JP6085554B2 - 抗vla−4抗体 - Google Patents
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- JP6085554B2 JP6085554B2 JP2013505169A JP2013505169A JP6085554B2 JP 6085554 B2 JP6085554 B2 JP 6085554B2 JP 2013505169 A JP2013505169 A JP 2013505169A JP 2013505169 A JP2013505169 A JP 2013505169A JP 6085554 B2 JP6085554 B2 JP 6085554B2
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Description
本出願は、2010年4月16日に出願の米国仮出願第61/324,944号の利益を主張するものであり、参照によりその全体が本明細書に組み込まれる。
本発明は、アルファ4結合抗体およびその断片に関する。
−本明細書で説明される抗VLA−4VL鎖(例えば、ドナー抗VLA−4抗体(例えば、本明細書で説明される抗VLA−4抗体)由来のCDRを有する抗VLA−4VL鎖)、およびVL鎖の生殖細胞系可変領域配列の配列由来のLCフレームワーク領域1、2、および3を有するか、またはそれとの差異が5つ、10、または15以下である、VLフレームワークを含む。一実施形態において、可変領域4は、ヒトコンセンサス配列であり、
−本明細書で説明される抗VLA−4VH鎖(例えば、ドナー抗VLA−4抗体(例えば、本明細書で説明される抗VLA−4抗体)由来のCDRを有する抗VLA−4VL鎖)、およびVL鎖の生殖細胞系可変領域配列の配列由来のLCフレームワーク領域1、2、および3を有するか、またはそれとの差異が5つ、10、または15以下である、VLフレームワークである。一実施形態において、可変領域4は、ヒトコンセンサス配列である。
1.a)、b)、およびc)のうちの1つ以上における残基の1つ以上に、非ヒトドナー重鎖と同じ残基を有する、安定したヒト受容体重鎖可変フレームワークを識別または選択する。
a)VH Kabat番号2、4、24、26、27、29、36、38、46、47、48、49、66、67、69、71、78、93、および94(これらは、理論に束縛されるものではないが、CDR立体配座を維持するために重要であると考えられる)。
b)VH Kabat番号1、2、27、28、30、43、66、68、70、72、73、74、および75(これらは、理論に束縛されるものではないが、抗原と相互作用することが可能であると考えられる)。
c)VH Kabat番号37、39、44、45、47、91、93、および103(理論に束縛されるものではないが、VH/VL界面の完全性に重要であると考えられる)。
2.a)、b)、およびc)のうちの1つ以上における残基の1つ以上に、ドナー軽鎖と同じ残基を有する、安定した受容体軽鎖可変フレームワーク識別または選択する。
a)VL Kabat番号2、4、38、43、44、48、58、64、71、および73(理論に束縛されるものではないが、CDR立体配座を維持するために重要であると考えられる)。
b)VL Kabat番号1、2、49、57、60、63、65、66、67、68、69、および70(理論に束縛されるものではないが、潜在的に、抗原と相互作用することが可能であると考えられる)。
c)VL Kabat番号36、38、43、44、46、49、87、および98(理論に束縛されるものではないが、VH/VL界面の完全性に重要であると考えられる)。
3.1および2で識別される残基での一致をさらに最大化するように、生殖細胞系配列を選択し、さらに生殖細胞系の1または2で識別される付加的な残基をマウス配列に復帰変異させること等によって、ドナーCDRを有する可変領域と、1または2で識別される一致した残基を有する、選択された生殖細胞系フレームワークとを提供する。
