CN1732017A - 用于治疗瘤形成的生长和激素调节因子的组合 - Google Patents
用于治疗瘤形成的生长和激素调节因子的组合 Download PDFInfo
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- CN1732017A CN1732017A CNA2003801075594A CN200380107559A CN1732017A CN 1732017 A CN1732017 A CN 1732017A CN A2003801075594 A CNA2003801075594 A CN A2003801075594A CN 200380107559 A CN200380107559 A CN 200380107559A CN 1732017 A CN1732017 A CN 1732017A
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Abstract
本发明涉及免疫学、内分泌学和肿瘤学领域,具体而言,涉及对确定的生长和激素因子产生组合的免疫应答。此处描述的生长调节因子(EGF,TGF和VEGF)和参与性激素释放级联或再生的激素(GnRH,LH,FSH)之间的协同作用刺激抗肿瘤应答,表现为肿块的减小和存活时间的增加。
Description
发明领域
本发明主要涉及免疫学、内分泌学和肿瘤学领域,具体而言,涉及包含生长调节因子(EGF、TGF、VEGF)和性激素和/或参与性激素释放级联或再生激素的激素的组合的药物组合物,其引起治疗瘤形成的组合的自身免疫应答。
现有技术
促性腺激素释放激素(GnRH),也称为促黄体生成激素释放激素(LHRH),是负责垂体前叶的黄体生成素(LH)和促卵泡激素(FSH)释放的下丘脑肽性(peptidic)激素。
除了下丘脑系统产生的GnRH之外,还有在其他大脑部位(JennesL,Conn P.M.‘’Gonodatripin-releasing hormone and its receptorsin the rat brain”.Front Neuroendocrinol.1994,vol.15,pp.51-77),以及大鼠卵巢颗粒体细胞(Peng C.,Fan N.C.,Ligier M.,Vaananen J.,Leung P.C.‘’Expression and regulation ofgonadotropin-releasing hormone(GnRH)and GnRH receptormessenger ribonucleic acids in human granulosa-luteal cells”.Endocrinology 1994,vol.135,pp.1740-1746),睾丸细胞(DiMatteo L.,Vallarino M.,Pierantoni R.“Localization of GnRHmolecular forms in the brain,pituitary and testis of the frog,Rana esculenta”.J.Exp.Zool.1996,vol.247,pp33-40),人胎盘(Gohar J.,Mazor M.,Lieberman J.R.“GnRH in pregnancy”Arch.Gynecol.Obstet.1996,vol 259,pp1-6),免疫系统(Jacobson J.D.,Crofford L.J.,Sun L.,Wilder R.L.“Cyclicalexpression of GnRH and GnRH receptor mRNA in lymphoid organs”.Neuroendocrinology 1998,vol.67,pp.117-125),和脑下垂体(Bauer T.W.,Moriarty C.M.,Childs G.V.“Studies ofimmunoreactive gonadotropin releasing hormone(GnRH)in the ratanterior pituitary”.J.Histochem.Cytochem,1981,vol 29,pp1171-1178)产生GnRH的证据。
