CN1299766C - TGF－β和生长因子在治疗和预防肠粘膜疾病中的用途 - Google Patents
TGF－β和生长因子在治疗和预防肠粘膜疾病中的用途 Download PDFInfo
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- CN1299766C CN1299766C CNB2004100749613A CN200410074961A CN1299766C CN 1299766 C CN1299766 C CN 1299766C CN B2004100749613 A CNB2004100749613 A CN B2004100749613A CN 200410074961 A CN200410074961 A CN 200410074961A CN 1299766 C CN1299766 C CN 1299766C
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Abstract
本发明涉及转化生长因子β(TGF-β)在制备用于治疗和/或预防肠粘膜功能障碍或肠粘膜疾病的药物或营养组合物中的用途，该药物或营养组合物包含TGF-β和一种或多种TGF-β结合因子，基本上不存在胰岛素样生长因子-1(IGF-1)，所述TGF-β从哺乳动物乳清产品提取获得。本发明还涉及一种药物或营养组合物，其包含转化生长因子β(TGF-β)和一种或多种TGF-β结合因子，基本上不存在胰岛素样生长因子-1(IGF-1)，所述TGF-β从哺乳动物乳清产品提取获得。
Description
本申请是2000年10月6日提交的，发明名称为“TGF-β和生长因子在治疗和预防肠粘膜疾病中的用途”的中国专利申请00814004.9的分案申请。
技术领域
本发明涉及含有转化生长因子β(TGF-β)的组合物和含有合成代谢生长因子(AGF)，尤其是胰岛素样生长因子1(IGF-1)的组合物在预防或治疗肠粘膜功能障碍或肠粘膜疾病中的用途。本发明还涉及同样可以用于这种治疗的，含有TGF-β和特定纤维和/或免疫球蛋白和/或钙的组合物，尤其是其可以与IGF-1组合用于该治疗。含有TGF-β的组合物在期望抑制细胞增殖和刺激细胞分化的时段内给予。给予含有IGF-1的组合物以修复肠上皮细胞。
背景技术
TGF-β是在所有哺乳动物组织中发现的多功能蛋白。目前已知五种形式的TGF-β，β1至β5。它与组织发育、分化和生长以及免疫系统功能控制和癌发生有关。可以从天然来源(例如血小板)、哺乳动物乳或初乳中分离TGF-β，或者可以由重组细胞产生TGF-β。
IGF-1是一种小蛋白质(分子量约7800)，它在骨代谢中起重要作用。已证明它刺激培养物中的细胞生长。动物在垂体缺乏、正常和分解代谢状态下的生长也得到刺激。肾功能也得到改善。已经使用重组DNA技术、固相肽合成生产之，并从血浆或从人乳或牛乳中分离之。
TGF-β及其用途在例如EP 852913中有所描述。该文献涉及肠内营养制剂，它含有富TGF-β2酪蛋白、脂质源如中链或长链甘油三酯或多不饱和脂肪酸和碳水化合物源，即麦芽糖糊精、玉米淀粉或蔗糖。该组合物用于治疗或预防胃肠道炎症，如局限性回肠炎。
EP 462398描述了用于治疗肿瘤疾病的TGF-β1和多不饱和脂肪酸(PUFA)的组合，多不饱和脂肪酸如亚油酸、α-亚麻酸、γ-亚麻酸、花生四烯酸、二同型γ-亚麻酸、二十碳五烯酸和/或二十二碳六烯酸(docosahexanoic acid)和/或它们的衍生物。
WO 96/34614描述了预防和/或治疗因化疗和/或放疗引起的消化道内层损伤的方法，其中将含有细胞生长因子混合物的乳产品提取物给予患者。该乳产品提取物优选是干酪乳清提取物，它可以含有乳铁蛋白和乳过氧化物酶，且它还可以补充有生长因子如IGF-1、IGF-2、TGF-β、TGF-α、EGF、PDGF、FGF或KGF。该文献没有提到为了实现期望的预防或治疗作用而应该存在哪种所提到的物质。
