Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), 8112 Zürich, Switzerland.
Bioconjug Chem. 2023 Aug 16;34(8):1374-1379. doi: 10.1021/acs.bioconjchem.3c00194. Epub 2023 Jul 18.
The targeted delivery of bioactive proteins, such as cytokines, for cancer immunotherapy approaches mostly relies on antibodies or antibody fragments. However, fusion proteins may display low tissue penetration due to a large molecular size. Small molecule ligands with high affinity toward tumor-associated antigens provide a promising alternative for the selective delivery of cytokines to tumor lesions. We developed a one-pot procedure for the site-specific thiazolidine formation between an aldehyde bearing small molecule and the generated N-terminal cysteine of a bioactive protein. Thereby, neoleukin-2/15 (Neo-2/15), a computationally engineered interleukin-2 and -15 mimic, was chemically conjugated to acetazolamide plus, a potent carbonic anhydrase IX (CAIX) ligand. The conjugate retained the biological activity of Neo-2/15 and revealed its ability to accumulate in renal cell carcinoma (SK-RC-52) xenografts upon systemic intravenous administration. The results highlight the potential of small molecule targeting moieties to drive the accumulation of a protein cargo to the respective disease site while conserving the small construct size.
针对生物活性蛋白（如细胞因子）的靶向递送，癌症免疫治疗方法主要依赖于抗体或抗体片段。然而，由于分子尺寸较大，融合蛋白可能表现出低组织穿透性。对于细胞因子向肿瘤病变的选择性递送，具有高亲和力的肿瘤相关抗原的小分子配体提供了一种很有前途的替代方法。我们开发了一种在含有醛的小分子和生物活性蛋白生成的 N 端半胱氨酸之间进行噻唑烷形成的一锅法。由此，计算工程化的白细胞介素-2 和 -15 模拟物 Neoleukin-2/15（Neo-2/15）被化学缀合到乙酰唑胺和一种有效的碳酸酐酶 IX（CAIX）配体上。该缀合物保留了 Neo-2/15 的生物学活性，并显示出在系统静脉内给药后能够在肾细胞癌（SK-RC-52）异种移植物中积累。这些结果突出了小分子靶向部分将蛋白质货物驱动到相应疾病部位的潜力，同时保持了小构建体的尺寸。
