靶向IL‑23A和TNF‑α的化合物及其用途的制作方法

相关申请本申请依据35u.s.c.§119要求2014年9月3日提交且标题为靶向il-23a和tnf-α的化合物及其用途(compoundtargetingil-23aandtnf-alphaandusesthereof)的美国临时申请序列no.62/045,498的提交日的权益，其全部内容通过引用并入本文。发明背景炎症涉及抵抗感染所需的先天性和适应性免疫应答。然而，当炎症变成未检查的自身免疫性或自身炎性疾病时，神经变性疾病且甚至是癌症可发展。已确定抑制诸如il1、tnf-α、il6、il12、il17、il18或il23的促炎性细胞因子的活性减少了炎症并抑制激活免疫细胞的特异性途径。白介素23(il23)是由两个亚基p40和p19组成的异二聚体细胞因子。p19亚基也被称为il-23a。p19亚基是il23独有的，而p40亚基是与细胞因子il12共有的。il23作为病理性th17、γδt和先天性淋巴样细胞(ilc)的关键调节因子存在，驱动il17、il22及其它导致局部组织炎症和损伤的细胞因子的产生。il23促进基质金属蛋白酶mmp9的上调、增加血管生成、减少cd8+t细胞浸润，并且已经牵涉于癌性肿瘤发展中。此外，连同il6和tgf-β1，il23刺激天然cd4+t细胞分化为th17细胞。继而，th17细胞产生il17，il17是一种促炎性细胞因子，可增强t细胞激发并刺激诸如il1、il6、tnf-α、nos-2的促炎性细胞因子的产生，并且还诱导趋化因子的表达，导致炎症和疾病发病。il23经由细胞表面受体发挥其作用，所述细胞表面受体由与独特的il23r亚基成对的il12受体的il12β1亚基组成。il23r的表达限于特异性免疫细胞群，并且主要存在于t细胞(αβ和γδtcr+)和nk细胞的亚群。在小鼠中，il23p19基因的遗传切除导致il23功能选择性缺失，伴随着严重受损的t-依赖性免疫应答，包括抗原特异性免疫球蛋白产生减少和受损延迟型超敏应答(ghilardin,等(2004)j.immunol.172(5):2827-33)。il23p40或il23p19或者il23受体的任一个亚基(il23r和il12-β1)中有缺陷的敲除小鼠在多发性硬化、关节炎和炎性肠病的动物模型中发展较不严重的症状。使用对il23p19特异性的抗体在eae中获得类似的结果，并且t细胞介导的结肠炎模型还证实il23在这些疾病环境中的作用(cheny.等(2006)j.clin.invet.116(5):1317-26；elsonco.等(2007)gastroenterology132(7):2359-70)。这突显了il23在慢性炎症中的重要性(langowski等(2006)nature442(7101):461-5；kiklyk,等(2006)curr.opin.immunol.18(6):670-5)。此外，增加的il23产生已被认为是炎性关节炎和炎性自身免疫性疾病中的主要因子(adamopoulos等(2011)j.immunol.187:593-594；和langris等(2005)j.exp.med.201:233-240)。在过表达il23的小鼠模型系统中已经公开了il23、其下游细胞因子il22与骨形成之间的联系(sherlock等(2012)nat.med.18:1069-76)。同三聚tnf-α细胞因子主要由巨噬细胞、淋巴细胞、内皮细胞和成纤维细胞表达，并结合两种不同的受体：几乎在所有细胞类型上表达的tnfri和在免疫细胞(cd4+t细胞，nk细胞)上表达更受限的tnfrii。像许多tnf超家族成员一样，tnf-α以膜和可溶形式两者存在，可溶形式通过由adam12金属蛋白酶(tace，tnfα转化酶)裂解膜形式形成。细胞因子的膜结合和可溶形式两者均具有生物活性。肿瘤坏死因子(tnf-α)是刺激炎症的急性期的促炎性细胞因子。肿瘤坏死因子通过诱导il8而增加血管通透性，从而募集巨噬细胞和嗜中性粒细胞至感染部位。一旦存在，激活的巨噬细胞继续产生tnf-α，从而保持和放大炎性应答。tnf-α的主要作用是调控免疫细胞；然而，tnf-α也参与包括细胞增殖、分化、凋亡、脂质代谢和凝血的广泛的生物过程的调控。tnf-α能够诱导炎症、诱导凋亡性细胞死亡、抑制肿瘤发生和抑制病毒复制。tnf-α产生的失调已牵涉于多种人类疾病中，包括自身免疫性疾病(如，类风湿性关节炎(ra)、克罗恩氏病(crohn'sdisease)、多发性硬化)、炎性肠病(ibd)、溃疡性结肠炎、银屑病、中毒性休克、移植物抗宿主病、胰岛素抗性、阿尔茨海默病(alzheimer'sdisease)、癌症和重性抑郁(swardfagerw,等(2010)biolpsychiatry68(10):930-941；(locksleyrm,等(2001)cell104(4):487-501；dowlati等,(2010)biolpsychiatry67(5):446-457；brynskovj.等(2002)gut51(1):37-43)。抗体已用作生物疗法用于抑制tnf-α和il23以治疗多种炎性疾病。美国专利no.6,277,969、6,284,471和6,790,444中描述的英利昔单抗(centocor,malvern,pa.)是携带人igg4恒定区和小鼠可变区的嵌合抗-tnf-α单克隆igg抗体，并在临床上用于治疗类风湿性关节炎、银屑病性关节炎、强直性脊柱炎、克罗恩氏病、溃疡性结肠炎和斑块状银屑病。美国专利no.6,090,382中所述的单克隆抗体阿达木单抗(克隆d2e7；abbottlaboratories,abbottpark,illinois)是抗-tnf-α疗法，在临床上用于治疗类风湿性关节炎、克罗恩氏病、银屑病、银屑病性关节炎、强直性脊柱炎和青少年特发性关节炎。戈利木单抗是tnf-α阻断剂，用于治疗类风湿性关节炎、银屑病性关节、强直性脊柱炎和溃疡性结肠炎。此外，描述于美国专利no.6,902,734和美国专利no.7,166,285中的人单克隆抗体优特克单抗(centocor,inc,malvern,pa.)针对白介素12和白介素23(特别是p40亚基)，在临床上用于治疗严重斑块状银屑病，并且进一步被研究用于治疗银屑病性关节炎、多发性硬化和结节病。然而，抗-tnf-α疗法已报道了副作用[参见例如：keanej等(2001)]。结核病与英利昔单抗(一种肿瘤坏死因子α-中和剂)相关。nengljmed345(15):1098-1104；scheinfeldn.(2005)adalimumab:areviewofsideeffects.expertopindrugsaf.4(4):637-41；chovel-sellaa等(2012)clinicalefficacyandadverseeffectsofgolimumabinthetreatmentofrheumatoidarthritis.isrmedassocj.14(6):390-4]。鉴定更有效的治疗应允许施用减少的剂量以及与该治疗相关的更低成本。仍然需要对治疗和预防自身免疫性或炎性疾病的功效增加的组合物。发明概述本文提供了对tnf-α和il23a具有特异性的化合物、包含此类化合物的组合物以及其使用和产生的方法。本公开的各方面涉及包含第一多肽和第二多肽的化合物，其中：(a)所述第一多肽包含：(i)对第一靶蛋白具有特异性的第一免疫球蛋白(vl1)的轻链可变结构域；(ii)对第二靶蛋白具有特异性的第二免疫球蛋白(vh2)的重链可变结构域；和(iii)铰链区、重链恒定区2(ch2)和重链恒定区3(ch3)；且(b)所述第二多肽包含：(i)对所述第二靶蛋白具有特异性的第二免疫球蛋白(vl2)的轻链可变结构域；(ii)对所述第一靶蛋白具有特异性的第一免疫球蛋白(vh1)的重链可变结构域；其中：(i)所述vl1和vh1缔合以形成结合所述第一靶蛋白的结合位点；(ii)所述vl2和vh2缔合以形成结合所述第二靶蛋白的结合位点；(iii)所述重链恒定区2(ch2)包含在位置252处的酪氨酸、在位置254处的苏氨酸和在位置256处的谷氨酸，根据如kabat中的eu索引对常见抗体编号；和(iv)所述第一靶蛋白是tnf-α且所述第二靶蛋白是il-23a或者所述第一靶蛋白是il-23a且所述第二靶蛋白是tnf-α，其中：(i)所述vl1包含seqidno:2，所述vh1包含seqidno:1，所述vl2包含seqidno:8且所述vh2包含seqidno:7；或(ii)所述vl1包含seqidno:4或6，所述vh1包含seqidno:3或5，所述vl2包含seqidno:8且所述vh2包含seqidno:7；或(iii)所述vl1包含seqidno:8，所述vh1包含seqidno:7，所述vl2包含seqidno:2且所述vh2包含seqidno:1；或(iv)所述vl1包含seqidno:8，所述vh1包含seqidno:7，所述vl2包含seqidno:4或6且所述vh2包含seqidno:3或5。在一些实施方案中，在(ii)中，所述vl1包含seqidno:4，所述vh1包含seqidno:3，所述vl2包含seqidno:8且所述vh2包含seqidno:7。在一些实施方案中，在(ii)中，所述vl1包含seqidno:6，所述vh1包含seqidno:5，所述vl2包含seqidno:8且所述vh2包含seqidno:7。在一些实施方案中，在(iv)中，所述vl2包含seqidno:4，所述vh2包含seqidno:3，所述vl1包含seqidno:8且所述vh1包含seqidno:7。在一些实施方案中，在(iv)中，所述vl2包含seqidno:6，所述vh2包含seqidno:5，所述vl1包含seqidno:8且所述vh1包含seqidno:7。在一些实施方案中，所述第一多肽还包含在所述vl1与所述vh2之间的第一接头且所述第二多肽还包含在所述vl2与所述vh1之间的第二接头。在一些实施方案中，所述第一接头或所述第二接头包含氨基酸序列gggsggg(seqidno:9)。在一些实施方案中，所述第一接头和所述第二接头包含氨基酸序列gggsggg(seqidno:9)。在一些实施方案中，所述第一多肽还包含重链恒定区1结构域(ch1)且所述第二多肽还包含轻链恒定区结构域(cl)，其中所述cl和所述ch1经由二硫键缔合在一起以形成c1结构域。在一些实施方案中，所述第一多肽还包含在所述vh2与所述ch1之间的第三接头且所述第二多肽还包含在所述vh1与所述cl之间的第四接头。在一些实施方案中，所述第三接头包含氨基酸序列fnrges(seqidno:11)。在一些实施方案中，所述第四接头包含氨基酸序列vepkss(seqidno:12)。在一些实施方案中，所述第三接头包含氨基酸序列fnrges(seqidno:11)且所述第四接头包含氨基酸序列vepkss(seqidno:12)。在一些实施方案中，第三接头或所述第四接头包含氨基酸序列lgggsg(seqidno:10)。在一些实施方案中，所述第三接头和所述第四接头包含氨基酸序列lgggsg(seqidno:10)。在一些实施方案中，所述重链恒定区2(ch2)包含在位置234处的丙氨酸和在位置235处的丙氨酸，根据eu索引如在kabat中对常见抗体编号。在一些实施方案中，所述铰链区的氨基酸序列、所述重链恒定区2(ch2)或所述重链恒定区3(ch3)源自igg1或igg4。在一些实施方案中，所述铰链区包含氨基酸序列epkscdkthtcppcp(seqidno:40)。在一些实施方案中，所述化合物包含两个所述第一多肽和两个所述第二多肽，其中所述两个第一多肽经由至少一个二硫键缔合在一起。在一些实施方案中，所述化合物包含两个所述第一多肽和两个所述第二多肽，其中所述两个第一多肽经由至少一个二硫键缔合在一起并且其中所述第一多肽的每一个经由至少一个二硫键与一个所述第二多肽缔合。在一些实施方案中，(i)所述第一多肽包含seqidno:13的氨基酸序列且所述第二多肽包含seqidno:14的氨基酸序列；(ii)所述第一多肽包含seqidno:15的氨基酸序列且所述第二多肽包含seqidno:16的氨基酸序列；(iii)所述第一多肽包含seqidno:17的氨基酸序列且所述第二多肽包含seqidno:18的氨基酸序列；(iv)所述第一多肽包含seqidno:19的氨基酸序列且所述第二多肽包含seqidno:20的氨基酸序列；(v)所述第一多肽包含seqidno:21的氨基酸序列且所述第二多肽包含seqidno:22的氨基酸序列；(vi)所述第一多肽包含seqidno:23的氨基酸序列且所述第二多肽包含seqidno:24的氨基酸序列；(vii)所述第一多肽包含seqidno:25的氨基酸序列且所述第二多肽包含seqidno:26的氨基酸序列；(viii)所述第一多肽包含seqidno:27的氨基酸序列且所述第二多肽包含seqidno:28的氨基酸序列；(ix)所述第一多肽包含seqidno:29的氨基酸序列且所述第二多肽包含seqidno:30的氨基酸序列；(x)所述第一多肽包含seqidno:31的氨基酸序列且所述第二多肽包含seqidno:32的氨基酸序列；(xi)所述第一多肽包含seqidno:33的氨基酸序列且所述第二多肽包含seqidno:34的氨基酸序列；或(xi)所述第一多肽包含seqidno:35的氨基酸序列且所述第二多肽包含seqidno:36的氨基酸序列。在一些实施方案中，其中所述化合物包含两个所述第一多肽和两个所述第二多肽，其中所述两个第一多肽经由至少一个二硫键缔合在一起。在一些实施方案中，所述化合物包含两个所述第一多肽和两个所述第二多肽，并且其中第一多肽的一个的ch2和ch3及ch1(如果存在)与第一多肽的另一个的ch2和ch3及ch1(如果存在)缔合以形成四价分子。在一些实施方案中，所述化合物包含两个所述第一多肽和两个所述第二多肽，其中所述第一多肽的每一个包含ch1、ch2和ch3且所述第二多肽的每一个包含cl，并且其中第一多肽的一个的ch2和ch3与第一多肽的另一个的ch2和ch3缔合并且每个所述第一多肽的ch1与一个所述第二多肽的cl缔合以形成四价分子。