JP2023532266A - 抗cd38抗体及びその使用 - Google Patents
抗cd38抗体及びその使用 Download PDFInfo
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Abstract
Description
本願は、2020年06月23日に米国特許庁に出願された米国仮出願US63042773の優先権を主張し、その全内容は参照により本願に組み込まれる。
CD38の細胞外ドメインは、ADP-リボシルシクラーゼ及びADP-リボシルヒドロラーゼの活性という二機能性酵素活性を有することが知られている。従って、CD38は、NADのcADPRへの変換(シクラーゼ)を触媒し、さらにそれを加水分解させてADP-リボース(ヒドロラーゼ)にすることができる。cADPRは、細胞増殖、分化及びアポトーシスに重要なセカンドメッセンジャー活性を有する胞内貯蔵からのカルシウムの動員に関与している。
本発明は、本明細書に記載されている治療用及び/又は診断用抗体と一般に呼ばれる抗CD38抗体を提供する。本発明で使用される抗体は、以下に記載される従来の抗体及びその抗原結合能力を保持する抗体変異体、誘導体、断片及び類似体を含む、本明細書に記載されている様々な形態をとることができる。基本的には、本発明は、本明細書で定義されるような6つのCDRセット(下記の少量のアミノ酸変化を含む)を含む抗体構造を提供する。
いくつかの実施形態においては、抗体は、異なる種からの混合物であってもよく、例としては、キメラ抗体及び/又はヒト化抗体が挙げられる。つまり、本発明においては、CDRセットは、本明細書の配列で具体的に表されるもの以外のフレームワーク領域及び定常領域と共に使用することができる。
また、本発明は、抗体の変異体を提供する。つまり、本発明に係る抗体に対して様々修飾を行うことができる。これらの修飾としては、特に限られないが、例えば、CDRにおけるアミノ酸修飾(親和性成熟)、Fc領域におけるアミノ酸修飾、グリコシル化変異体、他のタイプの共有結合修飾が挙げられる。
別種の共有結合修飾としては、グリコシル化の改変がある。別の実施形態では、本明細書に開示される抗体は、1つまたは複数の操作されたグリコフォームを含むように修飾されてもよい。本明細書で使用される「操作されたグリコフォーム」とは、抗体に共有結合した糖鎖組成物を意味し、ここで、糖鎖組成物は親抗体と化学的に異なる。操作されたグリコフォームは、エフェクター機能の増強又は低減を含むがこれらに限定されない様々な目的に使用することができる。操作されたグリコフォームの好ましい形態としては、脱フコシル化のものがあり、ADCC機能の増加に関連することが示されており、FcγRIIIa受容体へのより緊密な結合により実現されると推測されている。このように、「脱フコシル化」とは、宿主細胞で産生される抗体の大半が実質的にフコースを含まないことを意味し、例えば、産生した抗体の90-95-98%は、抗体の糖鎖部分の成分として明らかなフコースを含まない(通常、Fc領域のN297に連結している)。機能的には、脱フコシル化された抗体は、通常、FcγRIIIa受容体に対して少なくとも50%又はそれ以上の親和性を示す。
本発明は、特定のセットのCDR(上記のように、いくつかのアミノ酸が置換されたCDRを含む)を有する様々な抗体を提供する。上記のように、抗体は、6つのCDRのセット、可変領域、又は重鎖と軽鎖の完全長(定常領域を含む)により定義される。また、上記のように、アミノ酸置換を行うことが可能である。CDR内の変化は、通常、CDRの長さが短いため、アミノ酸の修飾をアミノ酸修飾の数に基づいて説明される。これは、可変配列、定常配列、又は完全長配列に導入されるアミノ酸修飾の数を議論するのにも適している。アミノ酸変化の数の以外には、これらの変化を「%同一性」について定義することも適切である。従って、本明細書に記載されているように、本発明では、本明細書に記載されている配列番号と80%、85%、90%、95%、98%又は99%の同一性を有する抗体も含まれる。なお、アミノ酸配列の類似性パーセントが定義される場合に、本明細書で使用される「相同性」という用語は「同一性」と同じ意味を有する。
