancer activity in mice bearing CT26-FAP colon carcinomas which could be boosted by the combination with immune checkpoint inhibitors, leading to durable cancer eradication. The targeted delivery of mIL12 to the tumor microenvironment increased the infiltrate of tumor-specific lymphocytes and Natural Killer (NK) cells as compared to the control group without apparent evidence of toxicity. Citation Format: Lisa Nadal, Frederik Peissert, Abdullah Elsayed, Chiara Libbra, Dario Neri, Roberto De Luca. A novel IL12-based immunocytokine targeting fibroblast activation protein (FAP) for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB535.