JP2021523117A - 慢性蕁麻疹を処置するための方法および組成物 - Google Patents
慢性蕁麻疹を処置するための方法および組成物 Download PDFInfo
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- 239000000941 radioactive substance Substances 0.000 description 1
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- 239000001632 sodium acetate Substances 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- PXLIDIMHPNPGMH-UHFFFAOYSA-N sodium chromate Chemical compound [Na+].[Na+].[O-][Cr]([O-])(=O)=O PXLIDIMHPNPGMH-UHFFFAOYSA-N 0.000 description 1
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- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
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- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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- 229960001128 triprolidine Drugs 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 101150057627 trxB gene Proteins 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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Images
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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Abstract
Description
本出願は、2018年5月4日に出願された米国仮出願第62/667,242号;2019年1月4日に出願された米国仮出願第62/788,719号;2019年1月28日に出願された米国仮出願第62/797,817号;2019年2月8日に出願された米国仮出願第62/803,211号;および2019年2月15日に出願された米国仮出願第62/806,657号の優先権を主張し、それらの各々は、その全体が本明細書において参考として援用される。
以下のASCIIテキストファイルでの提出の内容は、参照によりその全体が本明細書に組み込まれる:コンピュータ可読形式(CRF)の配列表(ファイル名:7017112000940SEQLIST.TXT、記録日:2019年5月2日、サイズ:123KB)。
本明細書において引用されているすべての参考文献は、特許出願、特許公開、および科学文献を含め、それぞれ個々の参考文献が、具体的かつ個別に参照により組み込まれることが示されているかのように、参照によりその全体が本明細書に組み込まれる。
本開示は、特定の組成物または生物学的系に制限されるものではなく、当然ながら、変動し得ることを理解されたい。本明細書において使用される用語は、特定の実施形態を説明する目的のものにすぎず、限定することを意図するものではないこともまた、理解されたい。本明細書および添付の特許請求の範囲において使用されるとき、単数形の「1つの(a)」、「1つの(an)」、および「その(the)」は、内容により別途明確に指示されない限り、複数形の参照物を含む。したがって、たとえば、「1つの分子」への言及は、必要に応じて、2つまたはそれを上回るそのような分子の組合せなども含む。
100を分数X/Yに乗じる
ここで、Xは、配列によるそのプログラムでのAとBとのアラインメントにおいて、同一なマッチとしてスコア付けされたアミノ酸残基の数であり、Yは、Bにおけるアミノ酸残基の総数である。アミノ酸配列Aの長さが、アミノ酸配列Bの長さと等しくない場合には、AのBに対するアミノ酸配列同一性%は、BのAに対するアミノ酸配列同一性%と等しくないことが、理解される。
