Immunization with N-propionyl polysialic acid-KLH conjugate in patients with small cell lung cancer is safe and induces IgM antibodies reactive with SCLC cells and bactericidal against group B meningococci.
Immunization with N-propionyl polysialic acid-KLH conjugate in patients with small cell lung cancer is safe and induces IgM antibodies reactive with SCLC cells and bactericidal against group B meningococci.
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DOI：
10.1007/s00262-011-1083-6
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发表时间：
2012-01
影响因子：
5.8
通讯作者：
Livingston, Philip O.
中科院分区：
文献类型：
--
作者：
Krug, Lee M.;Ragupathi, Govind;Hood, Chandra;George, Constantine;Hong, Feng;Shen, Ronglai;Abrey, Lauren;Jennings, Harold J.;Kris, Mark G.;Livingston, Philip O.
聚唾液酸（Polysialic acid, polySA）是一种与神经细胞粘附分子结合的聚合物侧链，广泛表达于小细胞肺癌（small cell lung cancer， SCLC）细胞表面。在我们之前的研究中，在SCLC患者接种30 μg的keyhole帽螺血青素（KLH）共轭n -丙酰化（NP-）多晶酸疫苗后，发现了强大的抗体应答，但在一些接种疫苗的患者中检测到周围神经病变和失调。当前试验的目的是确定最低最佳剂量，并确认np -多晶硅疫苗诱导多晶硅抗体的安全性。完成初始治疗且无疾病进展迹象的SCLC患者在第1,2,3,4,8和16周注射10或3 μg结合KLH的np -多晶硅，并与100 μg免疫佐剂（QS-21）混合。两种剂量水平各有9名患者入组。在接种疫苗之前，每组中有一名患者具有抗聚唾液酸的低滴度抗体。所有10 μg疫苗剂量水平的患者接种后均产生抗聚唾液酸的IgM抗体效价（ELISA法中位效价为1/ 1280），除1例患者外，其余患者均产生抗人工疫苗免疫原np -聚唾液酸的IgM和IgG抗体（中位效价为1/ 10240）。3 μg疫苗剂量水平下抗体应答较低；9例患者中有6例出现抗聚唾液酸抗体（中位滴度为1/160）。10和3 μg组接种后6/9和3/9患者血清与人SCLC细胞有较强的荧光活化细胞分选反应。10 μg剂量组患者血清对B群脑膜炎球菌也具有兔补体杀菌活性。18例患者中有1例出现病因不明的自限性3级共济失调。接种np -多晶硅- klh可产生一致的高滴度抗体应答，10 μg剂量的免疫原性显著高于3 μg剂量。本研究确定了np -聚唾液酸- klh结合疫苗的最低最佳免疫原剂量至少为10 μg，并确定了疫苗的安全性。我们计划将np -多晶硅纳入一种针对SCLC的多价疫苗中，该疫苗含有四种糖脂抗原，这些糖脂抗原也广泛表达于SCLC - gd2、GD3、聚焦GM1和globo H中。
Polysialic acid (polySA) is a polymer side chain bound to the neural cell adhesion molecule that is extensively expressed on the surface of small cell lung cancer (SCLC) cells. In our previous study, a robust antibody response was noted in patients with SCLC after vaccination with 30 μg of keyhole limpet hemocyanin (KLH)-conjugated N-propionylated (NP-) polySA, but peripheral neuropathy and ataxia were detected in several vaccinated patients. The objectives of the current trial were to establish the lowest optimal dose and to confirm the safety of the induction of antibodies against polySA with the NP-polySA vaccine. Patients with SCLC who completed initial treatment and had no evidence of disease progression were injected with either 10 or 3 μg of NP-polySA conjugated to KLH and mixed with 100 μg of immunologic adjuvant (QS-21) at weeks 1, 2, 3, 4, 8, and 16. Nine patients were enrolled at each of the two dose levels. Prior to vaccination, one patient in each group had low-titer antibodies against polysialic acid. All patients at the 10 μg vaccine dose level responded to vaccination with IgM antibody titers against polysialic acid (median titer 1/1,280 by ELISA), and all but one patient made IgM and IgG antibodies against the artificial vaccine immunogen, NP-polysialic acid (median titer 1/10,240). The antibody responses at the 3 μg vaccine dose level were lower; six of nine patients developed antibodies against polysialic acid (median titer 1/160). Post-vaccination sera from 6/9 and 3/9 patients in the 10 and 3 μg groups reacted strongly with human SCLC cells by fluorescent-activated cell sorting (FACS). Sera from all patients in the 10 μg dose group also had bactericidal activity against group B meningococci with rabbit complement. Self-limited grade 3 ataxia of unclear etiology was seen in 1 of 18 patients. Vaccination with NP-polySA–KLH resulted in consistent high-titer antibody responses, with the 10 μg dose significantly more immunogenic than the 3 μg dose. This study establishes the lowest optimally immunogenic dose of NP-polysialic acid in this NP-polysialic acid–KLH conjugate vaccine to be at least 10 μg, and it establishes the vaccine’s safety. We plan to incorporate NP-polySA into a polyvalent vaccine against SCLC with four glycolipid antigens also widely expressed in SCLC–GD2, GD3, fucosylated GM1, and globo H.
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影响因子：
5.6
作者：
Lantuejoul, S;Moro, D;Brambilla, E
通讯作者：
Brambilla, E
影响因子：
11.5
作者：
Krug, LM;Ragupathi, G;Livingston, PO
通讯作者：
Livingston, PO
影响因子：
1.9
作者：
Yao, TJ;Begg, CB;Livingston, PO
通讯作者：
Livingston, PO
DOI：
10.1073/pnas.96.10.5710
发表时间：
1999-05-11
影响因子：
11.1
作者：
Slovin, SF;Ragupathi, G;Scher, HI
通讯作者：
Scher, HI
DOI：
10.1084/jem.185.11.1929
发表时间：
1997-06-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pon RA;Lussier M;Yang QL;Jennings HJ
通讯作者：
Jennings HJ