TW202309069A - 糖鏈修飾rbd及其用途 - Google Patents
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Abstract
作為有效地製造具有交叉反應性之抗冠狀病毒抗體之方法，本發明提供一種多肽，其包含與序列編號2之胺基酸序列具有至少60%以上之同一性之胺基酸序列，且包含以於相當於序列編號2之胺基酸序列之85位、164位及172位之位置結合糖鏈之方式經過修飾之胺基酸序列。
Description
本發明揭示一種SARS-CoV-2之刺突蛋白之受體結合域(RBD)之糖鏈修飾之相關技術。
由作為β-冠狀病毒之嚴重急性呼吸道症候群冠狀病毒2(SARS-CoV-2)導致之COVID-19大流行病成為全球健康危機。冠狀病毒向宿主細胞之侵入係由病毒表面上形成刺突蛋白三聚體之病毒S蛋白所介導。SARS-CoV-2及SARS-CoV(此處稱為SARS-CoV-1)之侵入受體為人細胞表面血管收縮素轉化酶2(ACE2)，該等兩種病毒之刺突蛋白之受體結合域(RBD)以高親和性與ACE2結合。因此，認為RBD可能成為中和抗體之主要靶點。
然而，以前之冠狀病毒之流行(例如SARS-CoV-1及MERS-CoV)係由跨越物種壁壘之人畜共患冠狀病毒引起(非專利文獻1)，基於此種考量，即便擁有對當前之病毒有效之疫苗，但未來出現相同病毒之可能性仍然對全球公共衛生造成巨大威脅。例如，於人類中尚未發現(芽前(pre-emergent))蝙蝠冠狀病毒之一的WIV1-CoV與SARS-CoV-1及SARS-CoV-2顯示高度同源性，從而表明有可能感染人類ACE2表現細胞(非專利文獻2)。然而發現，除具有低水平之中和抗體之罕見個體以外，SARS-CoV-2感染者之血清普遍缺乏與WIV1-CoV之交叉中和作用(非專利文獻3)。
[先前技術文獻]
[非專利文獻]
[非專利文獻1]Wacharapluesadee, S., Tan, C.W., Maneeorn, P., Duengkae, P., Zhu, F., Joyjinda, Y., Kaewpom, T., Chia, W.N., Ampoot, W., Lim, B.L., et al. (2021). 「SARS-CoV-2相關冠狀病毒於東南亞蝙蝠及穿山甲中傳播之證據(Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in Southeast Asia)」. Nat Commun 12, 972.
[非專利文獻2]Menachery, V.D., B.L. Yount Jr., K. Debbink, S. Agnihothram, L.E. Gralinski, J.A. Plante, R.L. Graham, T. Scobey, X.Y. Ge, E.F. Donaldson, et al. 2015. 「一種傳播性類SARS蝙蝠冠狀病毒群顯示感染人類的可能性(A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence)」. Nat. Med. 21:1508-1513.
[非專利文獻3]Garcia-Beltran, W.F., Lam, E.C., Astudillo, M.G., Yang, D., Miller, T.E., Feldman, J., Hauser, B.M., Caradonna, T.M., Clayton, K.L., Nitido, A.D., et al. (2021). 「COVID-19中和抗體預測疾病之嚴重程度及存活情況(COVID-19-neutralizing antibodies predict disease severity and survival)」. Cell 184, 476-488 e411.
[發明所欲解決之問題]
本發明之一課題在於提供一種獲得具有交叉反應性之抗冠狀病毒抗體之方法。
[解決問題之技術手段]
SARS-CoV-2 RBD由2個亞結構域構成(圖1A)。RBD-核心亞結構域包含被α螺旋夾在中間之中央β片層，成為對ACE2結合及受體特異性進行編碼之受體結合基序(RBM，殘基437～508個)(Shang等人, 2020, 「SARS-CoV-2受體識別之結構基礎(Structural basis of receptor recognition by SARS-CoV-2)」. Nature 581, 221-224)的穩定之摺疊骨架(此處，將編碼成RBM之區域稱為RBD-頭部亞結構域)(Shang等人, 2020, 同上)。根據SARS-Cov-2感染者之恢復期血清之初期分析，證實有多個中和抗體(Class1及2)識別RBD-頭部亞結構域(圖1B)，但如上所述，已知之抗體之交叉中和作用普遍缺乏。因此，本發明者等人經過反覆、銳意研究後發現，就廣泛之防禦應答之方面而言，RBD-核心亞結構域可能成為更有前景之靶點。
以RBD-核心亞結構域為標靶時存在之潛在阻礙之一在於：該亞結構域中之表位為免疫隱性(immuno-recessive)。作為用以避免該問題之方法，可從至少以下幾點考慮：i)藉由靶點突變及缺失使免疫原表面發生變化(Jardine等人, 2013, 「以特定生殖系B細胞受體為靶點之理性HIV免疫原設計(Rational HIV immunogen design to target specific germline B cell receptors)」. Science 340, 711-716；Impagliazzo等人, 2015, 「穩定三聚體結構流感病毒血凝素莖桿作為廣泛保護性免疫原(A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen)」. Science 349, 1301-1306；Valkenburg等人, 2016, 「通過接種融合前無頭HA微型莖桿來跟蹤流行性感冒(Stalking influenza by vaccination with pre-fusion headless HA mini-stem)」. Sci Rep 6, 22666)；ii)藉由NxS/T序列子(sequon)來導入被認為掩蔽相鄰表位之N-結合型聚糖(Duan等人, 2018, 「聚糖掩蔽集中對HIV-1 CD4結合位點之免疫反應並增強VRC01類前體抗體之誘導(Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies)」. Immunity 49, 301-311 e305；Eggink等人, 2014, 「藉由球狀頭區高糖基化來誘導對抗流感病毒血凝素之免疫應答指向保守莖區(Guiding the immune response against influenza virus hemagglutinin toward the conserved stalk domain by hyperglycosylation of the globular head domain)」. J Virol 88, 699-704)。本發明者等人已證實，為了促進針對RBD-核心亞結構域之免疫應答，藉由在SARS-CoV-2之RBD-頭部亞結構域之特定部位導入聚糖，將會促進誘導針對SARS-CoV-1及WIV1-CoV(進化枝1沙貝病毒(Clade 1 Sarbecovirus))之強效之交叉中和抗體。於此見解之基礎上，經過更深入之探索研究，最終提供以下各項為代表之發明。
項1
一種多肽，其包含與序列編號2之胺基酸序列具有至少60%以上之同一性之胺基酸序列，且包含以於相當於序列編號2之胺基酸序列之85位、164位及172位之位置結合糖鏈之方式經過修飾之胺基酸序列。
項2
如項1記載之多肽，其中上述修飾胺基酸序列進而以於相當於序列編號2之胺基酸序列之118位及/或147位之位置結合糖鏈之方式修飾。
項3
如項1或2記載之多肽，其中糖鏈為N型糖鏈。
項4
如項1至3中任一項記載之多肽，其中於相當於序列編號2之胺基酸序列之85位、164位及172位之位置結合有糖鏈。
項5
如項4記載之多肽，其中進而於118位及/或147位結合有糖鏈。
項6
如項4或5記載之多肽，其中糖鏈為N型糖鏈。
項7
一種聚核苷酸，其包含編碼如項1或2記載之多肽之鹼基序列。
項8
一種組合物，其含有如項1至6中任一項記載之多肽或如項7記載之聚核苷酸。
項9
如項8記載之組合物，其為疫苗。
項10
一種抗冠狀病毒抗體之製造方法，其包括利用如項1至6中任一項記載之多肽對動物進行免疫。
項11
一種抗體，其係藉由如項10記載之方法獲得。
[發明之效果]
本發明提供一種有效地製造具有交叉反應性之抗冠狀病毒抗體之方法。
1.定義
於本說明書中，「含有」及「包含」之表述囊括「含有」、「包含」、「實質上由～構成」及「僅由～構成」之概念。
於本說明書中，所謂胺基酸序列之「同一性」，指可進行比對之2個以上之胺基酸序列的相互對應之胺基酸序列之一致程度。因此，某2個胺基酸序列之一致性越高，該等序列之同一性或類似性越高。胺基酸序列之同一性之程度例如使用序列分析用工具FASTA，採用預設參數來確定。或者，可使用Karlin及Altschul之演算法BLAST來確定。業界已開發出基於此種BLAST演算法之稱為BLASTX之程式。該等解析方法之具體手法公知，可參考美國國家生物技術資訊中心(NCBI)之網站(http://www.ncbi.nlm.nih.gov/)。又，鹼基序列之「同一性」亦按照上文定義。
於本說明書中，關於胺基酸序列及核苷酸序列之「相當於～位置」可藉由使對象序列與參照序列(例如序列編號2之胺基酸序列)以使各序列中存在之殘基具有最大同源性之方式對齊(比對)來確定。可使用公知之演算法實施比對，其程序為業者公知。例如，可藉由在預設設定下使用Clustal W多序列比對程式(Nucleic Acids Res, 1994, 22 : 4673-4680)來進行比對。或者，亦可使用Clustal W之修訂版Clustal W2、或Clustal omega。例如可利用歐洲生物信息研究所(EBI[www.ebi.ac.uk/index.html])或日本國立遺傳學研究所運營之日本DNA資料庫(DDBJ[www.ddbj.nig.ac.jp/Welcome-j.html])之網站上之Clustal W、Clustal W2及Clustal omega。
於本說明書中，所謂「保守性置換」，意指將胺基酸殘基置換為具有類似側鏈之胺基酸殘基。例如，離胺酸、精胺酸、組胺酸等具有鹼性側鏈之胺基酸殘基彼此間之置換屬於保守性置換。此外，天冬胺酸、麩胺酸等具有酸性側鏈之胺基酸殘基；甘胺酸、天冬醯胺、麩醯胺、絲胺酸、蘇胺酸、酪胺酸、半胱胺酸等具有非帶電性極性側鏈之胺基酸殘基；丙胺酸、纈胺酸、白胺酸、異白胺酸、脯胺酸、苯丙胺酸、甲硫胺酸、色胺酸等具有非極性側鏈之胺基酸殘基；蘇胺酸、纈胺酸、異白胺酸等具有β-分枝側鏈之胺基酸殘基；酪胺酸、苯丙胺酸、色胺酸、組胺酸等具有芳香族側鏈之胺基酸殘基彼此間之置換亦同樣屬於保守性置換。
2.多肽
多肽較佳為與序列編號2之胺基酸序列具有一定以上之同一性。所謂一定以上，例如為60%以上、65%以上、70%以上、75%以上、80%以上85%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、或99%以上。
序列編號2係由SARS-CoV-2之S蛋白之胺基酸序列(序列編號1)之331位～529位之199個胺基酸殘基構成的RBD之胺基酸序列。於一實施方式中，多肽之長度可比199個殘基之長度短，亦可比199個胺基酸殘基之長度長。於一實施方式中，多肽之長度比199個殘基之長度長1個殘基、2個殘基、3個殘基、4個殘基、5個殘基、6個殘基、7個殘基、8個殘基、9個殘基或10個殘基，或者比199個殘基之長度短1個殘基、2個殘基、3個殘基、4個殘基、5個殘基、6個殘基、7個殘基、8個殘基、9個殘基或10個殘基。於多肽之長度比199個殘基之長度長之情形時，長出來之部分之序列較佳為與對應之序列編號1之胺基酸序列具有一定以上之同一性。此處，一定以上如上所述。於一實施方式中，多肽例如可於C末端或N末端包含標籤序列。
於一實施方式中，當多肽之胺基酸序列與序列編號1或2之胺基酸序列不完全一致時，不一致之胺基酸殘基較佳為相當於對序列編號1或2之胺基酸序列中對應之胺基酸殘基進行之保守性胺基酸置換。
多肽較佳為包含以於相當於序列編號2之胺基酸序列之85位、164位及172位之位置結合糖鏈之方式經過修飾之胺基酸序列。糖鏈之種類並無限制，可為N型糖鏈及O型糖鏈之任意者。於一實施方式中，糖鏈較佳為N型糖鏈。
用以使糖鏈結合於多肽之特定位置之手法公知。例如，為了於相當於序列編號2之胺基酸序列之85位之位置結合N型糖鏈，較佳為相當於序列編號2之胺基酸序列之85位之胺基酸殘基為天冬胺酸殘基、相當於87位之胺基酸殘基為絲胺酸殘基或蘇胺酸殘基(較佳為蘇胺酸殘基)。同樣地，為了於相當於序列編號2之胺基酸序列之164位之位置結合N型糖鏈，較佳為相當於序列編號2之胺基酸序列之164位之胺基酸殘基為天冬胺酸殘基、相當於166位之胺基酸殘基為絲胺酸殘基或蘇胺酸殘基(較佳為蘇胺酸殘基)。同樣地，為了於相當於序列編號2之胺基酸序列之172位之位置結合N型糖鏈，較佳為相當於序列編號2之胺基酸序列之172位之胺基酸殘基為天冬胺酸殘基、相當於174位之胺基酸殘基為絲胺酸殘基或蘇胺酸殘基。
於一實施方式中，多肽較佳為包含以除了於相當於序列編號2之胺基酸序列之85位、164位及172位之位置以外還在相當於118位及/或147位之位置結合糖鏈之方式經過修飾之胺基酸序列。於一實施方式中，多肽較佳為包含以除了於相當於序列編號2之胺基酸序列之85位、164位及172位之位置以外還在相當於118位及147位之位置結合糖鏈之方式經過修飾之胺基酸序列。於一實施方式中，多肽較佳為包含以於相當於序列編號2之胺基酸序列之85位、164位及172位之位置結合糖鏈之方式修飾、且未以於相當於序列編號2之胺基酸序列之118位及/或147位之位置結合糖鏈之方式修飾之胺基酸序列。於一實施方式中，就穩定地表現之觀點而言，多肽較佳為包含未以於相當於序列編號2之胺基酸序列之選自由87位、126位、141位、152位、154位及157位所組成之群中之至少一個位置結合糖鏈之方式修飾之胺基酸序列。此處，所謂「至少一個」，可為至少兩個、至少三個、至少四個、至少五個或六個。糖鏈之種類並無限制，可為N型糖鏈及O型糖鏈之任意者。於一實施方式中，糖鏈較佳為N型糖鏈。
為了於相當於序列編號2之胺基酸序列之118位之位置結合N型糖鏈，較佳為相當於序列編號2之胺基酸序列之118位之胺基酸殘基為天冬胺酸殘基、相當於120位之胺基酸殘基為絲胺酸殘基或蘇胺酸殘基(較佳為蘇胺酸殘基)。同樣地，為了於相當於序列編號2之胺基酸序列之147位之位置結合N型糖鏈，較佳為相當於序列編號2之胺基酸序列之147位之胺基酸殘基為天冬胺酸殘基、相當於149位之胺基酸殘基為絲胺酸殘基或蘇胺酸殘基(較佳為蘇胺酸殘基)。
於一實施方式中，多肽較佳為於序列編號2之胺基酸序列中，85位、164位及172位之胺基酸殘基被置換為天冬胺酸殘基，87位、166位及174位之胺基酸殘基被置換為絲胺酸殘基或蘇胺酸殘基(較佳為蘇胺酸殘基)。於一實施方式中，多肽較佳為於序列編號2之胺基酸序列中，85位、118位、147位、164位及172位之胺基酸殘基被置換為天冬胺酸殘基，87位、120位、149位、166位及174位之胺基酸殘基被置換為絲胺酸殘基或蘇胺酸殘基(較佳為蘇胺酸殘基)。
於一實施方式中，多肽較佳為於相當於序列編號2之胺基酸序列之選自由85位、118位、147位、164位及172位所組成之群中之1個以上之位置的位置，具有一定以上之聚糖佔有率。聚糖佔有率可藉由後述實施例中記載之方法測定。所謂一定以上，例如為30%以上、40%以上、50%以上、60%以上、70%以上、80%以上或90%以上。於一實施方式中，「1個以上」為2個以上、3個以上或4個以上。
多肽亦可為與酸或鹼之藥學上容許之鹽之形態。鹽只要為藥學上容許者，便無特別限定，可採用酸性鹽、鹼性鹽之任意者。作為酸性鹽之例，可列舉：鹽酸鹽、氫溴酸鹽、硫酸鹽、硝酸鹽、磷酸鹽等無機酸鹽；乙酸鹽、丙酸鹽、酒石酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、蘋果酸鹽、檸檬酸鹽、甲磺酸鹽、對甲苯磺酸鹽等有機酸鹽；天冬胺酸鹽、麩胺酸鹽等胺基酸鹽等。作為鹼性鹽之例，可列舉：鈉鹽、鉀鹽等鹼金屬鹽；鈣鹽、鎂鹽等鹼土金屬鹽等。
多肽亦可為溶劑合物之形態。溶劑只要為藥學上容許者，便無特別限定，例如可列舉：水、乙醇、甘油、乙酸等。
多肽可根據其胺基酸序列，藉由公知之基因工程手法容易地製作。例如，可利用PCR、限制酶切割、DNA連接技術、體外(in vitro)轉錄/轉譯技術、重組蛋白製作技術等來製作。於一實施方式中，多肽可藉由使編碼其之聚核苷酸於適宜之宿主中表現而獲得。
多肽可於合成後進行純化。例如，可藉由離心、過濾等自培養物集菌，自所收集之菌體萃取獲得多肽。具體而言，作為萃取第一階段之菌體破碎，可採用酶分解、滲透壓破壞、急遽之加壓減壓、超音波、各種均質機等。其次，作為用以將菌體破碎物分級之方法，可組合採用物理低速離心、超離心、過濾、分子篩、膜濃縮等、化學沈澱劑、助溶劑、吸附脫附劑、分散劑等、物理化學電泳、管柱層析、載體、透析、鹽析等。又，於採用該等方法時，可適當地設定溫度、壓力、pH值、離子強度等物理化學條件。
多肽可用於有效地製造具有交叉反應性之抗冠狀病毒抗體。於一實施方式中，所謂交叉反應性，意指針對SARS-CoV-2及SARS-CoV-2以外之冠狀病毒之反應性。於一實施方式中，SARS-CoV-2以外之冠狀病毒為屬於β-冠狀病毒屬者，較佳為屬於β-冠狀病毒屬沙貝病毒亞屬者。於一實施方式中，SARS-CoV-2以外之冠狀病毒為SARS相關冠狀病毒。於一實施方式中，作為SARS-CoV-2以外之冠狀病毒，例如可列舉：SARS-CoV-1、WIV1-CoV、MERS-CoV、及Pangolin-Cov等。於一實施方式中，具有交叉反應性之抗冠狀病毒抗體較佳為中和抗體，較佳為廣譜中和抗體。此種抗體可用於由冠狀病毒引起之疾病或症狀之預防、治療或緩解。因此，多肽可用作以此等為目的之疫苗或治療藥。
3.聚核苷酸
聚核苷酸較佳為包含編碼上述多肽之鹼基序列。於一實施方式中，聚核苷酸較佳為上述多肽之表現盒之形態。表現盒只要為能夠於細胞內表現多肽之聚核苷酸，便無特別限制。作為表現盒之典型例，可列舉具有啟動子、及於該啟動子之控制下編碼多肽之鹼基序列之聚核苷酸。