性腺切除术(Gonadectomy)是众所周知的治疗依赖性类固醇的肿瘤所必需的治疗方法。GnRH类似物能不仅通过化学去势(castration)而且通过对肿瘤细胞的直接作用发挥其抗肿瘤活性(Couillard S.,Labrie C.,Belanger A.,Candas B.,Pouliot F.,Labrie F.“Effect of dehydroepiandrosterone and anti-androgenEM-800 on growth of human ZR-75-1 breast cancer xenografts”.J.Nat.Cancer Inst.1998,May 20,pp.772-778;Kolle S.等人,“Expression of growth hormone receptor in human prostaticcarcinoma and hyperplasia”.Int.J.Oncol.1999,vol.14,No.5,pp.911-916)。
同样,已经报道GnRH拮抗剂(MZ-4-71)能抑制雄激素非依赖性前列腺癌症细胞系PC-3,DU-145和Dunning AT-1的生长(AJungwirth等人,“Inhibition of in vivo proliferation ofandrogen-independent prostate cancers by an antagonist ofgrowth hormone-releasing hormone”.British Journal of Cancer1997,vol.75,No.11,pp.1585-1592)。
Dunning cell line R3327-G已经被广泛用于通常与治疗前列腺肿瘤相关的不同研究,以及现今建立完善的方法。在对雄激素敏感的前列腺肿瘤模型Dunning R3327中已经发现EGF受体(Damber J.E.,Bergh B.,Gafvels M.“Epidermal growth factor receptor contentin rat prostatic adenocarcinoma:effects of endocrinetreatment”.Urol.Res.1995,vol 23,No.2,pp.119-25)。也已经表明在Dunning R3327-G亚系中,EGF受体的表达在促成雄性性状的协调控制下(Coordinate loss of growth factors followingcastration of rats carrying the Dunning R3327 G prostatictumor“Clin Physiol Biochem,1992,vol.9,No.2,pp.47-50.)。
表皮生长因子(EGF)是53个氨基酸的多肽,具有大约6045Da的分子量,其体内和体外刺激上皮细胞和间充质细胞的增殖(CohenS.,Carpenter G.,“Human Epidermal Growth Factor:Isolation andchemical and biological properties”PNAS USA,1975,vol.72pp.1317)。EGF的作用通过在细胞膜上的特定受体发挥。首次在鼠颌下腺中分离和纯化了EGF(Cohen S.J.Biol.Chem.1962,vol.237,No.1,pp.555)。后来在人尿中获得类似的分子(Cohen S.“HumanEpidermal Growth Factor:Isolation and Chemical and BiologicalProtperties“,PNAS USA 1975,vol 72,pp.1317)。
通过膜受体(EGF-R)发挥EGF的生物调节作用,所述的膜受体为大约170KDa的糖蛋白,其基因已经被克隆和测序。该受体的分子内结构域与特定的酪氨酸激酶蛋白活性相关,与癌基因v-erb-B具有结构同源性,这表明与恶性转化过程有某种关系(Helding C.H.Cell,1984,vol.37,pp.9-20)。