本明細書に開示される抗体は、リガンド-受容体の相互作用を遮断するか、又は受容体成分の相互作用を阻害するのに使用することができる。本発明に係る抗CD38抗体としては、「遮断された」又は「中和された」ものであり得る。「中和抗体」とは、リガンドと相互作用する能力や、酵素活性、シグナル伝達能力、特にリンパ球を活性化する能力といったCD38の生物学的活性がCD38に結合することにより阻害される抗体を指す。CD38の生物学的活性の阻害は、当技術分野で知られているいくつかのインビトロ又はインビボアッセイでの標準により評価することができる。
また、本発明は、開示された抗CD38抗体を産生するための方法を提供する。これらの方法は、本発明に係る抗体をコードする単離された核酸を含む宿主細胞を培養することを含む。これは抗体の性質に応じて様々な方法で達成できることが当業者なら理解するであろう。いくつかの実施形態においては、本発明に係る抗体は、完全長の従来の抗体であり、例えば、重鎖可変領域及び軽鎖可変領域は、産生した抗体が単離され得る条件下にある。
本発明に係る抗体はCD38に関連する疾患の診断及び治療を含む様々な用途で使用することができる。
一様態では、本発明は、炎症性及び免疫性疾患に関連する障害、特に活性化リンパ球に関連する疾患を診断及び治療するための方法を提供する。本明細書に示されるように、CD38は未成熟造血細胞で発現され、成熟細胞で下方制御され、活性化リンパ球及び形質細胞で高レベルで再発現される。例えば、CD38の高発現は、活性化B細胞、形質細胞、活性化CD4+T細胞、活性化CD8+T細胞、NK細胞、NKT細胞、成熟樹状細胞(DC)及び活性化単球で見られる。
B-CLLは、骨髓及び末梢血に蓄積する無反応のモノクローナルB系統細胞が長期にわたって持続的に増加していることを特徴とする不治の病である。CD38の発現は、B-CLLの予後不良の独立要因として考えられている(Hamblin et al.,Blood99:1023-9(2002))。
多発性骨髄腫は、骨髓における形質細胞の腫瘍性増殖を特徴とするB細胞系統の悪性疾患である。現在の治療レジメンでは、中程度の反応率を示している。しかし、全生存期間として僅かな変化しか観察されないし、生存期間中央値が約3年であった。従って、多発性骨髄腫の治療には、満たされていない重大な医学的ニーズがある。いくつかの実施形態においては、本発明に開示される抗体を使用して多発性骨髄腫を治療するための方法が提供される。
いくつかの実施形態においては、本開示の抗体を使用して単クローン性免疫グロブリン血症を治療するための方法が提供される。他の実施形態においては、本開示の抗体を使用してくすぶり型多発性骨髄腫を治療するための方法が提供される。
本発明で使用される抗体は、所望の純度の抗体を任意選択的な薬学的に許容される担体、賦形剤又は安定剤と混合することにより、凍結乾燥製剤又は水溶液形態の製剤を貯蔵のために製造することができる(Remington’s Pharmaceutical Sciences16th edition,Osol,A.Ed.[1980])。許容される担体、賦形剤又は安定剤としては、使用される用量及び濃度下で受容者に無毒であり、例えば、リン酸塩や、クエン酸塩、他の有機酸などの緩衝液;アスコルビン酸やメチオニンといった酸化防止剤;オクタデシルジメチルベンジルアンモニウムクロライド、ヘキサメチルアンモニウムクロライド、塩化ベンザルコニウム、塩化ベンゼトニウム、フェノール、ブタノール又はベンジルアルコール、メチルパラベンやプロピルパラベンなどのアルキルパラベン、カテコール、レゾルシノール、シクロヘキサノール、3-ペンタノール及びm-クレゾールといった防腐剤;低分子量(約10残基未満)のポリペプチド;血清アルブミンや、ゼラチン、免疫グロブリンなどのタンパク質;ポリビニルピロリドンのような親水性ポリマー;グリシンや、グルタミン、アスパラギン、ヒスチジン、アルギニン、リジンなどのアミノ酸;単糖類、二糖類、及びグルコースや、マンノース、デキストリンなどの他の糖;EDTAのようなキレート剤;ショ糖や、マンニトール、トレハロース、ソルビトールなどの糖;ナトリウムのような塩形成対イオン;亜鉛タンパク質錯体のような金属錯体、及び/又はTWEEN(商標)や、PLURONICS(商標)、ポリエチレングリコール(PEG)などの非イオン界面活性剤が挙げられる。