本公开的其它方面涉及与第二化合物竞争结合至il-23a和tnf-α的第一化合物，其中所述第一化合物包含第三多肽和第四多肽，其中：(a)所述第三多肽包含：(i)对第一靶蛋白具有特异性的第一免疫球蛋白(vl1)的轻链可变结构域；(ii)对第二靶蛋白具有特异性的第二免疫球蛋白(vh2)的重链可变结构域；和(iii)铰链区、重链恒定区2(ch2)和重链恒定区3(ch3)；且(b)所述第四多肽包含：(i)对所述第二靶蛋白具有特异性的第二免疫球蛋白(vl2)的轻链可变结构域；(ii)对所述第一靶蛋白具有特异性的第一免疫球蛋白(vh1)的重链可变结构域；并且其中(i)所述vl1和vh1缔合以形成结合所述第一靶蛋白的结合位点；(ii)所述vl2和vh2缔合以形成结合所述第二靶蛋白的结合位点；且(iii)所述第一靶蛋白是tnf-α且所述第二靶蛋白是il-23a或所述第一靶蛋白是il-23a且所述第二靶蛋白是tnf-α，并且其中所述第二化合物包含第一多肽和第二多肽，其中：(i)所述第一多肽包含seqidno:13的氨基酸序列且所述第二多肽包含seqidno:14的氨基酸序列；(ii)所述第一多肽包含seqidno:15的氨基酸序列且所述第二多肽包含seqidno:16的氨基酸序列；(iii)所述第一多肽包含seqidno:17的氨基酸序列且所述第二多肽包含seqidno:18的氨基酸序列；(iv)所述第一多肽包含seqidno:19的氨基酸序列且所述第二多肽包含seqidno:20的氨基酸序列；(v)所述第一多肽包含seqidno:21的氨基酸序列且所述第二多肽包含seqidno:22的氨基酸序列；(vi)所述第一多肽包含seqidno:23的氨基酸序列且所述第二多肽包含seqidno:24的氨基酸序列；(vii)所述第一多肽包含seqidno:25的氨基酸序列且所述第二多肽包含seqidno:26的氨基酸序列；(viii)所述第一多肽包含seqidno:27的氨基酸序列且所述第二多肽包含seqidno:28的氨基酸序列；(ix)所述第一多肽包含seqidno:29的氨基酸序列且所述第二多肽包含seqidno:30的氨基酸序列；(x)所述第一多肽包含seqidno:31的氨基酸序列且所述第二多肽包含seqidno:32的氨基酸序列；(xi)所述第一多肽包含seqidno:33的氨基酸序列且所述第二多肽包含seqidno:34的氨基酸序列；或(xii)所述第一多肽包含seqidno:35的氨基酸序列且所述第二多肽包含seqidno:36的氨基酸序列。本公开的又其它方面涉及包含诸如以上所述的化合物的本文所述的化合物的药物组合物。本公开的其它方面涉及治疗自身免疫性或炎性疾病的方法，所述方法包括向受试者施用本文所述的化合物，诸如以上所述的化合物，或者包含所述化合物的药物组合物。本公开的又其它方面涉及用于医学用途的本文所述的化合物，诸如以上所述的化合物。在一些实施方案中，所述用途是治疗自身免疫性或炎性疾病。本公开的其它方面涉及用于医学用途的包含诸如以上所述的化合物的本文所述的化合物的药物组合物。在一些实施方案中，所述用途是治疗自身免疫性或炎性疾病。本公开的又其它方面涉及诸如以上所述的化合物的本文所述的化合物用于制造医学中所用的药物的用途。在一些实施方案中，所述用途是治疗自身免疫性或炎性疾病。本公开的其它方面涉及诸如以上所述的药物组合物的本文所述的药物组合物用于制造医学中所用的药物的用途。在一些实施方案中，所述用途是治疗自身免疫性或炎性疾病。本公开的又其它方面涉及包含编码诸如以上所述的多肽的本文所述的多肽的核苷酸序列的核酸。本公开的其它方面涉及包含所述核酸的载体。在一些实施方案中，载体包含可操作地连接至所述核酸的启动子。本公开的其它方面涉及包含所述核酸或所述载体的细胞。本公开的其它方面涉及产生诸如以上所述的多肽的如本文所述的化合物或多肽的方法，所述方法包括获得诸如以上所述的细胞的本文所述的细胞，和在所述细胞中表达如本文所述的核酸。在一些实施方案中，所述方法还包括分离和纯化所述多肽或化合物。本公开的一个或多个实施方案的细节示于以下描述中。本公开的其它特征或优势将根据以下附图和若干个实施方案的详述以及还根据随附权利要求而显而易见。附图详述以下附图形成本说明书的一部分，并且被包含以进一步证明本公开的某些方面，其可通过参考这些附图的一个或多个结合本文呈现的特定实施方案的详述而更容易被理解。图1a是对tnf-α和il23a具有特异性的示例性化合物的图表。第一多肽链含有ch3、ch2、vh2(vhii)和vl1(vli)结构域。第二多肽链含有vh1(vhi)和vl2(vlii)结构域。vl1和vh1对第一靶蛋白(tnf-α或il23a)具有特异性，且vl2和vh2对第二靶蛋白(il23a或tnf-α)具有特异性。上图分别显示了每条多肽链。下图显示了通过一个第一多肽的ch2和ch3结构域与另一个第一多肽的ch2和ch3结构域的缔合形成的四价化合物。第一和第二靶蛋白的结合结构域分别通过vh1和vl1的缔合以及vh2和vl2的缔合形成。图1b是对tnf-α和il23a具有特异性的另一种示例性化合物的图表。第一多肽链含有ch3、ch2、ch1、vh2(vhii)和vl1(vli)结构域。第二多肽链含有cl、vh1(vhi)和vl2(vlii)结构域。vl1和vh1对第一靶蛋白(tnf-α或il23a)具有特异性且vl2和vh2对第二靶蛋白(il23a或tnf-α)具有特异性。上图分别显示了每条多肽链。下图显示了通过一个第一多肽的ch2和ch3结构域与另一个第一多肽的ch2和ch3结构域的缔合形成的四价化合物。第一和第二靶蛋白的结合结构域分别通过vh1和vl1的缔合以及vh2和vl2的缔合形成。该化合物通过cl与ch1结构域之间的相互作用进一步缔合。图2是显示在1mg/kgiv10分钟输注后化合物m及其yte突变体化合物a在雄性食蟹猴中的血清浓度(平均值±sd；n＝3)的图。图3是显示在1mg/kgiv10分钟输注后化合物o及其相应的yte突变体化合物e在雄性食蟹猴中的血清浓度(平均值±sd；n＝3)的图。图4是显示化合物e对比il23在体内保持功能效能的一系列图和一个表。向小鼠用对照抗体3(il23a单克隆抗体)或化合物e等摩尔给药并且两次用人il23激发以诱导耳部炎症。最后注射后二十四小时，收集耳部并分析小鼠il17a和小鼠il22作为il23的功能性阻断的量度。基于终端暴露和功效水平，化合物e对比对照抗体3(il23a单克隆抗体)在体内保持功能效能。对照抗体3：空心正方形、三角形和菱形。化合物e：实心正方形、三角形和菱形。mw：分子量。图5是显示化合物e对比tnf在体内保持功能效能的一系列图和一个表。向小鼠用对照抗体2(tnfa单克隆抗体)或化合物e等摩尔给药并用人tnf激发。激发后两小时，收集全血并分析小鼠kc和小鼠il-6的血清作为tnf的功能阻断的量度。基于终端暴露和功效水平，化合物e对比抗-tnf在体内保持功能效能。对照抗体3：空心正方形、三角形和菱形。化合物e：实心正方形、三角形和菱形。mw：分子量。发明详述本文所述的化合物结合至的tnf-α(在本文中也被称为tnf-α或tnfa)和il23a(在本文中也被称为il23p19或il-23a)两者。迄今为止，尚未批准靶向tnf-α和il23a两者的化合物。使用生物治疗方法对两种/多种关键炎性介体的同时中和的研究有限。尽管这些研究不能显示对类风湿性关节炎(ra)测量的临床结果的改善，迄今为止尚未描述靶向相同组合的双功能治疗剂。此外，此类组合可增加副作用，诸如感染的风险(参见，例如genovese,m.c.,cohen,s.,moreland,l.,lium,d.,robbins,s.,等(2004).arth.rheum.50,1412-9；genovese,m.c.,cohen,s.,moreland,l.,lium,d.,robbins,s.,等(2004).arth.rheum.50,1412-9；和weinblatt,m.,schiff,m.,goldman,a.kremer,j.,luggen,m.,等(2007).ann.rheum.dis.66,228-34)。此外，由于与溶解度(如，聚集)和稳定性(如，药代动力学不良)相关的问题，此类双特异性化合物难以设计。令人惊讶的是，与靶向il23a或tnf-α的单独抗体相比，发现结合至tnf-α和il23a两者的本文所述的化合物具有类似或改善的性质。还发现这些化合物具有适合的药代动力学并且在适用于给药目的的范围内可溶。此外，在一些实施方案中，从单独疗法和更低剂量的副作用角度看，单次施用具有优于多次单剂量施用的优势。此外，在一些实施方案中，该化合物的cmc性质显示化合物具有低聚集。在一方面，示例性化合物特别显示低聚集。还显示将接头优化以改善稳定性并防止裂解，且yte突变改善fcrn亲和力。本文所述的化合物据信与标准抗体分子(如，igg分子或抗原-结合片段(fab))具有一个或多个优势性质，如副作用减少、施用便利性和安全性增加、半寿期增加、结合亲和力增加或抑制活性增加。因此，本公开的各方面涉及对tnf-α和il23a两者具有特异性的化合物，以及此类化合物的使用和产生的方法。化合物本公开的各方面涉及对tnf-α和il23a两者具有特异性的化合物。以下显示了tnf-α的示例性蛋白质序列和il23a的示例性蛋白质序列。＞np_000585.2-tnf-α[智人]mstsmirdvelaeealpkktggpqgsrrclflslfsflivagattlfcllhfgvigpqreefprdlslisplaqavrsssrtpsdrpvahvvanpqaegqlqwlnrranallangvelrdnqlvvpseglyliysqvlfkgqgcpsthvllthtisriavsyqtkvnllsaikspcqretpegaeakpwyepiylggvfqlekgdrlsaeinrpdyldfaesgqvyfgiial(seqidno：144)＞np_057668.1-il23a[智人]mlgsravmlllllpwtaqgravpggsspawtqcqqlsqklctlawsahplvghmdlreegdeettndvphiqcgdgcdpqglrdnsqfclqrihqglifyekllgsdiftgepsllpdspvgqlhasllglsqllqpeghhwetqqipslspsqpwqrlllrfkilrslqafvavaarvfahgaatlsp(氨基酸1-19是预测的信号序列)(seqidno：145)在一些实施方案中，该化合物包含第一多肽和第二多肽。在一些实施方案中，第一多肽包含(i)对第一靶蛋白具有特异性的第一免疫球蛋白(vl1)的轻链可变结构域，(ii)对第二靶蛋白具有特异性的第二免疫球蛋白(vh2)的重链可变结构域；和(iii)铰链区、重链恒定区2(ch2)和重链恒定区3(ch3)。在一些实施方案中，第一多肽还包含重链恒定区1(ch1)。在一些实施方案中，第二多肽包含：(i)对第二靶蛋白有特异性的第二免疫球蛋白(vl2)的轻链可变结构域；(ii)对第一靶蛋白具有特异性的第一免疫球蛋白(vh1)的重链可变结构域。在一些实施方案中，第一多肽还包含轻链恒定区(cl)。应理解第一多肽的可变结构域和恒定结构域/区可呈任何顺序且第二多肽的可变结构域和恒定结构域/区(如果存在)可呈任何顺序。以下显示了从n-末端至c-末端第一和第二多肽上的结构域/区的多个示例性构型。第一多肽构型1：n-vl1-vh2-铰链-ch2-ch3-c第一多肽构型2：n-vh2-vl1-铰链-ch2-ch3-c第一多肽构型3：n-vl1-vh2-ch1-铰链-ch2-ch3-c第一多肽构型4：n-vh2-vl1-ch1-铰链-ch2-ch3-c第二多肽构型1：n-vl2-vh1-c第二多肽构型2：n-vh1-vl2-c第二多肽构型3：n-vl2-vh1-cl-c第二多肽构型4：n-vh1-vl2-cl-c该化合物的示例性构型示于图1a和1b中。在一些实施方案中，该化合物包含呈构型1的第一多肽和呈构型1的第二多肽。在一些实施方案中，该化合物包含呈构型3的第一多肽和呈构型3的第二多肽。在一些实施方案中，第一多肽和第二多肽的可变区彼此缔合以形成第一靶蛋白的结合位点和第二靶蛋白的结合位点。在一些实施方案中，第一多肽的vl1和第二多肽的vh1缔合以形成结合第一靶蛋白的结合位，并且第二多肽的vl2和第一多肽的vh2缔合以形成结合第二靶蛋白的结合位点。在一些实施方案中，第一靶蛋白是tnf-α且第二靶蛋白是il23a。在其它实施方案中，第一靶蛋白是il23a且第二靶蛋白是tnf-α。应理解术语“第一”和“第二”并非意指对任一靶蛋白的重要性水平。在以下表1并且还在实施例1的表2a中提供了vl1、vh1、vl2和vh2的每一个的序列的示例性组合。表1.vl1、vh1、vl2和vh2的序列的示例性组合。在一些实施方案中，该化合物包含vl1序列(包含第一轻链cdr1、cdr2和cdr3)和vh1序列(包含第一重链cdr1、cdr2和cdr3)，vl2序列(包含第二轻链cdr1、cdr2和cdr3)和vh2序列(包含第二重链cdr1、cdr2和cdr3)。在一些实施方案中，cdr是表1或表2a中提供的一个或多个vl1、vh1、vl2和vh2序列的cdr。以下显示了表1中提供的vl1、vh1、vl2和vh2序列的示例性轻链和重链cdr序列：seqidno:1cdr：dyamh(seqidno:146)(cdr1),aitwnsghidyadsveg(seqidno:147)(cdr2),vsylstassldy(seqidno:148)(cdr3)seqidno:2cdr：rasqgirnyla(seqidno:149)(cdr1),aastlqs(seqidno:150)(cdr2),qrynrapyt(seqidno:151)(cdr3)seqidno:3和seqidno:5cdr：syamh(seqidno:152)(cdr1),fmsydgsnkkyadsvkg(seqidno:153)(cdr2),nyyyygmdv(seqidno:154)(cdr3)seqidno:4和seqidno:6cdr：rasqsvysyla(seqidno:155)(cdr1),dasnrat(seqidno:156)(cdr2),qqrsnwppft(seqidno:157)(cdr3)seqidno:7cdr：dqtih(seqidno:158)(cdr1),yiyprddspkynenfkg(seqidno:159)(cdr2),pdrsgyawfiy(seqidno:160)(cdr3)seqidno:8cdr：kasrdvaiava(seqidno:161)(cdr1),wastrht(seqidno:162)(cdr2),hqyssypft(seqidno:163)(cdr3)在一些实施方案中，该化合物包含包含与表1所述的序列具有至少80％(如85％、90％、95％、96％、97％、98％或99％)同一性的序列的vh1、vl1、vh2和/或vl2。两个氨基酸序列的“百分比同一性”使用karlin和altschulproc.natl.acad.sci.usa87:2264-68,1990，在karlin和altschulproc.natl.acad.sci.usa90:5873-77,1993中修改的算法测定。将该算法并入altschul，等j.mol.biol.215:403-10,1990的nblast和xblast程序(2.0版)中。blast蛋白质搜索可用xblast程序，评分＝50，字长＝3进行，以获得与目标蛋白质分子同源的氨基酸序列。当两个序列之间存在空位时，可如altschul等,nucleicacidsres.25(17):3389-3402,1997所述使用空位blast(gappedblast)。当使用blast和空位blast程序时，可使用各个程序(如xblast和nblast)的默认参数。在一些实施方案中，该化合物所包含的vh1、vl1、vh2和/或vl2包含的序列包含在表1所述的序列中的一个或多个(如1、2、3、4、5、6、7、8、9、10或更多个)突变。此类突变可为保守的氨基酸取代。如本文所用，“保守的氨基酸取代”是指不改变其中进行氨基酸取代的蛋白质的相对电荷或尺寸特征的氨基酸取代。保守的氨基酸取代包括例如在以下组内的氨基酸之间进行的取代：(a)m、i、l、v；(b)f、y、w；(c)k、r、h；(d)a、g；(e)s、t；(f)q、n；和(g)e、d。该化合物的铰链区、ch2和ch3(及任选的ch1和cl，如果该化合物含有此类区域)的氨基酸序列可源自任何适当的来源，如诸如igg1、igg2、igg3或igg4的抗体的恒定区。