EGF-R在肿瘤细胞中的存在支持了有关人乳腺癌的保守性预测。大约40%的乳腺肿瘤具有EGF的高亲和性特异结合位点(Rios M.A.等,“Receptors for Epidermal Growth Factor and EstrogenPredictors of Relapse in Patients with Mammary Carcinoma”Anticancer Research 1998,vol.8,pp.173-176)。也与针对EGF-R的雌激素受体的存在逆相关,所述的针对EGF-R的雌激素受体作为差异标记或恶性细胞的潜在增殖能力的指示剂(Perez R.,Pascual M.R.,Macias A.,Lage A.Breast Cancer Research and Treatment 1984,vol.4.pp189-193)。
以前建立在Balb/c小鼠Ehrlich腹水肿瘤模型中的研究(Lombardero J.等人,Neoplasma 1987,vol.33 pp.4)证实了EGF的体内抑制作用,表明将该分子视为生物学应答转换器(transformer)的可能性。
已经建立了含有偶联于载体蛋白的自体EGF的疫苗组合物,其抑制EGF依赖型肿瘤生长,具有免疫作用,没有副作用(US 5894018:具有抗肿瘤活性的包含自体表皮生长因子或其片段或衍生物的疫苗组合物,及其在治疗恶性疾病中的用途)。
以前的研究已经报道,与腹部前列腺相比,Dunning肿瘤表达高水平的血管内皮生长因子(VEGF)及其受体的mRNA(“Expression ofvascular endothelial growth factor and its receptors in theventral prostate and Dunning R3327 PAP adenocarcinoma beforeand after castration”,Prostate 1998,vol.36,No.2,pp.71-79)。在动物模型中的检测已经表明雄性性状的丧失可能导致血管衰退,VEGF可能受雄激素调节。在人类前列腺癌症中,腺上皮细胞的VEGF的组成型产生由于雄性性征切除疗法而受到抑制。VEGF的丧失导致缺乏外周内皮细胞的血管中内皮细胞的选择性凋亡(Laura E.等:“Selective ablation of immature blood vessels in establishedhuman tumors follows vascular endothelial growth factorwithdrawal”J.Clin.Inveest.1999,vol.103,No.2,pp.159-165)。
VEGF是内皮细胞的特异促血管生成和维管形成的促分裂原,在病理性血管形成重发挥作用,其与许多临床病理学相关,包括癌症和类风湿性关节炎。VEGF是glycosilated、二硫化物连接的同型二聚体,在人体中表达为121-206个残基的不同同种型(VEGF 121,VEGF 165,VEGF 189和VEGF 206)(Yves A.Muller等,“The crystal structureof vascular endothelial growth factor(VEGF)refined to 1.93A resolution:Multiple copy flexibility and receptor binding”Structure,1997,vol.5,No.10pp.1325-1338.)。
通常,肿瘤细胞对外源生长信号表现极低的依赖性,并能够产生许多其自身的生长信号。该信号非依赖性以许多方式产生,损害非常重要的稳态行为,所述的稳态行为通常用于保证组织内几种细胞的适当的行为。
为达到生长信号自治,细胞已经产生了改变细胞外生长信号的机制,由这些信号的跨细胞转换器起作用(Douglas H.and Robert A.W.“The Hallmarks of Cancer(Review)”Cell 2000,vol.100,pp.57-70)。尽管大多数生长因子由一种细胞类型产生以刺激其他细胞的增殖(异源型信号传递过程(process of heterotypical signaling)),但是大量的癌症细胞能够合成生长因子,通过正反馈连接(自分泌刺激)对其应答。
某些生长因子的受体,其通常在其胞质结构域具有酪氨酸激酶活性,在许多种类的癌症细胞中过表达,并导致对正常浓度的生长因子过度反应。生长因子受体的过表达可能引起配体非依赖性信号传导。受体的结构性改变(EGF受体可能丢失其部分胞质结构域并因此产生信号)也可能引起配体非依赖性信号传导。
