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（CXCR 4）在超过23种人类癌症中的病理性过表达指定CXCR 4为肿瘤学中的“广谱”分子靶标。在核医学中，放射性标记的分子可以特异性地靶向这些细胞表面受体，并且可以被设计用于在同一分子内混合诊断和治疗特性（放射治疗诊断学）。最近，申请人已经鉴定了CXCR 4的内源性拮抗剂和反向激动剂，称为EPI-X4。EPI-X4是来源于人血清白蛋白的16聚体肽，其特异性结合CXCR 4，但不结合其他G蛋白偶联受体（GPCR）。已经开发了几种EPI-X4的合成衍生物，其对CXCR 4的亲和力增加，对血液中的蛋白水解降解具有抗性，并且具有高的全身保留时间。因此，基于EPI-X4的放射治疗诊断学可能为患有CXCR 4表达恶性肿瘤的患者提供新的成像测试和治疗选择。拟议的研究项目将是第一项旨在评估一类基于人体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.