本発明に係る方法では、治療は疾患又は障害に対して積極的な治療応答を提供することである。「積極的な治療応答」とは、疾患又は障害の改善、及び/又は疾患又は障害に関連する症状の改善を意味する。例えば、積極的な治療応答とは、(1)腫瘍細胞数の減少、(2)腫瘍細胞死亡の増加、(3)腫瘍細胞生存の阻害、(5)腫瘍増殖の阻害(即ち、ある程度に減速し、好ましくは停止する)、(6)患者の生存率の向上、(7)疾患又は障害に関連する1つまたは複数の症状の緩和などの疾患のうちの1つまたは複数の改善を指す。
本開示で提供される抗CD38抗体は、CD38に関連する腫瘍又は自己免疫疾患状態のインビトロ又はインビボでのイメージングにも使用することができる。いくつかの実施形態においては、本明細書に記載されている抗体は、診断及び治療のために、又は診断のみに使用される。
他の実施形態においては、上記の疾患の治療に有用な材料を含む製品が提供され、前記製品は容器及びラベルを含む。適切な容器としては、例えば、ボルト、バイアル、注射器及び試験管が挙げられる。容器としては、ガラスやプラスチックなどの様々な材料で形成することができる。容器は、疾患を治療するのに効果的な組成物を含み、そして滅菌進入口を有することができる(例えば、容器は、静脉溶液バッグ又は皮下注射針が貫通可能なストッパー付きのバイアルであってもよい)。組成物中の活性剤は抗体である。容器上又は容器に関連するラベルは、組成物が選択した疾患を治療するために使用されることを示している。製品は、リン酸塩緩衝食塩水や、リンゲル液、デキストロース溶液などの薬学的に許容される緩衝液を含む第2の容器をさらに含むことができる。ビジネス及びユーザーの観点から、製品は、他の緩衝液、希釈剤、フィルター、針、注射器及び使用説明書付きの添付文書など、他の必要な材料を含んでもよい。
1×1011酵母ディスプレイの初期ヒトscFvライブラリーを構築し、ヒトCD38の細胞外ドメインをACRO biosystemsから購入した。ライブラリースクリーニングの方法は、文献(Zhao et al.,J Immunol Methods.2011;363(2):221-32)に記載されている。簡単に言えば、組換えビオチン化CD38-aviタンパク質を誘導された酵母ディスプレイscFvライブラリーとともにインキュベートした。単離CD38に結合する酵母細胞は、ストレプトアビジン(SA)に抱合されたマイクロビーズを使用した後、フローサイトメーター活性化セルソーティング(FACS)使用して分離した。同定されたscFvはインタクト抗体に操作され、293F細胞によって発現された。
酵母ディスプレイscFvライブラリーを-80℃から解凍し、3000rpmで5分間遠心分離した。上澄みを廃棄し、酵母細胞を12LのSD-CAA培地(1リットルのSD-CAA培地には、カゼインアミノ酸5g、硫酸アンモニウムとアミノ酸とを含まない酵母窒素塩基1.7g、硫化アンモニウム5.3g、Na2HPO4・7H2O 10.2g、NaH2PO4・H2O8.6g及びデキストロース20gが含まれる)に再懸濁した。細胞を30℃で200rpmで振とうしながら一晩培養した。翌日、3000rpmで5分間遠心分離して酵母細胞を回収し、培養物の最終濃度がOD600=0.5になるように、適切な量の酵母細胞を12LのS-CAA-GRD誘導培地(1リットルのS-CAA-GRD培地には、5gのカゼインアミノ酸、1.7gの硫酸アンモニウム及びアミノ酸を含まない酵母窒素塩基、5.3gの硫化アンモニウム、10.2gのNa2HPO4・7H2O、8.6gのNaH2PO4・H2O、1gのデキストロース、20gのガラクトース及び20gのラフィノースが含まれる)に再懸濁し、20℃で一晩誘導した。3000rpmで5分間遠心分離して誘導された酵母細胞を回収し、2LのPBE緩衝液(PBE緩衝液は2mMのEDTA及び0.5%BSAを含むPBS緩衝液である)で2回洗浄し、最後に200mlのPBEに再懸濁した。細胞を40μgのビオチン化CD38タンパク質と室温(RT)で1.5時間インキュベートし、次いで4℃で0.5時間インキュベートした。以下の工程は4℃又は氷上で実行された。3000rpmで5分間遠心分離して細胞を回収し、2LのPBEで2回洗浄し、200mlのPBEに再懸濁した。次に、2mlのストレプトアビジンマイクロビーズ(Miltenyi Biotec)を細胞に添加し、ゆっくりと振とうしながら1時間インキュベートした。1リットルのPBEを細胞に添加し、細胞が単一の細胞に分散しているように振とうし、70μmフィルターでろ過した。CD38に結合した酵母細胞をAUTOMACS装置により分離した。回収された細胞をSD-CAAプレートに敷き、30℃で2日間培養した。1回目の磁気ビーズソーティングから合計2.5×107個のクローンを得た。細胞をこすり取り、2回目の磁気ビーズソーティングのために誘導した。その一部を10%グリセリンを含有するSD-CAAに入れ、-80℃で保存した。