表現盒包含之啟動子並無特別限制，可根據導入表現盒之細胞之種類等適當選擇。例如pol II系啟動子，具體而言，可列舉：CMV啟動子、EF1啟動子、SV40啟動子、MSCV啟動子、hTERT啟動子、β肌動蛋白啟動子、CAG啟動子等。除此以外，例如亦可列舉：色胺酸啟動子、lac啟動子、T7啟動子、T5啟動子、T3啟動子、SP6啟動子、阿拉伯糖誘導啟動子、冷休克啟動子、四環素誘導性啟動子等。
用於導入聚核苷酸以生產多肽之細胞種(來源)並無特別限制。例如可列舉：動物細胞、植物細胞、酵母等真菌等。作為動物，尤其可列舉：人、猴、小鼠、大鼠、狗、貓、兔、豬、馬、牛、綿羊、山羊、鹿等各種哺乳類動物、非哺乳類脊椎動物、無脊椎動物等。於一實施方式中，較佳為哺乳類動物細胞。細胞之種類並無特別限制，可為源自各種組織之細胞或各種性質之細胞，例如可列舉：血液細胞、造血幹細胞/前驅細胞、配子(精子、卵子)、纖維母細胞、上皮細胞、血管內皮細胞、神經細胞、肝細胞、角蛋白生成細胞、肌細胞、表皮細胞、內分泌細胞、ES細胞(Embryonic Stem Cell，胚胎幹細胞)、iPS細胞(induced Pluripotent Stem Cell，誘導性多能幹細胞)、組織幹細胞、癌細胞等。
表現盒視需要可包含其他元件(例如可列舉：多選殖位點(MCS)、抗藥性基因、複製起點、增強子序列、抑制子序列、絕緣子序列、報告蛋白(例如螢光蛋白等)編碼序列、抗藥性基因編碼序列等)。MCS只要為包含複數(例如2～50、較佳為2～20、更佳為2～10)個限制酶位點者，便無特別限制。
作為抗藥性基因，例如可列舉：抗氯黴素性基因、抗四環素性基因、抗新黴素性基因、抗紅黴素性基因、抗壯觀黴素性基因、抗康黴素性基因、抗潮黴素性基因、抗嘌呤黴素性基因等。
作為報告蛋白，只要為與特定受質反應而發光(顯色)之發光(顯色)蛋白、或於激發光作用下發出螢光之螢光蛋白，則無特別限定。作為發光(顯色)蛋白，例如可列舉：螢光素酶、β-半乳糖苷酶、氯黴素乙醯轉移酶、β-葡萄糖醛酸酶等。作為螢光蛋白，例如可列舉：GFP、Azami-Green、ZsGreen、GFP2、HyPer、Sirius、BFP、CFP、Turquoise、Cyan、TFP1、YFP、Venus、ZsYellow、Banana、KusabiraOrange、RFP、DsRed、AsRed、Strawberry、Jred、KillerRed、Cherry、HcRed、mPlum等。
表現盒視需要可與其他序列一起構成表現載體。載體之種類並無特別限制，例如可列舉：動物細胞表現質粒等質粒載體；反轉錄病毒、慢病毒、腺病毒、腺相關病毒、疱疹病毒、仙台病毒等病毒載體等。
聚核苷酸可藉由公知之基因工程手法容易地製作。例如，可利用PCR、限制酶切割、DNA連接技術等製作。
聚核苷酸能夠用於生產上述多肽。因此，聚核苷酸可用於與上述多肽相同之目的(例如針對由冠狀病毒引起之疾病或症狀之疫苗)。
4.組合物
組合物較佳為含有上述多肽或聚核苷酸。含有上述多肽或聚核苷酸之組合物可用作疫苗或醫藥組合物。
組合物亦可根據目的含有其他成分。作為其他成分，例如可列舉：增強疫苗之耐熱性之穩定劑、作為提高免疫原性之輔助劑的佐劑等。作為穩定劑，例如可列舉：糖類或胺基酸類。作為佐劑，例如可列舉：鋁化合物(例如氫氧化鋁凝膠等)、CpG寡去氧核苷酸、礦物油、植物油、明礬、膨潤土、二氧化矽、胞壁醯二肽(muramyl dipeptide)衍生物、胸腺肽、介白素等。佐劑可為單獨1種，亦可為2種以上之組合。
組合物視需要可含有基劑、載體、溶劑、分散劑、乳化劑、緩衝劑、穩定劑、賦形劑、黏合劑、崩解劑、潤滑劑、增黏劑、保濕劑、著色料、香料、螯合劑等。
疫苗或醫藥組合物之劑形並無特別限定，例如可列舉：水性注射劑、非水性注射劑、懸浮性注射劑、固體注射劑等注射劑；錠劑、膠囊劑、顆粒劑、散劑、細粒劑、糖漿劑、腸溶劑、緩釋性膠囊劑、咀嚼錠、滴劑、丸劑、內用液劑、口含錠、緩釋劑、緩釋性顆粒劑等經口劑；滴鼻劑、吸入劑、肛門栓劑、插入劑、灌腸劑、凍膠劑等外用劑等。
組合物之有效成分之含量可基於投予對象、投予路徑、劑形、患者之狀態、及醫師之判斷等設定。例如，組合物中之多肽或聚核苷酸之含量可設為0.0001～95重量%、較佳為0.001～50重量%。
疫苗或醫藥組合物之使用量可考慮到投予路徑、對象之健康狀態、對象之年齡齢、性別、體重、藥物動力學及毒物學特徵等藥理學知識、有無利用藥物傳遞系統、以及是否作為其他藥物之組合之一部分來投予、後天免疫或增強免疫效果等各因素來設定。例如，可以使1次投予中之有效成分投予量為1 μg～100 mg/kg(體重)、50 μg～10 mg/kg(體重)之方式使用。投予間隔及次數並無特別限制，較佳為例如以約1～30週之間隔進行投予。
5.抗體及其製造方法
藉由使用上述多肽作為抗原，可製造具有交叉反應性之抗冠狀病毒抗體。
作為抗體之種類，包括多株抗體、單株抗體、人嵌合抗體、人源化抗體、全人源抗體、單鏈抗體、抗原結合性片段(Fab、F(ab')2、微型抗體(minibody)、scFv‐Fc、Fv、scFv、雙功能抗體(diabody)、三功能抗體(triabody)、四功能抗體(tetrabody))。再者，所謂人嵌合抗體，指抗體之可變區為源自人類以外之動物(例如小鼠、牛等)之序列、抗體之恆定區為源自人之序列的抗體。
該等抗體之製造方法公知，可按照常規方法製造(「分子生物學實驗手冊(Current protocols in Molecular Biology)」, 第11章第12～13節(2000))。具體而言，於多株抗體之情形時，可使家兔等非人動物對抗原產生免疫，按照常規方法自該免疫動物之血清中獲得。於單株抗體之情形時，可使小鼠、牛等非人動物對抗原產生免疫，使獲得之脾臟細胞與骨髓瘤細胞進行細胞融合而製備融合瘤，並自該融合瘤細胞中獲得(「分子生物學實驗手冊」, Ausubel等人(1987), John Wiley and Sons出版, 第11章第4～11節)。動物免疫可藉由對動物投予上述多肽、或對動物投予上述聚核苷酸，使其於動物之體內表現而進行。
製造抗體時，亦可藉由根據宿主之種類使用各種佐劑來增強免疫學反應而進行。作為佐劑，可列舉：弗氏佐劑、氫氧化鋁之類的礦物凝膠、以及脫脂酸卵磷脂、普朗尼克多元醇(Pluronic Polyol)、聚陰離子、肽、油乳劑、鑰孔血藍蛋白及二硝基苯酚之類的表面活性物質、BCG(Bacille Calmette-Guerin(卡介苗))、短棒狀桿菌等人類佐劑。
於一實施方式中，抗體所具有之所謂交叉反應性，意指針對SARS-CoV-2及SARS-CoV-2以外之冠狀病毒之反應性。於一實施方式中，SARS-CoV-2以外之冠狀病毒為屬於β-冠狀病毒屬者，較佳為屬於β-冠狀病毒屬沙貝病毒亞屬者。於一實施方式中，SARS-CoV-2以外之冠狀病毒為SARS相關冠狀病毒。於一實施方式中，作為SARS-CoV-2以外之冠狀病毒，例如可列舉：SARS-CoV-1、WIV1-CoV、MERS-CoV、及Pangolin-Cov等。於一實施方式中，抗體較佳為識別SARS-CoV-2之S蛋白之RBD-核心亞結構域。於一實施方式中，具有交叉反應性之抗冠狀病毒抗體較佳為中和抗體，較佳為廣譜中和抗體。此種抗體可用於由冠狀病毒引起之疾病或症狀之預防、治療或緩解。
[實施例]
材料及試驗方法
小鼠
自Japan SLC股份有限公司購入BALB/c小鼠，於去除特定病原體之條件下飼育。將性別配對之7週齡～8週齡小鼠用於全部實驗。全部動物實驗均依照大阪大學之動物實驗準則實施。
受試人
於東京品川醫院採集人類血液樣本，使用Vacutainer CPT Tube(Becton, Dickinson)單離血漿。研究方案已獲得日本國立感染症研究所之以人類為對象之醫學研究倫理審查委員會、東京品川醫院之倫理委員會及大阪大學之批准。全體參加者均根據赫爾辛基宣言提交了書面之知情同意書。
疫苗設計
母rRBD(pCAGGS-CoV-2 RBD-His-Avi)之哺乳動物表現構建物編碼SARS CoV-2 S之aa 331～530，於N末端具有源自MERS S蛋白之訊號肽(MIHSVFLLMFLLTPTESYVD)、C末端具有6×His-Avi標籤(HHHHHHGLNDIFEAQKIEWHE)。為了實現聚糖掩蔽，於圖1S所示之RBD表面殘基上導入NxT序列子。避免產生預測會破壞RBD之結構之突變、或基於NetNGlyc(http://www.cbs.dtu.dk/services/NetNGlyc/)工具之糖基化評分較低(未達0.5)之突變。將候補構建物轉染至Expi293F細胞，測試所附加之糖基化是否阻礙RBD之表現。藉由使用公知之抗RBD抗體之ELISA，評估GM突變體之抗原性。
重組蛋白之表現及純化
使用ExpiFectamine 293轉染套組(Thermo Fisher Scientific)，按照製造業者之操作說明，將重組SARS-CoV RBD及GM突變體之質粒瞬時轉染至Expi293F細胞(Thermo Fisher Scientific)。3天～4天後，回收上清液，使其通過0.45 µm之過濾器。利用Talon金屬親和樹脂(Talon metal affinity resin)(Takara Bio股份有限公司)，按照製造業者之操作說明，自上清液純化重組蛋白。對經樹脂純化而得之溶離液利用將溶離緩衝液交換成PBS之Amicon Ultra 4 10,000 NWML進行濃縮。對於奈米粒子抗原及探針，藉由共轉染BirA-Flag表現載體(Addgene)來同時表現BirA酶，藉此於培養物中進行rRBD及GM突變體之轉譯後生物素化。於經過如上所述之轉染後添加100 μM生物素(Sigma-Aldrich)之培養物中培養細胞。
為了製備ELISA或ELISPOT抗原，將於C末端6×His-Avi標籤前具有凝血酶切割部位(LVPRGS)之CoV-2 RBD WT、GM9、GM14及SARS相關CoV RBD之哺乳動物表現構建物瞬時轉染至Expi293F細胞。使用凝血酶套組(Thrombin kit)(Merck)，按照製造業者之操作說明，利用凝血酶對純化蛋白進行處理。分別利用Talon金屬親和樹脂(Takara Bio股份有限公司)及苯甲脒瓊脂糖凝膠(Benzamidine Sepharose)(GE)去除所切割之6×His-Avi標籤及凝血酶。藉由十二烷基硫酸鈉-聚丙烯醯胺凝膠電泳(SDS-PAGE)確認重組蛋白之純度或生物素化效率。
抗CoV-2 S RBD單株抗體
合成編碼公知之抗CoV-2 mAb(Pinto等人, 2020, 「通過人類SARS-CoV單株抗體對SARS-CoV-2產生交叉中和反應(Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody)」. Nature 583, 290-295；Yuan等人, 2020, 「SARS-CoV-2共有抗體應答之結構基礎(Structural basis of a shared antibody response to SARS-CoV-2)」. Science 369, 1119-1123；Zhou等人, 2020, 「來自恢復期患者之抗體中和SARS-CoV-2之結構基礎(Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient)」. Nat Struct Mol Biol 27, 950-958)之重鏈及κ鏈或λ鏈可變區的DNA片段(Eurofins公司)，分別選殖至人類IgG1、Igκ及Igλ表現載體。將重鏈及輕鏈表現載體共轉染至Expi293F。使用蛋白G-瓊脂糖凝膠(Protein G Sepharose)(GE)，按照製造業者之操作說明純化各mAb。
藉由液相層析/質譜分析(LC/MS)進行之N-結合型聚糖佔有率分析
參考Tajiri-Tsukada等人, 2020(「建立用於治療性單株抗體表徵與質量控制之高精度多屬性方法(Establishment of a highly precise multi-attribute method for the characterization and quality control of therapeutic monoclonal antibodies)」. Bioengineered 11, 984-1000)，進行樣本製備。使用MPEX PTS試劑(GL Sciences)對樣本蛋白質(10 μg)進行處理。使用2 μg之胰凝乳蛋白酶(1 μg/ml，Promega)，於37℃下對經還原之羧甲基化蛋白質進行3天分解。使用Oasis HLB μElution板(Waters)將獲得之肽脫鹽，乾燥後溶解於50 μl之0.1%FA溶液。藉由採用使用高能碰撞解離(HCD)及電子轉移/高能碰撞解離(EThcD)之平行採集模式(parallel acquisition mode)之液相層析/質譜分析(LC/MS)，對樣本溶液進行分析。EThcD-MS/MS條件如下所示：輔助活化碰撞能23%、隔離窗(isolation window)2 m/z、最大注入時間100 ms。藉由使用BioPharma Finder(商標)3.1(Thermo Fisher Scientific)之資料庫檢索，對肽進行特定。檢索參數如下所示：質量公差±5ppm、信度分數超過80、ID類型MS2。將羧甲基化(＋58.005Da)設定為Cys殘基之靜態修飾。使用軟體中保存之人類聚糖資料庫對糖肽進行特定。算出源自各糖肽之複數個前體離子之積分峰面積，根據下式計算相對峰面積及聚糖佔有率(%)：
相對峰面積＝(糖肽之峰面積)/(糖肽與非糖基化肽之總峰面積)
聚糖佔有率(%)＝(糖肽之總相對峰面積)/(糖肽與非糖基化肽之總相對峰面積)×100
奈米粒子之包覆
將經鏈黴親和素(streptavidin)包覆之0.11 μm奈米粒子(Bangs Laboratories)用PBS清洗2次，將5.5 μg奈米粒子與每隻小鼠80 ul之PBS中之50 ug生物素化蛋白一起於4℃下培養5小時。藉由流式細胞分析來測定包覆效率。
免疫化
於7週齡～8週齡時，藉由對各抗原組接種疫苗進行初次免疫，3週後藉由第2次疫苗接種對小鼠進行增強免疫。接種前，將免疫原懸浮液與AddaVax佐劑(Invivogen)按2：1之體積比輕柔混合，使抗原之最終濃度成為0.4 mg/mL。使用29G×1/2針注射器(Terumo股份有限公司)，對小鼠於異氟醚麻醉下向肌肉內注射免疫原，每個注射部位注射60 μL(合計120 μL)。初次免疫化時使用奈米粒子作為抗原，增強免疫化時使用單體蛋白作為抗原。
流式細胞分析
由鼠蹊部及髂骨淋巴結或脾臟製備單細胞懸浮液。自各小鼠採集鼠蹊部及髂骨淋巴結，進行混合。CoV-1或CoV-2 RBD特異性B細胞之檢測係使用已利用螢光團偶聯鏈黴親和素預標記之生物素化rRBD來進行。為了排除所誘導之6×His、Avi標籤、生物素及鏈黴親和素特異性B細胞，利用誘餌探針對樣本進行預染色。使用Attune NxT流式細胞儀(Thermo Fisher Scientific)對細胞樣本進行分析，使用FACS Aria II細胞分選儀(BD Bioscience)進行分選。使用FlowJo軟體V10(Tree Star)進行資料分析。
BCR選殖及抗體表現
自距增強免疫經過7天後之免疫化小鼠之淋巴結以如上所述之方式單細胞分選CoV-1及CoV-2-S RBD特異性B細胞。採用公知方法進行抗體之選殖及表現(von Boehmer等人, 2016, 「源自小鼠記憶B細胞之抗原特異性抗體之定序及選殖(Sequencing and cloning of antigen-specific antibodies from mouse memory B cells)」. Nat Protoc 11, 1908-1923；Inoue等人, 2021, Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming and provision of a survival signal. J Exp Med 218)。使用Expi293表現系統(Thermo Fisher Scientific)使單株抗體表現，藉由蛋白G-瓊脂糖凝膠(GE)自Expi293F細胞之培養上清液進行純化。
mAb與抗原之結合的流式細胞分析
將抗小鼠Igκ微粒子及陰性對照粒子(BD之CompBeads)按1：1之比率混合。其次，將粒子與250 ng純化mAb(mIgG2c/mIgκ)混合20分鐘，用含2%FBS之PBS洗淨，繼而用PE偶聯抗原進行20分鐘標記。藉由流式細胞分析(BD之FACSCanto II及FACS Aria II)評定mAb對抗原之結合能力。
ELISA
用各rRBD(100 ng/50 μl)塗覆Nunc Maxisorp免疫培養板(Thermo Fisher Scientific)。使用BlockingOne溶液(Nacalai Tesque股份有限公司)進行阻斷。將培養板依序與連續稀釋之血清樣本或自單個GC B細胞選殖之單株抗體、及IgG1-HRP檢測抗體(Southern Biotech)一起培養。使用KPL SureBlue TMB微孔過氧化酶底物(SeraCare)進行檢測。採用CR3022小鼠IgG1e3單株抗體(Invivogen)作為標準。
關於親和ELISA，於經1 ug/ml CoV-1 RBD蛋白(低密度)或8 ug/ml CoV-1 RBD蛋白(高密度)塗覆之培養板上培養連續稀釋血清。與Wang等人, 2015(「抗血凝素糖形驅動B細胞之免疫親和力選擇並決定流感疫苗效力(Anti-HA Glycoforms Drive B Cell Affinity Selection and Determine Influenza Vaccine Efficacy)」. Cell 162, 160-169)之記載同樣地，以與低密度CoV-1 RBD塗覆培養板之結合：與高密度CoV-1 RBD塗覆培養板之結合的比率表示CoV-1 RBD特異性IgG1之親和性。
關於基於mAb之表位阻斷ELISA，準備血清樣本或選殖單株抗體各自對應之CoV-1 RBD或CoV-2 RBD塗覆培養板。進行阻斷後，添加CR3022(Class4)、EY6A(Class4)及/或S309(Class3)人類IgG1 mAb(分別為150 ng/50 μl)之單獨一種或混合物。於室溫下培養3小時後，將培養板用PBST洗淨，繼而添加血清樣本或選殖單株抗體，於37℃下培養1小時。清洗3次後，分別添加HRP偶聯(conjugate)山羊抗小鼠IgG1或IgG2c，於室溫下培養1小時。藉由減去利用表位阻斷ELISA及先前之血清力價ELISA測得之力價，算出抗CoV-1 RBD抗體整體中之Class3/4型抗體之佔有率，以百分比表示。
