Abstract
Immune checkpoint inhibitors such as monoclonal antibodies (mAbs) are amongst the most important breakthroughs in cancer therapeutics. However, high cost and short acting time limits its affordability and clinical application. Therefore, an economical and durable alternative is urgently needed. Previously, we identified an IL-17RB targeting mAb which intercepts IL-17B/IL-17RB signal transduction and suppresses tumorigenesis in many types of cancer. We reason that active immunity against the antigenic epitope of IL-17RB can reproduce the anti-cancer effect of mAbs with better sustainability. Here, we present a cancer vaccine composed of multiple synthesized epitope peptides chemically conjugated onto CRM197, a highly immunogenic carrier protein. Combining mass spectrometry with immunoassay, we standardized hapten density determination and optimized vaccine design. Furthermore, orthotopically transplanted syngeneic mouse tumor 4T1 showed that administration of this vaccine therapeutically mitigates primary cancer growth as well as distance metastasis. In conclusion, we demonstrate preparation, characterization and pre-clinical application of a novel peptide cancer vaccine.
Highlights
It is well known that paracrine/autocrine cytokine signaling pathways are taken advantage of by cancer cells to promote disease progression, immune evasion and metastasis [1,2,3]
IL-17RB inactivation site (IRIS) is a 13-residue-long linear epitope located at position 19–31 of bovine interleukin 17 receptor B (IL-17RB) (UniProt accession number: A3KN55), which was used in crystal structure determination (Table 1, ID1)
The homologous IRIS sequences in mice and humans were aligned in the same range, 19–31 (UniProt accession number: Q9JIP3, Q9NRM6) (Table 1, ID2, 3), revealing a 92% and a 77% similarity with bovine IRIS, respectively, suggesting that IRIS is highly conserved across species, especially towards its C-terminus
Summary
It is well known that paracrine/autocrine cytokine signaling pathways are taken advantage of by cancer cells to promote disease progression, immune evasion and metastasis [1,2,3]. Immune checkpoint inhibitors, including monoclonal antibodies (mAbs), have been shown effective in disrupting extracellular signaling and successfully applied in clinical use [4,5,6]. Their short half-life nature dictates a high cost for prolonged usage [7] which, in extreme cases, can reach over USD 750,000 annually per patient [8]. Short peptides with suboptimal immunogenicity often induce immunotolerance towards these epitopes and even enhance tumor growth [14,15,16] Different strategies such as conjugation, adjuvant addition or both have been applied in the hope of promoting immunogenicity of the peptide vaccine. A potent and specific IgG response against mouse programmed cell death protein 1 (mPD1) was achieved through conjugating mPD1 mimotope onto cross reactive material 197 (CRM197), a non-toxic, highly immunogenic mutant of diphtheria toxoid (DT), which has been widely applied to vaccine preparation [17]
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