)に開示されているものなどの動物モデルにおいて、評価することができる。ADCC活性および他の抗体特性を変化させる他のFcバリアントとしては、Ghetieら、Nat Biotech.、15巻:637〜40頁、1997年;Duncanら、Nature、332巻:563〜564頁、1988年;Lundら、J. Immunol、147巻:2657〜2662頁、1991年;Lundら、Mol Immunol、29巻:53〜59頁、1992年;Alegreら、Transplantation、57巻:1537〜1543頁、1994年;Hutchinsら、Proc Natl. Acad Sci USA、92巻:11980〜11984頁、1995年;Jefferisら、Immunol Lett.、44巻:111〜117頁、1995年;Lundら、FASEB J、9巻:115〜119頁、1995年;Jefferisら、Immunol Lett、54巻:101〜104頁、1996年;Lundら、J Immunol、157巻:4963〜4969頁、1996年;Armourら、Eur J Immunol、29巻:2613〜2624頁、1999年;Idusogieら、J Immunol、164巻:4178〜4184頁、200;Reddyら、J Immunol、164巻:1925〜1933頁、2000年;Xuら、Cell Immunol、200巻:16〜26頁、2000年;Idusogieら、J Immunol、166巻:2571〜2575頁、2001年;Shieldsら、J Biol Chem、276巻:6591〜6604頁、2001年;Jefferisら、Immunol Lett、82巻:57〜65頁、2002年;Prestaら、Biochem Soc Trans、30巻:487〜490頁、2002年;Lazarら、Proc. Natl. Acad. Sci. USA、103巻:4005〜4010頁、2006年;米国特許第5,624,821号、同第5,885,573号、同第5,677,425号、同第6,165,745号、同第6,277,375号、同第5,869,046号、同第6,121,022号、同第5,624,821号、同第5,648,260号、同第6,194,551号、同第6,737,056号、同第6,821,505号、同第6,277,375号、同第7,335,742号、および同第7,317,091号によって開示されているものが挙げられる。
II.方法
重鎖
EVQLVESGGGLVQPGGSLRLSCAVSGYSITSGYSWNWIRQAPGKGLEWVASITYDGSTNYADSVKGRFTISRDDSKNTFYLQMNSLRAEDTAVYYCARGSHYFGHWHFAVWGQGTLVTVSSGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号125)
軽鎖
DIQLTQSPSSLSASVGDRVTITCRASQSVDYDGDSYMNWYQQKPGKAPKLLIYAASYLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHEDPYTFGQGTKVEIKRTVAAPSVF
IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR(配列番号126)
VHドメイン
QVQLVQSGAEVMKPGSSVKVSCKASGYTFSWYWLEWVRQAPGHGLEWMGEIDPGTFTTNYNEKFKARVTFTADTSTSTAYMELSSLRSEDTAVYYCARFSHFSGSNYDYFDYWGQGTLVTVSS(配列番号127)
VLドメイン
EIVMTQSPATLSVSPGERATLSCRASQSIGTNIHWYQQKPGQAPRLLIYYASESISGIPA
RFSGSGSGTEFTLTISSLQSEDFAVYYCQQSWSWPTTFGGGTKVEIK(配列番号128)
A.慢性蕁麻疹
B.処置に対する応答
C.投与
D.抗体
a)HVR−H1(IYGAH(配列番号61));
b)HVR−H2(VIWAGGSTNYNSALMS(配列番号62));および
c)HVR−H3(DGSSPYYYSMEY(配列番号63);DGSSPYYYGMEY(配列番号67);DGSSPYYYSMDY(配列番号68);DGSSPYYYSMEV(配列番号69);またはDGSSPYYYGMDV(配列番号70))
a)HVR−H1(SYAMS(配列番号88);DYYMY(配列番号89);またはSSWMN(配列番号90));
b)HVR−H2(IISSGGSYTYYSDSVKG(配列番号91);RIAPEDGDTEYAPKFQG(配列番号92);またはQIYPGDDYTNYNGKFKG(配列番号93));およびc)HVR−H3(HETAQAAWFAY(配列番号94);EGNYYGSSILDY(配列番号95);またはLGPYGPFAD(配列番号96))
a)HC−FR1(EVQLVESGGGLVQPGGSLRLSCAASGFSLT(配列番号26);EVQLVESGGGLVQPGGSLRLSCAVSGFSLT(配列番号27);QVQLQESGPGLVKPSETLSLTCTVSGGSIS(配列番号28);またはQVQLQESGPGLVKPSETLSLTCTVSGFSLT(配列番号29));
b)HC−FR2(WVRQAPGKGLEWVS(配列番号31);WVRQAPGKGLEWLG(配列番号32);WVRQAPGKGLEWLS(配列番号33);WVRQAPGKGLEWVG(配列番号34);WIRQPPGKGLEWIG(配列番号35);またはWVRQPPGKGLEWLG(配列番号36));