抗体重链和轻链恒定区氨基酸序列是本领域熟知的，如imgt数据库(www.imgt.org)或www.vbase2.org/vbstat.php.提供的那些序列，这两个网站通过引用并入本文。在一些实施方案中，ch2和ch3的氨基酸序列源自igg1或igg4(如seqidno:39或37)。在一些实施方案中，cl包含κcl或λcl的氨基酸序列。在一些实施方案中，铰链区包含氨基酸序列epkscdkthtcppcp(seqidno:40)。在一些实施方案中，该化合物的ch2和/或ch3(及任选的ch1和cl，如果该化合物含有此类区域)可包含与野生型ch2或ch3不同的一个或多个氨基酸取代，如在野生型igg1ch2或ch3中的一个或多个氨基酸取代或者在野生型igg4ch2或ch3中的一个或多个氨基酸取代(seqidno:39提供示例性野生型igg1)。此类取代是本领域已知的(参见，例如us7704497、us7083784、us6821505、us8323962、us6737056和us7416727)。在一些实施方案中，ch2包含在根据eu索引如在kabat中对常见抗体编号的234、235、252、254和/或256处的氨基酸取代(kabat等sequencesofproteinsofimmunologicalinterest,u.s.departmentofhealthandhumanservices,1991，其通过引用以其整体并入本文)。应理解，本文所述的所有氨基酸位置是指如在kabat中对常见抗体的eu索引的编号。在一些实施方案中，ch2包含位置252、254和/或256处的氨基酸取代。在一些实施方案中，位置252处的氨基酸是酪氨酸、苯丙氨酸、丝氨酸、色氨酸或苏氨酸。在一些实施方案中，位置254处的氨基酸是苏氨酸。在一些实施方案中，位置254处的氨基酸是丝氨酸、精氨酸、谷氨酰胺、谷氨酸或天冬氨酸。在一些实施方案中，ch2包含位置252处的酪氨酸、位置254处的苏氨酸和位置256处的谷氨酸(在本文中被称为yte突变体)。在一些实施方案中，ch2包含在位置234和/或235处的氨基酸取代。在一些实施方案中，ch2包含在位置234处的丙氨酸和在位置235处的丙氨酸，在本文中也被称为ko突变体。在一些实施方案中，ch2包含在位置252处的酪氨酸、在位置254处的苏氨酸、在位置256处的谷氨酸、在位置234处的丙氨酸和在位置235处的丙氨酸，在本文中也被称为ko-yte突变体。在一些实施方案中，一个或多个接头可用于将第一和/或第二多肽上的结构域/区连接在一起。例如，第一多肽可包含vl1与vh2之间的接头。如果第一多肽包含ch1，则第一多肽可包含在vl1或vh2(根据以上讨论的构型)与ch1(如vl1-接头-ch1或vh2-接头-ch1)之间的接头。在另一个实例中，第二多肽可包含在vl2与vh1之间的接头。如果第二多肽还包含cl，则第二多肽还可包含在vl2或vh1(根据以上讨论的构型)与cl(如vl2-接头-cl或vh1-接头-cl)之间的接头。应理解任何个数的接头可用于将任何结构域或区连接至第一多肽上的任何其它另一个结构域或区，和/或任何个数的接头可用于将任何结构域或区连接至第二多肽上任何其它另一个结构域或区。考虑本领域已知的任何适合的接头在本文中使用。在一些实施方案中，接头是肽接头。在一些实施方案中，肽接头包含至少两个氨基酸，如2、3、4、5、6、7、8、9、10或更多个氨基酸。在一些实施方案中，肽接头的长度不超过50、40、30、25、20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3或2个氨基酸。在一些实施方案中，肽接头的长度在2与50、2与40、2与30、2与20、2与10、2与9、2与8、2与7或2与6个氨基酸之间。在一些实施方案中，肽接头包含氨基酸序列gggsggg(seqidno:9)、lgggsg(seqidno:10)、fnrges(seqidno:11)、vepkss(seqidno:12)或其组合。在一些实施方案中，肽接头可包含多个拷贝的接头序列，如多个拷贝的序列gggsggg(seqidno:9)、lgggsg(seqidno:10)、fnrges(seqidno:11)、vepkss(seqidno:12)或其组合。在一些实施方案中，该化合物包含两个第一多肽和两个第二多肽。在一些实施方案中，第一多肽的一个的ch2和ch3与第一多肽的另一个的ch2和ch3缔合以形成四价分子(如两个第一多肽通过它们各自的ch2与ch3结构域之间的缔合二聚化以形成包含对第一靶蛋白具有特异性的两个结合位点和对第二靶蛋白具有特异性的两个结合位点的四价分子)。如果第一多肽还包含ch1结构域，所述ch1结构域还可参与四价分子的形成(如两个第一多肽通过它们各自ch1、ch2与ch3结构域之间缔合二聚化以形成包含第一靶蛋白的两个结合位点和第二靶蛋白的两个结合位点的四价分子)。在一些实施方案中，两个第一多肽经由至少一个二硫键缔合在一起。本文还考虑了与如本文所述的化合物竞争结合的其它化合物，如与本文所述的化合物竞争结合至tnf-α和il23a的测试化合物。在一些实施方案中，测试化合物可与如本文所述的化合物具有至少80％、85％、90％、95％、96％、97％、98％或99％序列同一性。竞争性结合可使用本领域已知的任何测定如平衡结合、elisa、表面等离子共振或光谱法。在一些实施方案中，本文所述的化合物特异性结合至tnf-α和il23a两者。“特异性结合”至抗原或表位的化合物是本领域熟知的术语，并且测定此类特异性结合的方法也是本领域中所熟知的。如果分子相较于其与可替代的靶更频繁、更快速、以更佳的持续时间和更佳的亲和力与特定靶抗原反应或缔合，则据说该分子展现出“特异性结合”。如果化合物相较于其与其它物质的结合以更佳的亲和力、亲合力、更容易地和/或以更佳的持续时间结合，则化合物“特异性结合”至靶抗原或表位。例如，特异性(或优先)结合至抗原(如tnf-α或il23a)或其中的抗原表位的化合物是相较于化合物与其它抗原或相同抗原中的其它表位的结合以更佳的亲和力、亲合力、更容易地和/或以更佳的持续时间结合该靶抗原的化合物。也应通过阅读该定义来理解例如特异性结合至第一靶抗原的化合物可或不可特异性或优先结合至第二靶抗原。因此，“特异性结合”或“优先结合”不一定需要(尽管其可包括)专一性结合。通常但不一定提及结合是指优先结合。在一些实例中，“特异性结合”至靶抗原或其表位的化合物不可结合至其它抗原或相同抗原中的其它表位。在一些实施方案中，如本文所述的化合物对tnf-α和il23或其抗原表位具有适合的结合亲和力。如本文所用，“结合亲和力”是指表观缔合常数或ka。ka是缔合常数(kd)的倒数。本文所述的化合物可具有至少10-5、10-6、10-7、10-8、10-9、10-10、10-11、10-12m或更低的对一种或两种靶抗原或抗原表位的结合亲和力(kd)。增加的结合亲和力对应于减小的kd。在一些实施方案中，本文所述的化合物对一种或两种靶抗原或抗原表位具有至少10-11m或更低的结合亲和力(kd)。化合物相对于第三抗原对第一抗原和第二抗原有更高的亲和力结合可由比结合第三抗原的ka(或数值kd)高的结合第一抗原和第二抗原的ka(或更小的数值kd)表示。在此类情况下，该化合物相对于第三抗原(如呈第二构象或其模拟物的相同的第一或第二蛋白质；或第三蛋白质)，对第一抗原和第二抗原(如呈第一构象或其模拟物的第一蛋白质和呈第一构象或其模拟物的第二蛋白质)具有特异性。结合亲和力(如用于特异性或其它比较)的差异可为至少1.5、2、3、4、5、10、15、20、37.5、50、70、80、91、100、500、1000、10,000或105倍。结合亲和力(或结合特异性)可通过多种方法测定，包括平衡结合、elisa、表面等离子共振或光谱法(如，使用荧光测定)。用于评价结合亲和力的示例性条件是在hbs-p缓冲液(10mmhepesph7.4,150mmnacl,0.005％(v/v)surfactantp20)中。这些技术可用于测量结合的结合蛋白的浓度作为靶蛋白浓度的函数。结合的靶蛋白([结合])的浓度与游离靶蛋白([游离])的浓度和靶上结合蛋白的结合位点的浓度相关，其中(n)是根据以下等式的每个靶分子的结合位点的个数：[结合]＝[n][游离]/(kd+[游离])然而并非总是必须精确测定ka，因为有时足以获得亲和力的定量测量值，如使用诸如efisa或facs分析的方法测定、与ka成比例并因此可用于比较，诸如确定更高的亲和力是否如高2-倍，以获得亲和力的定量测量值或获得亲和力的推断值，如通过功能测定(如体外或体内测定)中的活性。在一些实施方案中，该化合物包含如表2a中所定义的第一多肽和第二多肽。在一些实施方案中，该化合物包含：(i)第一多肽包含seqidno:13的氨基酸序列且第二多肽包含seqidno:14的氨基酸序列；(ii)第一多肽包含seqidno:15的氨基酸序列且第二多肽包含seqidno:16的氨基酸序列；(iii)第一多肽包含seqidno:17的氨基酸序列且第二多肽包含seqidno:18的氨基酸序列；(iv)第一多肽包含seqidno:19的氨基酸序列且第二多肽包含seqidno:20的氨基酸序列；(v)第一多肽包含seqidno:21的氨基酸序列且第二多肽包含seqidno:22的氨基酸序列；(vi)第一多肽包含seqidno:23的氨基酸序列且第二多肽包含seqidno:24的氨基酸序列；(vii)第一多肽包含seqidno:25的氨基酸序列且第二多肽包含seqidno:26的氨基酸序列；(viii)第一多肽包含seqidno:27的氨基酸序列且第二多肽包含seqidno:28的氨基酸序列；(ix)第一多肽包含seqidno:29的氨基酸序列且第二多肽包含seqidno:30的氨基酸序列；(x)第一多肽包含seqidno:31的氨基酸序列且第二多肽包含seqidno:32的氨基酸序列；(xi)第一多肽包含seqidno:33的氨基酸序列且第二多肽包含seqidno:34的氨基酸序列；(xii)第一多肽包含seqidno:35的氨基酸序列且第二多肽包含seqidno:36的氨基酸序列；(xiii)第一多肽包含seqidno:44的氨基酸序列且第二多肽包含seqidno:45的氨基酸序列；(xiv)第一多肽包含seqidno:46的氨基酸序列且第二多肽包含seqidno:47的氨基酸序列；(xv)第一多肽包含seqidno:48的氨基酸序列且第二多肽包含seqidno:49的氨基酸序列；(xvi)第一多肽包含seqidno:50的氨基酸序列且第二多肽包含seqidno:51的氨基酸序列；(xvii)第一多肽包含seqidno:52的氨基酸序列且第二多肽包含seqidno:53的氨基酸序列；(xviii)第一多肽包含seqidno:54的氨基酸序列且第二多肽包含seqidno:55的氨基酸序列；(xix)第一多肽包含seqidno:56的氨基酸序列且第二多肽包含seqidno:57的氨基酸序列；(xx)第一多肽包含seqidno:58的氨基酸序列且第二多肽包含seqidno:59的氨基酸序列；(xxi)第一多肽包含seqidno:60的氨基酸序列且第二多肽包含seqidno:61的氨基酸序列；(xxii)第一多肽包含seqidno:62的氨基酸序列且第二多肽包含seqidno:63的氨基酸序列；(xxiii)第一多肽包含seqidno:64的氨基酸序列且第二多肽包含seqidno:65的氨基酸序列；(xxiv)第一多肽包含seqidno:66的氨基酸序列且第二多肽包含seqidno:67的氨基酸序列；(xxv)第一多肽包含seqidno:68的氨基酸序列且第二多肽包含seqidno:69的氨基酸序列；(xxvi)第一多肽包含seqidno:70的氨基酸序列且第二多肽包含seqidno:71的氨基酸序列；(xxvii)第一多肽包含seqidno:72的氨基酸序列且第二多肽包含seqidno:73的氨基酸序列；(xxviii)第一多肽包含seqidno:74的氨基酸序列且第二多肽包含seqidno:75的氨基酸序列；(xxix)第一多肽包含seqidno:76的氨基酸序列且第二多肽包含seqidno:77的氨基酸序列；(xxx)第一多肽包含seqidno:78的氨基酸序列且第二多肽包含seqidno:79的氨基酸序列；(xxxi)第一多肽包含seqidno:80的氨基酸序列且第二多肽包含seqidno:81的氨基酸序列；(xxxii)第一多肽包含seqidno:82的氨基酸序列且第二多肽包含seqidno:83的氨基酸序列；(xxxiii)第一多肽包含seqidno:84的氨基酸序列且第二多肽包含seqidno:85的氨基酸序列；(xxxiv)第一多肽包含seqidno:86的氨基酸序列且第二多肽包含seqidno:87的氨基酸序列；(xxxv)第一多肽包含seqidno:88的氨基酸序列且第二多肽包含seqidno:89的氨基酸序列；(xxxvi)第一多肽包含seqidno:90的氨基酸序列且第二多肽包含seqidno:91的氨基酸序列；(xxxvii)第一多肽包含seqidno:92的氨基酸序列且第二多肽包含seqidno:93的氨基酸序列；(xxxviii)第一多肽包含seqidno:94的氨基酸序列且第二多肽包含seqidno:95的氨基酸序列；(xxxix)第一多肽包含seqidno:96的氨基酸序列且第二多肽包含seqidno:97的氨基酸序列；(xl)第一多肽包含seqidno:98的氨基酸序列且第二多肽包含seqidno:99的氨基酸序列；(xli)第一多肽包含seqidno:100的氨基酸序列且第二多肽包含seqidno:101的氨基酸序列；(xlii)第一多肽包含seqidno:102的氨基酸序列且第二多肽包含seqidno:103的氨基酸序列；(xliii)第一多肽包含seqidno:104的氨基酸序列且第二多肽包含seqidno:105的氨基酸序列；(xliv)第一多肽包含seqidno:106的氨基酸序列且第二多肽包含seqidno:107的氨基酸序列；(xlv)第一多肽包含seqidno:108的氨基酸序列且第二多肽包含seqidno:109的氨基酸序列；(xlvi)第一多肽包含seqidno:110的氨基酸序列且第二多肽包含seqidno:111的氨基酸序列；(xlvii)第一多肽包含seqidno:112的氨基酸序列且第二多肽包含seqidno:113的氨基酸序列；(xlviii)第一多肽包含seqidno:114的氨基酸序列且第二多肽包含seqidno:115的氨基酸序列；(xlix)第一多肽包含seqidno:116的氨基酸序列且第二多肽包含seqidno:117的氨基酸序列；(l)第一多肽包含seqidno:118的氨基酸序列且第二多肽包含seqidno:119的氨基酸序列；(li)第一多肽包含seqidno:120的氨基酸序列且第二多肽包含seqidno:121的氨基酸序列；(lii)第一多肽包含seqidno:122的氨基酸序列且第二多肽包含seqidno:123的氨基酸序列；(liii)第一多肽包含seqidno:124的氨基酸序列且第二多肽包含seqidno:125的氨基酸序列；(liv)第一多肽包含seqidno:126的氨基酸序列且第二多肽包含seqidno:127的氨基酸序列；(lv)第一多肽包含seqidno:128的氨基酸序列且第二多肽包含seqidno:129的氨基酸序列；(lvi)第一多肽包含seqidno:130的氨基酸序列且第二多肽包含seqidno:131的氨基酸序列；(lvii)第一多肽包含seqidno:132的氨基酸序列且第二多肽包含seqidno:133的氨基酸序列；(lviii)第一多肽包含seqidno:134的氨基酸序列且第二多肽包含seqidno:135的氨基酸序列；(lix)第一多肽包含seqidno:136的氨基酸序列且第二多肽包含seqidno:137的氨基酸序列；(lx)第一多肽包含seqidno:138的氨基酸序列且第二多肽包含seqidno:139的氨基酸序列；(lxi)第一多肽包含seqidno:140的氨基酸序列且第二多肽包含seqidno:141的氨基酸序列；或(lxii)第一多肽包含seqidno:142的氨基酸序列且第二多肽包含seqidno:143的氨基酸序列。