ELISPOT分析
於具有纖維素薄膜之底部的培養板上塗覆CoV-1 RBD或CoV-2 RBD(100 ng/50 μl)。向孔中添加骨髄細胞，於添加有10%FBS、50 μM 2-ME及2 mM丙酮酸鈉之RPMI1640培養基中，於5%CO
2、37℃下培養5小時。用含0.05%Tween 20之PBS洗淨後，向孔中添加山羊抗小鼠IgG1 Ab，繼而添加鹼性磷酸酶標記抗山羊IgG Ab。藉由BCIP/NBT受質(Promega)使斑點可見化，進行計數。
假病毒分析
關於SARS CoV S蛋白假型化VSVΔG-luc之製作，按照Tani等人, 2010(「神經醯胺與日本腦炎病毒傳播的關係(Involvement of ceramide in the propagation of Japanese encephalitis virus)」. J Virol 84, 2798-2807)及Yoshida等人, 2021(SARS-CoV-2-induced humoral immunity through B cell epitope analysis in COVID-19 infected individuals). Sci Rep 11, 5934)中之記載進行製作。使用TransIT-LT1(Mirus)，按照製造業者之說明書，將各CoV S蛋白(SARS-CoV-2武漢株S、SARS-CoV-1 S及SARS相關CoV WIV1 S)之表現質粒轉染至HEK293T細胞。距轉染經過24小時後，將VSVΔG-luc病毒(MOI＝0.1)接種至轉染物。經過2小時培養後，將細胞用DMEM洗淨，再繼續培養24小時～48小時。採集無細胞之上清液，按照Nie等人, 2020(「藉由基於假型病毒之測定法定量SARS-CoV-2中和抗體(Quantification of SARS-CoV-2 neutralizing antibody by a pseudotyped virus-based assay)」. Nat Protoc 15, 3699-3715)中之記載，用於中和分析。將小鼠血清及人類血漿樣本於56℃下培養30分鐘後，於潛伏期培養基中自1/20起開始連續稀釋。將SARS-CoV S假型化VSVΔG-luc與稀釋率不同之小鼠血清、人類血漿或重組抗體一起於4℃下培養1小時後，接種於96孔板之VeroE6-TMPRSS2之單層培養物上。距接種經過16小時後，將細胞用PBS洗淨，繼而利用螢光素酶細胞培養物溶胞試劑(luciferase cell culture lysis reagent)(Promega)進行溶解。離心分離後，將澄清之細胞溶解物於96孔白色聚苯乙烯培養板(Corning)中與螢火蟲螢光素酶檢測受質(Promega)一起培養。利用GloMax Discover照度計(Promega)測定螢光素酶活性。利用Prism軟體(GraphPad)算出NT50或IC
50。
抗體依賴性增強(ADE)分析
按照Matsuda等人, 2018(《使用登革熱病毒I型報道基因複製子，基於單輪感染性顆粒，對多種黃病毒進行高通量中和測定(High-throughput neutralization assay for multiple flaviviruses based on single-round infectious particles using dengue virus type 1 reporter replicon)》. Sci Rep 8, 16624)中之記載，製作DENV1單輪感染性顆粒(SRIP)。為了進行使用RAW264.7細胞之ADE分析系統之評估，將抗E小鼠單株抗體3H12(Yamanaka等人, 2013, A mouse monoclonal antibody against dengue virus type 1 Mochizuki strain targeting envelope protein domain II and displaying strongly neutralizing but not enhancing activity. J Virol 87, 12828-12837)與DENV1 SRIP(感染複數[MOI]＝0.1)一起於4℃下預培養1小時後，接種於96孔板之RAW264.7細胞。2小時後，將細胞用PBS洗淨，於新鮮培養基中培養3天。使用NanoLuc分析套組(Promega)測定感染性。為了檢驗抗血清是否具有CoV-2感染之ADE，將SARS-CoV-2 S假型化VSVΔG-luc與免疫化小鼠之血清一起於4℃下培養1小時後，接種於96孔板之RAW264.7細胞。2小時後，將細胞用PBS洗淨，於新鮮培養基中培養16小時～20小時。藉由上述方法測定感染細胞之螢光素酶活性。
病毒中和分析
將100 TCID50病毒與經連續稀釋之熱失活血漿樣本(自1：40稀釋起以2倍進行連續稀釋)之混合物於37℃下培養1小時後，置於已接種於96孔平底培養板(TPP)之VeroE6-TMPRSS2細胞上。將VeroE6-TMPRSS2細胞於含有10%熱失活胎牛血清、1 mg/mL遺傳黴素(Thermo Fisher Scientific)及100 U/mL青黴素/鏈黴素(Thermo Fisher Scientific)之低葡萄糖DMEM(FUJIFILM Wako Pure Chemical股份有限公司)中，一面供給5%CO
2一面於37℃下培養。培養4天後，用20%福馬林(FUJIFILM Wako Pure Chemical股份有限公司)固定細胞，利用結晶紫溶液(Sigma-Aldrich)染色。採用超過50%之細胞變性效果之臨界稀釋指數來表示微中和力價。將未達檢測極限(1：40稀釋)之樣本之微中和力價設定為20。
生物膜干涉法分析
採用OctetRED96e系統(ForteBio)，一面以1000 rpm振盪一面於30℃下確定單株抗體與抗原之結合動力學。使源自CoV-1、CoV-2、WIV1-CoV、蝙蝠SARS相關AL-103及BM48-31之生物素化RBD蛋白於1×動力學分析緩衝液(含0.1%BSA、0.02%Tween-20之PBS)中，以6 μg/ml於鏈黴親和素生物感測器(ForteBio)上加載900秒，與經連續稀釋之Fab抗體(100 nM、33.3 nM、11.1 nM及0 nM)一起培養120秒，繼而於1×動力學分析緩衝液中浸漬300秒進行解離。將結合曲線擬合至1：1結合模型，利用Octet資料分析軟體(ForteBio)計算解離常數(KD)值。
抗體選殖之系統產生分析
針對各細胞，採用Igblast及IMGT小鼠參照，對全長BCR序列進行V、D、J基因及CDR3分配。僅基於重鏈，採用Change-O組件之DefineClones功能，針對各實驗分別定義選殖，將GM14#1之38/38細胞及GM14#2之26/31細胞視為相同選殖。使用Alakazam對該等2種主要選殖進行選殖樹重建(Change-O及Alakasam均為Immcantation分析架構之一部分)(Gupta等人, 2015, 「Change-O：用於分析大規模B細胞免疫球蛋白庫測序資料之工具包(Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data)」. Bioinformatics 31, 3356-3358)。最後使用Cytoscape繪製重建之選殖樹的圖。
統計
使用GraphPad Prism軟體，藉由非配對及有配對之雙側學生t檢定進行統計分析。將p值未達0.05視為有意義差。誤差線表示±SD。
SARS-CoV-2 RBD 聚糖突變體之設計為了對SARS-CoV-2 RBD-頭部亞結構域(圖1A)進行操作，於包含ACE-2連結所必需之殘基之該亞結構域導入N-結合型糖基化部位(NxT基序)(Barnes等人, 2020, Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies. Cell 182, 828-842 e816)(圖1A及圖1C)。識別SARS-CoV-2 RBD之既已確立之單株抗體(mAb)分為4類：如圖1B所示，Class1/2識別RBD-頭部亞結構域內之表位，Class3/4識別RBD-核心亞結構域內之表位。根據以下基準，特定出用以導入NxT序列子(GM14)之5個潛在部位：(1)Class1或2表位上之表面殘基；(2)RBD-核心亞結構域內之Class3及4表位之外側之殘基(Barnes等人, 2020, 同上)(圖1C)；(3)RBD-頭部亞結構域之非保守片段(patch)內之、或於立體結構上與其接近之殘基(圖1S之A)；(4)預測NxT突變不會破壞RBD之整體結構；(5)預測不會使RBD之蛋白表現或穩定性降低(Starr等人, 2020, 「SARS-CoV-2受體結合域之深度突變掃描揭示了摺疊及ACE2結合之限制(Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding)」. Cell 182, 1295-1310 e1220)。N415部位位於距RBD-頭部亞結構域稍遠之位置(圖1C)，但據報告，該部位為被Class1 mAb CB6識別之表位之一部分(Shi等人, 2020, 「一種人類中和抗體靶向SARS-CoV-2之受體結合位點(A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2)」. Nature 584, 120-124)。設計兩種聚糖突變體GM9及GM14，GM9具有3個附加糖基化部位，GM14具有5個附加糖基化部位。藉由結構模型化，預測該等附加之聚糖會阻礙Class1及2抗體之抗原識別(Barnes等人, 2020, 同上；Yuan等人, 2020, 同上)。
結果
使6×His-Avi標籤結合於聚糖突變體之C末端，於哺乳動物Expi293細胞中表現。該等於SDS-PAGE中顯示出高於野生型RBD之分子量(圖1S之B)。藉由液相層析-質譜分析(LC-MS)，確定所導入之各糖基化部位之聚糖佔有率。GM9之N494及N502聚糖之附加分別顯示為70%及57%，除此以外，所附加之全部糖基化部位具有超過75%之佔有率(圖1D)。內質網(ER)中之N-糖基化過程受到立體結構制約之影響(Breitling與Aebi, 2013, 「內質網中之N-連接蛋白糖基化(N-linked protein glycosylation in the endoplasmic reticulum)」. Cold Spring Harb Perspect Biol 5, a013359)。N494及N502上之聚糖佔有率稍低，其原因可能在於，該等之天冬醯胺殘基於位置上彼此極其接近，從而限制了寡糖基轉移酶於天冬醯胺殘基上之連接。
其次，對聚糖修飾阻礙Class1/2抗體之結合，但是否維持針對Class3/4抗體之抗原表位進行調查。於ELISA中，受驗之全部抗體均為儘可能與野生型RBD結合之物質(圖1E)。典型之Class1中和抗體mAb CB6完全未能與聚糖突變體(GM9及GM14)之各者結合。Class2抗體mAb C002(Robbiani等人, 2020, 「恢復期個體對SARS-CoV-2病毒之趨同抗體反應(Convergent antibody responses to SARS-CoV-2 in convalescent individuals)」. Nature 584, 437-442)與RBD之結合因GM14而消失，但該mAb依然較弱地與GM9結合，表明完全阻斷Class2 mAb C002需要5個突變。相對於此，以RBD-核心亞結構域為標靶之mAb S309(Class3)、mAb CR3022(Class4)及mAb EY6A(Class4)(Pinto等人, 2020, 同上；Yuan等人, 2020, 同上；Zhou等人, 2020, 同上)以同等水平結合於野生型RBD、GM9或GM14，表明因附加糖基化而導入之突變不影響RBD-核心亞結構域之整體結構(圖1E)。
藉由 SARS-CoV-2 頭部 -RBD 之聚糖工程，以更高之親和性生成更多之針對核心 -RBD 之抗體為了克服相對較小之SARS-CoV-2 RBD之有限之免疫原性，使其於鏈黴親和素聚苯乙烯奈米粒子上多價展示。與Walls等人, 2020(「藉由針對SARS-CoV-2設計之蛋白質奈米顆粒疫苗引發有效之中和抗體反應(Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2)」. Cell 183, 1367-1382 e1317)中之記載一致，顆粒狀RBD引發比作為對照之可溶性單體RBD更強之一次抗體應答(圖2S)。將該等顆粒狀抗原(野生型RBD、GM9或GM14)與Addavax佐劑一起注射於BALB/c小鼠肌肉內。距初次免疫經過3週後，利用各自之非顆粒狀抗原對小鼠實施增強免疫(圖2A)。距增強免疫經過7天後，採集血清，將該血清用於針對SARS-CoV-2 RBD之反應性之試驗。由於AddaVax與明礬同樣於小鼠中具優勢性地誘導IgG1型抗體(Sato等人, 2020, 「將銀屑病藥物Oxarol重新用於流感疫苗的軟膏佐劑(Repurposing the psoriasis drug Oxarol to an ointment adjuvant for the influenza vaccine)」. Int Immunol 32, 499-507)，故測定IgG1應答。首先，為了應對小鼠開始產生無法被母SARS-CoV-2 RBD探針檢測到之針對藉由聚糖工程生成之新表位之免疫應答的可能性，使用與免疫原適配之糖基化突變體探針及母探針，按照各自之免疫化試驗方案進行血清及GC B細胞應答之試驗。根據ELISA分析，探針組間顯示出同樣之RBD特異性血清力價；根據流式細胞分析，約10%或15%之GC B細胞僅結合於與免疫原適配之糖基化突變體探針(圖3S之A及B)。由此表明，藉由GM9或GM14免疫化，或於某種程度上出現了識別新表位之B細胞。儘管如此，由於超過85%之應答細胞係對母CoV-2 RBD探針顯示出反應性，故本分析中通常使用母SARS-CoV-2 RBD探針。
根據ELISA之評定，源自經聚糖突變體免疫化之小鼠的IgG1對CoV-2顯示出與野生型RBD免疫化同樣之反應性(圖2B之左側)。關於針對CoV-1之反應性，經GM9或GM14免疫化之小鼠顯示出約比野生型RBD免疫化高8倍之反應性(圖2B之右側)。考慮到SARS-CoV-2與CoV-1之間的RBD-核心亞結構域之序列保守性(圖1S之A)，藉由GM9或GM14免疫化使針對CoV-1之交叉反應性增強之原因最有可能在於，生成了更多之針對CoV-2之保守性RBD-核心亞結構域的IgG1。該可能性亦由如下結論證實：與野生型RBD免疫化同樣地，藉由GM9或GM14免疫化所誘導之CoV-1反應性IgG1分別被經驗證過之Class3/4抗CoV-2核心-RBD抗體(mAb S309、mAb CR3022及mAb EY6A之混合物)之預處理抑制了約90%或85%(圖2C之左側)。其次，對藉由GM9或GM14免疫化所誘導之交叉反應性IgG1之親和性進行特性評估。採用由硝基苯系統改良而成之親和ELISA分析來測定IgG1對CoV-1 RBD之親和性；該分析測定的是高親和性結合IgG1相對於總親和性結合IgG1之比率。如圖2C之右側所示，相對於野生型RBD免疫化，藉由GM9或GM14免疫化所誘導之交叉反應性IgG1具有顯著高之親和性。於使用WIV1-CoV代替SARS-CoV-1 RBD探針之情形時，各聚糖突變體均誘導了約高8倍之血清力價(圖2D之左側)。關於親和性，11隻野生型RBD免疫化小鼠中之2隻顯示出較高之高親和性結合相對於總親和性結合之比率，但剩餘9隻小鼠之血清所具有之親和性相對而言低於GM9或GM14免疫化小鼠(圖2D之右側)。總而言之，藉由SARS-CoV-2 RBD-頭部亞結構域之聚糖工程，容易生成具有更高親和性之RBD-核心亞結構域特異性抗體。
藉由 SARS-CoV-2 頭部 -RBD 之聚糖工程，誘導針對 SARS-CoV-1 及其他相關病毒之交叉中和抗體為了確定中和活性，主要採用水泡性口炎病毒(VSV)基質之假病毒法(Nie等人, 2020, 同上)，計算50%(half maximal)中和力價(NT50)。CoV-2野生型RBD、GM9或GM14免疫化對SARS-CoV-2產生了相同之中和活性。相較於CoV-2野生型RBD免疫化，GM9或GM14免疫化各自之活性出現少許上升或降低(圖3A)。藉由採用病毒中和分析，亦觀察到GM9或GM14免疫化引起之該傾向(圖4S)。
為了測定針對CoV-2變異體之中和活性，採用具有源自B.1.351變異體之K417N/E484K/N501Y變異的VSV基質病毒。藉此表明，即便是CoV-2野生型RBD免疫化，亦較野生型CoV-2而言誘導稍高之中和活性。鑒於利用mRNA疫苗獲得之人類血清對包含E484K變異之病毒顯示出較低之中和活性(Chen等人, 2021, 「SARS-CoV-2變異株對單株及血清衍生多株抗體中和之抗性(Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies)」. Nat. Med. 27:717-726)，藉由本發明之免疫手法，能夠生成更具抵抗性之血清。
根據VSV基質之假病毒法之評定結果，藉由GM9或GM14免疫化所誘導之抗血清分別以約比CoV-2野生型RBD免疫化高15倍或10倍之效力，對SARS-CoV-1具有中和活性(圖3A)。同樣地，該等血清對於WIV1-CoV、SHC014、及PaGX亦頗具中和活性(圖3A)。重要的是，GM9或GM14免疫化後觀察到之針對SARS-CoV-1及WIV1-CoV之中和水平與同一研究室基於相同分析形式所分析得出之自SARS-CoV-2感染者採集之恢復期血漿樣本之SARS-CoV-2之中和活性相同(圖3B及圖3C)。考慮到藉由GM9或GM14免疫化所誘導之CoV-1反應性抗體之主要表位位於RBD-核心亞結構域內(圖2C之左側)，該等抗核心-RBD抗體有助於SARS-CoV-1、WIV1-CoV、SHC014、及PaGX之交叉中和之可能性最高。