因为生长因子的作用,SOS-Ras-Raf-MAPK级联在信号转导中发挥重要作用。25%的人类肿瘤具有调节Ras蛋白表达的问题,尽管生长信号途径在所以人类肿瘤中发生改变(几乎一半的人结肠癌具有突变的ras癌基因,其余的在其他信号转导途径元件中有缺陷)。
正常细胞,如成纤维细胞和内皮细胞可能在肿瘤细胞的增殖中发挥关键的作用。在正常组织中,细胞通过其相邻信号(旁分泌)或全身信号(内分泌)促进生长。因此,为解释肿瘤增殖,应该将肿瘤内几种类型细胞间的异向(heterotrophic)信号传导视为与上述的自主机制同样重要。在此意义上,由维管结构供给的氧和其他营养是这些功能以及肿瘤细胞存活所必须的。
诱导持续的血管生成的能力是肿瘤发展的各个步骤所需的,通过血管静止的“促血管生成开关(angiogenic switch)”。新血管形成是与大的肿瘤形成相关的克隆性扩增的先决条件。
细胞系中的生长因子的mytogenic作用可以被GnRH类似物抵抗,其显示GnRH与信号转导mytogenic途径的相互作用。这种假设由酪氨酸激酶活性抑制得到证明,所述的酪氨酸激酶活性抑制由来自由于GnRH激动剂导致的卵巢和子宫内膜的人肿瘤细胞中的生长因子诱导,其部分由于GnRH活化诱导的磷酸酪氨酸磷酸酶。
用GnRH类似物的处理与肿瘤细胞膜上的生长因子受体(EGF,胰岛素样生长因子1(IGF-1))的极大降低以及肿瘤中EGF-R的mRNA水平的极大增加相关。另外,已经报道了某些肿瘤系中抗增殖活性和针对雌激素和雄激素的受体表达的改变。
超过四分之一世纪的癌症研究的进步积累了确定的证据,其证实了肿瘤的形成为多阶段的恶性动态过程。大量的恶性细胞表型是细胞生理学实质改变的体现。这些转化一起促进了不同类型的肿瘤中组织恶性生长。因此,尚未解决的有关癌症治疗的重要问题是实现主动和被动免疫应答的调节。
发明简述
本发明是前述问题的解决方案,使用包含生长调节因子(EGF,TGF,VEGF)和性激素,和/或参与性激素释放级联或参与再生的激素(GnRH,LH,FSH)的新的药物组合。该组合用于治疗肿瘤形成,并根据情况,该组合的活性组分可以同时、分开或顺序使用。
在临床前实验中,针对上述生长因子和激素的组合的免疫应答的产生获得的结果比独立产生的针对这些因子和激素的免疫应答获得的结果好。这些结果证明了对于不同来源的肿瘤形成的患者的治疗提供了更有效的方法,因为存在表现为肿块的降低和存活时间延长的改善的抗肿瘤应答。
具体而言,本发明涉及用于治疗肿瘤形成的药物组合物,用于同时、分开或顺序给药,其包含化合物A和化合物B;其中A和B选自下列分子:
A:
a.1.GnRH,或其类似物,或抗GnRH抗体,或GnRH受体(GnRH-R),或其突变的变体,或衍生肽,或抗GnRH抗体,偶联或没有偶联免疫增强载体蛋白;
a.2.天然或重组的促性腺激素,或其类似物,或其突变的变体,偶联或没有偶联免疫增强载体蛋白,抗促性腺激素抗体,其Fabs,scFV片段,人源化或非人源化;
a.3.促性腺激素受体,或其突变的变体,或衍生肽,偶联或没有偶联免疫增强载体蛋白;
a.4.抗促性腺激素受体抗体,其Fabs,scFV片段,人源化或非人源化;
B:
b.1.天然或重组的EGF或其突变的变体,或衍生肽,或EGF模拟肽,或EGF类似物,偶联或没有偶联免疫增强载体蛋白;
b.2.抗EGF抗体,其Fabs、scFV片段,人源化或非人源化;
b.3.EGF受体(EGF-R),或其突变的变体,或衍生肽,偶联或没有偶联免疫增强载体蛋白;
b.4.抗EGF受体抗体,其Fabs,scFV片段,人源化或非人源化;
b.5.天然或重组的VEGF或其突变的变体,或衍生肽,或VEGF模拟肽,或VEGF类似物,偶联或没有偶联免疫增强载体蛋白;
b.6.抗VEGF抗体,其Fabs,scFV片段,人源化或非人源化;
b.7.VEGF受体,或其突变的变体,或来自VEGF受体的衍生肽,偶联或没有偶联免疫增强载体蛋白;
b.8.抗VEGF受体抗体,其Fabs,scFV片段,人源化或非人源化;
b.9.天然或重组的TGF或其突变的变体,或衍生肽,或TGF模拟肽,或TGF类似物,偶联或没有偶联免疫增强载体蛋白;
b.10.抗TGF抗体,其Fabs,scFV片段,人源化或非人源化;
b.11.TGF受体(TGF-R),或其突变的变体,或衍生肽。