在一些实施方案中，该化合物包含：(i)第一多肽包含seqidno:13的氨基酸序列且第二多肽包含seqidno:14的氨基酸序列；(ii)第一多肽包含seqidno:15的氨基酸序列且第二多肽包含seqidno:16的氨基酸序列；(iii)第一多肽包含seqidno:17的氨基酸序列且第二多肽包含seqidno:18的氨基酸序列；(iv)第一多肽包含seqidno:19的氨基酸序列且第二多肽包含seqidno:20的氨基酸序列；(v)第一多肽包含seqidno:21的氨基酸序列且第二多肽包含seqidno:22的氨基酸序列；(vi)第一多肽包含seqidno:23的氨基酸序列且第二多肽包含seqidno:24的氨基酸序列；(vii)第一多肽包含seqidno:25的氨基酸序列且第二多肽包含seqidno:26的氨基酸序列；(viii)第一多肽包含seqidno:27的氨基酸序列且第二多肽包含seqidno:28的氨基酸序列；(ix)第一多肽包含seqidno:29的氨基酸序列且第二多肽包含seqidno:30的氨基酸序列；(x)第一多肽包含seqidno:31的氨基酸序列且第二多肽包含seqidno:32的氨基酸序列；(xi)第一多肽包含seqidno:33的氨基酸序列且第二多肽包含seqidno:34的氨基酸序列；或(xii)第一多肽包含seqidno:35的氨基酸序列且第二多肽包含seqidno:36的氨基酸序列。产生化合物、核酸、载体和细胞的方法本公开的各方面还包括编码本文所述的化合物或本文所述的多肽(如本文所述的第一或第二多肽)的核酸，所述化合物或多肽可一起或单独编码。可获得编码本文所述的化合物或本文所述的多肽的多核苷酸，并且多核苷酸的核苷酸序列通过本领域已知的任何方法测定。在一些实施方案中，该核酸被包含在诸如表达载体的载体内。在一些实施方案中，载体包含可操作地连接至核酸的启动子。多种启动子可用于表达本文所述的化合物或本文所述的多肽，包括但不限于巨细胞病毒(cmv)立即早期启动子，病毒ltr诸如劳斯氏肉瘤病毒ltr(roussarcomavirusltr)、hiv-ltr、htlv-1ltr，猿猴病毒40(sv40)早期启动子，大肠杆菌lacuv5启动子及单纯性疱疹tk病毒启动子。还可使用可调控启动子。此类可调控启动子包括使用来自大肠杆菌的lac阻遏物作为转录调节因子以调控从携带lac操纵子的哺乳动物细胞启动子转录的那些[brown,m.等,cell,49:603-612(1987)]，使用四环素阻遏物(tetr)的那些[gossen,m.,和bujard,h.,proc.natl.acad.sci.usa89:5547-5551(1992)；yao,f.等,humangenetherapy,9:1939-1950(1998)；shockelt,p.,等,proc.natl.acad.sci.usa,92:6522-6526(1995)]。其它系统包括使用雌二醇(astradiol)、ru486、联苯酚米勒甾酮或雷帕霉素的fk506二聚体、vp16或p65。可诱导系统可从invitrogen、clontech和ariad获得。可使用可包括操纵子的阻遏物的可调控启动子。在一个实施方案中，来自大肠杆菌(escherichiacoli)的lac阻遏物可用作转录调节因子以调控从携带lac操纵子的哺乳动物细胞启动子转录[m.brown等,cell,49:603-612(1987)]；gossen和bujard(1992)；[m.gossen等,natl.acad.sci.usa,89:5547-5551(1992)]合并四环素阻遏物(tetr)与转录激活物(vp16)以创造tetr-哺乳动物细胞转录激活物融合蛋白tta(tetr-vp16)、与源自人巨细胞病毒(hcmv)主要立即早期启动子的携带teto的最小启动子以创造tetr-tet操纵子系统以控制在哺乳动物中的基因表达。在一个实施方案中，使用四环素可诱导的转换(yao等,humangenetherapy；gossen等,natl.acad.sci.usa,89:5547-5551(1992)；shockett等,proc.natl.acad.sci.usa,92:6522-6526(1995))。此外，载体可含有例如以下的一些或所有：可选择的标记基因，诸如用于在哺乳动物细胞中选择稳定或瞬时转染子的新霉素基因；用于高水平转录的来自人cmv的立即早期基因的增强子/启动子序列；用于mrna稳定性的来自sv40的转录终止和rna加工信号；sv40多瘤复制起点和cole1(用于适当的附加型复制)；内部核糖体结合位点(ires)，多用多克隆位点；及用于正义和反义rna的体外转录的t7和sp6rna启动子。适用于产生含转基因载体的载体和方法是本领域熟知且可获得的。可通过常见技术(如电穿孔、脂质体转染和磷酸钙沉淀)将包含该核酸的表达载体转移至宿主细胞，然后将转染的细胞通过常见技术培养以产生本文所述的化合物。在一些实施方案中，本文所述的化合物的表达通过组成性、可诱导性或组织特异性启动子调控。用于表达本文所述的化合物或本文所述的多肽的宿主细胞可为细菌细胞诸如大肠杆菌或优选真核细胞。具体来说，哺乳动物细胞(诸如中国仓鼠卵巢细胞(cho))结合载体诸如来自人巨细胞病毒的主要立即早期基因启动子元件是免疫球蛋白的有效表达系统(foecking等(1986)“powerfulandversatileenhancer-promoterunitformammalianexpressionvectors,”gene45:101-106；cockett等(1990)“highlevelexpressionoftissueinhibitorofmetalloproteinasesinchinesehamsterovarycellsusingglutaminesynthetasegeneamplification,”biotechnology8:662-667)。多种宿主表达载体系统可用于表达本文所述的化合物或本文所述的多肽。此类宿主表达载体系统代表可产生并随后扩增本文所述的化合物或本文所述的多肽的编码序列的媒介物，但也可代表可在用适当的核苷酸编码序列转化或转染时原位表达本文所述的化合物的细胞。这些包括但不限于微生物，诸如用含有本文所述的化合物的编码序列的重组噬菌体dna、质粒dna或粘粒dna表达载体转染的细菌(如大肠杆菌和枯草芽孢杆菌(b.subtilis))；用含有编码本文所述的化合物的序列的重组酵母表达载体转化的酵母(如毕氏酵母(saccharomycespichia))；用含编码本文所述的化合物的序列的重组病毒表达载体(如杆状病毒)感染的昆虫细胞系统；用重组病毒表达载体(如花椰菜花叶病毒(camv)和烟草花叶病毒(tmv)感染或用含有编码本文所述的分子化合物的序列的重组质粒表达载体(如ti质粒)转化的植物细胞系统；或哺乳动物细胞系统(如cos、cho、bhk、293、293t、3t3细胞、淋巴细胞(参见美国专利no.5,807,715)、perc.6细胞(由crucell开发的人肾细胞)，其具有含有源自哺乳动物细胞基因组(如金属硫因启动子)或源自哺乳动物病毒(如腺病毒晚期启动子；牛痘病毒7.5k启动子)的启动子的重组表达构建体。在细菌系统中，多种表达载体可根据意在用于所表达化合物的用途而有利地选择。例如，当产生大量的该蛋白质时，为了产生本文所述的化合物的药物组合物，指导可容易纯化的高水平的融合蛋白质产物表达的载体可能是需要的。此类载体包括但不限于大肠杆菌表达载体pur278(rüther等(1983)“easyidentificationofcdnaclones,”emboj.2:1791-1794)，其中编码序列可单独连接至与lacz编码区同在框内的载体中，使得产生融合蛋白；pin载体(inouye等(1985)“up-promotormutationsinthelppgeneofescherichiacoli,”nucleicacidsres.13:3101-3110；vanheeke等(1989)“expressionofhumanasparaginesynthetaseinescherichiacoli,”j.biol.chem.24:5503-5509)；等。pgex载体还可用于表达外源多肽作为与谷胱甘肽s-转移酶(gst)的融合蛋白。通常，此类融合蛋白是可溶的且可容易地通过吸附和结合至基质谷胱甘肽-琼脂糖珠、然后在游离谷胱甘肽的存在下洗脱从裂解的细胞纯化。pgex载体经设计包含凝血酶或因子xa蛋白酶裂解位点，使得经克隆的靶基因产物可从gst部分释放。在昆虫系统中，苜蓿银纹夜蛾(autographacalifomica)核型多角体病毒(acnpv)用作表达外源基因的载体。病毒在草地贪夜蛾(spodopterafrugiperda)细胞中生长。可将编码序列单独克隆至病毒的非必需区域(如多角体蛋白基因)中，并置于acnpv启动子(如多角体蛋白启动子)的控制下。在哺乳动物宿主细胞中，可使用多种基于病毒的表达系统。在使用腺病毒作为表达载体的情况下，目标编码序列可被连接至腺病毒转录/翻译控制复合物，如晚期启动子和三联体前导序列。然后可将该嵌合基因通过体外或体内重组插入腺病毒基因组中。在非必需区域(如区域e1或e3)插入病毒基因组将产生在感染的宿主中是活的且能够表达免疫球蛋白分子的重组病毒(如参见logan等(1984)“adenovirustripartiteleadersequenceenhancestranslationofmrnaslateafterinfection,”proc.natl.acad.sci.usa81:3655-3659)。特异性起始信号还可为插入的抗体编码序列的有效翻译所需。这些信号包括atg起始密码子和毗邻序列。此外，起始密码子必须与所需编码序列的阅读框同相以确保所需的插入物的翻译。这些外源翻译控制信号和起始密码子可具有多种来源(天然的和合成的)。表达效率可通过并入适当的转录增强子元件、转录终止子等来增强(参见bitter等(1987)“expressionandsecretionvectorsforyeast,”methodsinenzymol.153:516-544)。此外，可选择调节插入的序列的表达或者以所需的特定方式修饰和加工基因产物的宿主细胞菌株。蛋白质产物的此类修饰(如糖基化)和加工(如裂解)可能对于蛋白质的功能是重要的。例如，在某些实施方案中，本文所述的化合物可表达为单一基因产物(如单个多肽链，即多蛋白前体)，需要通过天然或重组细胞机制进行蛋白水解裂解以形成本文所述的化合物的单独多肽。本公开因此涵盖工程化核酸序列以编码包含本文所述的化合物的多肽的多蛋白前体分子，所述多肽包含能够指导翻译后裂解所述多蛋白前体的编码序列。翻译后裂解所述多蛋白前体产生本文所述的化合物的多肽。翻译后裂解包含本文所述的化合物的多肽的前体分子可在体内发生(即，在宿主细胞内通过天然或重组细胞系统/机制，如在适当的位点处弗林蛋白酶裂解)或可在体外发生(如，在包含具有已知活性的蛋白酶或肽酶的组合物中和/或在包含已知促进所需的蛋白水解作用的条件或试剂的组合物中孵育所述多肽链)。重组蛋白质的纯化和修饰是本领域熟知的，使得多蛋白前体的设计可包括多个可容易由技术人员容易理解的实施方案。本领域已知的任何已知的蛋白酶或肽酶可用于所描述的前体分子的修饰，如凝血酶或因子xa(nagai等(1985)“oxygenbindingpropertiesofhumanmutanthemoglobinssynthesizedinescherichiacoli,”proc.nat.acad.sci.usa82:7252-7255，并综述于jenny等(2003)“acriticalreviewofthemethodsforcleavageoffusionproteinswiththrombinandfactorxa,”proteinexpr.purif.31:1-11中，其各自通过引用以其整体并入本文))、肠激酶(collins-racie等(1995)“productionofrecombinantbovineenterokinasecatalyticsubunitinescherichiacoliusingthenovelsecretoryfusionpartnerdsba,”biotechnology13:982-987，其在此通过引用以其整体并入))、弗林蛋白酶和actev(parks等(1994)“releaseofproteinsandpeptidesfromfusionproteinsusingarecombinantplantvirusproteinase,”anal.biochem.216:413-417，其在此通过引用以其整体并入))及口蹄疫病毒蛋白酶c3。不同的宿主细胞具有蛋白质和基因产物的翻译后加工和修饰的特征和特定机制。可选择适当的细胞系或宿主系统以确保对表达的外源蛋白质的正确的修饰和加工。为此，可使用具有用于适当加工初始转录物、糖基化和磷酸化基因产物的细胞器的真核宿主细胞。此类哺乳动物宿主细胞包括但不限于cho、very、bhk、hela、cos、mdck、293、293t、3t3、wi38、bt483、hs578t、htb2、bt20和t47d、crl7030和hs578bst。对于长期高产率产生重组蛋白质，优选稳定的表达。例如，可工程化稳定表达本文所述的化合物的细胞系。而非使用含有病毒复制起点的表达载体，可用有适当的表达控制元件(如启动子、增强子、序列、转录终止子、聚腺苷酸化位点等)控制的dna和可选标记转化宿主细胞。在引入外源dna后，可使工程化的细胞在富集培养基中生长1-2天，然后转换至可选培养基。重组质粒中的可选标记物赋予选择耐受性并使得细胞稳定整合质粒至其染色体中并生长以形成病灶，所述病灶继而可克隆并扩增至细胞系中。该方法可有利地用于工程化表达本文所述的化合物的细胞系。此类工程化的细胞系在筛选和评价与本文所述的化合物直接或间接相互作用的化合物方面特别有用。