磁気ビーズソーティングから得られた酵母細胞をさらにフローソーティングで分取した。特に明記しない限り、すべての遠心分離を3000rpmで5分間で行い、すべての工程を4℃又は氷上で行った。磁気ビーズ分取から分離された2×109個の細胞を100mlのS-CAA-GRD培地に20℃で一晩誘導し、そこから1×108個の細胞を取り出してフローソーティングに使用した。細胞を沈殿させて15mlのPBEで2回洗浄した後、1mlのPBEに再懸濁し、0.2mgのビオチン化CD38タンパク質と室温で1.5時間インキュベートし、次に4℃で30分間インキュベートした。細胞をPBEで3回洗浄した後、1mlのPBE中の50μlのアビジン-PE(インビトロジェン)と4℃、暗所で1時間インキュベートした。染色後、細胞を15mlのPBEで3回洗浄して1mlのPBEに再懸濁した。CD38に結合する酵母細胞をフローサイトメトリーで分取した。分取した細胞を30℃でSD-CAAプレート上に2日間増殖させた。
V-base和IMGTデータベースに基づいて、scFv418の重鎖と軽鎖の生殖系列を同定し、シグナルペプチドと定常領域を可変領域に追加し、重鎖と軽鎖の完全長ペプチドをコードする遺伝子を構成した。重鎖及び軽鎖の遺伝子を自己構築されたインタクト抗体発現ベクターLh1にクローン化し、293F細胞により発現し、プロテインA(Protein A)アフィニティークロマトグラフィーを使用して精製を行った。
CD38組換えタンパク質に対するIgG418とダラザレックスの親和性を捕捉ELISAで測定した。簡単に言えば、抗ヒトFc抗体をELISAプレート上に10μg/mlの濃度で4℃で一晩被覆した。プレートをPBSTで2回洗浄し、室温でPBSTMで2時間ブロックし、50nMから0.012nMまで4倍に連続的に希釈した1式3部のIgG418とともにインキュベートした。プレートをPBSTで6回洗浄した後、PBSTM中で0.5μg/mlのビオチン化CD38-avi組換えタンパク質と室温で1時間インキュベートした。6回洗浄した後、PBSTM中でプレートを1:1000希釈したストレプトアビジン-HRP(BD Bioscience)と室温で30分間インキュベートした。プレートをさらに6回洗浄し、室温でTMBで20分間インキュベートし、比色反応を停止緩衝液で停止し、OD450で吸光度を読み取った。親和性をGraphPad Prismソフトウェアを使用して計算したところ、ダラザレックスのKd=1.64nM,IgG418のKd=0.082nMであった(図1)。表1にELISAの測定値を示す。
ダラザレックスを対照として、Daudi細胞表面での天然の立体配座をしているCD38に対するIgG418の親和性をフローサイトメトリーにより測定した。表2に示すように、Daudi細胞をPBSで2回洗浄し、氷上でFACS緩衝液(2%FBS含有PBS)中で連続的に希釈した抗体と1時間インキュベートした。細胞をPBSで3回洗浄し、FACS緩衝液中で1:200希釈した抗ヒトIgG-Alexa647と4℃で30分間遮光してインキュベートした。PBSで3回洗浄した後、フローサイトメーターを使用して細胞を分析した。表2は、各サンプルの抗体濃度と平均蛍光測定値を示す。ダラザレックスのKd=3.256nM、IgG418のKd=3.1nMのGraphPad Prismソフトウェアを使用して親和性を計算した(図2)。