在优选的方案中,所述的包含A或B组的分子的药物组合通过缀合或形成嵌合蛋白与免疫增强蛋白偶联。更具有而言,在A分子内,GnRH类似物肽具有序列pGlu-His-Trp-Ser-Tyr-Pro-Leu-Arg-Pro-Gly。
本发明的另外的实施方案中,所选择的免疫增强蛋白可以是脑膜炎奈瑟氏球菌(Neisseria meningitides)P1或P64外膜蛋白之一,或破伤风类毒素(Teatanic Toxoid)(TT)的T辅助表位。
同样,本发明涉及药物组合,其中缀合的或嵌合的蛋白是下列变体之一:
b)结合于载体蛋白和EGF的GnRH;
c)结合于载体蛋白和VEGF的GnRH;
d)结合于载体蛋白和TGF的GnRH;
e)结合于载体蛋白、EGF和TGF的GnRH;
f)结合于载体蛋白、VEGF和EGF的GnRH。
本发明提供了产生组合免疫应答的方法,其包括用可以被同时、分开或顺序使用的本发明定义的药物组合的处理。
利用下列方法进一步详细描述本发明。获得包含偶联于破伤风类毒素T辅助表位(D3-1)的突变的GnRH作为组合的制剂的组分之一的免疫原性制剂。
为了实现针对GnRH的抗体应答,使用了缀合载体蛋白(哺乳动物免疫去势疫苗,EPO 959079)的GnRH类似物肽免疫。使用两个甘氨酸作为间隔子,通过固相法和Boc/Bzl策略,使用“4-甲基-benzhydrilamine”(MBH A-0.75mmol/g,BACHEM,Swiss)化学合成GnRH类似物肽(pGlu-His-Trp-Ser-Tyr-Pro-Leu-Arg-Pro-Gly)和载体蛋白(破伤风类毒素T-辅助表位)。
通过用偶联载体蛋白的天然GnRH或其任一类似物的主动免疫可以获得针对GnRH的体液应答。另外,GnRH类似物、激动剂或拮抗剂,可用于该类组合制剂,对降低肿块具有协同作用,因为它们阻断或削弱带有其受体的细胞中通过蛋白G的信号传导。抗GnRH抗体可以用作组合组分产生被动免疫应答。如果与生长因子组合来产生自身免疫应答,垂体促性腺激素黄体生成素(LH)和促卵泡激素(FSH)可同样在某些类型的肿瘤中具有协同效果。
获得包含偶联载体蛋白的重组的表皮生长因子(hrEGF)作为组合制剂的一种组分的免疫原性制剂。
将PBS/MgCl2 10mM中的重组人表皮生长因子(hrEGF)(NationalMedicament Register Office,Cuba,HEBERMIN,No.1266)的溶液与相同溶剂中的载体蛋白溶液(重组P64,脑膜炎奈瑟氏球菌外膜)混合,每mol蛋白1-5mol的hrEGF。接着,加入0.05%的戊二醛至终浓度0.05-0.1%。混合物室温温育1-3小时,并在PBS/MgCl2 10mM中透析,至少更换3次透析液(具有抗肿瘤活性的包含类似物表皮生长因子或其片段或衍生物的疫苗组合物及其在治疗恶性疾病中的用途,US,5894018)。
对EGF的体液应答可以通过偶联免疫增强载体蛋白的EGF或其受体的肽免疫,被动地获得或直接给药抗EGF抗体或抗EGF受体获得。
EGF与转化生长因子TGF有大约30%的序列相同。它们竞争膜受体的相同结合位点。另外,据报道在不同类型的人类肿瘤中有大量的αTGF/EGF受体复合物。因此很明显,在肿瘤形成中对TGF的体液应答非常重要,在对于EGF所述的协同性上同样重要。
获得包含偶联载体蛋白的人血管内皮生长因子(hVEGF)作为组合制剂的组分之一的免疫原性制剂。
通过使用缀合于载体蛋白(KLH,匙孔血蓝蛋白)的VEGF肽(hVEGF-KLH)免疫获得对VEGF的体液应答。缀合于KLH的HVEGF121同种型使用可溶性碳二亚胺偶联制备。
对VEGF的体液应答也可以通过用偶联任何免疫增强载体蛋白的VEGF或其受体的免疫被动获得或直接使用抗VEGF受体获得。
获得GnRH和hrEGF的组合免疫原性制剂。
通过在0.5ml的终体积中混合750μg的D3-1和250μg的hrEGF-P64获得组合组合免疫原性制剂。
获得GnRH和hVEGF的组合免疫原性制剂。
通过在0.5ml的终体积中混合750μg的D3-1和100μg的hVEGF-KLH获得组合免疫原性制剂。
附图简述
图1显示了接受不同处理的植入肿瘤系Dunning R 3327-G的哥本哈根大鼠的存活时间评价。
特定实施方案/实施例的详细描述
本发明通过下列实施例来举例说明
1.在哥本哈根大鼠中植入肿瘤细胞系R3327-G。