可使用多种选择系统，包括但不限于单纯疱疹病毒胸苷激酶(wigler等(1977)“transferofpurifiedherpesvirusthymidinekinasegenetoculturedmousecells,”cell11:223-232)、次黄嘌呤-鸟嘌呤磷酸核糖转移酶(szybalska等(1992)“useofthehprtgeneandthehatselectiontechniqueindna-mediatedtransformationofmammaliancellsfirststepstowarddevelopinghybridomatechniquesandgenetherapy,”bioessays14:495-500)和腺嘌呤磷酸核糖转移酶(lowy等(1980)“isolationoftransformingdna:cloningthehamsteraprtgene,”cell22:817-823)基因可分别用于tk-、hgprt-或aprt-细胞中。此外，抗代谢物耐受性可用作选择以下基因的基础：dhfr，其赋予对氨甲蝶呤的耐受性(wigler等(1980)“transformationofmammaliancellswithanamplifiabledominant-actinggene,”proc.natl.acad.sci.usa77:3567-3570；o'hare等(1981)“transformationofmousefibroblaststomethotrexateresistancebyarecombinantplasmidexpressingaprokaryoticdihydrofolatereductase,”proc.natl.acad.sci.usa78:1527-1531)；gpt，其赋予对霉酚酸的耐受性(mulligan等(1981)“selectionforanimalcellsthatexpresstheescherichiacoligenecodingforxanthine-guaninephosphoribosyltransferase,”proc.natl.acad.sci.usa78:2072-2076)；neo，其赋予对氨基糖苷g-418的耐受性(tolstoshev(1993)“genetherapy,concepts,currenttrialsandfuturedirections,”ann.rev.pharmacol.toxicol.32:573-596；mulligan(1993)“thebasicscienceofgenetherapy,”science260:926-932；和morgan等(1993)“humangenetherapy,”ann.rev.biochem.62:191-217)及hygro，其赋予对潮霉素的耐受性(santerre等(1984)“expressionofprokaryoticgenesforhygromycinbandg418resistanceasdominant-selectionmarkersinmouselcells,”gene30:147-156)。可使用的重组dna
技术领域：
通常已知的方法描述于ausubel等(编辑),1993,currentprotocolsinmolecularbiology,johnwiley&sons,ny；kriegler,1990,genetransferandexpression,alaboratorymanual,stocktonpress,ny；及第12和13章,dracopoli等(编辑),1994,currentprotocolsinhumangenetics,johnwiley&sons,ny.；colberre-garapin等(1981)“anewdominanthybridselectivemarkerforhighereukaryoticcells,”j.mol.biol.150:1-14。本文所述的化合物或本文所述的多肽的表达水平可通过载体扩增提高(对于综述，参见bebbington和hentschel,theuseofvectorsbasedongeneamplificationfortheexpressionofclonedgenesinmammaliancellsindnacloning,第3卷(academicpress,newyork,1987)。当表达本文所述的化合物的载体系统中的标记物可扩增时，宿主细胞培养物中存在的抑制剂水平提高将增加标记基因的拷贝数。因为扩增的区域与本文所述的化合物或本文所述的多肽的核苷酸序列相关，多肽的产生也将增加(crouse等(1983)“expressionandamplificationofengineeredmousedihydrofolatereductaseminigenes,”mol.cell.biol.3:257-266)。可用两种表达载体(编码本文所述的化合物的第一多肽的第一载体和编码本文所述的化合物的第二多肽的第二载体)共转染宿主细胞。该两种载体可含有相同的使得能够等表达两种多肽的可选择标记物。可替代地，可使用编码两个多肽的单个载体。本文所述的化合物的多肽的编码序列可包含cdna或基因组dna。一旦本文所述的化合物或本文所述的多肽被重组表达，其可通过本领域已知的用于纯化多肽、多蛋白或抗体的任何方法(如类似于基于抗原选择性的抗体纯化方案)纯化，例如通过色谱法(如离子交换、亲和力，特别通过对特异性抗原的亲和力(任选地，在蛋白质a选择之后，其中该化合物包含fc结构域(或其部分))，和尺寸柱色谱法)、离心、差别溶解度或通过用于纯化多肽或抗体的任何其它标准技术。本公开的其它方面涉及包含本文所述的核酸或本文所述的载体的细胞。该细胞可为原核或真核细胞。在一些实施方案中，该细胞是哺乳动物细胞。本文描述了示例性细胞类型。本公开的又其它方面涉及产生本文所述的化合物或本文所述的多肽(如第一多肽或第二多肽)的方法，所述方法包括获得本文所述的细胞和在所述细胞中表达本文所述的核酸。在一些实施方案中，该方法还包括分离和纯化本文所述的化合物或本文所述的多肽。用于医学用途的治疗方法和组合物本公开的其它方面涉及治疗方法和用于医学用途的组合物。用于此类方法和组合物中的化合物的非限制性实例是包含以下的那些：(i)第一多肽包含seqidno:13的氨基酸序列且第二多肽包含seqidno:14的氨基酸序列；(ii)第一多肽包含seqidno:15的氨基酸序列且第二多肽包含seqidno:16的氨基酸序列；(iii)第一多肽包含seqidno:17的氨基酸序列且第二多肽包含seqidno:18的氨基酸序列；(iv)第一多肽包含seqidno:19的氨基酸序列且第二多肽包含seqidno:20的氨基酸序列；(v)第一多肽包含seqidno:21的氨基酸序列且第二多肽包含seqidno:22的氨基酸序列；(vi)第一多肽包含seqidno:23的氨基酸序列且第二多肽包含seqidno:24的氨基酸序列；(vii)第一多肽包含seqidno:25的氨基酸序列且第二多肽包含seqidno:26的氨基酸序列；(viii)第一多肽包含seqidno:27的氨基酸序列且第二多肽包含seqidno:28的氨基酸序列；(ix)第一多肽包含seqidno:29的氨基酸序列且第二多肽包含seqidno:30的氨基酸序列；(x)第一多肽包含seqidno:31的氨基酸序列且第二多肽包含seqidno:32的氨基酸序列；(xi)第一多肽包含seqidno:33的氨基酸序列且第二多肽包含seqidno:34的氨基酸序列；或(xii)第一多肽包含seqidno:35的氨基酸序列且第二多肽包含seqidno:36的氨基酸序列。在一些实施方案中，治疗方法或用途是治疗自身免疫性或炎性疾病的方法或在该方法中的用途。在一些实施方案中，该方法包括向受试者(如患有或有风险患有自身免疫性或炎性疾病的受试者)施用本文所述的化合物或包含所述化合物的药物组合物。待由本文所述的方法治疗的受试者可为哺乳动物，更优选人。哺乳动物包括但不限于农场动物、运动动物、宠物、灵长类动物、马、狗、猫、小鼠和大鼠。需要治疗的人受试者可为患有、有风险患有或疑似患有疾病的人受试者。患有疾病的受试者可通过常规医学检查(如体检、实验室试验、器官功能试验、ct扫描或超声)鉴定。疑似患有任何该疾病的受试者可能显示该疾病的一个或多个症状。如自身免疫性和炎性疾病的疾病的体征和症状是本领域普通技术人员所熟知的。处于该疾病的风险的受试者可为具有一个或多个此疾病的风险因素的受试者。自身免疫性疾病的非限制性实例包括类风湿性关节炎、银屑病、1型糖尿病、全身性红斑狼疮、移植排斥、自身免疫性甲状腺疾病(桥本氏病(hashimoto'sdisease))、结节病、硬皮病、肉芽肿性动脉炎、克罗恩氏病、溃疡性结肠炎、斯耶格伦氏病(sjogren'sdisease)、强直性脊柱炎、银屑病性关节炎、多发性肌炎皮肌炎、结节性多动脉炎、免疫介导性水疱皮肤病、贝切特综合征(behcet'ssyndrome)、多发性硬化、系统性硬化、古帕斯捷氏病(goodpasture'sdisease)或免疫介导的肾小球性肾炎。炎性疾病的非限制性实例包括类风湿性关节炎、全身性红斑狼疮、斑形脱发、强直性脊柱炎、抗磷脂综合征、自身免疫性爱迪生氏病(addison'sdisease)、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳病、自身免疫性免疫淋巴增生综合征(alps)、自身免疫性血小板减少性紫癜(atp)、白塞氏病(behcet'sdisease)、大疱性类天疱疮、心肌病、口炎性腹泻-皮炎、慢性疲劳综合征免疫缺陷综合征(cfids)、慢性炎性脱髓鞘性多神经病、瘢痕性类天疱疮、冷凝集素病、crest综合征、克罗恩氏病、德氏病(dego'sdisease)、皮肌炎、青少年型皮肌炎、盘状狼疮、原发性混合型冷球蛋白血症、纤维肌痛-纤维肌炎、格雷夫斯病(grave'sdisease)、格林-巴利(guillain-barre)、桥本氏甲状腺炎(hashimoto'sthyroiditis)、特发性肺纤维化、特发性血小板减少性紫癜(itp)、iga肾病、胰岛素依赖型糖尿病(i型)、青少年型关节炎、美尼尔氏病(meniere'sdisease)、混合性结蒂组织病、多发性硬化、重症肌无力、寻常天疱疮、恶性贫血、结节性多动脉炎、多软骨炎、多腺体综合征、风湿性多肌痛、多肌炎和皮肌炎、原发性无丙种球蛋白血症、原发性胆汁性肝硬化、银屑病、雷诺氏现象(raynaud'sphenomenon)、莱特尔氏综合征(reiter'ssyndrome)、风湿热、结节病、硬皮病、斯耶格伦氏综合征(sjogren'ssyndrome)、僵人综合征、高安氏动脉炎(takayasuarteritis)、颞动脉炎/巨细胞动脉炎、溃疡性结肠炎、葡萄膜炎、血管炎、vitiligo和韦格纳氏肉芽肿病(wegener'sgranulomatosis)。在一些实施方案中，自身免疫性或炎性疾病是克罗恩氏病、强直性脊柱炎或银屑病性关节炎。为了实践本文公开的方法，可将有效量的本文所述的化合物或药物组合物施用于需要治疗的受试者(如人)。各种递送系统是已知的且可用于施用本发明的化合物。施用方法包括但不限于皮内、肌内、腹腔内、静脉内、皮下、鼻内、硬膜外和经口途径。本发明的化合物可例如通过输注、团注或注射施用，且可与诸如抗炎剂的其它生物活性剂一起施用。施用可是全身或局部的。在优选的实施方案中，通过皮下注射施用。用于此类注射的制剂可例如在预填充注射器中制备，其可每隔一周施用一次。如本文所述的“有效量”是指单独或与一种或多种其它化合物组合对受试者赋予治疗作用的每种化合物所需的量。有效量如本领域技术人员所认识到根据正治疗的特定疾患、疾患的严重程度、各个受试者参数(包括年龄，身体状况，尺寸，性别和体重)、治疗持续时间、同时疗法(如果存在)的性质、特定施用条件及健康护理人员的知识和经验内的类似因素变化。这些因素是本领域普通技术人员熟知的，且可仅用常规实验解决。通常优选的是施用各个组合或其组合的最大剂量，即根据合理医疗判断的最高安全剂量。然而，本领域普通技术人员应理解受试者可能出于医学原因、心理原因或几乎出于任何其他原因坚持更低的剂量或可耐受剂量。诸如半寿期的经验考虑通常将有助于测定剂量。例如，与人免疫系统相容的化合物，诸如包含来自人源化抗体或完全人抗体的区域的化合物可用于延长该化合物的半寿期和预防该化合物被宿主的免疫系统攻击。施用频率可在疗法过程期间测定和调整，并且通常但非必要基于疾病的治疗和/或抑制和/或缓解和/或延迟。可替代地，化合物的持续连续释放制剂可以是适当的。用于获得持续释放的各种制剂和设备是本领域已知的。在一些实施方案中，剂量是每天、每隔一天、每三天、每四天、每五天或每六天。在一些实施方案中，给药频率是每周一次、每2周一次、每4周一次、每5周一次、每6周一次、每7周一次、每8周一次、每9周一次或每10周一次；或每月一次、每2个月一次或每3个月一次或更久。该疗法的进展可通过常见技术和测定容易地监测。给药方案(包括所用的化合物)可随时间变化。在一些实施方案中，对于正常体重的成人受试者，可施用在约0.01至1000mg/kg范围内的剂量。在一些实施方案中，剂量在1至200mg之间。特定的剂量方案，即剂量、定时和重复将取决于特定的受试者和该受试者的医学史、以及化合物的性质(诸如化合物的半寿期，以及本领域熟知的其它考虑)。为了本公开的目的，如本文所述的化合物的适当剂量将取决于采用的特定化合物(或其组合物)、制剂和施用途径、疾病类型和严重程度、施用化合物是用于预防目的还是用于治疗目的、之前的疗法、受试者的临床病史和对拮抗剂的响应，及主治医生的判断。通常，临床医师将施用化合物直至达到获得所需结果的剂量。一种或多种化合物的施用可以是连续或间歇的，这取决于例如接受者的生理条件，施用目的是治疗性的还是预防性的及技术人员已知的其它因素。化合物的施用在预选的时间段内可基本上是连续的或可呈一系列间隔的剂量，如在发展疾病之前、期间或之后。如本文所用，术语“治疗”是指出于治愈、痊愈、缓和、缓解、改变、弥补、减轻、改善或影响疾病、疾病症状或疾病易患性的目的向患有疾病、具有疾病症状或患病倾向的受试者施加或施用化合物或包含化合物的组合物。缓和疾病包括延迟疾病发展或进展，或降低疾病严重程度。缓和疾病不一定需要治愈结果。如其中所用，"延迟"疾病发展意指推迟、阻碍、减缓、妨碍、稳定和/或延缓疾病进展。该延迟可具有不同长度的时间，这取决于病史和/或所治疗的个体。“延迟”或缓和疾病发展或者延迟疾病发作的方法是当与不使用该方法比较时降低在给定的时间范围内发展疾病的一个或多个症状的概率和/或降低在给定的时间范围内的症状的程度的方法。此类比较通常基于使用足以得到统计学显著结果的多名受试者的临床研究。疾病的“发展”或“进展”意指疾病的初始表现和/或随之发生的进展。疾病的发展可使用如本领域所熟知的标准临床技术检测和评估。然而，发展也是指可能不可检测的进展。为了本公开的目的，发展或进展是指症状的生物过程。“发展”包括发生、复发和发作。如本文所用，疾病的“发作”或“发生”包括初始发作和/或发作。在一些实施方案中，将本文所述的化合物以足以体内或体外抑制tnf-α或il23a的一者或两者的活性至少20％(如30％、40％、50％、60％、70％、80％、90％或更大)的量施用于需要治疗的受试者。测定化合物的抑制能力的方法是本领域已知的。实施例中提供了示例性tnf-α和il23a抑制测定。医学领域的普通技术人员已知的常见方法可用于向受试者施用化合物或药物组合物，这取决于待治疗的疾病的类型或疾病部位。该组合物还可经由其它常见途径施用，如经口、胃肠外、通过吸入喷雾、局部、经直肠、经鼻、经颊、经阴道或经由植入的贮库施用。如本文所用的术语“胃肠外”包括皮下、皮内、静脉内、肌内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内和颅内注射或输注技术。