c)HC−FR3(RFTISKDNSKNTVYLQMNSLRAEDTAVYYCAR(配列番号38);RLSISKDNSKNTVYLQMNSLRAEDTAVYYCAR(配列番号39);RLTISKDNSKNTVYLQMNSLRAEDTAVYYCAR(配列番号40);RFSISKDNSKNTVYLQMNSLRAEDTAVYYCAR(配列番号41);RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR(配列番号42);またはRLSISKDNSKNQVSLKLSSVTAADTAVYYCAR(配列番号43));および
d)HC−FR4(WGQGTTVTVSS(配列番号45);またはWGQGTLVTVSS(配列番号46))
a)HVR−L1(SATSSVSYMH(配列番号64));
b)HVR−L2(STSNLAS(配列番号65));および
c)HVR−L3(QQRSSYPFT(配列番号66);またはQQRSSYPYT(配列番号71))
a)HVR−L1(SASSSVSYMH(配列番号97);RASQDITNYLN(配列番号98);またはSASSSVSYMY(配列番号99));
b)HVR−L2(DTSKLAY(配列番号100);FTSRLHS(配列番号101);またはDTSSLAS(配列番号102));および
c)HVR−L3(QQWSSNPPT(配列番号103);QQGNTLPWT(配列番号104);またはQQWNSDPYT(配列番号105))
(i)配列番号88のアミノ酸配列を含むHVR−H1、(ii)配列番号91のアミノ酸配列を含むHVR−H2、および(iii)配列番号94のアミノ酸配列を含むHVR−H3を含む、重鎖可変領域、ならびに/もしくは(i)配列番号97のアミノ酸配列を含むHVR−L1、(ii)配列番号100のアミノ酸配列を含むHVR−L2、および(iii)配列番号103のアミノ酸配列を含むHVR−L3を含む、軽鎖可変領域、
(i)配列番号89のアミノ酸配列を含むHVR−H1、(ii)配列番号92のアミノ酸配列を含むHVR−H2、および(iii)配列番号95のアミノ酸配列を含むHVR−H3を含む、重鎖可変領域、ならびに/もしくは(i)配列番号98のアミノ酸配列を含むHVR−L1、(ii)配列番号101のアミノ酸配列を含むHVR−L2、および(iii)配列番号104のアミノ酸配列を含むHVR−L3を含む、軽鎖可変領域、または
(i)配列番号90のアミノ酸配列を含むHVR−H1、(ii)配列番号93のアミノ酸配列を含むHVR−H2、および(iii)配列番号96のアミノ酸配列を含むHVR−H3を含む、重鎖可変領域、ならびに/もしくは(i)配列番号99のアミノ酸配列を含むHVR−L1、(ii)配列番号102のアミノ酸配列を含むHVR−L2、および(iii)配列番号105のアミノ酸配列を含むHVR−L3を含む、軽鎖可変領域
を含む。
a)LC−FR1(EIVLTQSPATLSLSPGERATLSC(配列番号48);またはEIILTQSPATLSLSPGERATLSC(配列番号49));
b)LC−FR2(WFQQKPGQAPRLLIY(配列番号51);WFQQKPGQAPRLWIY(配列番号52);またはWYQQKPGQAPRLLIY(配列番号53));
c)LC−FR3(GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC(配列番号55);GVPARFSGSGSGTDYTLTISSLEPEDFAVYYC(配列番号56);GVPARFSGSGSGTDFTLTISSLEPEDFAVYYC(配列番号57);またはGIPARFSGSGSGTDYTLTISSLEPEDFAVYYC(配列番号58));および
d)LC−FR4(FGPGTKLDIK(配列番号60))
(a)重鎖可変ドメインであって、
(1)配列番号26〜29から選択されるアミノ酸配列を含むHC−FR1、
(2)配列番号61のアミノ酸配列を含むHVR−H1、
(3)配列番号31〜36から選択されるアミノ酸配列を含むHC−FR2、
(4)配列番号62のアミノ酸配列を含むHVR−H2、
(5)配列番号38〜43から選択されるアミノ酸配列を含むHC−FR3、
(6)配列番号63のアミノ酸配列を含むHVR−H3、および
(7)配列番号45〜46から選択されるアミノ酸配列を含むHC−FR4を含む、重鎖可変ドメイン、
ならびに/または
(b)軽鎖可変ドメインであって、
(1)配列番号48〜49から選択されるアミノ酸配列を含むLC−FR1、
(2)配列番号64のアミノ酸配列を含むHVR−L1、
(3)配列番号51〜53から選択されるアミノ酸配列を含むLC−FR2、
(4)配列番号65のアミノ酸配列を含むHVR−L2、
(5)配列番号55〜58から選択されるアミノ酸配列を含むLC−FR3、
(6)配列番号66のアミノ酸配列を含むHVR−L3、および
(7)配列番号60のアミノ酸配列を含むLC−FR4を含む、軽鎖可変ドメイン
を含む。
1.抗体の親和性
2.抗体のアビディティー
3.競合アッセイ
4.熱安定性
5.生物学的活性のアッセイ
E.抗体の調製
1.抗体断片
2.ヒト化抗体
3.ヒト抗体
4.二重特異性抗体
5.単一ドメイン抗体
6.抗体バリアント