在S.T.Sonis等，Cancer Res.54：1135-1138(1994)；“Prevention of chemotherapy induced ulcerativemucositis by transforming growth factor β3(通过转化生长因子β3预防化疗诱导的溃疡性粘膜炎)一文中，描述了给予TGF-β3降低体内和体外口腔上皮的增殖。在化疗前给叙利亚金黄仓鼠的口粘膜局部施用TGF-β3显著降低口粘膜炎的发生率、严重性和持续时间，降低与化疗相关的体重减轻并增加存活率。根据该文献预防粘膜炎基于通过预先给予负生长调节物以限制基底上皮细胞增殖。
US 5,842,297描述了可以给予TGF-β3以减慢个体中正常细胞的生长，从而抑制正常细胞的细胞毒素中毒。通常在抗肿瘤治疗前给予TGF-β3。进一步建议在肿瘤治疗后，可以给予上皮细胞促有丝分裂剂。该文献的方法的缺点在于优选使用得自重组技术的生长因子。但是，已经证明这种类型的生长因子在灭菌处理期间不太稳定。而且这些生长因子在胃肠道中的生物利用度还不令人满意。
发明内容
根据本发明发现，为了最好地保护肠粘膜免受化疗和放疗的损伤，应在化疗或放疗期间，在不存在IGF-1的情况下，尤其是不存在任何合成代谢生长因子的情况下给予TGF-β。从哺乳动物乳产品提取获得的TGF-β导致更好的生长因子生物利用度和增加的稳定性。进一步发现，化疗或放疗后，在该治疗期间可能已经发生的损伤效应可以通过在基本上不存在TGF-β的情况下给予合成代谢因子，尤其是IGF-1而得到治疗。根据本发明，还发现在炎症性肠病(IBD)，如局限性回肠炎的情况中，同样顺序地给予TGF-β和IGF-1可能是有益的。
因此，本发明提供TGF-β和AGF在制备用于治疗和/或预防肠粘膜功能障碍和肠粘膜疾病的产品中的用途；所述产品包含：
a)基本上不存在IGF-1的包含从哺乳动物乳产品提取获得的TGF-β的第一药物组合物；
b)基本上不存在TGF-β的包含AGF的第二药物组合物；其中依次给予第一和第二组合物。
优选地，第一药物组合物中TGF-β/IGF-1的重量比为至少100。
已经发现当使用生长因子混合物时，例如使用乳产品提取物时，TGF-β的有益效果因合成代谢生长因子的存在而降低。因此，优选在基本上不存在这种生长因子的情况下给予TGF-β。
具体实施方案
根据本发明的优选实施方案，第一药物组合物包含TGF-β，基本上不存在AGF。AGF指任何合成代谢生长因子，即任何促进细胞生长的生长因子。其实例是：IGF-1、胰岛素样生长因子2(IGF-2)、生长激素、上皮细胞生长因子(EGF)、转化生长因子α(TGF-α)、哺乳动物乳生长因子(MMGF＝β-动物纤维素)和成纤维细胞生长因子(FGF)。例如，EGF在EP 0546 068中有所描述，MMGF在WO99/24470中有所描述。TGF-β/AGF的比优选为至少50。
优选地，第二药物组合物中的AGF是IGF-1。这意味着优选至少IGF-1存在于第二药物组合物中。
根据本发明，当提到生长因子时，也包括这些生长因子的活性肽类似物。肽类似物指任何具有与生长因子基本上相同活性的肽，尤其是那些与生长因子90％或90％以上同源的肽类似物。
根据本发明，术语“药物组合物”包括任何常规药物制剂，如胶囊剂、片剂等，以及饮食制剂如饮食补充(feed supplement)或完全饮食(total feed)。
根据本发明，含有TGF-β的第一药物组合物和含有AGF，优选至少含有IGF-1的第二药物组合物的依次给予尤其适用于可以区分为两个阶段的肠疾病。第一阶段是期望抑制代谢的阶段。在第一阶段后的第二阶段期间，需要修复肠上皮细胞。在第一阶段期间给予含有TGF-β的组合物，在第二阶段期间给予含有合成代谢生长因子，尤其是IGF-1的组合物。
更具体地说，依次给予TGF-β和IGF-1，用于预防和/或治疗因化疗和/或放疗引起的肠粘膜损伤。术语“损伤”指正常结构或功能的任何改变。这种损伤包括粘膜炎、粘膜隐窝区和/或粘膜绒毛长度的至少部分损失，或者消化道的细菌转运增加。
化疗和/或放疗在破坏肿瘤方面有效，因为它们靶向于快速增长组织。当抗癌治疗选择性地靶向于肿瘤细胞时，宿主的快速生长组织也易感，尤其是机体免疫细胞和消化道内层。这可能导致口和食管内层损伤(粘膜炎，也称为口炎)和肠内层损伤，通常在小肠，较少发生在大肠，导致严重的腹泻和疼痛。