此外，可将其经由可注射的贮库施用途径施用于受试者，诸如使用1-、3-或6-月贮库可注射或可生物降解的材料和方法。药物组合物本公开的又其它方面涉及包含本文所述的化合物的药物组合物。可将包含本发明的化合物(如对tnf-α和il23a两者具有特异性的化合物)的组合物施用于患有或有风险患有自身免疫性或炎性疾病的受试者。本发明还提供本发明的化合物在用于治疗自身免疫性或炎性疾病的医药制造中的用途。可将该化合物单独或与其它组合物组合施用以预防或治疗自身免疫性或炎性疾病。用于此类药物组合物中的本发明的化合物的非限制性实例是包含以下的那些：(i)第一多肽包含seqidno:13的氨基酸序列且第二多肽包含seqidno:14的氨基酸序列；(ii)第一多肽包含seqidno:15的氨基酸序列且第二多肽包含seqidno:16的氨基酸序列；(iii)第一多肽包含seqidno:17的氨基酸序列且第二多肽包含seqidno:18的氨基酸序列；(iv)第一多肽包含seqidno:19的氨基酸序列且第二多肽包含seqidno:20的氨基酸序列；(v)第一多肽包含seqidno:21的氨基酸序列且第二多肽包含seqidno:22的氨基酸序列；(vi)第一多肽包含seqidno:23的氨基酸序列且第二多肽包含seqidno:24的氨基酸序列；(vii)第一多肽包含seqidno:25的氨基酸序列且第二多肽包含seqidno:26的氨基酸序列；(viii)第一多肽包含seqidno:27的氨基酸序列且第二多肽包含seqidno:28的氨基酸序列；(ix)第一多肽包含seqidno:29的氨基酸序列且第二多肽包含seqidno:30的氨基酸序列；(x)第一多肽包含seqidno:31的氨基酸序列且第二多肽包含seqidno:32的氨基酸序列；(xi)第一多肽包含seqidno:33的氨基酸序列且第二多肽包含seqidno:34的氨基酸序列；或(xii)第一多肽包含seqidno:35的氨基酸序列且第二多肽包含seqidno:36的氨基酸序列。如本文所用，术语“药物组合物”是指本文所述的化合物与药学上可接受的载体组合的制剂。药物组合物还可包含另外的试剂(如，用于特定递送、增加半寿期或其它治疗化合物)。如本文所用，术语“药学上可接受的载体”意指参与从身体的一个部位(如递送部位)运载或运输化合物至另一个部位(如身体的器官、组织或部分)的药学上可接受的材料、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌，或硬脂酸)或溶剂包封材料。药学上可接受的载体就与制剂的其它成分相容且不损害受试者组织方面是“可接受的”(如生理相容的、无菌、生理ph等)。可用作药学上可接受的载体的材料的一些实例包括：(1)糖，诸如乳糖、葡萄糖和蔗糖；(2)淀粉，诸如玉米淀粉和马铃薯淀粉；(3)纤维素及其衍生物，诸如羧甲基纤维素钠、甲基纤维素、乙基纤维素、微晶纤维素和乙酸纤维素；(4)黄蓍胶粉；(5)麦芽；(6)明胶；(7)润滑剂，诸如硬脂酸镁、十二烷基硫酸钠和滑石；(8)赋形剂，诸如可可脂和栓剂蜡；(9)油，诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；(10)二醇，诸如丙二醇；(11)多元醇，诸如甘油、山梨糖醇、甘露醇和聚乙二醇(peg)；(12)酯，诸如油酸乙酯和月桂酸乙酯；(13)琼脂；(14)缓冲剂，诸如氢氧化镁和氢氧化铝；(15)藻酸；(16)无热原水；(17)等渗盐水；(18)林格氏溶液(ringer'ssolution)；(19)乙醇；(20)ph缓冲溶液；(21)聚酯，聚碳酸酯和/或聚酸酐；(22)填充剂，诸如多肽和氨基酸(23)血清组分，诸如血清白蛋白、hdl和ldl；(22)c2-c12醇，诸如乙醇；和(23)药物制剂中采用的其它无毒可相容的物质。润湿剂、着色剂、释放剂、包衣剂、甜味剂、调味剂、芳香剂、防腐剂和抗氧化剂还可存在于制剂中。术语诸如“赋形剂”、“载体”、“药学上可接受的载体”等在本文中可互换使用。在一些实施方案中，呈组合物形式的本发明的化合物通过注射、通过导管、通过栓剂或通过植入物施用，所述植入物是多孔、非多孔或胶凝材料的，包括膜(诸如唾液酸膜)或纤维。通常，当施用组合物时，使用本发明的化合物不吸收的物质。在其它实施方案中，本发明的化合物在控制释放的系统中递送。在一个实施方案中，可使用泵(参见，例如langer,1990,science249:1527-1533；sefton,1989,crccrit.ref.biomed.eng.14:201；buchwald等,1980,surgery88:507；saudek等,1989,n.engl.j.med.321:574)。在另一个实施方案中，可使用聚合物材料。(参见，例如medicalapplicationsofcontrolledrelease(langer和wise编辑,crcpress,bocaraton,fla.,1974)；controlleddrugbioavailability,drugproductdesignandperformance(smolen和ball编辑,wiley,newyork,1984)；ranger和peppas,1983,macromol.sci.rev.macromol.chem.23:61。还参见levy等,1985,science228:190；during等,1989,ann.neurol.25:351；howard等,1989,j.neurosurg.71:105.)例如在langer，同上中讨论了其它控制释放系统。本发明的化合物可作为包含治疗有效量的结合剂和一种或多种药学上相容的成分的药物组合物施用。在典型的实施方案中，根据常规程序配制药物组合物为适用于静脉内或皮下施用于如人类的受试者的药物组合物。通常，用于通过注射施用的组合物是无菌等渗水性缓冲液中的溶液。当需要时，药物还可包含增溶剂和局部麻醉剂诸如利诺卡因以减轻注射部位处的疼痛。通常，所述成分是单独或混合在一起以单位剂型(例如作为干燥冻干粉末或无水浓缩物)提供于指示活性剂的量的气密性密封容器(如安瓿或药囊)中。当药物待通过输注施用时，可将所述药物用含无菌药物级水或盐水的输注瓶分配。当药物待通过注射施用时，可提供无菌注射用水或盐水的安瓿，使得可在施用之前混合成分。用于全身施用的药物组合物可为液体，如无菌盐水、乳酸林格氏溶液(lactatedringer'ssolution)或汉克溶液(hank’ssolution)。此外，药物组合物可呈固体形式并在使用之前立即重新溶解或悬浮。还考虑了冻干形式。可将药物组合物包含在也适用于胃肠外施用的脂质颗粒或囊泡，诸如脂质体或微晶内。颗粒可具有任何适合的结构，诸如单层或多层，只要组合物包含其中。可将化合物包埋在'稳定化的质粒-脂质颗粒'(splp)中，所述splp含有促融合脂质二油酰磷脂酰乙醇胺(dope)、低水平(5-10mol％)的阳离子脂质并由聚乙二醇(peg)包衣稳定(zhangy.p.等,genether.1999,6:1438-47)。带正电的脂质诸如n-[1-(2,3-二油酰氧基)丙基]-n,n,n-三甲基-铵甲基硫酸盐或"dotap"特别优选用于此类颗粒和囊泡。此类脂质颗粒的制备是熟知的。参见，例如美国专利no.4,880,635；4,906,477；4,911,928；4,917,951；4,920,016；和4,921,757。本公开的药物组合物可例如作为单位剂量施用或包装。术语"单位剂量"当用于指代本公开的药物组合物时是指适用作受试者的单位剂量的物理分散的单位，每个单位含有预定量的活性物质，其经计算与所需的稀释剂(即，载体或媒介物)结合产生所需的治疗作用。在一些实施方案中，可将本文所述的化合物缀合至治疗部分，如抗炎剂。用于缀合此类治疗部分至多肽(包括如fc结构域)的技术是熟知的；参见，例如amon等,“monoclonalantibodiesforimmunotargetingofdrugsincancertherapy”，见于monoclonalantibodiesandcancertherapy,reisfeld等(编辑),1985,第243-56页,alanr.liss,inc.)；hellstrom等,“antibodiesfordrugdelivery”，见于controlleddrugdelivery(第2版),robinson等(编辑),1987,第623-53页,marceldekker,inc.)；thorpe,“antibodycarriersofcytotoxicagentsincancertherapy:areview”，见于monoclonalantibodies'84:biologicalandclinicalapplications,pinchera等(编辑),1985,第475-506页)；“analysis,results,andfutureprospectiveofthetherapeuticuseofradiolabeledantibodyincancertherapy”，见于monoclonalantibodiesforcancerdetectionandtherapy,baldwin等(编辑),1985,第303-16页,academicpress；和thorpe等(1982)“thepreparationandcytotoxicpropertiesofantibody-toxinconjugates,”immunol.rev.,62:119-158。此外，药物组合物可提供为药物试剂盒，其包含(a)含有呈冻干形式的本发明的化合物的容器和(b)用于注射的含有药学上可接受的稀释剂(如无菌水)的第二容器。药学上可接受的稀释剂可用于复溶或稀释本发明的冻干化合物。任选地，由管理药物或生物产品制造、使用或销售的政府机构规定形式的公告可以与这类容器结合，所述公告反映该机构批准制造、使用或销售用于人类施用。在另一方面，包括含有可用于治疗以上所述的疾病的材料的制品。在一些实施方案中，该制品包含容器和标签。适合的容器包括例如瓶、小瓶、注射器和试管。所述容器可由多种材料诸如玻璃或塑料形成。在一些实施方案中，该容器保存有效治疗本文所述的疾病并可具有无菌入口的组合物。例如，该容器可为具有通过皮下注射针可刺穿的塞子的静脉内溶液袋或小瓶。该组合物中的活性剂是本发明的化合物。在一些实施方案中，容器上的标签或与容器结合的标签标示该组合物可用于治疗所选疾病。该制品还可包含含药学上可接受的缓冲液(诸如磷酸盐缓冲盐水、林格氏溶液或右旋糖溶液)的第二容器。所述制品可还包括在商业和使用者看来可取的其它材料，包括其它缓冲剂、稀释剂、过滤器、针、注射器和具有使用说明的说明书。在不进一步详细描述下，据信本领域技术人员可基于先前描述在本发明的最大程度上利用本发明。因此，以下特定的实施方案应解释为仅具有说明性，而不以任何方式限制本公开的剩余部分。本文引用的所有公布为了本文提及的目的或主题通过引用并入。实施例实施例1.靶向il23a和tnf-α的示例性化合物的构建.下表2a提供用于以下实施例的结合至il23a和tnf-α两者的示例性化合物。这些化合物通过本领域已知的重组方法产生(参见，例如pct公布wo2006/113665、wo2008/157379和wo2010/080538，其全部通过引用并入本文)。简而言之，使用freestylemaxreagent(cho)将编码每种化合物的第一和第二多肽的质粒一起转染至cho-s细胞中。将细胞培养13-14天并使用蛋白质-a色谱法纯化由细胞产生的化合物。使用尺寸排除色谱法进一步纯化该化合物。表2a.示例性il23a和tnf-α结合化合物tnfa＝tnf-α，vl＝可变结构域轻链，vh＝可变结构域重链，gs＝gggsgggg(seqidno:9)、lgggsg(seqidno:10)或两者，vf＝fnrges(seqidno:11)、vepkss(seqidno:12)或两者，igg1wt＝igg1野生型；igg1ko-yte＝在fc区域中具有m252y/s254t/t256e三重突变且还包含l234a/l235a突变的igg1，igg4pro-yte＝在fc区域中具有m252y/s254t/t256e三重突变且还包含s241p突变的igg4，igg1ko＝包含f234a/f235a突变的截短的fc区域，igg4pro＝包含s241p突变。第1＝第一多肽，第2＝第二多肽。突变的编号是以抗体惯例在ch1处开始的常见抗体的kabat编号。以下对照抗体还用于比较的目的。对照是靶向tnfa或il23的单克隆抗体。表2b.实施例2.示例性化合物的表面等离子共振(spr)亲和力通过spr分析测试化合物以测定对tnf-α和il23a的亲和力。材料和方法在proteonxpr36(biorad)仪器上进行spr实验。以30μl/min的流动速率以垂直和水平方向用连续注射0.5％sds、50mmnaoh和100mmhcl60秒预处理glm芯片。然后通过以1:1的比率注射edc(76.7mg/ml)和磺基-nhs(21.7mg/ml)混合物在6个水平通道中激活预处理的glm芯片。将浓度为于10mm,ph5.0乙酸钠缓冲液中的30μg/ml的山羊-抗-人igg(gaha)fcγ(invitrogen)固定至6个水平通道中激活的glm芯片上的8,000共振单位。最后，用在6个水平通道中的1m乙醇胺hcl使芯片失活。使制备的gaha芯片旋转至垂直方向以捕获越过5个垂直的通道的测试化合物，并且最后的通道用作柱参考。然后将捕获的芯片再次旋转至水平方向用于结合。将五个浓度10.0nm、5.00nm、2.50nm、1.25nm和0.625nm的连接的人il-23(boehringeringelheimpharmaceuticals,inc)以40μl/min的流动速率水平注射越过测试化合物表面在以下运行缓冲液(biorad)：磷酸盐缓冲液盐水(ph7.4)、0.005％tween20中持续10分钟。使解离进行2小时。在10分钟缔合和2小时解离之后，以100μl/min的流动速率以水平和垂直方向使用短脉冲注射(18秒)0.85％磷酸(biorad)再生gaha表面。再生的gaha准备用于另一个结合循环。以类似的方式进行化合物至人tnf-α或食蟹猴tnf-α的结合。结果表3中的结果显示测试的两种化合物能够以在皮摩尔范围内的缔合常数(kd)结合tnf-α和il23。表3.实施例3.结合至膜结合的tnf-α的流式细胞术评估评估测试化合物剂量依赖性结合至转染的细胞系以表达膜结合的tnf-α的能力。材料和方法在流式细胞术染色缓冲液(biolegend)中制备所有试剂。将膜表达的tnf-α转染的细胞系(jurkat和cho)和亲本细胞系从组织培养容器获得、洗涤、计数和重悬至在流式细胞术染色缓冲液中的1x10^6个细胞/ml。将一百微升的细胞悬浮液添加至96孔微量滴定板并置于冰上。制备测试化合物的滴定液并添加50ul至细胞。在冰上六十分钟孵育之后，洗涤细胞+测试化合物并添加50ul的二抗(jacksonimmunoresearch)。将样品在黑暗中在4c下孵育60分钟，然后洗涤。在最后的洗涤之后，将细胞重新悬浮于60ul固定剂(bdbioscience)中。在流式细胞仪中测定每个样品的荧光中值，并将其对比测试样品的浓度作图。