多发性骨髓瘤（MM）起源于已经通过胚细胞园反应的浆细胞，这是Ig V区的体细胞高度突变发生的地方。骨髓瘤蛋白V区经常表达多种突变，因此是新抗原（传统称为傻傻的标志（Id））的丰富资源。因此，它们高度特异性且是免疫治疗的优良靶点。我们开发了一种DNA Id疫苗，将翻译的蛋白靶向传统树突状细胞（cDC），通过CCL3介导的运送机制将骨髓瘤蛋白V区以单链抗体片段（scFv）的形式提供给细胞。我们在小鼠MM模型中研究了疫苗的有效性，该模型为矿物油诱导的浆细胞瘤315.BM.用Id疫苗保护的小鼠免受MM细胞的挑战。此外，该疫苗具有治疗效果。然而，在部分已接种的小鼠中，不产生H链的MM细胞逃脱了排斥反应，导致出现自由轻链（FLC）MM。CD8+ T细胞的消失消除了疫苗的有效性，并且观察到保护作用依赖于使用Batf3-/-小鼠的cDC1。疫苗中scFv的改进表明，CD8+ T细胞对两个突变的VH序列具有特异性。CCL3-含量的Id疫苗诱导的VH新抗原特异性CD8+ T细胞对小鼠模型中的MM具有治疗效果。MM细胞可能通过失去H链的表达逃避排斥，从而产生FLC MM。©作者（或其雇主）2023。在CC BY-NC下允许重新使用。不允许商业再利用。由BMJ发布。

Multiple myeloma (MM) cancers originate from plasma cells that have passed through the germinal center reaction where somatic hypermutation of Ig V regions takes place. Myeloma protein V regions often express many mutations and are thus a rich source of neoantigens (traditionally called idiotopes (Id)). Therefore, these are highly tumor-specific and excellent targets for immunotherapy.We have developed a DNA Id vaccine which as translated protein targets conventional dendritic cells (cDC) for CCL3-mediated delivery of myeloma protein V regions in a single-chain fragment variable (scFv) format. Vaccine efficacy was studied in the mouse MM model, mineral oil-induced plasmacytoma 315.BM.The Id vaccine protected mice against a challenge with MM cells. Moreover, the vaccine had a therapeutic effect. However, in some of the vaccinated mice, MM cells not producing H chains escaped rejection, resulting in free light chain (FLC) MM. Depletion of CD8+ T cells abrogated vaccine efficacy, and protection was observed to be dependent on cDC1s, using Batf3-/- mice. Modifications of scFv in the vaccine demonstrated that CD8+ T cells were specific for two mutated VH sequences.VH neoantigen-specific CD8+ T cells elicited by CCL3-containing Id vaccines had a therapeutic effect against MM in a mouse model. MM cells could escape rejection by losing expression of the H chain, thus giving rise to FLC MM.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.