Development of a new class of radiopharmaceuticals for diagnosis and therapy of CXCR4-expressing malignancies based on the endogenous CXCR4 antagonist EPI-X4

C-X-C基序趋化因子受体4 （CXCR4）在超过23种人类癌症中的病理性过表达使CXCR4成为肿瘤学中的“广谱”分子靶点。在核医学中，放射性标记的分子可以专门针对这种细胞表面受体，并且可以在同一分子中设计用于混合诊断和治疗特性（放射治疗学）。最近，一种内源性的CXCR4拮抗剂和反向激动剂，称为EPI-X4，已被申请人确定。EPI-X4是一种从人血清白蛋白中提取的16聚肽，特异性结合CXCR4，但不结合其他g蛋白偶联受体（gpcr）。EPI-X4的几种合成衍生物已被开发出来，这些衍生物对CXCR4的亲和力增强，抗血液中的蛋白水解降解，并具有较高的全身保留时间。因此，基于EPI-X4的放射治疗可能为患有表达cxcr4的恶性肿瘤的患者提供新的影像学检查和治疗选择。拟议的研究项目将是第一个旨在评估基于人体内天然存在的内源性肽的新型放射性药物的研究，与小分子相比，这种药物可能具有更少的脱靶效应。

The pathological overexpression of the C-X-C motif chemokine receptor 4 (CXCR4) in more than 23 human cancers designate CXCR4 as a “wide spectrum” molecular target in oncology. In nuclear medicine, radiolabeled molecules can specifically target such cell surface receptors and can be designed for blending diagnostic and therapeutic properties within the same molecule (radio-theranostics). Recently, an endogenous antagonist and inverse agonist of CXCR4, termed EPI-X4, has been identified by the applicants. EPI-X4 is a 16-mer peptide derived from human serum albumin that specifically binds CXCR4 but no other G-protein coupled receptors (GPCRs). Several synthetic derivatives of EPI-X4 with increased affinity for CXCR4, resistance against proteolytic degradation in blood and high systemic retention times have been developed. Radio-theranostics based on EPI-X4 may thus offer new imaging tests and therapeutic options to patients suffering from CXCR4-expressing malignancies. The proposed research project would be the first study aiming to evaluate a new class of radiopharmaceuticals based on an endogenous peptide naturally present in the human body, which may have less off-target effects as compared to small molecules.