使用由excel插件xlfit启用的4参数逻辑(logistic)(activitybase软件，idbusinesssolutions,ltd.)计算ec50值。以下显示的ec50值是在多个实验中计算的每个测试样品的几何平均值并且示于表4中。结果下表4所示的结果证明测试的化合物以剂量依赖性方式结合至膜结合的tnf-α。表4.膜结合的tnf-α的ec50值。实施例4.体外l929细胞毒性测定测试化合物抑制tnf-α诱导的细胞活性的能力。方法和材料该方法使用prestobluetm0细胞存活力试剂(prestobluetm0cellviabilityreagent)测定重组人tnf-α的细胞毒性。prestoblue细胞存活力方案(prestobluecellviabilityprotocol)的详细方案可从invitrogen网站(invitrogen.com)下载。将l929细胞生长并收获。将1.5x104个细胞转移至96-孔板的每个孔用于在37℃下孵育过夜。从5nm开始在含有10μg/ml的放线菌素d和1000pg/ml的rhtnf-α的完全测定培养基中制备化合物的连续稀释液。阳性对照含有20ng/mlrhtnf-α和1pg/ml放线菌素d。阴性对照不含tnf-α。将10μl的稀释液添加至相应的孔并在37℃下在5％co2中孵育过夜。添加prestobluetm试剂至各孔，并将板在37℃下在5％co2中孵育2小时。使用victortmx2酶标仪(激发：560nm，发射：590nm)测量每个孔的相对荧光单位。将荧光单位(y-轴)对比测试化合物浓度(x-轴)作图，并通过使用graphpad软件计算测试化合物的ic50和ic90值。结果下表5中的结果显示测试的化合物能够以剂量依赖性方式抑制tnf-α诱导的细胞毒性。表5.实施例5.hela细胞中tnf-α依赖性il-8释放的抑制.评估抗-tnf测试样品抑制tnf从人细胞系hela依赖性释放il8的能力。针对高浓度和低浓度的重组人tnf-α和单一(高)浓度的重组食蟹猴tnf-α测试样品。材料和方法简而言之，将hela细胞(atcc)收获、洗涤、计数并在具有1％青霉素和链霉素(cm)的(v/v)10％胎牛血清的标准完全培养基中重悬至4x10^5个细胞/ml。将一百微升的hela细胞悬浮液添加至96孔微量滴定板。将两个浓度(147nm或4.4nm)的重组人tnl-α(r&dsystems)以及产生的重组食蟹猴tnl-α(boehringeringelheimpharmaceuticals,inc.)(147nm)在37c下与单独的cm或与测试样品的滴定液预孵育30分钟。测试样品+tnl-α的预孵育之后，将100ul的混合物添加至细胞并将测试板在37c与5％co2-加湿空气下孵育20小时。对照样品接受cm(未刺激的对照)或在cm中稀释的重组tnl-α(刺激的对照)。在孵育后，按照制造商的说明书在elisa试剂盒(mesoscalediscovery)中测定上清液的il8。测定每个样品的内插的il8pg/ml值并将其转化为对照百分比(poc)。将poc对比测试样品的浓度作图并使用由excel插件xlfit启用的4参数逻辑模型(activitybase软件，idbusinesssolutions,ltd.)计算ic50和ic90值。就如上所述的ic50/ic90而言分析测试化合物，并在多个实验中计算每个测试样品的几何平均值并且示于表6中。结果表6中的结果显示测试的化合物的ic50和ic90几何平均值类似于对照抗体1和对照抗体2的ic50和ic90几何平均值。数据证明测试化合物剂量依赖性地抑制用人(在两个测试的浓度下)或食蟹猴(cyno)重组tnf-α进行的tnf-α诱导的il-8分泌。表6.实施例6.全血中tnf-α依赖性il8的抑制tnf是从人细胞释放if8的有效诱导剂。测试化合物抑制全血样品中tnf-α诱导的if-8释放的能力。方法和材料简而言之，将120ul肝素化人全血添加至96孔微量滴定板中的每个孔。在标准t细胞培养基(tcm)中制备测定试剂。将测试样品的滴定液制备为10x浓度并在37c下与10x浓度的人重组tnf(100ng/ml,r&dsystems)预孵育1小时。在该预孵育之后，将30ul细胞因子/测试化合物混合物连同30ul于tcm中的适当对照添加至全血，并在37c与5％co2-加湿空气下孵育48小时。对照样品接受tcm(未刺激的对照)或于tcm中稀释的重组人tnf-α(刺激的对照)。在孵育之后，按照制造商的说明书在elisa试剂盒(mesoscalediscovery)中测定上清液的il8。测定每个样品的内插的il8pg/ml值并将其转化为对照百分比(poc)。将poc对比测试样品的浓度作图并使用由excel插件xlfit启用的4参数逻辑模型(activitybase软件，idbusinesssolutions,ltd.)计算ic50和ic90值。就如上所述的ic50/ic90而言分析测试化合物，并在多个实验中计算每个测试样品的几何平均值并且示于表7中。结果表7中的结果显示测试的化合物的ic50和ic90几何平均值类似于对照抗体1和对照抗体2的ic50和ic90几何平均值。数据证明测试化合物在人全血中剂量依赖性抑制tnf-α诱导的il8释放。表7.实施例7.nf-κb和stat3磷酸化测定il23与其异二聚体受体复合物(il12rβ1-il23r)的接合导致信号转导和转录活化因子3(stat3)的下游磷酸化。tnf与其受体(tnfr1/tnfr2)的接合导致b-细胞(nf-κb)中κ轻多肽基因增强子的核因子的下游磷酸化。评估化合物抑制jurkat细胞中nf-κb的tnf-依赖性磷酸化和db细胞中stat3的il23-依赖性磷酸化的能力。方法和材料：简而言之，将在对数期生长的jurkat细胞(atcc)和db细胞(atcc)的培养物收集、洗涤、计数并在标准完全培养基(cm；具有(v/v)10％fcs和1x青霉素-链霉素(invitrogen)的rpmi1640)中重悬至2x10^7个细胞/ml。将测试样品的滴定液制备为4x浓度并在37c下与4x人重组il23(boehringeringelheimpharmaceuticals,inc.)和重组人tnf(r&dsystems)的混合物预孵育1小时。在测试试剂+细胞因子混合物的预孵育之后，将100μl的混合物以一式两份添加至含有100μl细胞的孔。如下设置对照：100μl稀释的tnf/il23+100μl合并的细胞(刺激的对照)，或100μlcm+100μl合并的细胞(未刺激的对照)。在37℃下将测定板精确与5％co2-加湿空气一起孵育10分钟。在孵育后，制备细胞裂解物并按照制造商的说明书(mesoscalediscovery)评估p-nf-κb和p-stat3。测定每个样品的p-nf-κb和p-stat-3原始值并将其转化为对照百分比(poc)。将poc对比测试剂浓度(x-轴)作图(y-轴)。使用由excel插件xlfit启用的4参数逻辑模型(activitybase软件，idbusinesssolutions,ltd.)计算ic50和ic90值。就如上所述的ic50/ic90而言分析测试化合物，并在多个实验中计算每个测试样品的几何平均值并且示于表10中。注意：该测定提供双分子能够中和两个下游信号传导事件的确实性。测定时间点仅对p-nf-κb信号是最优的，且因此计算的ic50/ic90不以定量方式反映总功效。结果表8中的结果显示测试化合物能够抑制tnf-α诱导的nf-kb磷酸化以及db细胞中的il23诱导的stat3磷酸化。表8.*结果是半定量的且更优化至tnf读出。na；无活性实施例8.db细胞中il23诱导的stat3磷酸化的抑制il23与其异二聚体受体复合物(il12rβ1-il23r)的接合导致信号转导和转录活化因子3(stat3)的下游磷酸化。评估抗-il23测试样品抑制人db细胞系中il23依赖性磷酸化的能力。材料和方法：简而言之，将在对数期生长的100ul人db细胞系(atcc)以1x10^7个细胞/ml的浓度添加至96孔微量滴定板的每个孔。在完全培养基(cm；具有(v/v)10％胎牛血清和1x青霉素-链霉素(invitrogen)的rpmi1640)中制备测定试剂。将测试样品的滴定液制备为4x浓度并在37c下与4x人重组il23(boehringeringelheimpharmaceuticals,inc.)预孵育1小时。在该预孵育之后，将100ul的细胞因子/测试样品混合物添加至100μl的db细胞并在37c与5％co2-湿润空气下孵育30分钟。对照样品接受cm(未刺激的对照)或于cm中稀释的重组人il23(刺激的对照)。孵育后，制备细胞裂解物，并按照制造商的说明书(mesoscalediscovery)评估pstat3。测定每个样品的原始pstat3值并将其转化为对照百分比(poc)。将poc对比测试样品的浓度作图并使用由excel插件xlfit启用的4参数逻辑模型(activitybase软件，idbusinesssolutions,ltd.)计算ic50和ic90值。就如上所述的ic50/ic90而言分析测试化合物，并在多个实验中计算每个测试样品的几何平均值并且示于表9中。结果表9中的结果显示测试的化合物的ic50和ic90几何平均值类似于抗-il23ap19对照抗体的ic50和ic90几何平均值。数据证明测试化合物剂量依赖性抑制db细胞中il23诱导的stat3磷酸化。表9.实施例9.人il-23依赖性小鼠脾细胞测定(msa)基于小鼠脾细胞的测定用于评估在小鼠脾细胞培养物中抗-人il23测试样品抑制由人重组il23和重组食蟹猴il23诱导小鼠il17的能力。材料和方法:简而言之，将来自小鼠脾(小于13周龄的雌性c57bl/6；jax)的单核细胞分离、洗涤、计数并在标准t细胞培养基(tcm)中重悬至4x10^6个细胞/ml。将一百微升的mil2/脾细胞混悬液添加至96孔微量滴定板。将重组人il23(boehringeringelheimpharmaceuticals,inc.)或重组食蟹猴il23(boehringeringelheimpharmaceuticals,inc.)在tcm中稀释并在37c下与单独的tcm或与测试样品的滴定液预孵育2小时。在测试样品+il23预孵育之后，将100ul的混合物添加至细胞并将测试板在37c与5％co2-湿润空气下孵育48小时。对照样品接受tcm(未刺激的对照)或于tcm中稀释的重组人il23(刺激的对照)。在孵育后，从上清液使用小鼠il-17免疫测定(mouseil-17immunoassay)根据制造商说明书(r&dsystems)测定小鼠il17水平。测定每个样品的内插的mil17pg/ml值并将其转化为对照百分比(poc)。将poc对比测试样品的浓度作图并使用由excel插件xlfit启用的4参数逻辑模型(activitybase软件，idbusinesssolutions,ltd.)计算ic50和ic90值。就如上所述的ic50/ic90而言分析抗-il23测试样品，并在多个实验中计算每个测试样品的几何平均值并且示于表10中。结果表10中的结果显示测试的化合物能够抑制人和食蟹猴-il23诱导的小鼠脾细胞释放il17。表10.实施例10.il23诱导的stat3磷酸化的抑制il23与其异二聚体受体复合物(il12rβ1-il23r)的接合导致信号转导和转录活化因子3(stat3)的下游磷酸化。测试化合物在db稳定转染的细胞中抑制il23诱导的stat3活化的能力。材料和方法用15ng/ml最终浓度的il23蛋白质刺激细胞。根据之前的实验估计该剂量为ec60，同时允许用测试的化合物抑制。将细胞涂铺、将化合物给药并添加il-23(以此顺序)并孵育过夜。如果化合物抑制细胞刺激，则下调stat3，导致更少的荧光素酶活性。结果表11中的结果显示测试的化合物能够抑制il23诱导的stat3磷酸化。表11.实施例11.进一步il23-astat3测定类似于实施例8进行进一步实验以测试il23诱导的stat3激活的抑制。方法和材料将db-stat3luc10克隆10悬浮液细胞在rpmi1640+10％fbs中生长。将20,000个细胞以80ul/孔的细胞悬浮液添加至96孔板的每个孔。将10ul的连续稀释的测试化合物之一添加至每个孔。将15ng/ml重组人il-23添加至每个孔，其中某些孔仅含有测试化合物和不含il-23以用于比较。将板在37℃/5％co2下孵育过夜。使用steady-glo(promega和one-glo(promega测定荧光素酶活性并在envision读数仪上读取结果。结果测试的化合物的ic50和ic90显示于表12和表13中。这些表显示该化合物以剂量依赖性方式抑制il-23-依赖性stat3激活。表12.表13.实施例12.由人重组il23诱导的小鼠il17a和il22释放的抑制评估测试化合物在c57/b16小鼠中抑制人il23诱导的细胞因子释放的能力。在皮内注射il23之后测量il17a和il22分泌材料和方法简而言之，将c57bl/6雌性小鼠(7-10周龄，charlesriver)随机分到8个组(8只动物/组)并分别以1.3、0.4和0.13mg/kg对比1、3和0.1mg/kg的等摩尔剂量给予柠檬酸盐缓冲液(20mm柠檬酸钠，115mmnacl，ph6.0)或测试化合物的100μl腹膜内注射液。测试化合物给药后一小时，将小鼠经由异氟烷(butlerschein)麻醉并向双耳给予于盐水(invitrogen)中稀释的0.1％bsa(sigma)对照或15μg/ml(0.3μg)rhil23(内部产生)的20μl皮内注射液。连续2天每天重复皮内激发。第二激发之后二十四小时，经由颈椎脱位将小鼠处死并去除每只耳。使用mpbiomedicalsfast-prep24匀浆器，将耳组织在1ml均质化缓冲液(hbss(gibco)；0.4％tritonx-100(sigma)；1xsigmafast蛋白酶抑制剂(1xsigmafastproteaseinhibitor，sigma))中均质化。将均质化样品在4c下离心10分钟并收集上清液。使用小鼠il-17和小鼠if-22免疫测定，根据制造商的说明书(r&dsystems)测定上清液是否存在小鼠il17a和il22。测定每个样品的内插细胞因子pg/ml值。测定每个治疗组的平均pg/ml水平，并使用单因素方差分析、之后邓奈特多项比较检验(dunnett’smultiplecomparisonstest)计算相较于对照的显著性。结果显示于图4中。结果图4中的结果显示用腹腔内单剂量的测试化合物治疗能够显著抑制小鼠il17和il22在由每天两次连续真皮内注射重组人il23诱导的皮肤中的释放。实施例13.c57/b16小鼠中外源性人tnf-α依赖性细胞因子释放的抑制评估测试化合物在外源暴露于人tnf之后抑制c57/b16中人tnf诱导的细胞因子释放的能力。在腹腔内施用人tnf之后测量血清kc和il-6分泌。材料和方法简而言之，将c57bl/6雌性小鼠(8-9周龄，jacksonlabs)随机分到8个组(8只动物/组)并分别以13.3、4和1.3mg/kg对比10、3和1mg/kg的等摩尔剂量给予磷酸盐缓冲液(sigma)或测试化合物的200μl腹膜内注射液。测试化合物给药之后两小时，将小鼠经由异氟烷(butlerschein)麻醉并给予于盐水(sigma)中稀释的0.1％bsa对照或15μg/ml(3μg)rhtnf(r&dsystems)的200μl腹腔内注射液。