Romanò Cecilia, Jiang Hao, Tahvili Sahar, Wei Peng, Keiding Ulrik B, Clergeaud Gael, Skovbakke Sarah Line, Blomberg Anne Louise, Hafkenscheid Lise, Henriksen Jonas R, Andresen Thomas L, Goletz Steffen, Hansen Anders E, Christensen Dennis, Clausen Mads H
Center for Nanomedicine & Theranostics, Department of Chemistry, Technical University of Denmark Kemitorvet 207 2800 Kgs. Lyngby Denmark
Department of Health Technology, Section for Biotherapeutic Engineering and Drug Targeting, Technical University of Denmark Ørsteds Plads 2800 Kgs Lyngby Denmark.
RSC Med Chem. 2024 Jun 21;15(8):2718-2728. doi: 10.1039/d4md00387j. eCollection 2024 Aug 14.
iNKT cells - often referred as the "Swiss Army knife" of the immune system - have emerged as central players in cancer vaccine therapies. Glycolipids activating iNKT cells, such as α-galactosylceramide (αGalCer), can enhance the immune response against co-delivered cancer antigens and have been applied in the design of self-adjuvanting anti-tumor vaccines. In this context, this work focuses on the chemical synthesis of ganglioside tumor-associated carbohydrate antigens (TACAs), namely GM3 and (Neu5Gc)GM3 antigens, their conjugation to αGalCer, and their formulation into liposomes as an efficient platform for their delivery. Liposomes containing GM3-αGalCer, (Neu5Gc)GM3-αGalCer, and equimolar amounts of the two conjugates have been fully characterized and their ability to activate iNKT cell has been confirmed in mouse and human cell assays. The candidates were tested in immunization studies, demonstrating an ability to induce both T1 and T2 cytokines leading to the production of all subclasses of IgG antibodies. Notably, the study also demonstrated that serum antibodies raised against the two TACAs, alone and in combination, were cross-reactive. This finding has consequences for future vaccine designs - even if a highly tumor-selective antigen is chosen, the resulting antibody response may be broader than anticipated.
自然杀伤T细胞（iNKT细胞）——常被称为免疫系统的“瑞士军刀”——已成为癌症疫苗疗法的核心参与者。激活iNKT细胞的糖脂，如α-半乳糖神经酰胺（αGalCer），可增强针对共同递送的癌症抗原的免疫反应，并已应用于自佐剂抗肿瘤疫苗的设计。在此背景下，这项工作聚焦于神经节苷脂肿瘤相关碳水化合物抗原（TACAs），即GM3和（Neu5Gc）GM3抗原的化学合成、它们与αGalCer的缀合，以及将它们制成脂质体作为其递送的有效平台。含有GM3-αGalCer、（Neu5Gc）GM3-αGalCer以及等摩尔量的这两种缀合物的脂质体已得到充分表征，并且它们激活iNKT细胞的能力已在小鼠和人类细胞试验中得到证实。这些候选物在免疫研究中进行了测试，证明能够诱导T1和T2细胞因子，从而产生所有亚类的IgG抗体。值得注意的是，该研究还表明，单独或联合针对这两种TACAs产生的血清抗体具有交叉反应性。这一发现对未来的疫苗设计具有影响——即使选择了高度肿瘤选择性的抗原，产生的抗体反应可能比预期的更广泛。