根据本发明发现，为了最好地保护肠粘膜免受化疗和放疗的损伤效应，在化疗或放疗期间，尤其是至少在最迟在所述化疗或放疗的第一天开始，最迟在治疗的最后一天结束的时段内，应该在不存在IGF-1，优选不存在任何合成代谢生长因子的情况下，给予含有TGF-β的第一药物组合物。进一步发现，在化疗或放疗后，在这些治疗期间可能已经发生的损伤效应可以通过在基本上不存在TGF-β的情况下，给予含有AGF，尤其是IGF-1的第二药物组合物而加以治疗。
根据本发明的另一实施方案，依次给予TGF-β和IGF-1，用于预防和/或治疗肠的炎症性症状，尤其是炎症性肠病(IBD)，如局限性回肠炎。
作为本发明使用的TGF-β，使用从哺乳动物乳产品，如乳或乳清，尤其是牛乳或乳清，最优选乳清提取的TGF-β。这种TGF-β的优点是，其来源于天然而非人们不愿接受的得自重组技术的产品，且其成本低，以及在乳或乳清提取物中存在其它有益成分，如免疫球蛋白。乳含有TGF-β1(约15％)和TGF-β2(约85％)。提取这种TGF-β的方法在本申请人的共同在审申请(PCT/NL99/00621)中有所描述。
优选地，使用含有TGF-β结合因子的提取物。可以通过使用提取方法，优选不包括酸提取步骤(pH＜5.5)，得到这种提取物。TGF-β结合因子定义为能够在含水介质中与TGF-β形成稳定复合物的成分。在牛乳中，这些成分是白蛋白和Latency AssociatedPeptide(LAP)。
结合因子的存在导致，例如在灭菌期间生长因子的稳定性增加。其还导致更好的TGF-β生物利用度，因而导致更高的活性。在肠内消化酶可能使生长因子降解，导致活性的(部分)丧失，而结合因子帮助生长因子在经过肠时不被降解。
本发明的发明者的重要发现之一是，在本申请中所提到的疾病的治疗中，乳产品可以用作生长因子源，但是，为了有用，应进行分离治疗，将转化生长因子和合成代谢生长因子分离。
从牛乳清或牛乳获得的TGF-β通常每克蛋白含有高于100，优选高于700μg的TGF-β。例如，这种提取物含有750μg TGF-β/g蛋白。该提取物中IGF-1含量少于4，优选少于1μg/g蛋白。
优选地，在组合物中TGF-β的量为每天给予50ng至150μg。在液体产品的情况中，其含有的TGF-β的浓度为每升0.5μg-1.5mgTGF-β。每天给予患者约100ml这种液体产品。
优选本发明的第一药物组合物还含有纤维，所述纤维在发酵时形成每100g短链脂肪酸多于15g的丁酸，优选每100g短链脂肪酸多于20g的丁酸。这种性质意指该组合物应该含有在肠(结肠)内发酵时释放相对大量的丁酸的纤维。丁酸的量可以通过Journalof Clinical Nutrition，1991，no.53，p.1418-1424中描述的方法测定。
肠功能的某些疾病，例如因化疗引起的疾病可能影响肠内菌群，其导致发酵成丁酸的暂时降低，尤其是在那些还给予患者大量抗生素的情况中。因此，给予患者刺激细菌合成丁酸的纤维是重要的，由此更多丁酸释放入肠道。在某些肠道细胞中，丁酸是优先的能量物质，它还抑制这些细胞的增殖并增加它们的分化。
如果丁酸以其自由盐的形式给予，可能产生令人不快的气味。而且只有部分丁酸到达结肠。缓释制剂可以克服这一问题，然而这些制剂相对较贵。
因此，根据本发明，建议给予特定的纤维，所述纤维在发酵时生成丁酸。这种纤维是：防腐淀粉(resistant starch)、燕麦麸，特别是β-葡聚糖少的富阿糖基木聚糖部分，一些大豆纤维提取物和麦麸。优选地使用麦麸。纤维的量是获得的每日剂量为1至30g，优选为3至10g。因此在液体制剂中浓度为10至300g/l。
根据本发明的TGF-β组合物优选含有免疫球蛋白，更具体地说是与上述纤维组合。它们的主要功能是与有害微生物如细菌相互作用。这阻止微生物进入血液循环系统。当患者的肠粘膜已经因化疗而受到损伤时，这种情况尤其会发生。
免疫球蛋白可以从已对某些病原体超免疫的哺乳动物的乳分离，或者它们可以从正常牛乳清或牛乳分离。用上述专利申请中提到的方法，使用正常牛乳作为原料，获得富含IgG和IgA的制剂。30至50％的蛋白部分由IgG和IgA型免疫球蛋白组成。在100ml液体制剂的情况中，制剂中免疫球蛋白的浓度为0.1至1500mg/l。
根据另一优选的实施方案，TGF-β组合物含有钙，优选与上述纤维组合，更优选与所述纤维和免疫球蛋白组合。钙可以是以下形式：精细分散的磷酸钙、碳酸钙、柠檬酸钙或来自牛乳的钙浓缩物。钙的添加降低感染风险。钙降低上皮细胞增殖速率。基于液体组合物，钙的量为大于50mg/100ml，优选大于100mg/100ml，例如120mg/100ml。