根據SARS-CoV-1及其他病毒之既往研究，提示出疫苗接種後可能引發感染之抗體依賴性增強作用(ADE)(Smatti等人, 2018, Viral-Induced Enhanced Disease Illness. Front Microbiol 9, 2991)。為了研究此種可能性，將VSV基質之假病毒與免疫化小鼠之連續稀釋血清一起培養後，接種於常用以評估SARS-CoV之ADE活性之人類B淋巴瘤細胞株Raji(Verma等人, 2009, 《基於炭疽毒素中和測定之Fcγ受體依賴性部分中和分析(Analysis of the Fc gamma receptor-dependent component of neutralization measured by anthrax toxin neutralization assays)》. Clin Vaccine Immunol 16, 1405-1412)。該分析之陽性對照表明，抗CoV-2 SRBD MW05嵌合人類/小鼠IgG1抗體之添加導致CoV-2 S假病毒之感染性明顯增強(圖3D之中間)。於該實驗設定中，與經SARS-CoV-2野生型RBD免疫化之小鼠之血清同樣地，經GM9或GM14免疫化之小鼠之血清未顯示明顯之ADE活性(圖3D之右側)。
交叉反應性 GC B 細胞之反應性分佈為了補充上述血清學特性評估，對初次免疫(priming)後單離之GC B細胞之反應性進行評定。藉由流式分析(flow analysis)證實，野生型RBD、GM9或GM14免疫化生成相同水平之GC B細胞總數(圖4A)。相較於野生型RBD免疫化，藉由GM9或GM14之免疫化，使CoV-2
＋細胞中之對CoV-2及CoV-1探針兩者均顯示陽性之GC B細胞之頻度增加(圖4B及C)。
為了試驗各CoV-2
＋/CoV-1
＋GC B細胞之交叉反應性分佈，對於源自對4隻獨立之小鼠(GM9-1、GM9-2、GM14-1或GM14-2)進行單細胞篩選獲得之GC B細胞的mAb進行特性評估。藉由序列分析，可知於各小鼠中，超過85%之單離mAb為增殖選殖系列之成員。尤其於GM14-1或GM14-2小鼠中，幾乎全部mAb係由DH及JK片段不同、組合相同之VH/VK編碼而成：GM14-1(VH14-3-DH3-2-JH4/VK4-111-JK2)及GM14-2(VH14-3-DH2-3-JH4/VK4-111-JK1)(圖7)。
所分析之全部mAb之中，除源自VH14-1/VK8-27基因對(gene pairs)之mAb被單純Class3 mAb阻斷以外，大多數mAb與CoV-2 RBD之結合被單純Class4 mAb阻斷(圖7)。為了評定上述mAb對沙貝病毒RBD之識別廣泛度，藉由採用基於流式細胞分析之測定，計算各抗體之相對結合指數(圖5A)(Bajic等人, 2019, 「流感抗原工程聚焦於對亞優勢但廣泛保護性之病毒表位之免疫反應(Influenza Antigen Engineering Focuses Immune Responses to a Subdominant but Broadly Protective Viral Epitope)」. Cell Host Microbe 25, 827-835 e826；Leach等人, 2019, 「防止異源流感病毒再感染需要記憶B細胞激活(Requirement for memory B-cell activation in protection from heterologous influenza virus reinfection)」. Int Immunol 31, 771-779)；相對結合指數與藉由Octet動力學分析所測得之二價IgG抗體之RMax高度一致(圖5S)。自進化枝1(作為進化枝1a之SARS-CoV-1及WIV1-CoV、作為進化枝1b之SARS-CoV-2及PaGX)、以及遠親之進化枝2(Anlong-103[AL-103])及進化枝3(BM48-31)(Lau等人, 2020, 「嚴重急性呼吸道症候群冠狀病毒2之可能蝙蝠起源(Possible Bat Origin of Severe Acute Respiratory Syndrome Coronavirus 2)」. Emerg Infect Dis 26, 1542-1547)(Letko等人, 2020, 「SARS-CoV-2與其他B族β冠狀病毒之細胞進入及受體使用之功能評估(Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses)」. Nat Microbiol 5, 562-569)之中選擇RBD。如所預料，自GM9-1、GM9-2、GM14-1或GM14-2小鼠單離之幾乎全部mAb對進化枝1a及進化枝1b RBD表現出結合反應性。於GM9或GM14免疫化小鼠中，CoV-1/WIV1/SHC014/PaGX之相對結合指數與CoV-2之相對結合指數高度相關(圖5B)。對於進化枝2及進化枝3 RBD，自GM9-1或GM9-2單離之mAb中有一些表現出顯著之結合反應性，但GM14-1小鼠則僅極小一部分表現出結合反應性(圖5A)。
其次，藉由上述VSV基質之假型分析，評估各mAb對CoV-1、WIV1、SHC014或PaGX或CoV-2之中和活性(圖5A及圖7)。由於抗體之數量較多，故採用以下2個基準進行篩選，聚焦於9個mAb(圖5C)。第一，對3種中之至少2種類型之病毒之中和活性以IC
50(50%抑制濃度)計未達10 μg/ml。對該等病毒之最高效力以IC
50計未達3 μg/ml。如圖5D所示，與單純mAb S309或CR3022同樣地，該等mAb對CoV-2具有比對CoV-1或WIV1觀察到之IC
50高的IC
50。於VH14-3-DH3-2-JH4/VK4-111-JK2(GM14-1)或VH14-3-DH2-3-JH4/VK4-111-JK1(GM14-2)系列中，對CoV-2具有最高結合指數之mAb對CoV-2並不具有最高之中和活性之效力(圖5C)。因此，抗體中和效力可能至少一部分受到結合親和性以外之因素之支配。
交叉反應性長壽命漿細胞及記憶 B 細胞之誘導最成功之疫苗方法取決於記憶B細胞及長壽命漿細胞(LLPC)之生成。如圖6A所示，於第7週進行分析。此時，藉由野生型RBD、GM9或GM14免疫化，同樣地生成了類型轉換之IgG1型記憶B細胞，但GM9及GM14生成了更多之CoV-1
＋CoV-2
＋細胞(圖6B)。進而，藉由骨髓中之SARS-CoV-1特異性抗體分泌細胞(ASC)進行評定，結果表明，由GM9或GM14免疫化，誘導了更多之CoV-1
＋ASC(圖6C)，簡言之，相較於野生型RBD免疫化，藉由使用GM9或GM14之本免疫化試驗方案，更有效地生成兩者之交叉反應性記憶區室。
[序列表]
P22-017WO_PCT_糖鏈修飾RBD及其_20220421_162838_0.txt
圖1-1、圖1-2係SARS-CoV-2 RBD聚糖掩蔽突變體之設計；(A)表示與ACE-2胞外域(PDB：6M0J)結合之CoV-2 S(PDB：6YZ5)之RBD之結構。(B)表示代表性之抗CoV-2 mAb之表位。(C)左圖表示RBD WT、GM9及GM14中之糖基化部位。(C)右圖表示RBD GM9及GM14之條帶模型(ribbon model)。球體表示所導入之N-聚糖部位。(D)表示藉由LC-MS測得之RBD WT、GM9及GM14之N-結合型糖基化部位上之聚糖佔有率。(E)表示先前報告之針對SARS-CoV-2 RBD(CB6、C002、S309、CR3022及EY6A)之mAb對於WT、GM9及GM14之ELISA結合。使用抗白色念珠菌(C. albicans)hIgG1 mAb 23B12作為陰性對照。熱圖表示結合之百分比(將各mAb與RBD WT之結合的ELISA曲線下面積[AUC]之值設定為100%)。示出基於3次獨立實驗所得之代表性結果。
圖1S-1、圖1S-2係CoV-2 RBD聚糖掩蔽突變體之設計及表現。(A)表示RBD-ACE2複合體之結構。(B)表示母胺基酸序列及所導入之NXT序列子。(C)表示RBD WT、GM9及GM14之SDS-PAGE。
圖2-1、圖2-2表示CoV-2 S RBD免疫原之聚糖突變體有效地誘導CoV-1 S RBD特異性抗體。(A)實驗設計之概要圖。(B)藉由ELISA測定免疫前小鼠、或者CoV-2 RBD、GM9、GM14或CoV-1 RBD WT免疫化小鼠之血清中之CoV-2 RBD(左圖)或CoV-1 RBD(右圖)特異性血清IgG1抗體濃度。收集來自3次獨立實驗(各組3隻或4隻小鼠)之樣本。(C)藉由使用CR3022/EY6A/S309人IgG1 mAb之混合物之表位阻斷ELISA來測定源自CoV-2 RBD、GM9、GM14或CoV-1 RBD WT免疫化小鼠之Class3/4型血清抗體(左圖)；藉由ELISA確定親和性，以與低密度之培養板結合CoV-1 RBD蛋白之結合/與高密度之培養板結合CoV-1 RBD蛋白之結合的結合比表示(右圖)。(D)藉由與(B)相同之方式測定WIV1 RBD特異性血清IgG1抗體濃度(左圖)，藉由與(C)之右圖相同之方式測定親和性(右圖)。橫線表示平均值；各符號表示1隻小鼠。
＊p＜0.05、
＊＊p＜0.01、
＊＊＊p＜0.001，非配對學生t檢定。
圖2S表示藉由利用奈米粒子抗原之免疫化，有效地誘導CoV-2 S RBD特異性抗體。源自距一次免疫化經過3週後分別利用生物素(+)RBD/St-avi奈米粒子、生物素(-)RBD/St-avi奈米粒子、或僅生物素(+)RBD進行了免疫化之小鼠之血清的關於CoV-2 RBD wt探針識別之ELISA圖。橫線表示平均值；各符號表示1隻小鼠。使用CR3022小鼠IgG1單株抗體(Invivogen)作為標準。
＊p＜0.05、
＊＊p＜0.01、
＊＊＊p＜0.001，非配對學生檢定。
圖3-1、圖3-2表示SARS-CoV-2 頭部-RBD之聚糖工程誘導針對SARS-CoV-1及WIV1-CoV之交叉中和活性。(A)利用CoV-2 RBD WT、GM9、GM14或CoV-1 RBD，如圖2所示般對BALB/c小鼠進行初次免疫-加強(prime-boost)免疫化。距增強免疫經過7天後採集血清，與CoV-2 S、CoV-1 S或WIV-1 CoV S假型化VSVΔG-luc一起預培養1小時。將混合物與VeroE6 TMPRESS2細胞一起培養一晩。圖中示出各組之小鼠之NT50。將未達檢測極限(1：20)之樣本之NT50設定為20。
＊P＜0.05，Wilcoxon檢定。RBD WT(n＝11)；GM9(n＝11)；GM14(n＝11)；CoV-1 RBD(n＝8)。(B)大流行前(pre-pandemic)健康供體(HC、n＝8)或恢復期COVID-19患者(n＝24)之血漿樣本針對CoV-2 S、CoV-1 S及WIV-1 CoV S假型化VSVΔG-luc之中和活性。將未達檢測極限(1：20)之樣本之NT50設定為20。(C)供體資訊。(D)由抗DENV1 E mAb 3H12引起之DENV1單輪感染性顆粒(SRIP)所導致之感染之ADE。將DENV1 SRIP與濃度不同之3H12或對照小鼠IgG
1一起預培養後，與RAW264.7細胞一起培養。於感染之72小時後測定螢光素酶活性。(E)將免疫化小鼠之血清進行連續稀釋，與CoV-2 S假型化VSVΔG-luc混合1小時，與RAW264.7細胞一起培養。於感染之24小時後測定螢光素酶活性。示出基於2次或3次獨立實驗獲得之代表性結果。資料為平均±SEM。圖(A及B)中之虛線(NT50＝20)表示檢測下限。
＊p＜0.05、
＊＊p＜0.01、
＊＊＊p＜0.001，非配對學生t檢定。
圖3S表示經GM9或GM14免疫化之小鼠之血清及GC B細胞之交叉反應性。(A)利用GM9或GM14進行初次免疫-加強免疫後之小鼠之血清的關於CoV-2 RBD wt探針識別之ELISA圖。距一次免疫化經過3週後採集血清。(B)源自免疫化後dLN(Draining Lymph Nodes，引流淋巴結)之GC B之代表性FACS圖。對細胞設立針對抗原結合IgG+GC B細胞(CD138-B220+IgG+GL7+Fas+)之門控。右圖示出GM9或GM14結合細胞中關於RBD wt結合之陽性細胞之百分比(分別為n＝4)。
圖4表示利用CoV-2 GM抗原之免疫化使CoV-1及CoV-2交叉反應性GC B細胞活化。(A)對源自距利用各抗原進行一次免疫化經過3週後之小鼠之淋巴結的GC B細胞(CD138-B220+IgG+GL7+Fas+)進行分析之代表性流式細胞分析圖。左圖係代表基於2次獨立實驗之所見者。右圖係1次實驗中之自複數隻小鼠採集之CD138-B220+IgG+GL7+Fas+GC B細胞之絕對數之定量化。結果係代表2次獨立實驗者。橫線表示平均值；各符號表示1隻小鼠。(B)表示藉由流式細胞分析對CoV-2 RBD結合MLN GC B細胞(CD138-B220+IgG+GL7+Fas+CoV-2 RBD(APC)+CoV-2 RBD(PE-Cy7+))進行分析所得之代表性結果。左圖係代表基於2次獨立實驗之所見者。右圖係1次實驗中之自複數隻小鼠採集之GC B細胞之絕對數。結果係代表2次獨立實驗者。
(C)藉由流式細胞分析所評定之CoV-2 RBD結合MLN GC B細胞(CD138-B220+IgG+GL7+Fas+CoV-2 RBD(APC)+CoV-2 RBD(PE-Cy7+))與CoV-1 RBD之交叉反應性。左圖係代表基於2次獨立實驗之所見者。右圖係1次實驗中之源自複數隻小鼠之CoV-1及CoV-2 RBD交叉反應性GC B細胞之頻度。結果係代表2次獨立實驗者。橫線表示平均值；各符號表示1隻小鼠。
＊P＜0.05、
＊＊P＜0.01、
＊＊＊P＜0.001，非配對學生t檢定。
圖4S係真病毒中和分析。將100 TCID50病毒與經過連續稀釋之熱失活血漿樣本之混合物培養1小時後，置於接種在96孔板之VeroE6-TMPRSS2細胞上。培養4天後，將細胞用福馬林固定後，利用結晶紫溶液進行染色。示出超過50%之細胞變性效果之臨界稀釋指數作為微中和力價。將未達檢測極限(1：40稀釋)之樣本之微中和力價設定為20。
＊P＜0.05、
＊＊P＜0.01，非配對學生t檢定。
圖5-1、圖5-2、圖5-3、圖5-4、圖5-5、圖5-6表示源自GC之mAb對進化枝1 SARS相關CoV表現出廣泛之RBD結合及中和。(A)CoV-1、WIV1-CoV、CoV-2、BatCoV Anlong-103(AL-103)及BtCoV BM48-31之選殖性、VH及VK突變、以及抗體類別、對S RBD之結合、源自經GM9(GM9-1及GM9-2)或GM14(GM14-1及GM14-2)免疫化之小鼠之GC B細胞的mAb對CoV-1、WIV1-CoV及CoV-2假病毒之中和活性。(B)mAb對CoV-2 RBD之結合與mAb對CoV-1或WIV1-CoV RBD之結合的關聯。藉由基於微球(bead-based)之流式細胞分析來測定mAb與CoV-1、WIV1及CoV-2 RBD之結合。於圖中繪出對各RBD之結合訊號(gMFI)。示出斯皮爾曼等級相關係數及p值。(C)mAb與RBD蛋白之結合親和性。示出各選殖株之平衡解離常數(M)及IC
50(μg/ml)。(D)代表性交叉反應性mAb、以及含有先前單離之S309(Class3)及CR3022(Class4)人類抗RBD抗體之可變區的小鼠IgG2c重組抗體之中和活性(IC
50[μg/ml])。
圖5S表示藉由基於微球之流式細胞分析所得之gMFI與藉由生物膜干涉法(Octet)分析所得之Rmax之間的關聯。示出二價mAb-CoV-2 RBD相互作用之gMFI、以及K
D(M)、RMax、k
on(1/Ms)及k
off(1/s)。斯皮爾曼等級檢驗。
圖6係經GM9或GM14免疫化之小鼠的交叉反應性記憶B細胞及長壽命漿細胞之生成。(A)實驗設計之概要圖。(B)CoV-2 RBD特異性記憶B細胞(CD138-B220+IgG1+CD38+GL7-CoV-2 RBD(APC)+CoV-2 RBD(PE-Cy7)+)與源自距利用各抗原進行增強免疫化經過1個月後之小鼠之脾臟之CoV-1 RBD的交叉反應性。上圖係1次實驗中之源自複數隻小鼠之CoV-1及CoV-2 RBD交叉反應性記憶B細胞之頻度，下圖係全部之CoV-2特異性記憶B細胞之絕對數之定量化(下)。結果係代表2次獨立實驗者。(C)免疫前小鼠之或距利用各抗原進行增強免疫化經過1個月後之CoV-1(左圖)或CoV-2(右圖)特異性IgG1 ASC應答之ELISPOT分析。結果係代表2次獨立實驗者。橫線表示平均值；各符號表示1隻小鼠。
＊P＜0.05、
＊＊P＜0.01、
＊＊＊P＜0.001，非配對學生t檢定。
圖7-1、圖7-2、圖7-3、圖7-4表示自經GM9或GM14免疫化之小鼠之GC B細胞所生成之mAb之相關特性。
圖8表示代表性β冠狀病毒屬沙貝病毒之RBD序列之比較。方框包圍之區域為受體結合基序(RBD頭區)。星型標記表示糖鏈修飾插入部位。圖8之比對中使用之各RBD之胺基酸序列從上至下，分別為序列編號2、107、108、109、110、111、112、113、114。
圖9表示代表性β冠狀病毒屬沙貝病毒之RBD序列之系統樹狀圖。括號內之數值表示與SARS-Cov-2 RBD之同源性。
圖10表示SARS-CoV-2之刺突蛋白之胺基酸序列(序列編號1)。粗體字表示之區域為受體結合域(序列編號2)。
<![CDATA[<110> 國立大學法人大阪大學(OSAKA UNIVERSITY)]]>
<![CDATA[<120> 糖鏈修飾RBD及其用途]]>
<![CDATA[<130> P22-017WO]]>
<![CDATA[<150> US 63/178346]]>
<![CDATA[<151> 2021-04-22]]>
<![CDATA[<160> 114 ]]>
<![CDATA[<170> PatentIn第3.5版]]>
<![CDATA[<210> 1]]>
<![CDATA[<211> 1273]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> SARS-CoV-2]]>
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Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
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Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
