Developing therapeutic TCR mimic monoclonal antibodies for cancer

T细胞受体模拟物（TCRm）单抗。TCRm单克隆抗体代表了一类新的单克隆抗体，在结构上与

T cell receptor mimic (TCRm) mAbs. TCRm mAbs represent a new class of mAbs, structurally identical to traditional mAbs. However, while traditional mAbs recognize 3D conformational structure of a surface protein, TCRm mAbs recognize peptides (9-10 amino acids) derived from intracellular proteins, displayed on cell surface by MHC class I molecules, the complexes traditionally recognized by TCR. This allows an antibody to have access to vast majority, truly tumor-specific antigens, most of them are intracellular proteins. The advantages of mAb therapy are well known that include their high target specificity, high efficacy, limited side effects, prolonged half-life, availability, low cost, and infrequent dosing. In addition to the immune effector functions of a mAb, mAb can also serve as antigen-specific vehicles that can deliver more potent cytotoxic agents such as toxins, drugs, or radiation. Finally, mAbs can be engineered into chimeric antigen receptors or bi-specific antibodies in order to enhance the specificity and the potency of T cell therapy. This project aimed at developing novel TCRm mAbs specific for two important, validated and tumor-specific antigens, as described below. Combining the best inherent features of both TCR recognition and the flexibility and potency of the mAbs as drugs, the new TCRm mAbs could offer a potent, controllable and widely applicable therapy. 1. Developing TCRm mAb to HPV-E7-derived epitope in the context of HLA-A*02:01. Human papilloma virus (HPV) causes hundreds of thousands of cancers worldwide. Most cervical carcinoma cells constitutively express HPV type 16 E6 and E7 oncoproteins, which provide an ideal and specific target for immunotherapies. We selected an immunogenic epitope derived from E7 protein (E7 p11-19) presented by HLA-A*02:01 as the target for the TCRm mAb. This epitope has been reproducibly detected in a majority of cervical cancer biopsies and cell lines in the context of HLA-A*02:01 molecule by mass spectrometry. 2. Developing TCRm mAb to pIRS2 in the context of HLA-A*02:01. Dysregulated protein phosphorylation is a hallmark of malignant transformation. Phosphorylation of serine and threonine residues is retained on peptides during MHC class I and class II antigen processing and presentation on the cell surface. Therefore, phosphopeptides derived from inappropriate phosphorylation of various proteins in malignant cells represent an extraordinary class of tumor specific neoantigens, that are also widely expressed and not patient-specific. We hypothesize that phosphopeptides could be used as shared tumor specific neoantigens. We selected a phosphopeptide of insulin receptor substrate2 (pIRS21097-1105) in the context of HLA-A*02:01 as the target for the TCRm development. This epitope has been identified in various cancer cells by mass spectrometry. We have a set of experimental tools and methods to select, characterize specific mAbs and to test their therapeutic efficacy both in vitro and in vivo.