已经发现，当给予含有TGF-β、产丁酸纤维和高水平钙盐的产品时，产生协同作用，导致组合物有效防止化疗和放疗以及炎症性肠病的治疗期间的肠上皮细胞损伤。
优选地，根据本发明的含有TGF-β的第一药物组合物还含有一种或多种以下成分：蛋白质、脂肪、矿物质、微量元素、维生素、脂肪酸和乳铁蛋白。
优选地，蛋白质以3至10％的蛋白质等价物的量存在，蛋白质等价物包括完整蛋白、肽和氨基酸。基于制剂的总重，脂肪的量优选为2至10％。矿物质、微量元素和维生素的量是每日推荐剂量。
优选的维生素是维生素A、C和E。需要维生素A和维生素A原。它们的浓度优选大于130μgRE/100ml，尤其是大于300μg/100ml。适宜地，部分维生素A以视黄酸或其代谢等价物给予。维生素C和生育酚由于它们在抗氧化级联中的作用而给予。在放疗期间，而且在有初始炎症反应时，它们可以保护上皮细胞。维生素C或其等价物的浓度为大于40mg/100ml，优选大于60mg/100ml。生育酚的浓度为大于5mg，优选为大于15mg/100ml。
脂肪应该提供充足的脂肪酸。优选地，加入十八碳四烯酸(stearidonic acid，STA)。适宜的脂肪酸和它们的用量和比率在PCT/EP98/08409中有所描述，即脂肪酸γ-亚麻酸、十八碳四烯酸和二十碳五烯酸一起构成10至500mg/g脂肪酸总量，γ-亚麻酸和二十碳五烯酸构成这三种脂肪酸的20到50％(重量)，十八碳四烯酸形成这三种脂肪酸的15至50％(重量)。
乳铁蛋白由于其对多种病原体的抗菌活性可以存在。这种物质在初始炎症反应时也具有调节作用，炎症反应被延迟。其期望的每日剂量为0.1至3g乳铁蛋白。
优选组合物含有少于11％，优选少于6％的可消化的碳水化合物。更高百分比的这些物质将影响组合物的味道。通常使用约4.5g/100ml。作为可消化的碳水化合物源，可以使用蔗糖，和缓慢消化的碳水化合物。
在第二组合物中，IGF-1的剂量优选为0.1至100μgIGF-1/kg体重/天。在液体产品中，这一浓度为每100ml 7μg至7mgIGF-1。第二组合物优选基本上不含TGF-β。IGF-1/TGF-β的比至少为50，优选至少为100。
根据本发明的IGF-1优选从哺乳动物乳产品，如乳或乳清，尤其是牛乳或乳清，最优选乳清提取获得。这种提取物在本申请人的共同在审申请(PCT/NL99/00621)中显示。
第二组合物可以另外含有免疫球蛋白。考虑已发生的粘膜炎的严重性，预防和/或治疗有害物质，例如微生物的转运是重要的。优选地，给予每日0.03mg至5mg免疫球蛋白。如果IGF-1从牛乳获得，通常得到含有10至1000mg Ig/100μg IGF-1的制剂。
除了免疫球蛋白外，可以存在纤维。由于该组合物在患者的肠内菌群被极度破坏的阶段内给予，所以优选给予纤维混合物。优选地，这些纤维是水溶性非淀粉多糖如阿拉伯胶或果胶，不溶性非淀粉多糖如纤维素和半纤维素和寡糖和/或防腐淀粉和/或木素。这种混合物的实例在EP 0756828中有所描述，该文献引入本文作参考。
第二组合物可以另外含有乳铁蛋白、谷氨酰胺和抗氧化剂中的一种或多种。谷氨酰胺必须具有稳定的形式。在液体产品中，应使用富含谷氨酰胺的肽或来自富含谷氨酰胺的蛋白质水解产物的提取物。乳铁蛋白和抗氧化剂的量和在第一组合物中的相同。另外，第二组合物可以含有脂肪、蛋白质和其它微量成分，如矿物质、维生素和微量元素。此外，可以存在支持总甲硫氨酸代谢的物质。
根据本发明的另一实施方案，在基本上不存在胰岛素样生长因子1IGF-1，尤其是不存在AGF的情况下，将TGF-β和发酵时形成每100g短链脂肪酸中多于15g的丁酸的纤维和/或免疫球蛋白用于制备药物组合物，所述药物组合物用于治疗和/或预防肠粘膜功能障碍或肠粘膜疾病，更具体地说用于治疗和/或预防因化疗或放疗引起的肠粘膜损伤，或者治疗和/或预防炎症性肠病。
本发明还涉及基本上不存在IGF-1，尤其是不存在AGF的含有TGF-β的药物组合物，所述药物组合物优选含有发酵时形成每100g短链脂肪酸多于15g的丁酸的纤维和/或免疫球蛋白。
在液体组合物的情况中，每100ml这种组合物含有