(1)非極性:Ala(A)、Val(V)、Leu(L)、Ile(I)、Pro(P)、Phe(F)、Trp(W)、Met(M)
(2)非荷電極性:Gly(G)、Ser(S)、Thr(T)、Cys(C)、Tyr(Y)、Asn(N)、Gln(Q)
(3)酸性:Asp(D)、Glu(E)(4)塩基性:Lys(K)、Arg(R)、His(H)
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile
(2)中性親水性:Cys、Ser、Thr、Asn、Gln
(3)酸性:Asp、Glu
(4)塩基性:His、Lys、Arg
(5)鎖の配向に影響を及ぼす残基:Gly、Pro
(6)芳香族:Trp、Tyr、Phe。
7.ベクター、宿主細胞、および組換え方法
原核生物宿主細胞を使用した抗体の生成
a)ベクターの構築
b)抗体の産生
c)抗体の精製
真核生物宿主細胞を使用した抗体の生成
a)シグナル配列成分
b)複製起点
c)選択遺伝子成分
d)プロモーター成分
e)エンハンサーエレメント成分
f)転写終結成分
g)宿主細胞の選択および形質転換
h)宿主細胞の培養
i)抗体の精製
フコシル化されていない抗体の産生
III.組成物
IV.製品またはキット
(実施例1)
抗ヒスタミン剤抵抗性慢性蕁麻疹を有する患者における、抗Siglec−8抗体処置の有効性および安全性を評価するための非盲検パイロット研究の構造
(a)年齢(18歳以上かつ85歳以下);
(b)185kg未満または125kg未満の体重;
(c)単回または4倍投与量での抗ヒスタミン剤処置に対して不応性の、少なくとも3ヶ月間にわたる慢性蕁麻疹の診断;
(d)登録時の制御されない慢性蕁麻疹(UCT<12);および
(e)妊娠検査が陰性であること(女性)。
(a)急性蕁麻疹;
(b)ベースラインの前4週間または5半減期(5 half-lives)のいずれか長い方以内の、免疫抑制薬(たとえば、シクロスポリン、メトトレキサート、ダプソンなど)による併用/進行中の処置;
(c)患者を免疫不全状態にする、有意な医学的状態;
(d)直近の3ヶ月以内、または直近の2ヶ月以内のオマリズマブの使用;
(e)ベースラインの前30日間に静脈内IgG療法を受けたこと;
(f)ベースラインの前30日間のプラスマフェレーシス;
(g)ベースラインの前14日間のドキセピンの使用(毎日または一日おき);
(h)ベースラインの前30日間に不活性または弱毒生ワクチンを受けたこと;
(i)ベースラインの前7日間のH2抗ヒスタミン剤の使用;
(j)登録の前7日以内のロイコトリエンアンタゴニストの摂取;
(k)登録の前14日以内の全身的コルチコステロイド(たとえば、経口またはデポー)の摂取;
(l)ベースライン時の卵および寄生虫をスクリーニングする検査で陽性であること;
(m)陽性のHIV血清学;
(n)スクリーニングの6ヶ月以内の駆虫性寄生虫の処置;
(o)ワクチン接種した患者または過去に肝炎を有したが消散した患者を除き、ベースラインにおける陽性の肝炎血清学;および
(p)研究薬物の投与の前56日以内の>500mLの血液の供血もしくは喪失、または薬物の投与の前7日以内の血漿供血。
(a)連続する7日間にわたって合計した自己報告型の自己評価スコア(UAS7)に基づく蕁麻疹活動性スコア(UAS)によって評価される、疾患活動性における変化;
(b)連続する7日間にわたって合計した自己報告型の自己評価スコア(CholUAS7)に基づくコリン性蕁麻疹活動性スコア(CholUAS)によって評価される、疾患活動性における変化;
(c)患者の日記ベースのスコアによって評価される、1週間当たりの無症状の日数における変化;
(d)皮膚科学生活の質インデックス(DLQI)、慢性蕁麻疹生活の質アンケート(CU−Q2oL)、血管性浮腫生活の質アンケート(AE−QoL)、SD−QoL、またはコリン性蕁麻疹生活の質アンケート(CholU−QoL)によって評価される、生活の質スコアにおける変化;
(e)血管性浮腫活動性スコア(AAS)によって評価される、血管性浮腫(存在する場合)の発症における変化;
(f)じんま疹の数における変化(UAS7/ChoUAS7から);
(g)そう痒重症度における変化(UAS7/ChoUAS7から);
(h)患者または医師の包括的評価における変化;
(i)パルス制御エルゴメトリー試験(PCE)、FricTest(登録商標)、またはTempTest(登録商標)によって評価される、トリガー閾値における変化;
(j)QoL、UCT、またはUAS7/CholUAS7に基づく、完全奏効(CR)率、部分奏効(PR)率、および無奏効(NR)率;
(k)トリプターゼ、好酸球、総IgE、好塩基球、および好酸球カチオン性タンパク質を含む、バイオマーカーのベースラインにおける血清レベル、および血清レベルの変化;および
(l)再燃、リバウンド、または持続性の処置効果を有する、処置された患者の比率。
(実施例2)
抗ヒスタミン剤処置に対して不適切な応答を有する抗IgEナイーブ患者における、慢性蕁麻疹に対する抗Siglec−8抗体処置の効果
UCT部分奏効は、ベースラインからの3ポイントよりも大きい改善として定義した。
UCT部分奏効は、12未満であるが、ベースラインからの3ポイントよりも大きい改善として定義した。