ELISAプレートを2μg/mlのダラザレックスで50μl/ウェルで(PBS中)4℃で一晩被覆した。次に、プレートを室温でPBSTMで2時間ブロックした。次に、ELISAウェルをそれぞれCD38又は抗体-CD38複合体とともにインキュベートした。ここでは、前記抗体-CD38複合体は、抗体(15μg/ml)とCD38(0.2μg/ml)を室温で1時間プレインキュベートして得られた。4℃で30分間インキュベートした後、プレートをPBSTで洗浄し、室温でストレプトアビジン-HRPと30分間インキュベートした。プレートを再度6回洗浄し、室温でTMBと20分間インキュベートした。比色反応を停止緩衝液で停止し、OD450で吸光度を読み取った(図3)。競合ELISAから、IgG418はダラザレックスとCD38の結合部位を競合しないことが示されたため、それらのエピトープが異なることが分かった。
群1:アイソタイプ対照抗体(Isotype)(10mg/kg)
群2:ダラザレックス(10mg/kg)(JBS2Y20西安楊森製薬有限公司)
群3:IgG418-WT(10mg/kg)
群4:IgG418-AF(10mg/kg)
実験手順及び腫瘍測定は実施例9と同じであった。
群1:アイソタイプ対照抗体(Isotype)(1mg/kg)
群2:ダラザレックス(1mg/kg)(JBS2Y20西安楊森製薬有限公司)、
群3:IgG418-WT(1mg/kg)
群4:IgG418-AF(0.1mg/kg)
群5:IgG418-AF(0.3mg/kg)
群5:IgG418-AF(1mg/kg)
結果を表6及び図8に示す。
本願に挙げられる配列は以下の通りである:
Claims (32)
- 抗体又は抗体断片を含む組成物であって、
前記抗体又は抗体断片が、一つまたは複数の下記の成分:
a)配列番号23及び配列番号23と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む軽鎖可変領域の第1のフレームワーク領域(FR1)、
b)配列番号25及び配列番号25と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む軽鎖可変領域の相補性決定領域1(CDR1)、
c)配列番号27及び配列番号27と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む軽鎖可変領域の第2のフレームワーク領域(FR2)、
d)配列番号29及び配列番号29と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む軽鎖可変領域の相補性決定領域2(CDR2)、
e)配列番号31及び配列番号31と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む軽鎖可変領域の第3のフレームワーク領域(FR3)、
f)配列番号33及び配列番号33と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む軽鎖可変領域の相補性決定領域3(CDR3)、
g)配列番号35及び配列番号35と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む軽鎖可変領域の第4のフレームワーク領域(FR4)、
h)配列番号7及び配列番号7と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む重鎖可変領域の第1のフレームワーク領域(FR1)、
i)配列番号9及び配列番号9と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む重鎖可変領域の相補性決定領域1(CDR1)、
j)配列番号11及び配列番号11と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む重鎖可変領域の第2のフレームワーク領域(FR2)、
k)配列番号13及び配列番号13と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む重鎖可変領域の相補性決定領域2(CDR2)、
l)配列番号15及び配列番号15と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む重鎖可変領域の第3のフレームワーク領域(FR3)、
m)配列番号17及び配列番号17と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む重鎖可変領域の相補性決定領域3(CDR3)、