a)50ng至150μg TGF-β
b)1至30g纤维
c)0.01至150mg免疫球蛋白
d)0.03至1g乳铁蛋白
e)＞50mg钙
f)脂肪酸
g)＞130μg RE维生素A
h)＞40mg维生素C
i)＞5mg生育酚
j)3至10％蛋白质等价物
例如，每100ml基于TGF-β的适宜的液体制剂含有
a)4μg TGF-β
b)5g麦麸
c)2mg免疫球蛋白
d)0.5g乳铁蛋白
e)80mg钙
f)4g含有30％MCT、26％棕榈油、16％大豆油、8％玻璃苣油、11％蓝蓟油、6.5％鱼油和2.5％卵脂质的脂肪混合物
g)300μg维生素A
h)70mg维生素C
i)15mgα-生育酚
j)4g酪蛋白
k)5g麦芽糖糊精
每天给予250ml该配方。
本发明还涉及基本上不存在TGF-β的含有AGF，优选为IGF-1，以及纤维的药物组合物，所述纤维选自可溶性非淀粉多糖如阿拉伯胶或果胶，不溶性非淀粉多糖如纤维素和半纤维素和寡糖和/或防腐淀粉和/或木素。该组合物优选另外含有乳铁蛋白、谷氨酰胺和抗氧化剂中的至少一员。
在液体组合物的情况中，每100ml这种组合物含有：
a)7μg至7mg IGF-1
b)1至30g纤维
c)5至300mg免疫球蛋白
d)0.3至3g乳铁蛋白
e)0.5至10g谷氨酰胺
f)＞130μg RE维生素A
g)＞40mg维生素C
h)＞5mg生育酚
例如，每100ml适宜的基于IGF-1的配方含有：
a)100μg IGF-1
b)5g纤维混合物：1g麦麸，3g菊粉，1g燕麦麸
c)200mg免疫球蛋白
d)0.5g牛乳铁蛋白
e)5g丙氨酰谷氨酰胺
f)300μg维生素A
g)70mg维生素C
h)15mgα-生育酚
每日给予250ml这种制剂。
根据本发明的组合物可以具有任何口服制剂的形式，例如胶囊剂、小药囊或片剂，它们各自含有预定量的活性成分；散剂或颗粒剂；在水或非水液体中的溶液剂或悬浮剂。优选的剂量形式为饮食补充或完全饮食或粉末，所述粉末在用液体如水重构后，给出完全饮食或饮食补充。本发明还涉及含有这些成分的管饲(tube feed)。
本发明还涉及由第一组合物和第二组合物的组合组成的产品，其用于依次给予，以预防和/或治疗因化疗或放疗引起的肠粘膜损伤，或者预防和/或治疗肠的炎症性症状，尤其是局限性回肠炎。
Claims (14)
1.转化生长因子β在制备用于治疗和/或预防肠粘膜功能障碍或肠粘膜疾病的药物或营养组合物中的用途，所述药物或营养组合物包含转化生长因子β和一种或多种转化生长因子β结合因子，基本上不存在胰岛素样生长因子-1，所述转化生长因子β从哺乳动物乳清产品提取获得，并且其中所述组合物另外包含纤维和/或免疫球蛋白，所述纤维的量为每天给予1至30g纤维。
2.根据权利要求1的用途，其中所述组合物包含转化生长因子β，基本上不存在AGF。
3.根据权利要求1或2的用途，用于制备用于治疗和/或预防因化疗或放疗引起的肠粘膜损伤的药物或营养组合物。
4.权利要求3的用途，其中在最迟在所述化疗或放疗的第一天开始，最迟在所述治疗的有效终点结束的时段内，给予所述组合物。
5.根据权利要求1或2的用途，用于制备用于治疗和/或预防炎症性肠病的药物或营养组合物。
6.根据权利要求1或2的用途，其中所述组合物含有转化生长因子β的量为每天给予50ng至150μg转化生长因子β。
7.根据权利要求1或2的用途，其中所述纤维是麦麸纤维。
8.根据权利要求1或2的用途，其中口服给予所述组合物。
9.药物或营养组合物，其包含转化生长因子β和一种或多种转化生长因子β结合因子，基本上不存在胰岛素样生长因子-1，所述转化生长因子β从哺乳动物乳清产品提取获得。
10.根据权利要求9的药物或营养组合物，其中所述组合物包含转化生长因子β，基本上不存在AGF。
11.根据权利要求9或10的药物或营养组合物，其中所述组合物是含有蛋白质、脂肪和碳水化合物的营养组合物。
12.根据权利要求9或10的药物或营养组合物，其中所述组合物另外包含：
-纤维，其在发酵时形成每100g短链脂肪酸多于15g的丁酸，和/或
-免疫球蛋白，和/或
-钙。
13.根据权利要求9或10的药物或营养组合物，其中所述结合因子包括Latency Associated Peptide。