4.3次元構造分析またはモデル化等によって、各一致した位置を評価し、例えばCDRの立体配座、抗原の相互作用、またはVH/VL界面の完全性を妨げる危険性に対する所定の基準をある位置が満たした場合、抗体構造に適合する、同等のマウス残基、または共通のヒト抗体残基を再導入する。
一実施形態では、(1.a)で識別される残基の少なくとも3個、4個、または5個が一致する。例えば、一実施形態では、残基24、29、または94が一致する。
したがって、本発明は、以下の項目を提供する:
(項目1) IGKV4−1由来の受容体配列を含む可変軽鎖フレームワークと、IGHV1−f由来の受容体配列を含む可変重鎖フレームワークと、を含み、かつマウス抗体HP1/2またはマウス抗体21.6由来の重鎖および軽鎖CDRを有する、組み換え抗体分子またはそのα4結合断片。
(項目2) 生殖細胞系を操作したAAH70335.1由来の受容体配列(配列番号15)を含む可変軽鎖フレームワークと、IGHV1−f由来の受容体配列を含む可変重鎖フレームワークとを含む、α4に結合することが可能な、組み換え抗体分子またはそのα4結合断片。
(項目3) マウス抗体HP1/2由来のCDRをさらに含む、項目1または2に記載の組み換え抗体分子またはそのα4結合断片。
(項目4) マウス抗体21.6由来のCDRをさらに含む、項目1または2に記載の組み換え抗体分子またはそのα4結合断片。
(項目5) 上記重鎖可変領域は、配列番号3、配列番号4、または配列番号5の配列を含む、項目1または2に記載の組み換え抗体分子またはそのα4結合断片。
(項目6) 上記軽鎖可変領域は、配列番号8、配列番号9、または配列番号10の配列を含む、項目1に記載の組み換え抗体分子またはそのα4結合断片。
(項目7) 上記軽鎖可変領域は、配列番号11の配列を含む、項目2に記載の組み換え抗体分子またはそのα4結合断片。
(項目8) 上記抗体は、VLA−4に結合する、項目1または2に記載の抗体。
(項目9) 配列番号3、4、または5の配列を含む、抗体重鎖またはそのα4結合断片をコードするDNAを含む、ベクター。
(項目10) 配列番号8、9、10、または11を含む、抗体軽鎖またはそのα4結合断片をコードするDNAを含む、ベクター。
(項目11) 組み換え抗α4抗体またはそのα4結合断片を作成する方法であって、
(a)(i)抗体重鎖またはそのα4結合断片をコードする、配列番号3、4、または5の配列を含むDNA配列と、(ii)抗体軽鎖またはそのα4結合断片をコードする、配列番号8、9、10、または11の配列を含むDNA配列と、を含む、宿主細胞を提供することと、
(b)組み換え抗α4抗体分子またはそのα4結合断片を産生するように、上記細胞を培養することと、
を含む、方法。
(項目12) 項目1または2に記載の組成物を患者に投与することを含む、上記患者を治療する方法。
(項目13) 上記患者は、癌を有する、項目12に記載の方法。
(項目14) 上記患者は、固形腫瘍を有する、項目13に記載の方法。
(項目15) 上記患者は、血液悪性腫瘍を有する、項目13に記載の方法。
(項目16) 上記患者は、多発性骨髄腫または急性骨髄性白血病(AML)を有する、項目13に記載の方法。
(項目17) 上記患者は、炎症性障害を有する、項目12に記載の方法。
(項目18) 上記患者は、多発性硬化症、喘息、関節リウマチ、糖尿病、視神経炎、またはクローン病を有する、項目12に記載の方法。
(項目19) 上記患者は、急性障害を有する、項目12に記載の方法。
(項目20) 上記患者は、脊髄損傷または外傷性脳損傷を有する、項目12に記載の方法。
(項目21) 上記組成物は、投薬計画として投与される、項目12に記載の方法。
(項目22) 第2の治療薬を上記患者に投与することをさらに含む、項目12に記載の方法。