(実施例3)
その症状が抗ヒスタミン剤処置によって適切に制御されていない、コリン性および症候性皮膚描記症を有する患者における、抗Siglec−8抗体処置の効果
(実施例4)
Xolair不応性慢性特発性蕁麻疹を有する患者における、抗Siglec−8抗体処置の効果
(実施例5)
制御されない慢性蕁麻疹を有する患者における抗Siglec−8抗体処置の効果についての、非盲検第2相研究からの追加のデータ
Claims (83)
- 個体における慢性蕁麻疹を処置するための方法であって、前記個体に、有効量の、ヒトSiglec−8に結合する抗体を含む組成物を投与するステップを含み、前記組成物の投与前に、H1−抗ヒスタミン剤による処置にもかかわらず、前記個体における前記蕁麻疹が適切に制御されていない、または蕁麻疹症状が残存する、方法。
- 前記個体が、抗IgE抗体による処置に対して不適切な応答を示している、または前記慢性蕁麻疹が、抗IgE抗体による処置によって不適切に制御されている、請求項1に記載の方法。
- 前記組成物の投与前に、前記個体が抗IgE抗体ナイーブである、請求項1に記載の方法。
- 前記抗IgE抗体が、オマリズマブまたはリゲリズマブである、請求項2または請求項3に記載の方法。
- 個体における慢性蕁麻疹を処置するための方法であって、前記個体に、有効量の、ヒトSiglec−8に結合する抗体を含む組成物を投与するステップを含み、前記組成物の投与前に、前記個体が、抗IgE抗体による処置に対して不適切な応答を示している、または前記個体における前記蕁麻疹が、抗IgE抗体による処置によって不適切に制御されている、方法。
- 前記抗IgE抗体が、オマリズマブまたはリゲリズマブである、請求項5に記載の方法。
- 前記組成物の投与前に、前記個体における前記蕁麻疹が、H1−抗ヒスタミン剤による処置にもかかわらず制御されない、請求項5または請求項6に記載の方法。
- 前記組成物の投与前に、前記個体における前記蕁麻疹が、ラベル投与量または4倍ラベル投与量でのH1−抗ヒスタミン剤による処置にもかかわらず制御されない、請求項1から4および7のいずれか一項に記載の方法。
- 前記組成物の投与前に、前記個体における前記蕁麻疹が、最大4倍ラベル投与量でのH1−抗ヒスタミン剤による処置にもかかわらず制御されない、請求項1から4および7のいずれか一項に記載の方法。
- 前記慢性蕁麻疹が、慢性コリン性蕁麻疹、皮膚描記性蕁麻疹、寒冷蕁麻疹、振動蕁麻疹、自己免疫性蕁麻疹、特発性(spontaneous)蕁麻疹、または特発性(idiopathic)蕁麻疹である、請求項1から9のいずれか一項に記載の方法。
- 前記慢性蕁麻疹が、慢性自己免疫性蕁麻疹であり、前記個体が、前記組成物の投与前に、以下の検査:好塩基球ヒスタミン放出アッセイ(BHRA)、好塩基球活性化マーカー発現、自己血清皮膚検査(ASST)、ならびにIgEおよび/またはFceRIに対するIgG自己抗体についてのイムノアッセイのうち1つまたは複数において陽性の結果を示している、請求項1から10のいずれか一項に記載の方法。
- 前記個体が、前記組成物の投与前に、12未満のUCTスコアを示している、請求項1から11のいずれか一項に記載の方法。
- 慢性蕁麻疹を有する前記個体における1つまたは複数の症状が、前記組成物の投与前のベースラインレベルと比較して、前記組成物の投与後に低減する、請求項1から12のいずれか一項に記載の方法。
- 自己評価された疾患活動性が、前記組成物の投与前のベースラインレベルと比較して、低減する、請求項13に記載の方法。
- 自己評価された疾患活動性が、以下の測定基準:UCT、UAS7、およびCholUAS7のうち1つまたは複数によって評価される、請求項14に記載の方法。
- 自己評価された生活の質スコアが、前記組成物の投与前のベースラインレベルと比較して改善される、請求項13に記載の方法。
- 自己評価された生活の質スコアが、以下の測定基準:DLQI、CU−Q2oL、AE−QoL、SD−QoL、およびCholU−QoLのうち1つまたは複数によって評価される、請求項16に記載の方法。
- 血管性浮腫の発症、じんま疹の数、およびそう痒重症度のうち1つまたは複数が、前記組成物の投与前のベースラインレベルと比較して、低減する、請求項13に記載の方法。
- 1週間当たりの無症状の日数およびトリガー閾値のうち1つまたは複数が、前記組成物の投与前のベースラインレベルと比較して、増加する、請求項13に記載の方法。
- 前記個体由来の血清試料中の好酸球の数、総IgE、トリプターゼの発現、好酸球カチオン性タンパク質の発現、および/または好塩基球の数が、前記組成物の投与前に前記個体から得られた血清試料中のベースラインレベルと比較して低減する、請求項1から19のいずれか一項に記載の方法。
- 前記組成物の投与が、処置に対して持続性の応答を生じる、請求項1から20のいずれか一項に記載の方法。
- 前記組成物の投与が、処置の10週間後に12またはそれよりも大きいUCTスコアを生じる、請求項1から20のいずれか一項に記載の方法。
- 前記組成物の投与が、処置の22週間後に12またはそれよりも大きいUCTスコアを生じる、請求項1から20のいずれか一項に記載の方法。