14.根据权利要求9或10的药物或营养组合物，其中所述组合物是液体并且每升含有0.5μg-1.5mg转化生长因子β。
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|---|---|---|---|
| WOPCT/NL99/00620 | 1999-10-06 | ||
| PCT/NL1999/000620 WO2001024812A1 (en) | 1999-10-06 | 1999-10-06 | USE OF TRANSFORMING GROWTH FACTOR β AND GROWTH FACTORS IN THE TREATMENT AND PREVENTION OF DISEASES OF THE INTESTINAL MUCOSA |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00814004A Division CN1378458A (zh) | 1999-10-06 | 2000-10-06 | TGF－β和生长因子在治疗和预防肠粘膜疾病中的用途 |
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| Publication Number | Publication Date |
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| CN1626239A CN1626239A (zh) | 2005-06-15 |
| CN1299766C true CN1299766C (zh) | 2007-02-14 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN00814004A Pending CN1378458A (zh) | 1999-10-06 | 2000-10-06 | TGF－β和生长因子在治疗和预防肠粘膜疾病中的用途 |
| CNB2004100749613A Expired - Fee Related CN1299766C (zh) | 1999-10-06 | 2000-10-06 | TGF－β和生长因子在治疗和预防肠粘膜疾病中的用途 |
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| CN00814004A Pending CN1378458A (zh) | 1999-10-06 | 2000-10-06 | TGF－β和生长因子在治疗和预防肠粘膜疾病中的用途 |
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| EP (2) | EP1221965A1 (zh) |
| JP (1) | JP2003510367A (zh) |
| CN (2) | CN1378458A (zh) |
| AU (2) | AU6232899A (zh) |
| BR (1) | BR0014563A (zh) |
| WO (2) | WO2001024812A1 (zh) |
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| DE3928186A1 (de) * | 1989-08-25 | 1991-03-14 | Niehoff Kg Maschf | Greifvorrichtung fuer drahtspulen und dergleichen |
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| GB0229658D0 (en) * | 2002-12-20 | 2003-01-22 | Cleeve Richard J | Bird feed |
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| US8075934B2 (en) | 2008-10-24 | 2011-12-13 | Mead Johnson Nutrition Company | Nutritional composition with improved digestibility |
