Sulfhydryl-based tumor antigen-carrier protein conjugates stimulate superior antitumor immunity against B cell lymphomas
Sulfhydryl-based tumor antigen-carrier protein conjugates stimulate superior antitumor immunity against B cell lymphomas
复制标题
DOI：
10.4049/jimmunol.181.6.4131
复制
发表时间：
2008-09-15
影响因子：
4.4
通讯作者：
Timmerman, John M.
中科院分区：
文献类型：
--
作者：
Betting, David J.;Kafi, Kamran;Timmerman, John M.
使用戊二醛将肿瘤特异性IG（独特型或Id）与免疫原性外源载体蛋白钥孔血蓝蛋白（KLH）化学偶联，对B细胞淋巴瘤患者进行治疗性疫苗接种，在早期临床试验中显示出有希望的结果，III期试验正在进行中。然而，戊二醛Id-KLH疫苗未能在许多患者中引发抗Id免疫和临床应答，这可能是因为戊二醛与赖氨酸、半胱氨酸、酪氨酸和组氨酸残基反应，破坏了关键的免疫原性表位。使用马来酰亚胺化学的基于巯基的肿瘤Ag-载体蛋白缀合系统用于增强Id-KLH疫苗的功效。马来酰亚胺Id-KLH偶联物根除了大多数荷瘤小鼠的A20淋巴瘤，而戊二醛Id-KLH几乎没有效力。马来酰亚胺Id-KLH可诱导肿瘤特异性IgG抗体和T细胞，其中CD 8（+）T细胞是抗淋巴瘤免疫的主要效应细胞。马来酰亚胺Id-KLH疫苗在3803和BCL-1淋巴瘤模型中也表现出上级功效，其中显示Ab对于保护至关重要。重要的是，标准戊二醛Id-KLH缀合程序可能导致肿瘤Ag的“过度缀合”，导致效力降低，而基于异双功能马来酰亚胺的缀合产生有效的疫苗产物，而不管缀合持续时间如何。在溶酶体加工条件下，Id-载体蛋白连接仅在马来酰亚胺缀合后才可裂解。与Id-KLH临床试验中使用的人Ig类似，马来酰亚胺KLH缀合容易地用人Ig进行。这些数据支持在淋巴瘤临床试验中评估基于巯基的Id-KLH疫苗，并可能使用肿瘤Ag载体蛋白疫苗治疗其他癌症。
Therapeutic vaccination of B cell lymphoma patients with tumor-specific Ig (idiotype, or Id) chemically coupled to the immunogenic foreign carrier protein keyhole limpet hemocyanin (KLH) using glutaraldehyde has shown promising results in early clinical trials, and phase III trials are underway. However, glutaraldehyde Id-KLH vaccines fail to elicit anti-Id immune and clinical responses in many patients, possibly because glutaraldehyde reacts with lysine, cysteine, tyrosine, and histidine residues, damaging critical immunogenic epitopes. A sulfhydryl-based tumor Ag-carrier protein conjugation system using maleimide chemistry was used to enhance the efficacy of Id-KLH vaccines. Maleimide Id-KLH conjugates eradicated A20 lymphoma from most tumorbearing mice, whereas glutaraldehyde Id-KLH had little efficacy. Maleimide Id-KLH elicited tumor-specific IgG Abs and T cells, with CD8(+) T cells being the major effectors of antilymphoma immunity. Maleimide Id-KLH vaccines also demonstrated superior efficacy in 3803 and BCL-1 lymphoma models, where Abs were shown to be critical for protection. Importantly, standard glutaraldehyde Id-KLH conjugation procedures could result in "overconjugation" of the tumor Ag, leading to decreased efficacy, whereas the heterobifunctional maleimide-based conjugation yielded potent vaccine product regardless of conjugation duration. Under lysosomal processing conditions, the Id-carrier protein linkage was cleavable only after maleimide conjugation. Maleimide KLH conjugation was easily performed with human Igs analogous to those used in Id-KLH clinical trials. These data support the evaluation of sulfhydryl-based Id-KLH vaccines in lymphoma clinical trials and possibly the use of tumor Ag-carrier protein vaccines for other cancers.