A TCR mimic monoclonal antibody reactive with the "public" phospho-neoantigen pIRS2/HLA-A*02:01 complex.
A TCR mimic monoclonal antibody reactive with the "public" phospho-neoantigen pIRS2/HLA-A*02:01 complex.
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DOI：
10.1172/jci.insight.151624
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发表时间：
2022-03-08
期刊：
影响因子：
8
通讯作者：
Scheinberg DA
中科院分区：
文献类型：
--
作者：
Dao T;Mun SS;Molvi Z;Korontsvit T;Klatt MG;Khan AG;Nyakatura EK;Pohl MA;White TE;Balderes PJ;Lorenz IC;O'Reilly RJ;Scheinberg DA
来源于癌细胞中失调的蛋白质磷酸化的磷酸肽可以由MHC I类和II类分子加工和呈递，因此代表了一类未开发的肿瘤特异性抗原，其可以用作广泛表达的“公共”癌症新抗原（NeoAg）。我们产生了TCR模拟物（TCRm）mAb，6 B1，其特异性针对由HLA-A*02：01呈递的胰岛素受体底物2（pIRS 2）衍生的磷酸肽。通过质谱法证实了pIRS 2表位通过HLA-A*02：01的呈递。TCRm 6 B1特异性结合在HLA-A*02：01的背景下表达pIRS 2的肿瘤细胞系上的pIRS 2/HLA-A2复合物。接合T细胞的CD 3的双特异性mAb能够以pIRS 2和HLA-A*02：01限制性方式杀死肿瘤细胞系。结构建模显示第一个位置的精氨酸或赖氨酸结合mAb的先决条件。因此，6 B1可以识别来源于具有相似氨基酸组成的各种磷酸化蛋白质的磷酸肽。这提出了对pIRS 2/HLA-A2复合物特异性的TCRm可以靶向各种肿瘤细胞中由HLA-A*02：01呈递的一系列磷酸肽的可能性。这是我们所知的第一个靶向磷酸肽/MHC I类复合物的TCRm mAb;这类药物用于临床应用的潜力值得进一步研究。
Phosphopeptides derived from dysregulated protein phosphorylation in cancer cells can be processed and presented by MHC class I and class II molecules and, therefore, represent an untapped class of tumor-specific antigens that could be used as widely expressed “public” cancer neoantigens (NeoAgs). We generated a TCR mimic (TCRm) mAb, 6B1, specific for a phosphopeptide derived from insulin receptor substrate 2 (pIRS2) presented by HLA-A*02:01. The pIRS2 epitope’s presentation by HLA-A*02:01 was confirmed by mass spectrometry. The TCRm 6B1 specifically bound to pIRS2/HLA-A2 complex on tumor cell lines that expressed pIRS2 in the context of HLA-A*02:01. Bispecific mAbs engaging CD3 of T cells were able to kill tumor cell lines in a pIRS2- and HLA-A*02:01–restricted manner. Structure modeling shows a prerequisite for an arginine or lysine at the first position to bind mAb. Therefore, 6B1 could recognize phosphopeptides derived from various phosphorylated proteins with similar amino acid compositions. This raised the possibility that a TCRm specific for the pIRS2/HLA-A2 complex could target a range of phosphopeptides presented by HLA-A*02:01 in various tumor cells. This is the first TCRm mAb to our knowledge targeting a phosphopeptide/MHC class I complex; the potential of this class of agents for clinical applications warrants further investigation.
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