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His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
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Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
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Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
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Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
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Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
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Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
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Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
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Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
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Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
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Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
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Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
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Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
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Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
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Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
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Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
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Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
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Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
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Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
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Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
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Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
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Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
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Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
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Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
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Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
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Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
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Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
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Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
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Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
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Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
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Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
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Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
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Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
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Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
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Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
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Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
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Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
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His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
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Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
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Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
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Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
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Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
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Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
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Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
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Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
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Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
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Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
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Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
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Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
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Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
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Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
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Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
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Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
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Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
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Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
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Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
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Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
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Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
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Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
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Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
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Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
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Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
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Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
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Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
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Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
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Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
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Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
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His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
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Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
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Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
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Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
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Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
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Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
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Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
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Val Leu Lys Gly Val Lys Leu His Tyr Thr
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<![CDATA[<210> 2]]>
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Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg
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Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys
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Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn
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Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile
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Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
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Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp
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Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys
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Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln
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Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe
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Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln
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Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala
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Thr Val Cys Gly Pro Lys Lys
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Ala Leu Ile Thr Thr Val Leu Pro Trp Phe Ala Phe
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Gln His His Tyr Gly Thr Pro Leu Thr
1 5
<![CDATA[<210> 21]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<40]]>0> 21]]>
<br/>
<br/><![CDATA[Gln His His Tyr Gly Asn Pro Leu Thr
1 5
<![CDATA[<210> 22]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 22]]>
Gln His His Tyr Gly Ser Pro Leu Thr
1 5
<![CDATA[<210> 23]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 23]]>
Gln His His Tyr Asp Ala Pro Leu Thr
1 5
<![CDATA[<210> 24]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<21]]>3> 小家鼠]]>
<br/>
<br/><![CDATA[<400> 24]]>
<br/>
<br/><![CDATA[Gln His His Tyr Gly Ala Pro Leu Thr
1 5
<![CDATA[<210> 25]]>
<![CDATA[<211> 8]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 25]]>
His Gln Tyr Leu Ser Ser Trp Thr
1 5
<![CDATA[<210> 26]]>
<![CDATA[<211> 10]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 26]]>
Gln His His Tyr Gly Ser Pro Pro Trp Thr
1 5 10
<![CDATA[<210> 27]]>
<![CDATA[<211> 10]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 27]]>
Gln His His Tyr Gly Thr Pro Pro Trp Thr
1 5 10
<![CDATA[<210> 28]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 28]]>
Gln His Phe Trp Asp Thr Pro Tyr Thr
1 5
<![CDATA[<210> 29]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 29]]>
Gln Gln His Tyr Ser Thr Pro Arg Thr
1 5
<![CDATA[<210> 30]]>
<![CDATA[<211> 11]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 30]]>
Thr Ile Gly Tyr Gly Tyr Gly Tyr Phe Asp Tyr
1 5 10
<![CDATA[<210> 31]]>
<![CDATA[<211> 11]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 31]]>
Thr Lys Gly Tyr Gly Tyr Gly Tyr Phe Asp Tyr
1 5 10
<![CDATA[<210> 32]]>
<![CDATA[<211> 11]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 32]]>
Thr Lys Gly Tyr Gly Tyr Gly Tyr Phe Asp Gln
1 5 10
<![CDATA[<210> 33]]>
<![CDATA[<211> 11]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 33]]>
Ser Ile Gly Tyr Gly Tyr Gly Tyr Phe Asp Tyr
1 5 10
<![CDATA[<210> 34]]>
<![CDATA[<211> 6]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 34]]>
Ala Arg Asn Phe Asp Val
1 5
<![CDATA[<210> 35]]>
<![CDATA[<211> 6]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 35]]>
Ala Arg Tyr Phe Asp Val
1 5
<![CDATA[<210> 36]]>
<![CDATA[<211> 11]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 36]]>
Val Arg Asp Tyr Gly Tyr Gly Tyr Phe Gly Val
1 5 10
<![CDATA[<210> 37]]>
<![CDATA[<211> 11]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 37]]>
Thr Ile Gly Phe Gly Tyr Gly Tyr Phe Asp Tyr
1 5 10
<![CDATA[<210> 38]]>
<![CDATA[<211> 12]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 38]]>
Ala Arg His Tyr Asp Tyr Asp Asp Gly Met Asp Tyr
1 5 10
<![CDATA[<210> 39]]>
<![CDATA[<211> 11]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 39]]>
Ala Arg Tyr Gly Asn Asp Trp Tyr Phe Asp Val
1 5 10
<![CDATA[<210> 40]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 40]]>
Thr Thr Pro Val Tyr Asp Gly Tyr Tyr Asp Tyr Ala Met Asp Cys
1 5 10 15
<![CDATA[<210> 41]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 41]]>
Gln His His Tyr Gly Thr Pro Tyr Thr
1 5
<![CDATA[<210> 42]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 42]]>
Gln His His Tyr Gly Ser Pro Tyr Thr
1 5
<![CDATA[<210> 43]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 43]]>
Gln Gln Trp Asn Asn Tyr Pro Tyr Thr
1 5
<![CDATA[<210> 44]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 44]]>
Gln Gln Trp Ser Ser Tyr Pro Tyr Thr
1 5
<![CDATA[<210> 45]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 45]]>
Gln His His Tyr Gly Pro Pro Tyr Thr
1 5
<![CDATA[<210> 46]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 46]]>
Gln His His Tyr Gly Pro Pro Phe Thr
1 5
<![CDATA[<210> 47]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<220>]]>
<![CDATA[<221> misc_feature]]>
<![CDATA[<222> (9)..(9)]]>
<![CDATA[<223> Xaa可為任意之天然存在之胺基酸]]>
<![CDATA[<400> 47]]>
Phe Gln Gly Ser His Val Pro Arg Xaa
1 5
<![CDATA[<210> 48]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 48]]>
Gln Gln Gly Gly Glu Asp Pro Trp Thr
1 5
<![CDATA[<210> 49]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 49]]>
Ala Arg Leu Asp Ser Ser Tyr Tyr Val Asp Tyr Pro Met Asp Tyr
1 5 10 15
<![CDATA[<210> 50]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400>]]> 50
Ala Arg Leu Asp Ser Ser Tyr Tyr Val Asp Tyr Pro Leu Asp Tyr
1 5 10 15
<![CDATA[<210> 51]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 51]]>
Ala Arg Leu Asp Ser Ser Ala Tyr Val Asp Tyr Pro Met Asp Tyr
1 5 10 15
<![CDATA[<210> 52]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 52]]>
Val Arg Leu Asp Ser Ser Ala Tyr Val Gly Tyr Pro Met Asp Tyr
1 5 10 15
<![CDATA[<210> 53]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 53]]>
Ala Arg Leu Asp Thr Ser Ser Tyr Val Asp Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 54]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 54]]>
Ala Arg Leu Asp Ser Ser Ala Tyr Val Glu Tyr Pro Met Asp Tyr
1 5 10 15
<![CDATA[<210> 55]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 55]]>
Ala Arg Leu Asp Ser Ser Thr Tyr Val Asp Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 56]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 56]]>
Ala Arg Leu Asp Ser Ser Ala Tyr Val Gly Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 57]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 57]]>
Ala Arg Leu Asp Ser Ser Ala Tyr Val Asp Tyr Pro Met Asp Phe
1 5 10 15
<![CDATA[<210> 58]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 58]]>
Ala Arg Leu Asp Ser Ser Ala Tyr Leu Gly Tyr Pro Leu Asp Tyr
1 5 10 15
<![CDATA[<210> 59]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 59]]>
Ala Arg Leu Asp Ser Ser Gly Tyr Val Gly Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 60]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 60]]>
Ala Arg Leu Asp Ser Ala Ala Tyr Val Gly Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 61]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 61]]>
Ile Arg Leu Asp Ser Ser Tyr Tyr Val Asp Tyr Pro Val Asp Tyr
1 5 10 15
<![CDATA[<210> 62]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 62]]>
Ala Arg Leu Asp Ser Ser Tyr Tyr Val Asp Tyr Pro Val Asp Tyr
1 5 10 15
<![CDATA[<210> 63]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 63]]>
Ala Arg Leu Asp Ile Ser Asp Tyr Val Asp Tyr Pro Met Asp His
1 5 10 15
<![CDATA[<210> 64]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 64]]>
Ala Arg Leu Asp Ser Ser Ser Tyr Val Asp Tyr Pro Met Asp Tyr
1 5 10 15
<![CDATA[<210> 65]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 65]]>
Ala Arg Leu Asp Ser Ser Ala Tyr Val Gly Tyr Pro Met Asp Tyr
1 5 10 15
<![CDATA[<210> 66]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 66]]>