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| CN101505781A (zh) * | 2006-06-22 | 2009-08-12 | 阿根尼克斯有限公司 | 作为辐射防护物质的乳铁蛋白 |
| US8367354B2 (en) | 2008-10-24 | 2013-02-05 | Mead Johnson Nutrition Company | Methods for determining the levels of TGF-β in a composition |
| US8986769B2 (en) | 2008-10-24 | 2015-03-24 | Mead Johnson Nutrition Company | Methods for preserving endogenous TGF-β |
| US8350006B2 (en) | 2008-10-24 | 2013-01-08 | Mead Johnson Nutrition Company | Methods for determining the bioactivity of TGF-β in a composition |
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| US20120171328A1 (en) | 2011-01-05 | 2012-07-05 | Dattatreya Banavara | Composition comprising heat labile milk proteins and process for preparing same |
| KR102148982B1 (ko) | 2011-06-03 | 2020-08-27 | 조마 테크놀로지 리미티드 | Tgf-베타에 특이적인 항체 |
| WO2014122143A1 (en) | 2013-02-05 | 2014-08-14 | Engmab Ag | Method for the selection of antibodies against bcma |
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| WO2016161410A2 (en) | 2015-04-03 | 2016-10-06 | Xoma Technology Ltd. | Treatment of cancer using inhibitors of tgf-beta and pd-1 |
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| CR20220408A (es) | 2016-09-14 | 2022-10-20 | Teneobio Inc | ANTICUERPOS DE UNIÓN A CD3(Divisional del Expediente 2019-198) |
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| BR112020023187A2 (pt) | 2018-05-16 | 2021-04-20 | Janssen Biotech, Inc. | métodos para tratamento de cânceres e de aumento da eficácia de agentes terapêuticos de redirecionamento de células t |
| CN110051698A (zh) * | 2019-03-18 | 2019-07-26 | 天津大学 | 基于微囊化处理的肠道原生菌基因改造的方法 |
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| WO2021018168A1 (zh) | 2019-07-30 | 2021-02-04 | 上海翰森生物医药科技有限公司 | 抗bcma抗体、其抗原结合片段及其医药用途 |