将肿瘤细胞系Dunning R3327-G植入9-12周龄的哥本哈根大鼠中(每个体重大约100g),在侧腹松弛区用移植培养基(RPMI 1640,无血清,0.5ml)中每只动物2×106个细胞的密度接受不同的处理。90天后在动物中获得100%的附着效率。
2.作为植入了肿瘤系Dunnning 3327-G的大鼠接受不同处理的抗肿瘤活性标准的存活时间的评价。
建立每组10只的8组动物用于实验,使用如前所述的哥本哈根大鼠。
实验组:
1.空白对照动物(用油佐剂中的PBS免疫)。
2.手术去势(castrated)动物。
3.用DES(dietilestilbestrol)处理的动物。
4.用肽D3-1(GnRHml-TT)免疫的动物。
5.用hrEGF-P64免疫的动物。
6.用hVEGF-KHL免疫的动物。
7.用组合制剂D3-1+hrEGF-P64免疫的动物。
8.用组合制剂D3-1+hVEGF-KLH免疫的动物。
用于处理的免疫方案包括7次(3次移植前和4次移植后),每两星期给药:750μg的D3-1,250μg的hrEGF-P64,100μg的hrEGF-KLH,以及组合D3-1+hrEGF-P64和D3-1+hVEGF-KLH在0.5ml体积的油性佐剂中(在第一次免疫时用弗氏完全佐剂,在进一步刺激时用弗氏不完全佐剂),在脊柱两侧的4个位点,皮下。在组合处理中保持如独立处理时所用的相同的抗原剂量。
间断(on and off)的进行DES处理,每周3次,1ml/kg/天,持续直至实验结束,并且一旦接种细胞时就开始。
在肿瘤移植程序前30-45天开始免疫,并持续直至完成7次免疫;因此表示为抗体滴度的ELISA检测中的体液应答高于细胞接种前的每种抗原的截断值(cut off value)。
在实验过程中(13个月)每周进行1次处理效果的评价。该效果评价为每个实验组中动物的存活时间。数据如图1所示。
3.作为植入了肿瘤细胞系Dunning R3327-G的大鼠接受不同处理的抗肿瘤活性标准的肿瘤减小的评价。
建立每组10只的8组动物用于实验,使用如前所述的哥本哈根大鼠。
实验组:
1.空白对照动物(用油佐剂中的PBS免疫)。
2.手术去势(castrated)动物。
3.用DES(dietilestilbestrol)处理的动物。
4.用肽D3-1(GnRHml-TT)免疫的动物。
5.用hrEGF-P64免疫的动物。
6.用hVEGF-KHL免疫的动物。
7.用组合制剂D3-1+hrEGF-P64免疫的动物。
8.用组合制剂D3-1+hVEGF-KLH免疫的动物。
如前所述,用于处理的免疫方案包括7次(3次移植前和4次移植后),每两星期给药:750μg的D3-1,250μg的hrEGF-P64,100μg的hVEGF-KLH以及他们的组合,0.5ml,在油性佐剂中(在第一次免疫时用弗氏完全佐剂,在进一步刺激时用弗氏不完全佐剂),在脊柱两侧的4个位点,皮下。
间断的进行DES处理,每周3次,1ml/kg/天,只要实验持续,并且一旦接种细胞时就开始。
在处死动物后进行实验的评价(肿瘤植入后3个月)。为评价每种处理的效果,干燥肿瘤并在技术天平上称重。处理效果(E处理)为1减去处理动物(P处理)的肿瘤平均重量和空白对照动物(P空白对照)的肿瘤平均重量的比:
E处理=1-(P处理/P空白对照)。 (1)
如果每种效果不互相排除,可以根据下式计算双组合制剂的预计效果(E理论的)(Caridad W.,Guerra Bustillo,Ernes to Menendez Acuna,Rolando Barrera Morena,Esteban Egana Morales.“Estadistica”,Editorial Pueblo y Educacion,1989):
E理论的=ET1+ET2-(ET1*ET2). (2)
其中:ET1处理1的效果,ET2是处理2的效果
如表1所示,组合物(组合的制剂)获得的实验效果高于预计的理论效果,因此证明了这些组合物降低肿瘤大小的协同作用。
表1.对植入肿瘤细胞系Dunning R3327-G的哥本哈根大鼠在处死时(肿瘤细胞系移植后3个月)的不同的处理效果。
处理 | 肿瘤重量(g)(10只动物的平均值) | 处理效果 | 理论效果 |
去势的 | 9.20 | 0.707 | - |
空白对照 | 31.41 | 0.000 | - |
