Angiogenesis Laboratory, Cancer Center Amsterdam, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
Vaccine. 2018 May 17;36(21):3054-3060. doi: 10.1016/j.vaccine.2018.03.064. Epub 2018 Apr 11.
The induction of an antibody response against self-antigens requires a conjugate vaccine technology, where the self-antigen is conjugated to a foreign protein sequence, and the co-application of a potent adjuvant. The choice of this foreign sequence is crucial as a very strong antibody response towards it may compromise the anti-self immune response. Here, we aimed to optimize the conjugate design for application of vaccination against the tumor vasculature, using two different approaches. First, the immunogenicity of the previously employed bacterial thioredoxin (TRX) was reduced by using a truncated from (TRXtr). Second, the Escherichia coli proteome was scrutinized to identify alternative proteins, based on immunogenicity and potency to increase solubility, suitable for use in a conjugate vaccine. This technology was used for vaccination against a marker of the tumor vasculature, the well-known extra domain B (EDB) of fibronectin. We demonstrate that engineering of the foreign sequence of a conjugate vaccine can significantly improve antibody production. The TRXtr construct outperformed the one containing full-length TRX, for the production of anti-self antibodies to EDB. In addition, efficient tumor growth inhibition was observed with the new TRXtr-EDB vaccine. Microvessel density was decreased and enhanced leukocyte infiltration was observed, indicative of an active immune response directed against the tumor vasculature. Summarizing, we have identified a truncated form of the foreign antigen TRX that can improve conjugate vaccine technology for induction of anti-self antibody titers. This technology was named Immuno-Boost (I-Boost). Our findings are important for the clinical development of cancer vaccines directed against self antigens, e.g. the ones selectively found in the tumor vasculature.
针对自身抗原产生抗体反应需要一种结合疫苗技术，即将自身抗原与一种外源蛋白序列结合，并同时应用一种有效的佐剂。选择这种外源序列非常关键，因为强烈的抗体反应可能会影响针对自身的免疫反应。在这里，我们旨在优化针对肿瘤血管的疫苗接种的结合设计，采用了两种不同的方法。首先，通过使用截短形式（TRXtr）来降低先前使用的细菌硫氧还蛋白（TRX）的免疫原性。其次，根据免疫原性和增加可溶性的效力，对大肠杆菌蛋白质组进行了仔细研究，以鉴定适合用于结合疫苗的替代蛋白。该技术用于针对肿瘤血管的标志物——众所周知的纤连蛋白外域 B（EDB）进行疫苗接种。我们证明，结合疫苗中外源序列的工程设计可以显著提高抗体产生。TRXtr 构建体在产生针对 EDB 的自身抗体方面优于包含全长 TRX 的构建体。此外，新的 TRXtr-EDB 疫苗可有效抑制肿瘤生长。观察到微血管密度降低和白细胞浸润增强，表明针对肿瘤血管的主动免疫反应。总之，我们已经确定了一种可改善针对自身抗体滴度的结合疫苗技术的外源抗原 TRX 的截断形式。该技术被命名为免疫增强（I-Boost）。我们的发现对于针对自身抗原的癌症疫苗的临床开发很重要，例如选择性地存在于肿瘤血管中的那些。