(項目23) 上記第2の治療薬は、血栓溶解剤、化学療法剤、神経保護剤、抗炎症剤、ステロイド、サイトカイン、または成長因子である、項目21に記載の方法。
VLA−4結合抗体等のα4結合剤は、薬学的組成物として調合することができる。一般的に、薬学的組成物は、薬学的に許容される担体を含む。本明細書で使用される「薬学的に許容される担体」としては、生理学的に適合性のある、任意および全ての溶媒、分散媒、被覆、抗菌剤および抗真菌剤、等張剤、ならびに吸収遅延剤等が挙げられる。
α4結合抗体は、種々の方法によって対象(例えば、ヒト対象)に投与することができる。多数の用途について、投与経路は、静脈内注射もしくは注入、皮下注射、または筋肉注射のうちの1つである。α4結合抗体は、固定用量として、またはmg/kgの用量で投与することができる。抗体は、静脈内(IV)または皮下(SC)投与することができる。例えば、抗体は、IVで、例えば4週間に1回、約50〜600mgの間の、またはSCで、例えば少なくとも週に1回(例えば、週に2回)、約50〜100mgの間(例えば、75mg)の固定単位用量で投与することができる一実施形態において、抗体は、IVで、50mg、60mg、80mg、100mg、120mg、130mg、140mg、150mg、160mg、180mg、200mg、300mg、400mg、500mg、または600mg以上の固定単位用量で投与する。IVでの用量の投与は、週に1回、2回、3回、もしくはそれ以上、2週間に1回、3週間に1回、4週間に1回、もしくは5週間に1回、またはより低い頻度とすることができる。
本明細書で説明される抗体を含有する製剤は、医療デバイスで投与することができる。デバイスは、その分野の未熟練者または救急隊員等が緊急時に使用して、医療施設および他の医療機器に移動させることができるように、携帯性、室温貯蔵、および使い易さ等の特徴を考慮して設計することができる。デバイスは、例えば、α4結合抗体を含む薬学的調製物を貯蔵するための1つ以上の筐体を含むことができ、また、1つ以上の単位用量の薬剤を送達するように構成することができる。
治療用組成物はまた、皮下投与または筋肉内投与のために、生分解性または非生分解性の持続放出製剤の形態とすることができる。そのような組成物のための方法は、当技術分野で知られている。また、連続投与を、移植可能なポンプまたは外部ポンプを使用して達成することができる。投与はまた、1日1回の注射等によって断続的に行うか、または持続放出製剤等において低用量で連続的に行うことができる。送達デバイスは、α4結合抗体の投与に最適となるように修正することができる。例えば、注射器は、抗体の貯蔵および送達に最適な程度に、シリコン処理することができる。当然、多数の他の、そのようなインプラント、送達系、およびモジュールも知られている。
本明細書で説明されるα4結合抗体および方法は、固形癌および血液悪性腫瘍を含む癌を治療するために使用することができる。例示的な固形癌としては、肺、乳房、膵臓、結腸、前立腺、膀胱、および脳等の肉腫および癌腫が挙げられる。血液悪性腫瘍としては、多発性骨髄腫、白血病、およびリンパ腫等の癌が挙げられる。
本明細書で説明される製剤および方法はまた、炎症性、免疫性、または自己免疫性障害、例えば、中枢神経系の炎症(例えば、多発性硬化症に加えて、髄膜炎、視神経脊髄炎、神経サルコイドーシス、CNS血管炎、脳炎、および横断性脊髄炎)、組織または臓器移植片拒絶反応または移植片対宿主疾患、急性CNS損傷(例えば、脳卒中または脊髄損傷(SCI))、慢性腎疾患、アレルギー(例えば、アレルギー性喘息、中度から重度のアレルギー性鼻炎、眼アレルギー)、1型真性糖尿病、炎症性腸疾患(例えば、クローン病、潰瘍性大腸炎(例えば、治療または寛解の維持))、好酸性胃腸炎、重症筋無力症、線維筋痛、関節炎障害等のリウマチ学/免疫学と関連する障害(例えば、関節リウマチ、乾癬性関節炎)、炎症性/免疫性皮膚障害等の皮膚科の障害(例えば、乾癬、白斑、皮膚炎(例えば、アトピー性皮膚炎)、扁平苔癬、中度から重度の慢性蕁麻疹)、全身性紅斑性狼瘡(SLE;例えば、狼瘡腎炎)、硬皮症(例えば、全身性進行性硬化症(PSS)、肺のPSS等)、急性または慢性一次好酸球性肺炎、シェーグレン症候群、急性冠動脈症候群(ACS)、急性心筋梗塞、アテローム性動脈硬化症、および線維性障害(例えば、肺線維症(例えば、突発性肺線維症)、肺線維症(例えば、誘発XRT誘発)、骨髄線維症、肝硬変、メサンギウム増殖性糸球体腎炎、半月形糸球体腎炎、糖尿病性腎症、および間質性腎線維症)を治療するために使用することができる。
本明細書で説明されるアルファ4結合抗体を含有する製剤は、多発性硬化症(MS)等の炎症性疾患の治療に有用である。多発性硬化症は、ミエリン鞘の炎症および損失を特徴とする、中枢神経系疾患である。
アルファ4に結合する組み換え抗体は、ファージディスプレイ等のインビボ法またはインビトロ法によって生成することができる。本方法は、本明細書で説明されるCDR移植抗体で使用するための抗α4CDRを供給するために使用することができる。加えて、ファージディスプレイ等の方法を、フレームワークが生殖細胞系フレームワークであるライブラリ等を使用することによって、本明細書で開示される生殖細胞系フレームワークとの関連において、そのようなCDRを選択するために使用することができる。
抗体は、原核細胞および真核細胞において産生することができる。一実施形態において、抗体(例えば、scFvs)は、イースト細胞、例えば、ピキア属(例えば、Powers et al.(2001)J Immunol Methods.251:123−35を参照のこと)、ハンゼヌラ属、またはサッカロマイセス属で発現させる。
いくつかの場合において、本明細書で説明される製剤、例えばアルファ4結合抗体を含有する製剤は、第2の薬剤を含むか、または第2の薬剤を含有する製剤と組み合わせて投与される。
・インターフェロン、例えば、ヒトインターフェロンベータ1a(例えば、AVONEX(登録商標)またはRebif(登録商標))およびインターフェロンベータ1b(BETASERON(商標)、位置17で置換したヒトインターフェロンベータ、Berlex/Chiron)、
・酢酸ガラティラメル(共重合体1(Cop−1)とも称される、COPAXONE(商標)、Teva Pharmaceutical Industries,Inc.)、
・Rituxan(登録商標)(リツキシマブ)または別の抗CD20抗体(例えば、リツキシマブを伴う重複エピトープと競合するか、またはこれに結合するもの)、
・ミトキサントロン(NOVANTRONE(登録商標)、Lederle)、
・化学療法薬、例えば、クラブリビン(LEUSTATIN(登録商標))、アザチオプリン(IMURAN(登録商標))、シクロホスファミド(CYTOXAN(登録商標))、シクロスポリンA、メトトレキサート、4−アミノピリジン、およびチザニジン、
・コルチコステロイド(例えば、メチルプレドニゾロン(MEDRONE(登録商標)、Pfizer)、プレドニゾン)、
・免疫グロブリン、例えば、Rituxan(登録商標)(リツキシマブ)、CTLA4Ig、アレムツズマブ(MabCAMPATH(登録商標))、またはダクリズマブ(CD25を結合する抗体)、
・スタチン、および
・TNF拮抗薬、が挙げられる。
抗VLA−4抗体を、生殖細胞系フレームワークIGKV4−1(設計L1およびL2)を使用するか、またはVL鎖について生殖細胞系を操作したAAH7033.1(設計L3)およびVH鎖について生殖細胞系フレームワークIGHV1−fを使用して構築した。これらの抗体は、米国特許第6,602,503号で説明されるヒト化HP1/2抗体よりも少ない復帰変異を有した。