DES | 12.66 | 0.597 | - |
D3-1 | 19.31 | 0.385 | - |
hrEGF-P64 | 25.43 | 0.190 | - |
hVEGF-KLH | 21.72 | 0.309 | - |
D3-1+hEGFr-P64 | 12.14 | 0.613 | 0.502 |
D3-1+hVEGF-KLH | 10.87 | 0.654 | 0.575 |
Claims (8)
1.用于通过同时、分开或顺序给药治疗肿瘤形成的药物组合,其包含化合物A和B,其中A和B选自下列分子:
A:
a.1.GnRH,或其类似物或抗GnRH抗体,或GnRH受体(GnRH-R),或其突变的变体,或衍生肽,或抗GnRH-R抗体,偶联或没有偶联免疫增强载体蛋白;
a.2.天然或重组的促性腺激素,或其类似物,或其突变的变体,偶联或没有偶联免疫增强载体蛋白,垂体抗促性腺激素抗体,其Fags,scFV片段,人源化或非人源化;
a.3.垂体促性腺激素受体,或其突变的变体,或衍生肽,偶联或没有偶联免疫增强载体蛋白;
a.4.垂体促性腺激素抗受体抗体,其Fabs、scFV片段,人源化或非人源化;
B:
b.1.天然或重组的EGF或其突变的变体,或衍生肽,或EGF模拟肽,或EGF类似物,偶联或没有偶联免疫增强载体蛋白;
b.2.抗EGF抗体,其Fabs、scFV片段,人源化或非人源化;
b.3.EGF受体(EGF-R),或其突变的变体,或衍生肽,偶联或没有偶联免疫增强载体蛋白;
b.4.抗EGF受体抗体,其Fabs、scFV片段,人源化或非人源化;
b.5.天然或重组的VEGF或其突变的变体,或衍生肽,或VEGF模拟肽,或VEGF类似物,偶联或没有偶联免疫增强载体蛋白;
b.6.抗VEGF抗体,其Fabs、scFV片段,人源化或非人源化;
b.7.VEGF受体,或其突变的变体,或来自VEGF受体的衍生肽,偶联或没有偶联免疫增强载体蛋白;
b.8.抗VEGF受体抗体,其Fabs、scFV片段,人源化或非人源化;
b.9.天然或重组的TGF或其突变的变体,或衍生肽,或TGF模拟肽,或TGF类似物,偶联或没有偶联免疫增强载体蛋白;
b.10.抗TGF抗体,其Fabs,scFV片段,人源化或非人源化;
b.11.TGF受体(TGF-R),或其突变的变体,或衍生肽,偶联或没有偶联免疫增强载体蛋白。
2.权利要求1的组合,其中A组和B组分子通过缀合或形成嵌合蛋白与免疫增强载体蛋白偶联。
3.权利要求1和2的组合,其中GnRH类似物肽具有序列pGlu-His-Trp-Ser-Tyr-Pro-Leu-Arg-Pro-Gly,偶联免疫增强载体蛋白。
4.权利要求1和2的组合物,其中的免疫增强载体蛋白选自脑膜炎奈瑟氏球菌(Neisseria meningitides)P1和P64外膜蛋白。
5.权利要求1和2的组合物,其中的免疫增强载体蛋白是破伤风类毒素(TT)T辅助表位。
6.权利要求1和2的组合物,其中缀合的嵌合蛋白是下列变体之
a)结合于载体蛋白和EGF的GnRH;
b)结合于载体蛋白和VEGF的GnRH;
c)结合于载体蛋白和TGF的GnRH;
d)结合于载体蛋白、EGF和TGF的GnRH;
e)结合于载体蛋白、VEGF和EGF的GnRH。
7.产生组合免疫应答的方法,其包括用权利要求1-6任一项定义的药物组合之一处理。
8.权利要求7的方法,其中所述的组合物可以同时,分开或顺序使用。
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CN110418799A (zh) * | 2017-01-20 | 2019-11-05 | 免疫系统调节控股有限公司 | 新型化合物(免疫刺激肽) |
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CN104004762B (zh) * | 2014-05-20 | 2016-03-30 | 南京医科大学附属南京儿童医院 | Tgf-r反义序列及其在制备抗气道炎症反应药物中的应用 |
CN110418799A (zh) * | 2017-01-20 | 2019-11-05 | 免疫系统调节控股有限公司 | 新型化合物(免疫刺激肽) |
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