Ala Arg Leu Asp Ser Ser Cys Tyr Val Asp Tyr Pro Val Asp Tyr
1 5 10 15
<![CDATA[<210> 67]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 67]]>
Ala Arg Leu Asp Ser Ser Tyr Phe Val Asp Tyr Pro Leu Asp Ser
1 5 10 15
<![CDATA[<210> 68]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 68]]>
Val Arg Leu Asp Ser Ser Tyr Tyr Val Asp Tyr Pro Val Asp Tyr
1 5 10 15
<![CDATA[<210> 69]]>
<![CDATA[<211> 17]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 69]]>
Ala Arg Gln Arg Gly Ser Tyr Tyr Arg Tyr Asp Asp Tyr Ala Met Asp
1 5 10 15
Tyr
<![CDATA[<210> 70]]>
<![CDATA[<211> 14]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 70]]>
Ala Arg Trp Gly Asn Tyr Val Ser Tyr Tyr Thr Met Asp Tyr
1 5 10
<![CDATA[<210> 71]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 71]]>
Leu Gln Tyr Asp Glu Phe Pro Tyr Thr
1 5
<![CDATA[<210> 72]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 72]]>
Leu Gln Tyr Asp Glu Phe Pro Phe Thr
1 5
<![CDATA[<210> 73]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 73]]>
Gln Gln Tyr Asp Glu Phe Pro Tyr Thr
1 5
<![CDATA[<210> 74]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> P]]>RT
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> ]]> 74
Leu Gln Tyr Asp Asp Phe Pro Tyr Thr
1 5
<![CDATA[<210> 75]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 75]]>
Leu Gln Tyr Ala Glu Phe Pro Tyr Thr
1 5
<![CDATA[<210> 76]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 76]]>
Leu His Tyr Asp Glu Phe Pro Tyr Thr
1 5
<![CDATA[<210> 77]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 77]]>
Phe Gln Gly Ser His Val Pro Trp Thr
1 5
<![CDATA[<210> 78]]>
<![CDATA[<211> 11]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 78]]>
Gln His Tyr His Ser Tyr Pro Pro Met Trp Thr
1 5 10
<![CDATA[<210> 79]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 79]]>
Ala Arg Leu Asp Tyr Asp Gly Tyr Tyr Glu Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 80]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 80]]>
Ala Arg Leu Asp Tyr Asp Thr Tyr Tyr Glu Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 81]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 81]]>
Ala Arg Leu Asp Phe Asp Gly Tyr Tyr Glu Tyr Pro Met Asp Tyr
1 5 10 15
<![CDATA[<210> 82]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 82]]>
Ser Arg Leu Asp Phe Asp Gly Tyr Tyr Glu Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 83]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 83]]>
Thr Arg Leu Asp Tyr Asp Gly Tyr Tyr Asp Tyr Ala Val Asp Tyr
1 5 10 15
<![CDATA[<210> 84]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 84]]>
Thr Arg Leu Asp Tyr Asp Gly Tyr Tyr Asp Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 85]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 85]]>
Ala Arg Leu Asp Tyr Asp Gly Tyr Tyr Asp Phe Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 86]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 86]]>
Ala Arg Leu Asp Tyr Asp Gly Tyr Tyr Glu Tyr Pro Met Asp Tyr
1 5 10 15
<![CDATA[<210> 87]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 87]]>
Ala Arg Leu Asp Tyr Asp Gly Tyr Tyr Glu Asn Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 88]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 88]]>
Ala Arg Leu Asp Tyr Asp Ala Tyr Tyr Glu Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> ]]> 89
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 89]]>
Ala Arg Leu Asp Tyr Ala Gly Tyr Tyr Glu Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 90]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 90]]>
Thr Arg Leu Asp Tyr Glu Gly Tyr Tyr Glu Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 91]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 91]]>
Thr Arg Leu Asp Tyr Asp Ser Tyr Tyr Glu Tyr Ala Leu Asp Tyr
1 5 10 15
<![CDATA[<210> 92]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 92]]>
Ser Arg Leu Asp Tyr Asp Gly Tyr Tyr Glu Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 93]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 93]]>
Ser Arg Leu Asp Tyr Asp Gly Tyr Tyr Glu Tyr Thr Met Asp Tyr
1 5 10 15
<![CDATA[<210> 94]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 94]]>
Ala Arg Leu Asp Tyr Asp Gly Tyr Tyr Asp Tyr Ala Leu Asp Tyr
1 5 10 15
<![CDATA[<210> 95]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 95]]>
Ala Arg Leu Asp Tyr Asp Gly Tyr Tyr Glu Tyr Pro Leu Asp Tyr
1 5 10 15
<![CDATA[<210> 96]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 96]]>
Ala Arg Leu Asp Tyr Asp Gly Tyr Tyr Asp Tyr Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 97]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 97]]>
Ala Arg Leu Asp Tyr Asp Gly Tyr Tyr Glu Tyr Ala Val Asp Tyr
1 5 10 15
<![CDATA[<210> 98]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 98]]>
Ala Arg Leu Asp Tyr Asp Gly Tyr Tyr Glu Tyr Ala Leu Asp Tyr
1 5 10 15
<![CDATA[<210> 99]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 99]]>
Ala Arg Leu Asp Tyr Asp Ala Tyr Tyr Glu Asn Ala Met Asp Tyr
1 5 10 15
<![CDATA[<210> 100]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 100]]>
Gly Arg Leu Asp Ser Leu His Tyr Tyr Asp Tyr Gly Phe Asp Tyr
1 5 10 15
<![CDATA[<210> 101]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 101]]>
Val Arg Leu Asp Tyr Asp Gly Tyr Tyr Glu Tyr Ser Met Asp Tyr
1 5 10 15
<![CDATA[<210> 102]]>
<![CDATA[<211> 15]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 102]]>
Thr Arg Leu Asp Tyr Asp Gly Tyr Tyr Glu Tyr Ala Leu Asp Tyr
1 5 10 15
<![CDATA[<210> 103]]>
<![CDATA[<211> 12]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 103]]>
Ala Arg Asp Gly Gly Asp Tyr Asp Trp Phe Ala Tyr
1 5 10
<![CDATA[<210> 104]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 104]]>
Leu Gln Tyr Asp Glu Phe Pro Arg Thr
1 5
<![CDATA[<210> 105]]>
<![CDATA[<211> 9]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 105]]>
Leu Gln Tyr Asp Asp Phe Pro Arg Thr
1 5
<![CDATA[<210> 106]]>
<![CDATA[<211> 8]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> 小家鼠]]>
<![CDATA[<400> 106]]>
Gln His His Tyr Gly Ser Ser Thr
1 5
<![CDATA[<210> 107]]>
<![CDATA[<211> 199]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> Pangolin-GX-P2V]]>
<![CDATA[<400> 107]]>
Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Ser Lys
1 5 10 15
Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val
20 25 30
Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Ser Phe Ser Thr Phe Lys
35 40 45
Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn
50 55 60
Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp Glu Val Arg Gln Ile
65 70 75 80
Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
85 90 95
Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Val Lys Gln Asp
100 105 110
Ala Leu Thr Gly Gly Asn Tyr Gly Tyr Leu Tyr Arg Leu Phe Arg Lys
115 120 125
Ser Lys Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln
130 135 140
Ala Gly Ser Thr Pro Cys Asn Gly Gln Val Gly Leu Asn Cys Tyr Tyr
145 150 155 160
Pro Leu Glu Arg Tyr Gly Phe His Pro Thr Thr Gly Val Asn Tyr Gln
165 170 175
Pro Phe Arg Val Val Val Leu Ser Phe Glu Leu Leu Asn Gly Pro Ala
180 185 190
Thr Val Cys Gly Pro Lys Leu
195
<![CDATA[<210> 108]]>
<![CDATA[<211> 198]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> SARS-CoV-1]]>
<![CDATA[<400> 108]]>
Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Lys
1 5 10 15
Phe Pro Ser Val Tyr Ala Trp Glu Arg Lys Lys Ile Ser Asn Cys Val
20 25 30
Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Phe Phe Ser Thr Phe Lys
35 40 45
Cys Tyr Gly Val Ser Ala Thr Lys Leu Asn Asp Leu Cys Phe Ser Asn
50 55 60
Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp Asp Val Arg Gln Ile
65 70 75 80
Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
85 90 95
Asp Asp Phe Met Gly Cys Val Leu Ala Trp Asn Thr Arg Asn Ile Asp
100 105 110
Ala Thr Ser Thr Gly Asn Tyr Asn Tyr Lys Tyr Arg Tyr Leu Arg His
115 120 125
Gly Lys Leu Arg Pro Phe Glu Arg Asp Ile Ser Asn Val Pro Phe Ser
130 135 140
Pro Asp Gly Lys Pro Cys Thr Pro Pro Ala Leu Asn Cys Tyr Trp Pro
145 150 155 160
