Hypothesizing that tumor endothelial cells (TECs) re-express fetal genes in tumor tissues, Huijbers et al. identified target genes selectively expressed in mouse embryos and in sorted TECs, but not in adult mice. Identified TEC self-antigens (Fbn2, Emilin2, Lox and Pai-1) were validated in in vitro angiogenesis assays and were used to generate fusion protein vaccines (with bacterial thioredoxin) that induced highly specific polyclonal Abs and inhibited tumor growth in preclinical models, without affecting healthy vasculature (Fbn2 and Emilin2 vaccines). High levels of FBN2 and EMILIN2 correlated with elevated levels of ECs in human CRC and melanoma.
Contributed by Katherine Turner
ABSTRACT: A sustained blood supply is critical for tumor growth, as it delivers the nutrients and oxygen required for development. Targeting of blood vessel formation via immunotherapies is an area of great importance. Knowing that certain embryonic genes, such as carcinoembryonic antigens (CEA) and oncofetal fibronectin, become reexpressed in malignant transformation, we hypothesized that a similar phenomenon holds true for tumor endothelial cells (TECs) as well. An approach for identification of highly selective tumor endothelial markers was conducted to develop targeted antiangiogenic immunotherapies. We first queried the transcriptome that is present during embryo development. We then performed a systematic search for genes selectively expressed in the mouse embryo at days E11 and E18, as compared to the transcriptome of the adult mouse. Subsequently, we queried for expression of these embryonic genes in sorted murine TECs. This approach identified among others the tumor endothelial antigens fibrillin-2 (Fbn2), elastin microfibril interface-located protein 2 (Emilin2) as well as the tumor endothelial antigens lysyl oxidase (Lox) and serine/cysteine protease inhibitor, clade E, member 1 (Serpine1; Pai-1). For these selected genes, functional involvement in angiogenesis was confirmed in in vitro bioassays. We subsequently used iBoost conjugate vaccine technology to develop vaccines against the selected targets. For all four targets, vaccination readily induced target-specific antibody responses in mice, resulting in inhibition of tumor growth. Access to highly specific tumor endothelial markers provides opportunities for direct targeting of the tumor vasculature with high specificity, without affecting healthy vasculature.
Author Info: (1) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. CimCure Besloten Venn
Author Info: (1) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. CimCure Besloten Vennootschap, Amsterdam 1066 CX, The Netherlands. (2) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (3) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (4) Laboratory of Experimental Oncology and Radiobiology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1105 AZ, The Netherlands. (5) Laboratory of Experimental Oncology and Radiobiology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1105 AZ, The Netherlands. (6) Vlaams Instituut voor Biotechnologie-Katolieke Universiteit Leuven Center for Cancer Biology, Leuven 3000, Belgium. (7) Vlaams Instituut voor Biotechnologie-Katolieke Universiteit Leuven Center for Cancer Biology, Leuven 3000, Belgium. (8) Department of Medical Oncology, Oncoproteomics Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (9) Department of Medical Oncology, Oncoproteomics Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (10) Department of Pathology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands. (11) Laboratory of Experimental Oncology and Radiobiology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1105 AZ, The Netherlands. (12) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. CimCure Besloten Vennootschap, Amsterdam 1066 CX, The Netherlands.
