肿瘤细胞治疗研究
英文原题：CD38 as theranostic target in oncology.
这涉及使用发射粒子（如 225 Ac、212 Pb 或 211 At）和 - -粒子（如 90 Y、131 I 或 177 Lu）的放射性核素，以发挥细胞毒性作用。
CD38是一种多功能跨膜糖蛋白，存在于多种组织中，并在许多癌细胞中过表达，尤其见于白血病和多发性骨髓瘤（MM）等血液系统恶性肿瘤。因此，靶向CD38仍是治疗血液系统恶性肿瘤以及实体瘤的一种有吸引力的策略。CD38通过其ADP-核糖基环化酶和环状ADP-核糖（cADPR）水解酶活性，在疾病进展中发挥关键作用。鉴于其重要性，研究者开发了多种抗CD38单克隆抗体（mAb），包括已获批治疗MM的达雷妥尤单抗和伊沙妥昔单抗。这些mAb通过Fc依赖的免疫机制和免疫调节发挥抗肿瘤作用，增强T细胞和NK细胞介导的应答。然而，达雷妥尤单抗治疗过程中会出现耐药机制，因此需要开发新疗法。本综述介绍CD38作为肿瘤学靶点的当前认识，并旨在阐述单域抗体（sdAb）作为核医学创新诊疗工具的应用。诊断中常用的正电子发射断层显像（PET）放射性核素包括68Ga和64Cu；单光子发射计算机断层成像（SPECT）放射性核素包括99mTc和111In。抗CD38抗体放射性配体治疗（RLT）已取得显著进展，有助于揭示肿瘤生物学和治疗效果。治疗方面，RLT是一种有前景的方法，可精准靶向恶性细胞，同时尽量减少健康组织受到的辐射。该方法使用发射α粒子的放射性核素（如225Ac、212Pb或211At），以及发射β粒子的放射性核素（如90Y、131I或177Lu）发挥细胞毒作用。sdAb源自骆驼科动物重链抗体，与常规mAb相比具有体积小、稳定性高、特异性强以及能够识别隐蔽表位等优势。本实验室表征的CD38特异性sdAb（如sdAb 2F8）显示出出色的肿瘤靶向能力；其工程化构建体（如双表位抗体和嵌合抗体）代表了诊断和治疗CD38表达恶性肿瘤的新一代诊疗药物。
CD38 is a multifunctional transmembrane glycoprotein found in multiple tissues and overexpressed in many cancer cells, notably in hematological malignancies such as leukemia and multiple myeloma (MM). Therefore, targeting CD38 remains an attractive strategy for cancer treatment in hematological malignancies as well as in solid tumors. It plays a critical role in the progression of these diseases through its ADP-ribosyl cyclase and cADPR-hydrolase activities. Its importance has led to the development of various anti-CD38 monoclonal antibodies (mAbs), including daratumumab and isatuximab, approved for MM treatment. These mAbs exert their anti-tumor effects through Fc-dependent immune mechanisms and immunomodulation, enhancing T-cell and NK-cell-mediated responses. However, resistance mechanisms arise during the treatment with daratumumab, creating the necessity for new therapies. This review explains current knowledge about the role of CD38 as a target in oncology and aims to delineate the use of single domain antibodies (sdAbs) as innovative theranostic tools in nuclear medicine. For diagnostic purposes, PET radionuclides like 68 Ga, 64 Cu, and SPECT radionuclides like 99m Tc and 111 In, are commonly used. Significant progress has been made in anti-CD38 radioligand therapy (RLT), with anti-CD38 antibodies providing insights into tumor biology and treatment efficacy. In terms of therapy, RLT is a promising approach that offers precise targeting of malignant cells while minimizing exposure to healthy tissue. This involves the use of radionuclides emitting particles, like 225 Ac, 212 Pb or 211 At, and - -particles like 90 Y, 131 I, or 177 Lu, to exert cytotoxic effects. Derived from Camelidae heavy chain antibodies, sdAbs offer advantages over conventional mAbs such as small size, high stability, specificity, and ability to recognize hidden epitopes. CD38-specific sdAbs, such as sdAb 2F8, characterized by our laboratory, showing excellent tumor targeting and their engineered constructs, such as biparatopic antibodies and chimeric antibodies, represent a new generation of theranostic agents for diagnosis and treatment CD38-expressing malignancies.
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