- 前記組成物の投与が、UAS7スコアにおける10よりも大きい減少を生じる、請求項1から20のいずれか一項に記載の方法。
- 前記組成物が、静脈内注入によって投与される、請求項1から24のいずれか一項に記載の方法。
- 前記組成物が、3ヶ月間またはそれよりも長い期間にわたって1ヶ月に1回、静脈内注入によって投与される、請求項25に記載の方法。
- 前記組成物が、皮下注射によって投与される、請求項1から24のいずれか一項に記載の方法。
- 前記組成物が、約0.3mg/kgから約3.0mg/kgの間の前記抗体を含む1つまたは複数の用量で、静脈内注入によって投与される、請求項1から24のいずれか一項に記載の方法。
- 約0.3mg/kgから約3.0mg/kgの間の前記抗体を含む2つまたはそれよりも多くの用量が、約28日間、約4週間、または毎月の間隔で、前記個体に投与される、請求項28に記載の方法。
- 前記個体に、約0.3mg/kgの前記抗体を含む第1の用量、約1.0mg/kgの前記抗体を含む第2の用量、約1.0mg/kgの前記抗体を含む第3の用量、約1.0mg/kg〜約3.0mg/kgの前記抗体を含む第4の用量、約1.0mg/kg〜約3.0mg/kgの前記抗体を含む第5の用量、および約1.0mg/kg〜約3.0mg/kgの前記抗体を含む第6の用量を投与するステップを含む、請求項28または29に記載の方法。
- 前記第1の用量が1日目に投与され、前記第2の用量が29日目に投与され、前記第3の用量が57日目に投与され、前記第4の用量が85日目に投与され、前記第5の用量が113日目に投与され、前記第6の用量が141日目に投与される、請求項30に記載の方法。
- 前記抗体が、Fc領域と、前記Fc領域に連結されたN−グリコシド結合型炭水化物鎖とを含み、前記組成物中の前記抗体の前記N−グリコシド結合型炭水化物鎖のうちの50%未満が、フコース残基を含む、請求項1から31のいずれか一項に記載の方法。
- 前記組成物中の前記抗体の前記N−グリコシド結合型炭水化物鎖のうちの実質的にすべてが、フコース残基を含まない、請求項32に記載の方法。
- 前記抗体が、重鎖可変領域および軽鎖可変領域を含み、前記重鎖可変領域が、(i)配列番号61のアミノ酸配列を含むHVR−H1、(ii)配列番号62のアミノ酸配列を含むHVR−H2、および(iii)配列番号63のアミノ酸配列を含むHVR−H3を含み、かつ/または前記軽鎖可変領域が、(i)配列番号64のアミノ酸配列を含むHVR−L1、(ii)配列番号65のアミノ酸配列を含むHVR−L2、および(iii)配列番号66のアミノ酸配列を含むHVR−L3を含む、請求項1から33のいずれか一項に記載の方法。
- 前記抗体が、重鎖可変領域および軽鎖可変領域を含み、前記重鎖可変領域が、(i)配列番号61のアミノ酸配列を含むHVR−H1、(ii)配列番号62のアミノ酸配列を含むHVR−H2、および(iii)配列番号67〜70から選択されるアミノ酸配列を含むHVR−H3を含み、かつ/または前記軽鎖可変領域が、(i)配列番号64のアミノ酸配列を含むHVR−L1、(ii)配列番号65のアミノ酸配列を含むHVR−L2、および(iii)配列番号71のアミノ酸配列を含むHVR−L3を含む、請求項1から33のいずれか一項に記載の方法。
- 前記抗体が、配列番号6のアミノ酸配列を含む重鎖可変領域、および/または配列番号16もしくは21から選択されるアミノ酸配列を含む軽鎖可変領域を含む、請求項1から33のいずれか一項に記載の方法。
- 前記抗体が、配列番号11〜14から選択されるアミノ酸配列を含む重鎖可変領域、および/または配列番号23〜24から選択されるアミノ酸配列を含む軽鎖可変領域を含む、請求項1から33のいずれか一項に記載の方法。
- 前記抗体が、配列番号2〜14から選択されるアミノ酸配列を含む重鎖可変領域、および/または配列番号16〜24から選択されるアミノ酸配列を含む軽鎖可変領域を含む、請求項1から33のいずれか一項に記載の方法。
- 前記抗体が、配列番号2〜10から選択されるアミノ酸配列を含む重鎖可変領域;および/または配列番号16〜22から選択されるアミノ酸配列を含む軽鎖可変領域を含む、請求項1から33のいずれか一項に記載の方法。
- 前記抗体が、
(a)(1)配列番号26〜29から選択されるアミノ酸配列を含むHC−FR1、
(2)配列番号61のアミノ酸配列を含むHVR−H1、
(3)配列番号31〜36から選択されるアミノ酸配列を含むHC−FR2、
(4)配列番号62のアミノ酸配列を含むHVR−H2、
(5)配列番号38〜43から選択されるアミノ酸配列を含むHC−FR3、
(6)配列番号63のアミノ酸配列を含むHVR−H3、および
(7)配列番号45〜46から選択されるアミノ酸配列を含むHC−FR4を含む、重鎖可変領域、ならびに/または
(b)(1)配列番号48〜49から選択されるアミノ酸配列を含むLC−FR1、
(2)配列番号64のアミノ酸配列を含むHVR−L1、(3)配列番号51〜53から選択されるアミノ酸配列を含むLC−FR2、
(4)配列番号65のアミノ酸配列を含むHVR−L2、
(5)配列番号55〜58から選択されるアミノ酸配列を含むLC−FR3、
(6)配列番号66のアミノ酸配列を含むHVR−L3、および