n)配列番号19及び配列番号19と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む重鎖可変領域の第4のフレームワーク領域(FR4)、を含む、組成物。 - 前記抗体又は抗体断片が、重鎖可変領域の相補性決定領域1(CDR1)と、重鎖可変領域の相補性決定領域2(CDR2)と、重鎖可変領域の相補性決定領域3(CDR3)とを含む重鎖可変領域と、
軽鎖可変領域の相補性決定領域1(CDR1)と、軽鎖可変領域の相補性決定領域2(CDR2)と、軽鎖可変領域の相補性決定領域3(CDR3)とを含む軽鎖可変領域とを含み、
前記重鎖可変領域のCDR1、CDR2及びCDR3が、配列番号9、13及び17で示されるアミノ酸配列、及び配列番号9、13及び17と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含み、
前記軽鎖可変領域のCDR1、CDR2及びCDR3が、配列番号25、29及び33で示されるアミノ酸配列、及び配列番号25、29及び33と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む、請求項1に記載の組成物。 - 前記重鎖可変領域のCDR1が、配列番号9及び配列番号9と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含み、
前記重鎖可変領域のCDR2が、配列番号13及び配列番号13と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含み、かつ、
前記重鎖可変領域のCDR3が、配列番号17及び配列番号17と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含み、
前記軽鎖可変領域のCDR1が、配列番号25及び配列番号25と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含み、
前記軽鎖可変領域のCDR2が、配列番号29及び配列番号29と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含み、かつ、
前記軽鎖可変領域のCDR3が、配列番号33及び配列番号33と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む、請求項2に記載の組成物。 - 前記抗体又は抗体断片が、配列番号21で示されるアミノ酸配列を含む軽鎖と、配列番号5で示されるアミノ酸配列を含む重鎖とを含む、請求項1に記載の組成物。
- 前記抗体又は抗体断片が、配列番号3で示されるアミノ酸配列を含む、請求項1に記載の組成物。
- 抗体又は抗体断片を含む組成物であって、前記抗体又は抗体断片が一つまたは複数の下記の成分:
a)配列番号39及び配列番号39と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む重鎖シグナルペプチド、
b)配列番号5及び配列番号5と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む重鎖可変領域、
c)配列番号43及び配列番号43と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む軽鎖シグナルペプチド、
d)配列番号21及び配列番号21と90%以上の相同性を有するアミノ酸配列からなる群より選択されたアミノ酸配列を含む軽鎖可変領域、を含む、組成物。 - 前記抗体又は抗体断片が、IgGl、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgAsec、IgD及びIgEからなる群より選択されたか、或いは
前記抗体又は抗体断片が、IgGl、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgAsec、IgA又はIgEの免疫グロブリンの定常領域及び/又は可変領域を有する、請求項1~6のいずれか一項に記載の組成物。 - 前記抗体又は抗体断片が、λ又はκの軽鎖定常領域或いはその変異体の配列の一部又は全部を含む、請求項1~6のいずれか一項に記載の組成物。