| MX2022007759A (es) | 2019-12-20 | 2022-07-19 | Novartis Ag | Combinacion del anticuerpo anti tim-3 mbg453 y anticuerpo anti tgf-beta nis793, con o sin decitabina o el anticuerpo anti pd-1 spartalizumab, para el tratamiento de mielofibrosis y sindrome mielodisplasico. |
| JP2023526774A (ja) | 2020-04-29 | 2023-06-23 | テネオバイオ， インコーポレイテッド | 重鎖定常領域が修飾された多重特異性重鎖抗体 |
| TWI838621B (zh) | 2020-04-29 | 2024-04-11 | 美商泰尼歐萬公司 | 具有經修飾重鏈恆定區之多特異性重鏈抗體 |
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| CR20230398A (es) | 2021-02-16 | 2023-11-15 | Janssen Pharmaceutica Nv | Anticuerpo triespecífico dirigido a bcma, gprc5d, y cd3 |
| TW202304979A (zh) | 2021-04-07 | 2023-02-01 | 瑞士商諾華公司 | 抗ＴＧＦβ抗體及其他治療劑用於治療增殖性疾病之用途 |
| TW202309522A (zh) | 2021-05-11 | 2023-03-01 | 美商健生生物科技公司 | 用於監測復發性及／或難治性多發性骨髓瘤之治療的方法及組成物 |
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- 2000-10-06 AU AU10632/01A patent/AU1063201A/en not_active Abandoned
- 2000-10-06 WO PCT/NL2000/000719 patent/WO2001024813A1/en not_active Application Discontinuation
- 2000-10-06 BR BR0014563-7A patent/BR0014563A/pt not_active IP Right Cessation
- 2000-10-06 CN CN00814004A patent/CN1378458A/zh active Pending
- 2000-10-06 JP JP2001527812A patent/JP2003510367A/ja active Pending
- 2000-10-06 EP EP07100978A patent/EP1779863A1/en not_active Withdrawn
- 2000-10-06 CN CNB2004100749613A patent/CN1299766C/zh not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2001024813A1 (en) | 2001-04-12 |
| WO2001024812A1 (en) | 2001-04-12 |
| EP1779863A1 (en) | 2007-05-02 |
| CN1626239A (zh) | 2005-06-15 |
| AU6232899A (en) | 2001-05-10 |
| BR0014563A (pt) | 2002-06-11 |
| CN1378458A (zh) | 2002-11-06 |
| AU1063201A (en) | 2001-05-10 |
| JP2003510367A (ja) | 2003-03-18 |
| EP1221965A1 (en) | 2002-07-17 |
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