(7)配列番号60のアミノ酸配列を含むLC−FR4を含む、軽鎖可変領域
を含む、請求項1から33のいずれか一項に記載の方法。 - 前記抗体が、
(a)(1)配列番号26のアミノ酸配列を含むHC−FR1、
(2)配列番号61のアミノ酸配列を含むHVR−H1、
(3)配列番号34のアミノ酸配列を含むHC−FR2、
(4)配列番号62のアミノ酸配列を含むHVR−H2、
(5)配列番号38のアミノ酸配列を含むHC−FR3、
(6)配列番号63のアミノ酸配列を含むHVR−H3、および
(7)配列番号45のアミノ酸配列を含むHC−FR4を含む、重鎖可変領域、ならびに/または
(b)(1)配列番号48のアミノ酸配列を含むLC−FR1、
(2)配列番号64のアミノ酸配列を含むHVR−L1、
(3)配列番号51のアミノ酸配列を含むLC−FR2、
(4)配列番号65のアミノ酸配列を含むHVR−L2、
(5)配列番号55のアミノ酸配列を含むLC−FR3、
(6)配列番号66のアミノ酸配列を含むHVR−L3、および
(7)配列番号60のアミノ酸配列を含むLC−FR4を含む、軽鎖可変領域
を含む、請求項1から33のいずれか一項に記載の方法。 - 前記抗体が、
(a)(1)配列番号26のアミノ酸配列を含むHC−FR1、
(2)配列番号61のアミノ酸配列を含むHVR−H1、
(3)配列番号34のアミノ酸配列を含むHC−FR2、
(4)配列番号62のアミノ酸配列を含むHVR−H2、
(5)配列番号38のアミノ酸配列を含むHC−FR3、
(6)配列番号63のアミノ酸配列を含むHVR−H3、および
(7)配列番号45のアミノ酸配列を含むHC−FR4を含む、重鎖可変領域、ならびに/または
(b)(1)配列番号48のアミノ酸配列を含むLC−FR1、
(2)配列番号64のアミノ酸配列を含むHVR−L1、
(3)配列番号51のアミノ酸配列を含むLC−FR2、
(4)配列番号65のアミノ酸配列を含むHVR−L2、
(5)配列番号58のアミノ酸配列を含むLC−FR3、
(6)配列番号66のアミノ酸配列を含むHVR−L3、および
(7)配列番号60のアミノ酸配列を含むLC−FR4を含む、軽鎖可変領域
を含む、請求項1から33のいずれか一項に記載の方法。 - 前記抗体が、
(i)配列番号88のアミノ酸配列を含むHVR−H1、(ii)配列番号91のアミノ酸配列を含むHVR−H2、および(iii)配列番号94のアミノ酸配列を含むHVR−H3を含む、重鎖可変領域、ならびに/もしくは(i)配列番号97のアミノ酸配列を含むHVR−L1、(ii)配列番号100のアミノ酸配列を含むHVR−L2、および(iii)配列番号103のアミノ酸配列を含むHVR−L3を含む、軽鎖可変領域、
(i)配列番号89のアミノ酸配列を含むHVR−H1、(ii)配列番号92のアミノ酸配列を含むHVR−H2、および(iii)配列番号95のアミノ酸配列を含むHVR−H3を含む、重鎖可変領域、ならびに/もしくは(i)配列番号98のアミノ酸配列を含むHVR−L1、(ii)配列番号101のアミノ酸配列を含むHVR−L2、および(iii)配列番号104のアミノ酸配列を含むHVR−L3を含む、軽鎖可変領域、または
(i)配列番号90のアミノ酸配列を含むHVR−H1、(ii)配列番号93のアミノ酸配列を含むHVR−H2、および(iii)配列番号96のアミノ酸配列を含むHVR−H3を含む、重鎖可変領域、ならびに/もしくは(i)配列番号99のアミノ酸配列を含むHVR−L1、(ii)配列番号102のアミノ酸配列を含むHVR−L2、および(iii)配列番号105のアミノ酸配列を含むHVR−L3を含む、軽鎖可変領域
を含む、請求項1から33のいずれか一項に記載の方法。 - 前記抗体が、
配列番号106のアミノ酸配列を含む重鎖可変領域、および/もしくは配列番号109のアミノ酸配列を含む軽鎖可変領域、
配列番号107のアミノ酸配列を含む重鎖可変領域、および/もしくは配列番号110のアミノ酸配列を含む軽鎖可変領域、または
配列番号108のアミノ酸配列を含む重鎖可変領域、および/もしくは配列番号111のアミノ酸配列を含む軽鎖可変領域
を含む、請求項1から33のいずれか一項に記載の方法。 - 前記抗体が、ヒトSiglec−8および非ヒト霊長類Siglec−8に結合する、請求項1から33のいずれか一項に記載の方法。
- 前記非ヒト霊長類が、ヒヒである、請求項45に記載の方法。
- 前記抗体が、ヒトSiglec−8のドメイン1内のエピトープに結合し、ドメイン1が、配列番号112のアミノ酸配列を含む、請求項45に記載の方法。
- 前記抗体が、ヒトSiglec−8のドメイン3内のエピトープに結合し、ドメイン3が、配列番号114のアミノ酸配列を含む、請求項45に記載の方法。
- 前記抗体が、抗体4F11と同じエピトープに結合する、請求項45に記載の方法。
- 前記抗体が、ヒトSiglec−8のドメイン2またはドメイン3内のエピトープに結合する、請求項1から33のいずれか一項に記載の方法。
- ドメイン2が、配列番号113のアミノ酸配列を含む、請求項50に記載の方法。
- 前記抗体が、抗体1C3と同じエピトープに結合する、請求項50に記載の方法。
- ドメイン3が、配列番号114のアミノ酸配列を含む、請求項50に記載の方法。