tnf激发之后两小时，经由异氟烷麻醉小鼠，收集全血并然后将小鼠经由颈椎脱位处死。将全血以12,000rpm离心10分钟并收集血浆。使用小鼠kc和小鼠il-6免疫测定，根据制造商的说明书(msd)测定血清是否存在小鼠kc和il-6。测定每个样品的内插细胞因子pg/ml值。测定每个治疗组的平均pg/ml水平，并使用单因素方差分析、之后邓奈特多项比较检验(dunnett’smultiplecomparisonstest)计算相较于对照的显著性。结果显示于图x中。结果图5中的结果显示用腹腔内单剂量的测试化合物治疗能够通过腹腔内注射重组人tnf显著抑制血清中小鼠kc和il-6释放。实施例14.食蟹猴中化合物的药代动力学材料和方法两对化合物(化合物m和化合物a；及化合物o和化合物e)的静脉内(iv)单剂量pk研究在未接触过生物制品的雄性食蟹猴(n＝3个/组)中进行，并根据动物管理和使用委员会(institutionalanimalcareandusecommittee)指南进行。以1mg/kg的10分钟iv输注液施用iv剂量。对于化合物m和化合物a，在给药前、给药当天1小时、4小时、8小时及给药后1天、2天、3天、4天、5天、7天、10天、14天、21天、28天、35天和42天(1008小时)收集血清样品；对于化合物o和化合物e，仅收集至第14天。通过配体结合测定(elisa)测量给药的分子的血清浓度。在100％血清中针对每种分析物制备校正标准曲线和质量对照(qc)样品。每条标准曲线由七个非零点(从10240ng/ml开始，然后连续稀释3x)组成。还包括空白样品(无分析物的基质)。制备从2560ng/ml开始、然后连续稀释四倍的在低、中和高范围内的四个qc样品。将标准曲线和qc样品冷冻贮藏直至样品分析，此时将它们稀释20倍以模拟研究样品。在每次分析运行期间以一式两份包含标准曲线和qc样品。将定量的下限和上限定义为最低和最高标准曲线点至可重现具有不超过标称浓度的25百分比(％)的反算浓度。标准曲线点和qc样品的标准限度是标称浓度的25百分比(％)。将nuncelisa板用作为捕获剂的1μl猴吸附的山羊抗-人igg(southernbiotech)涂覆并在2-8℃下孵育过夜。在用洗涤缓冲液(于磷酸盐缓冲盐水(pbs)中的0.05％(v/v)tween20)和阻断缓冲液(于pbs中的5％牛血清白蛋白(bsa))洗涤和阻断板之后，用5％猴血清(来自innovativeresearch的猴血清)稀释1:20、1:400和1:8000的标准品、qc和未知的样品添加至板孔并在室温下孵育1小时。将板孔用洗涤缓冲液洗涤并添加猴吸附的生物素化山羊抗-人igg(southernbiotech)作为第二试剂并在室温下孵育1小时。将板洗涤3次并在室温下经15分钟添加100μl的1μg/ml过氧化物酶-缀合的链霉亲和素，然后再洗涤3次并在室温下经3-4分钟添加100μl的3,3',5,5'-四甲基联苯胺(tmb,biofx)底物。将反应通过添加100μl的终止溶液(biofx)终止并使用带softmaxpro软件，5.4.1版的moleculardevices酶标仪测量吸光度。结果在未接触过生物制品的雄性食蟹猴(n＝3只/组)中进行两对测试化合物(化合物m和化合物a；及化合物o和化合物e)的iv单剂量pk研究。将测试化合物作为10分钟iv输注液以1mg/kg给药。对于化合物m和化合物a，在给药前、给药当天1小时、4小时、8小时及给药后1天、2天、3天、4天、5天、7天、10天、14天、21天、28天、35天和42天(1008小时)收集血清样品；对于化合物o和化合物e，仅收集至第14天。通过配体结合测定(elisa)测量给药的分子的血清浓度。每个分子的血清浓度(平均值和sd)概述于表14中。表14：食蟹猴中测试化合物的血清浓度(平均值±sd，n＝3)bql：低于定量限nc：未计算，n＝1使用软件phoenixwinnonlin6.1(certara,md,usa)使用iv输注剂量的非隔室法计算这些测试化合物的药代动力学(pk)参数。在给药后任何时间点显示浓度急剧下降的血样样品和在此特定动物中的所有随后样品均被排除出pk参数估计。另外的分析显示起初数天之后浓度的这种突然的下降是由于在猴中发展出人源化生物分子的抗-化合物抗体。仅来自单独动物的前七天数据包含在pk分析中。在图2和3中显示两对测试化合物的浓度-时间曲线。两对测试化合物的关键pk参数(平均值±sd)概述于表15中。表15：1mg/kgiv10分钟输注剂量之后食蟹猴中两个测试化合物对的关键pk参数(平均值±sd；n＝3)与不含yte突变的相应测试化合物(化合物m)相比，化合物a(具有yte突变的测试化合物)显示清除率(cl)的3.3-倍减少和终末半寿期(t1/2)的3.9-倍增加。与不含yte突变的相应测试化合物(化合物o)相比，化合物e(具有yte突变的测试化合物)显示cl的2.4-倍减少。实施例15.预测示例性化合物的人pk和人剂量预测人pk：化合物e的人pk预测通过异速生长标度(allometricscaling)从使用与猴相比人体内的清除率减少1/2的因子同时保持相同的体积分布在食蟹猴中获得的pk参数进行。因此，在人体内的预测的清除率是12.1ml/天/kg，其终末半寿期为7.4天。预测人剂量：人剂量预测基于从在多个患者群体中戈利木单抗的临床试验获得的广泛暴露-功效数据进行。戈利木单抗经批准以50mg每月皮下(sc)剂量治疗类风湿性关节炎(ra)、强直性脊柱炎(as)和银屑病性关节炎(psa)患者，并以100mg每月sc剂量治疗溃疡性结肠炎(uc)患者。在ra患者(50mg每月sc剂量)中获得约3.2nm的和在uc患者(100mg每月sc剂量)中获得9.7nm的c谷(bla,2009；sandbom,2013)。这些分别用作as和cd的治疗性c谷的基准。在临床批准的stelara剂量下c谷水平为约6nm。基于观察到化合物e的效力比优特克单抗高3-倍，对于化合物e需要c谷值(约2nm)以覆盖il23。因为用于覆盖tnf的c谷浓度大于覆盖il23的c谷浓度，的9.7nmc谷用于剂量投影(doseprojections)。食蟹猴中的pk数据的隔室建模(2-隔室模型)、随后使用cl的2-倍减少标度、73％生物利用率及同时变化的清除率和分配速率常数(具有公称30％cv和对数-正态分布)的蒙特卡罗模拟(monte-carlosimulations)显示每2周施用的54mg(90％置信区间31-90mg)sc剂量将保持9.7nm的c谷。实施例16.化合物的纯化方法使用mabselectsure作为亲和力纯化步骤纯化化合物。避免高盐洗涤以预防聚集。使用乙酸钠缓冲液ph3.5进行洗脱。mabselectsure纯化之后，将样品中和并且上样至羟磷灰石i型树脂并使用各浓度的磷酸盐缓冲液洗脱。单体峰洗脱约140mm磷酸钠100mmnaclph7.0并且聚集物峰在约200mm磷酸钠100mmnaclph7.0下洗脱。羟磷灰石之后，样品始终是>95％的单体。经由分析超速离心(auc)的沉降速度(sv)实验用于提供关于样品纯度和聚集状态的信息。在20℃下使用以40,000rpm运行的an60ti四孔转子，在最佳xl-i(beckmancoulter,fullerton,ca)中离心样品。通过280nm紫外线吸光度使用相应的稀释缓冲液作为参考缓冲液，监测沉降过程。使用xl-i操作软件收集超速离心池中浓度分布随时间的变化，并使用sedfit软件(14.1版)中的连续c(s)分布模型分析以得到沉降系数的分布。基于完整峰面积计算单体百分比。结果该化合物的纯化结果显示于表16中。数据显示该化合物具有高纯度和匀质性，指示了良好的稳定性。表16.实施例17：化合物的质谱图谱方法天然样品该程序产生化合物或蛋白质的完整质量。将2ul的样品注射到agilentporoshell300sb-c8柱,5um,(75x1.0mm)上。柱温为80℃并且流动速率为50ul/min。将该化合物或蛋白质用20％b(0分钟)至85％b(10分钟)的梯度从柱洗脱。流动相a是水/乙腈/甲酸(99/1/0.1)且流动相b是乙腈/水/甲酸(95/5/0.1)。引导流出物至agilent6210tof质谱仪，其从质量600扫描至质量3200。用程序masshunter对原始数据去卷积。还原的样品该程序产生蛋白质或轻链的质量和重链的质量。将2ul的50mmtcep添加至10ul样品和10ul的8m胍并在37℃下孵育15分钟。如上注射2ul的该样品，其具有以下差异：柱温为60℃并且重量范围为600-2000。去糖基化样品该程序产生蛋白质或轻链和重链的去糖基化质量。将10ul样品、10ul200mmnh4hco3、2ul50mmtcep和1ul(1:10)pngasef(或1ulqa去糖基化混合物，如果o-连接的糖基化存在)在37℃下孵育3小时。对于重度糖基化样品，将孵育增加至过夜。然后，添加25ul8m胍和4ul50mmtcep并在37℃下孵育15分钟。如上对还原样品那样注射该样品。通过质谱进行的蛋白质肽作图将25ul样品添加至25ul8m于400mm碳酸氢铵中的脲。然后添加5ul50mmtcep并将样品在60℃下孵育15分钟。在冷却样品至室温后，添加5ul150mm碘乙酰胺并将样品在室温下孵育15分钟。在添加40ul水后，添加5ul于1mmhcl中的胰蛋白酶以得到1:50的最终的酶：底物比。将样品在37℃下孵育过夜。然后将5ul注射到thermohypurityc18柱，100x1.0mm上。流动速率为80ul/min。将蛋白质用0％b(0分钟)至40％b(33分钟)的梯度从柱洗脱。流动相a是水/乙腈/甲酸(99/1/0.1)且流动相b是乙腈/水/甲酸(95/5/0.1)。引导流出液至thermoorbitrapvelos质谱仪。第一扫描事件在ft中，并且以30,000的分辨率从质量300扫描至质量2000。第二至第七扫描事件在it(离子阱)中，并从第一扫描事件片段化为6种最强的离子。通过人工提取和基于峰高度计算的百分比对含糖基化的肽作图谱。结果结果显示于表17中。数据表明期望的氨基酸序列和结构已得以表达并在没有非期望的异质性的情况下回收。糖基化形式为在cho细胞中表达的常见抗体独有的，且不显示任何非典型结构。表17.实施例18：化合物的热稳定性方法从20℃至110℃以60℃/h的扫描速率经由自动化毛细管dsc(microcal,llc,boston)，监测化合物于磷酸盐缓冲液中的2mg/ml溶液的热去折叠和聚集。进行用相应的缓冲液的两次扫描以对每个样品建立仪器热历史并获得仪器基线，从随后的蛋白质热谱图减去这些扫描的平均值以获得表观热容。然后用origin7.0分析归一化的扫描。从每次产生的热容热图谱中减去转变前基线以得到为温度函数的所得过剩热容(cp,ex)。转变温度(tm)的报道值代表通过目视检查实验热谱图测定的峰最大值的位置。结果结果显示于表18中。数据显示该化合物是稳定的且将预计能具有长货架期。表18.参数化合物a化合物e热稳定性(℃)57.9，72.1，82.967.6，83.1实施例19：化合物的溶解度方法使用截留分子量为50,000道尔顿的amiconultra离心过滤器(millipore,billerica)逐渐浓缩化合物样品至尽可能高的浓度且观察不到沉淀。然后在sv实验中经由auc分析浓缩的蛋白质溶液以提供关于样品纯度和聚集状态的信息(关于纯化方法详述，参考实施例16)。结果结果显示于表19中。数据显示该化合物是可溶的且稳定的，保留了高百分比的单体且无制剂或添加的赋形剂。表19.参数化合物a化合物e溶解度(浓度)48mg/ml51mg/ml单体百分比98.697.0实施例20：化合物的化合价方法在装配有紫外线(uv)吸光度检测器且工作波长为214nm的beckmancoulter(fullerton,california)proteomelabpa800tm装置上进行50mmkcl和10mm乙酸钠缓冲液(ph5.0)中的化合物样品的化合价测量。将该系统保持在20℃下且使用内径为50μm的ecap胺毛细管(beckmancoulter，部件编号477431)。将毛细管在每次样品注射之前用100mmnaoh、胺再生溶液(beckmancoulter，部件编号477433)和运行缓冲液冲洗。在10kv、14kv和18kv的电压下测量样品的迁移次数。将二甲基甲酰胺(dmf)(0.005％)(pierce)用作电渗流(eof)标记物。使用32karattm软件(v7.0)获取数据。经由auc从sv实验测定扩散系数。结果化合价数据(参见表20)表明溶液中化合物的胶体稳定性，即溶液中蛋白质与蛋白质净相互作用。化合价大于15的化合物具有强净排斥相互作用和在高浓度下配制的高潜能。表20.参数化合物a化合物e化合价，ph5.020.924.4实施例21：预测的计算机免疫原性方法通过使用计算工具epimatrix(由epivax,inc.(providence,ri)开发)，在计算机上预测蛋白质治疗剂的免疫原性。epimatrix涵盖t-辅助细胞表位以及t-区域表位(t-regitope)的预测，其中前者诱发免疫应答而后者是抑制性的。简而言之，首先解析蛋白质序列为重叠的9-聚体肽框，所述9-聚体肽框已被证明是ii类hla结合的核心。基于实验数据或计算机预测评价9-聚体肽与八种常见的ii类hla等位基因的结合潜力。产生反映9-聚体肽与每种hla等位基因的结合潜力的评分，并且进行归一化以使得跨越多种hla等位基因比较任何9-聚体成为可能并且使得能够进行综合量表的免疫原性预测。最后，该程序产生总‘免疫原性评分’，treg调整的epx评分，其连同其它免疫原性决定簇有助于作出该化合物将诱发体内免疫应答的可能性的知情决定。结果结果显示于表21中。这些化合物的总免疫原性评分较低并预测这些化合物不可能在体内引发强免疫应答。表21.等位基因-特异性评分的归一化实施例22：化合物的全血稳定性方法在octetred96上开发全血干扰测定以检测在全血(wb)的存在下化合物的非-特异性结合或脱靶结合的作用。将全血中的化合物溶液和1x动力学运行缓冲液(1xkb)在37℃的温度下孵育48小时。在27℃下用装备有链霉亲和素(sa)生物传感器尖端的octetred96(fortebio,menlopark,ca)进行孵育的化合物样品的动力学测定。报道了缓冲液和全血中结合率/结合信号的比率。认为<2的比率显示无干扰。结果结果显示于表22中。表22.实施例23：测试参数的概述某些化合物的参数数据的概述示于下表23中。表23.序列其它实施方案本说明书中所公开的所有特征可以任何组合相组合。本说明书中所公开的每个特征可由用作相同、等效或类似目的的可替代的特征代替。因此，除非另外明确表达，所公开的每个特征仅是一个通用系列的等效或类似特征的实例。根据以上描述，本领域技术人员可容易地确定本公开的本质特征，且在不偏离其精神和范围的情况下可对本公开进行各种改变和修改以使其适应于各种用途和条件。因此，其它实施方案也在权利要求内。序列表<110>boehringeringelheimcorporationgmbhmacrogenics,inc.<120>靶向il-23a和tnf-α的化合物及其用途<130>b1204.70007wo00<140>尚未授予<141>同时附上<1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