Leu Asn Asp Tyr Gly Phe Tyr Thr Thr Thr Gly Ile Gly Tyr Gln Pro
165 170 175
Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala Thr
180 185 190
Val Cys Gly Pro Lys Leu
195
<![CDATA[<210> 109]]>
<![CDATA[<211> 198]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> WIV1]]>
<![CDATA[<400> 109]]>
Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Thr
1 5 10 15
Phe Pro Ser Val Tyr Ala Trp Glu Arg Lys Arg Ile Ser Asn Cys Val
20 25 30
Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Ser Phe Ser Thr Phe Lys
35 40 45
Cys Tyr Gly Val Ser Ala Thr Lys Leu Asn Asp Leu Cys Phe Ser Asn
50 55 60
Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp Asp Val Arg Gln Ile
65 70 75 80
Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
85 90 95
Asp Asp Phe Thr Gly Cys Val Leu Ala Trp Asn Thr Arg Asn Ile Asp
100 105 110
Ala Thr Gln Thr Gly Asn Tyr Asn Tyr Lys Tyr Arg Ser Leu Arg His
115 120 125
Gly Lys Leu Arg Pro Phe Glu Arg Asp Ile Ser Asn Val Pro Phe Ser
130 135 140
Pro Asp Gly Lys Pro Cys Thr Pro Pro Ala Phe Asn Cys Tyr Trp Pro
145 150 155 160
Leu Asn Asp Tyr Gly Phe Tyr Ile Thr Asn Gly Ile Gly Tyr Gln Pro
165 170 175
Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala Thr
180 185 190
Val Cys Gly Pro Lys Leu
195
<![CDATA[<210> 110]]>
<![CDATA[<211> 198]]>
<![CDATA[<212> PR]]>T
<![CDATA[<213> SHC014]]>
<![CDATA[<400> 110]]>
Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Thr
1 5 10 15
Phe Pro Ser Val Tyr Ala Trp Glu Arg Lys Arg Ile Ser Asn Cys Val
20 25 30
Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Ser Phe Ser Thr Phe Lys
35 40 45
Cys Tyr Gly Val Ser Ala Thr Lys Leu Asn Asp Leu Cys Phe Ser Asn
50 55 60
Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp Asp Val Arg Gln Ile
65 70 75 80
Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
85 90 95
Asp Asp Phe Leu Gly Cys Val Leu Ala Trp Asn Thr Asn Ser Lys Asp
100 105 110
Ser Ser Thr Ser Gly Asn Tyr Asn Tyr Leu Tyr Arg Trp Val Arg Arg
115 120 125
Ser Lys Leu Asn Pro Tyr Glu Arg Asp Leu Ser Asn Asp Ile Tyr Ser
130 135 140
Pro Gly Gly Gln Ser Cys Ser Ala Val Gly Pro Asn Cys Tyr Asn Pro
145 150 155 160
Leu Arg Pro Tyr Gly Phe Phe Thr Thr Ala Gly Val Gly His Gln Pro
165 170 175
Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala Thr
180 185 190
Val Cys Gly Pro Lys Leu
195
<![CDATA[<210> 111]]>
<![CDATA[<211> 180]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> Anlong-103]]>
<![CDATA[<400> 111]]>
Asn Ile Thr Asn Arg Cys Pro Phe Asp Ser Ile Phe Asn Ala Ser Arg
1 5 10 15
Phe Pro Ser Val Tyr Ala Trp Glu Arg Thr Lys Ile Ser Asp Cys Val
20 25 30
Ala Asp Tyr Thr Val Leu Tyr Asn Ser Thr Ser Phe Ser Thr Phe Lys
35 40 45
Cys Tyr Gly Val Ser Pro Ser Lys Leu Ile Asp Leu Cys Phe Thr Ser
50 55 60
Val Tyr Ala Asp Thr Phe Leu Ile Arg Phe Ser Glu Val Arg Gln Val
65 70 75 80
Ala Pro Gly Glu Thr Gly Val Ile Ala Asp Tyr Asn Tyr Arg Leu Pro
85 90 95
Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Thr Ala Asn Gln Asp
100 105 110
Val Gly Ser Tyr Phe Tyr Arg Ser His Arg Ser Thr Lys Leu Lys Pro
115 120 125
Phe Glu Arg Asp Leu Ser Ser Asp Glu Asn Gly Val Arg Thr Leu Ser
130 135 140
Thr Tyr Asp Phe Asn Pro Tyr Val Pro Leu Asp Tyr Gln Ala Thr Arg
145 150 155 160
Val Val Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala Thr Val Cys
165 170 175
Gly Pro Lys Leu
180
<![CDATA[<210> 112]]>
<![CDATA[<211> 180]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> Rf1-2004]]>
<![CDATA[<400> 112]]>
Asn Ile Thr Asn Leu Cys Pro Phe Asp Lys Val Phe Asn Ala Thr Arg
1 5 10 15
Phe Pro Ser Val Tyr Ala Trp Glu Arg Thr Lys Ile Ser Asp Cys Val
20 25 30
Ala Asp Tyr Thr Val Phe Tyr Asn Ser Thr Ser Phe Ser Thr Phe Asn
35 40 45
Cys Tyr Gly Val Ser Pro Ser Lys Leu Ile Asp Leu Cys Phe Thr Ser
50 55 60
Val Tyr Ala Asp Thr Phe Leu Ile Arg Phe Ser Glu Val Arg Gln Val
65 70 75 80
Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
85 90 95
Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Thr Ala Lys Gln Asp
100 105 110
Val Gly Ser Tyr Phe Tyr Arg Ser His Arg Ser Ser Lys Leu Lys Pro
115 120 125
Phe Glu Arg Asp Leu Ser Ser Glu Glu Asn Gly Val Arg Thr Leu Ser
130 135 140
Thr Tyr Asp Phe Asn Gln Asn Val Pro Leu Glu Tyr Gln Ala Thr Arg
145 150 155 160
Val Val Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala Thr Val Cys
165 170 175
Gly Pro Lys Leu
180
<![CDATA[<210> 113]]>
<![CDATA[<211> 180]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> Rs4081]]>
<![CDATA[<400> 113]]>
Asn Ile Thr Asn Arg Cys Pro Phe Asp Lys Val Phe Asn Ala Ser Arg
1 5 10 15
Phe Pro Asn Val Tyr Ala Trp Glu Arg Thr Lys Ile Ser Asp Cys Val
20 25 30
Ala Asp Tyr Thr Val Leu Tyr Asn Ser Thr Ser Phe Ser Thr Phe Lys
35 40 45
Cys Tyr Gly Val Ser Pro Ser Lys Leu Ile Asp Leu Cys Phe Thr Ser
50 55 60
Val Tyr Ala Asp Thr Phe Leu Ile Arg Ser Ser Glu Val Arg Gln Val
65 70 75 80
Ala Pro Gly Glu Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
85 90 95
Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Thr Ala Lys Gln Asp
100 105 110
Gln Gly Gln Tyr Tyr Tyr Arg Ser Ser Arg Lys Thr Lys Leu Lys Pro
115 120 125
Phe Glu Arg Asp Leu Thr Ser Asp Glu Asn Gly Val Arg Thr Leu Ser
130 135 140
Thr Tyr Asp Phe Tyr Pro Asn Val Pro Ile Glu Tyr Gln Ala Thr Arg
145 150 155 160
Val Val Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala Thr Val Cys
165 170 175
Gly Pro Lys Leu
180
<![CDATA[<210> 114]]>
<![CDATA[<211> 195]]>
<![CDATA[<212> PRT]]>
<![CDATA[<213> BM48-31]]>
<![CDATA[<400> 114]]>
Asn Ile Thr Gln Leu Cys Pro Phe Asn Glu Val Phe Asn Ile Thr Ser
1 5 10 15
Phe Pro Ser Val Tyr Ala Trp Glu Arg Met Arg Ile Thr Asn Cys Val
20 25 30
Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ser Ala Ser Phe Ser Thr Phe
35 40 45
Gln Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Ser
50 55 60
Ser Val Tyr Ala Asp Tyr Phe Val Val Lys Gly Asp Asp Val Arg Gln
65 70 75 80
Ile Ala Pro Ala Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu
85 90 95
Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Thr Asn Ser Leu
100 105 110
Asp Ser Ser Asn Glu Phe Phe Tyr Arg Arg Phe Arg His Gly Lys Ile
115 120 125
Lys Pro Tyr Gly Arg Asp Leu Ser Asn Val Leu Phe Asn Pro Ser Gly
130 135 140
Gly Thr Cys Ser Ala Glu Gly Leu Asn Cys Tyr Lys Pro Leu Ala Ser
145 150 155 160
Tyr Gly Phe Thr Gln Ser Ser Gly Ile Gly Phe Gln Pro Tyr Arg Val
165 170 175
Val Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala Thr Val Cys Gly
180 185 190
Pro Lys Gln
195
Claims (11)
- 一種多肽，其包含與序列編號2之胺基酸序列具有至少60%以上之同一性之胺基酸序列，且包含以於相當於序列編號2之胺基酸序列之85位、164位及172位之位置結合糖鏈之方式經過修飾之胺基酸序列。
- 如請求項1之多肽，其中上述修飾胺基酸序列進而以於相當於序列編號2之胺基酸序列之118位及/或147位之位置結合糖鏈之方式修飾。
- 如請求項1或2之多肽，其中糖鏈為N型糖鏈。
- 如請求項1或2之多肽，其中於相當於序列編號2之胺基酸序列之85位、164位及172位之位置結合有糖鏈。
- 如請求項4之多肽，其中進而於118位及/或147位結合有糖鏈。
- 如請求項4之多肽，其中糖鏈為N型糖鏈。
- 一種聚核苷酸，其包含編碼如請求項1之多肽之鹼基序列。
- 一種組合物，其含有如請求項1至6中任一項之多肽或如請求項7之聚核苷酸。
- 如請求項8之組合物，其為疫苗。
- 一種抗冠狀病毒抗體之製造方法，其包括利用如請求項1至6中任一項之多肽對動物進行免疫。
- 一種抗體，其係藉由如請求項10之方法獲得。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202163178346P | 2021-04-22 | 2021-04-22 | |
| US63/178,346 | 2021-04-22 |
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| Publication Number | Publication Date |
|---|---|
| TW202309069A true TW202309069A (zh) | 2023-03-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW111115459A TW202309069A (zh) | 2021-04-22 | 2022-04-22 | 糖鏈修飾rbd及其用途 |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP4328236A1 (zh) |
| JP (1) | JPWO2022225033A1 (zh) |
| CN (1) | CN117177988A (zh) |
| TW (1) | TW202309069A (zh) |
| WO (1) | WO2022225033A1 (zh) |
-
2022
- 2022-04-22 WO PCT/JP2022/018507 patent/WO2022225033A1/ja active Application Filing
- 2022-04-22 CN CN202280030060.0A patent/CN117177988A/zh active Pending
- 2022-04-22 TW TW111115459A patent/TW202309069A/zh unknown
- 2022-04-22 JP JP2023515526A patent/JPWO2022225033A1/ja active Pending
- 2022-04-22 EP EP22791804.2A patent/EP4328236A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPWO2022225033A1 (zh) | 2022-10-27 |
| EP4328236A1 (en) | 2024-02-28 |
| WO2022225033A1 (ja) | 2022-10-27 |
| CN117177988A (zh) | 2023-12-05 |
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