- 前記抗体が、抗体1H10と同じエピトープに結合する、請求項50に記載の方法。
- 前記抗体が、ヒトSiglec−8のドメイン1内のエピトープに結合し、Siglec−8への結合について、抗体4F11と競合する、請求項1から33のいずれか一項に記載の方法。
- 前記抗体が、Siglec−8への結合について、抗体2E2と競合しない、請求項55に記載の方法。
- 前記抗体が、抗体2E2ではない、請求項56に記載の方法。
- ドメイン1が、配列番号112のアミノ酸配列を含む、請求項55に記載の方法。
- 前記抗体が、ヒト抗体、ヒト化抗体、またはキメラ抗体である、請求項34から58のいずれか一項に記載の方法。
- 前記抗体が、血中好酸球を枯渇させ、マスト細胞の活性化を阻害する、請求項34から59のいずれか一項に記載の方法。
- 前記抗体が、ヒトIgG Fc領域を含む重鎖Fc領域を含む、請求項1から60のいずれか一項に記載の方法。
- 前記ヒトIgG Fc領域が、ヒトIgG1 Fc領域を含む、請求項61に記載の方法。
- 前記ヒトIgG1 Fc領域が、フコシル化されていないか、またはフコシル化が低減されている、請求項62に記載の方法。
- 前記ヒトIgG Fc領域が、ヒトIgG4 Fc領域を含む、請求項61に記載の方法。
- 前記ヒトIgG4 Fc領域が、アミノ酸置換S228Pを含み、アミノ酸残基が、KabatにおけるようにEUインデックスに従って番号付けされている、請求項64に記載の方法。
- 前記抗体が、抗体依存性細胞媒介性細胞傷害(ADCC)活性を向上させるように操作されている、請求項1から58のいずれか一項に記載の方法。
- 前記抗体が、前記Fc領域に、ADCC活性を向上させる少なくとも1つのアミノ酸置換を含む、請求項66に記載の方法。
- 前記抗体の前記重鎖のうちの少なくとも1つまたは2つが、フコシル化されていない、請求項1から60のいずれか一項に記載の方法。
- 前記抗体が、配列番号75のアミノ酸配列を含む重鎖、および/または配列番号76もしくは77から選択されるアミノ酸配列を含む軽鎖を含む、請求項1から33のいずれか一項に記載の方法。
- 前記抗体が、モノクローナル抗体である、請求項1から69のいずれか一項に記載の方法。
- 前記組成物が、慢性蕁麻疹を処置または予防するための1つまたは複数の追加の治療剤と組み合わせて投与される、請求項1から70のいずれか一項に記載の方法。
- 慢性蕁麻疹を処置または予防するための前記1つまたは複数の追加の治療剤が、H−2受容体アンタゴニスト、H1−抗ヒスタミン剤、H2−抗ヒスタミン剤、抗IgE抗体、コルチコステロイド、ドキセピン、ロイコトリエン受容体アンタゴニスト(LTRA)、シクロスポリン、およびタクロリムスからなる群から選択される、請求項71に記載の方法。
- 前記個体がヒトである、請求項1から72のいずれか一項に記載の方法。
- 前記処置が、前記組成物の単回投与後に、前記個体において完全奏効を生じる、請求項1から73のいずれか一項に記載の方法。
- 前記処置が、処置前の前記個体におけるUCTスコアと比較して、前記個体においてUCTスコアにおける少なくとも3ポイントの改善を生じる、請求項1から73のいずれか一項に記載の方法。
- 前記処置が、処置前の前記個体におけるUAS7スコアと比較して、前記個体においてUAS7スコアにおける少なくとも50%の低減を生じる、請求項1から73のいずれか一項に記載の方法。
- 前記処置が、処置前の前記個体におけるUAS7スコアと比較して、前記個体においてUAS7スコアにおける少なくとも10の低減を生じる、請求項1から73のいずれか一項に記載の方法。
- 前記組成物が、前記抗体および薬学的に許容される担体を含む、請求項1から77のいずれか一項に記載の方法。
- ヒトSiglec−8に結合する抗体を含む組成物を含む医薬と、請求項1から78のいずれか一項に記載の、前記医薬の投与を必要とする個体における前記医薬の投与のための指示を含む添付文書とを含む、製品。
- 請求項1から78のいずれか一項に記載の個体における慢性蕁麻疹を処置する方法における使用のための、ヒトSiglec−8に結合する抗体を含む組成物。
- 前記抗体が、配列番号6のアミノ酸配列を含む重鎖可変領域;および/または配列番号16もしくは21から選択されるアミノ酸配列を含む軽鎖可変領域を含む、請求項80に記載の使用のための組成物。
- 前記抗体が、配列番号75のアミノ酸配列を含む重鎖;および/または配列番号76もしくは77から選択されるアミノ酸配列を含む軽鎖を含む、請求項80に記載の使用のための組成物。
- 前記抗体の前記重鎖のうちの少なくとも1つまたは2つがフコシル化されていない、請求項80から82のいずれか一項に記載の使用のための組成物。
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CN112384535A (zh) | 2021-02-19 |
AU2019262167A1 (en) | 2020-12-10 |
EP3788078A4 (en) | 2022-03-02 |
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