- 前記抗体又は抗体断片が組換え抗体である、請求項1~8のいずれか1項に記載の組成物。
- 前記抗体又は抗体断片がモノクローナル抗体である、請求項1~8のいずれか1項に記載の組成物。
- 前記抗体又は抗体断片がポリクローナル抗体である、請求項1~8のいずれか1項に記載の組成物。
- 前記抗体又は抗体断片がモノクローナル抗体及び/又はポリクローナル抗体の混合物である、請求項1~8のいずれか1項に記載の組成物。
- 前記抗体又は抗体断片がヒト抗体である、請求項1~8のいずれか1項に記載の組成物。
- 前記抗体又は抗体断片がヒト化抗体である、請求項1~8のいずれか1項に記載の組成物。
- 前記抗体又は抗体断片がキラメ抗体である、請求項1~8のいずれか1項に記載の組成物。
- 請求項1~15のいずれか1項に記載の組成物に含まれる抗体又は抗体断片をコードする単離された核酸分子を含む、組成物。
- 前記組成物が、前記単離された核酸分子を含むベクターである、請求項16に記載の組成物。
- 前記ベクターが、DNA、RNA、プラスミド、レンチウイルスベクター、アデノウイルスベクター及びレトロウイルスベクターからなる群より選択される、請求項17に記載の組成物。
- 前記組成物が、前記抗体又は抗体断片を含む細胞である、請求項1~15のいずれか一項に記載の組成物。
- 前記組成物が、前記単離された核酸分子を含む細胞である、請求項16に記載の組成物。
- 前記細胞が、バクテリオファージ、大腸菌、酵母細胞、昆虫細胞又は哺乳動物の細胞、例えばCHO、HEK293又はPER.C6である、請求項19~20のいずれか一項に記載の組成物。
- 前記細胞が、タンパク質発現のために操作された動物などのインビトロ又はインビボの発現系である、請求項19~21のいずれか一項に記載の組成物。
- CD38発現に関連する疾患を患っている対象を治療するための方法であって、前記対象に有効量の請求項1~20のいずれか一項に記載の組成物を投与することを含む、方法。
- 前記組成物が、毒素、同位体、ナノ粒子、酵素、生物活性ペプチド又は核酸である生物活性剤に共有結合又は非共有結合で操作可能に連結された前記抗体又は抗体断片を含む抗体薬物複合体である、請求項1~15のいずれか一項に記載の組成物。
- 前記組成物が、同一または異なる抗原の上の2つ以上の異なるエピトープに結合する多重特異性抗体を含み、前記エピトープの1つがCD38のエピトープである、請求項1~15のいずれか一項に記載の組成物。
- 前記多重特異性抗体が二重特異性抗体である、請求項25に記載の組成物。
- CD38発現に関連する疾患を患っている対象を治療するための方法であって、前記対象に有効量の請求項1~26のいずれか一項に記載の組成物を投与することを含む、方法。
- 哺乳動物におけるCD38発現に関連する疾患の存在を診断するための方法であって、請求項1~26のいずれか一項に記載の組成物を含む組成物を使って、哺乳動物から分離された組織サンプルを検出又は分析することを含み、
前記抗体又は抗体断片の前記組織サンプルへの特異的結合が、前記哺乳動物におけるCD38発現に関連する疾患の存在を示唆する、方法。 - 薬学的に許容される担体、賦形剤、安定剤、希釈剤、アジュバント、サイトカイン、ケモカイン、化学療法薬、他の治療用薬物、又はそれらの組み合わせをさらに含む、請求項1~26のいずれか一項に記載の組成物。
- 対象においてCD38発現に関連する疾患を画像化するための方法であって、前記抗体又は抗体断片が試薬に操作可能に連結されている、請求項1~26のいずれか一項に記載の組成物を適用する工程を含む、方法。
- 前記試薬が、光活性化剤、蛍光染料、同位体、生物発光タンパク質、生物発光ペプチド、蛍光ラベル、蛍光タンパク質、蛍光ペプチド、イメージ増強剤、酵素、核磁気共鳴活性化剤、又はナノ粒子である、請求項30に記載の方法。
- 前記CD38発現に関連する疾患が、がんや、悪性腫瘍、前癌病変といった増殖型疾患、関節リウマチ(RA)や、全身性エリテマトーデス(SLE)、全身性硬化症(SSc)、多発性硬化症(MS)といった自己免疫疾患、及びCD38発現に関連する非癌性自己免疫疾患に関連する適応症からなる群より選択される、請求項27~31のいずれか一項に記載の方法。
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