重鎖の3つの変異の配列を、設計H0、設計H1、設計H2として、図1に示す。各設計は、IGHV1−fフレームワークの中に移植されるマウスHP1/2のCDRを有する。設計H0は、フレームワーク領域のいかなる復帰変異も含まない一方で、設計H1および設計H2は、ヒト化抗体の親和性を最適化するように、フレームワーク領域配列において、種々の程度の復帰変異を有する。
軽鎖の4つの変異の配列を、設計L0、設計L1、設計L2、設計L3(L0、L1、L2、L3とも呼ばれる)として、図2に示す。各設計は、生殖細胞系フレームワークに移植されるマウスHP1/2のCDRを有する。IGKV4−1生殖細胞系フレームワークを設計L0、設計L1、および設計L2に使用し、AAH70335生殖細胞系を操作したフレームワークを設計L3に使用した。設計L0は、フレームワーク領域のいかなる復帰変異も含まない一方で、設計L1、設計L2、および設計L3は、ヒト化抗体の親和性を最適化するように、フレームワーク領域において、種々の程度の復帰変異を有する。
種々の細胞系への抗VLA−4抗体HuHP1/2の結合は、フローサイトメトリによって試験した。結合は、CLL(慢性的なリンパ球白血病患者)細胞系Mec1およびJM1、MM(多発性骨髄腫)細胞系U266およびH929、およびAML(急性骨髄性白血病患者)細胞系HL60およびKG1に関して試験した。HuHP1/2は、試験した全ての腫瘍細胞系に結合した(図6)。フローサイトメトリデータは、異なる細胞系のそれぞれに結合する抗体についてEC50値を計算するために使用した。この情報を、下記表3に示す。
Claims (20)
- IGKV4−1由来の可変軽鎖フレームワーク配列と、IGHV1−f由来の可変重鎖フレームワーク配列と、を含み、かつマウス抗体HP1/2由来の重鎖および軽鎖CDRの各々を有する、組み換え抗体またはそのα4結合断片であって、
(i)前記可変軽鎖フレームワークが、Kabat番号付けスキームに従ったフレームワーク位置1、67および87に非ヒト残基を含み;かつ
(ii)前記可変重鎖フレームワークが、Kabat番号付けスキームに従ったフレームワーク位置24および94に非ヒト残基を含む;
組み換え抗体またはそのα4結合断片。 - 前記重鎖可変領域は、配列番号4の配列を含む、請求項1に記載の組み換え抗体またはそのα4結合断片。
- 前記軽鎖可変領域は、配列番号10の配列を含む、請求項1に記載の組み換え抗体またはそのα4結合断片。
- VLA−4に結合する、請求項1に記載の組み換え抗体またはそのα4結合断片。
- IGHV1−f由来の可変重鎖フレームワーク配列を含み、かつマウス抗体HP1/2由来の重鎖CDRを有する、抗体重鎖またはそのα4結合断片をコードするDNAを含むベクターであって、前記可変重鎖フレームワークが、Kabat番号付けスキームに従ったフレームワーク位置24および94に非ヒト残基を含む、ベクター。
- 配列番号4の配列を含む重鎖可変領域をコードするDNAを含む、請求項5に記載のベクター。
- IGKV4−1由来の可変軽鎖フレームワーク配列を含み、かつマウス抗体HP1/2由来の軽鎖CDRを有する、抗体軽鎖またはそのα4結合断片をコードするDNAを含むベクターであって、前記可変軽鎖フレームワークが、Kabat番号付けスキームに従ったフレームワーク位置1、67および87に非ヒト残基を含む、ベクター。
- 配列番号10の配列を含む軽鎖可変領域をコードするDNAを含む、請求項7に記載のベクター。
- 組み換え抗α4抗体またはそのα4結合断片を作製する方法であって、
(a)抗体重鎖またはそのα4結合断片をコードするDNA配列であって、IGHV1−f由来の可変重鎖フレームワーク配列の配列を含み、かつマウス抗体HP1/2由来の重鎖CDRを有する、DNA配列と、(b)抗体軽鎖またはそのα4結合断片をコードするDNA配列であって、IGKV4−1由来の可変軽鎖フレームワーク配列の配列を含み、かつマウス抗体HP1/2由来の軽鎖CDRを有する、DNA配列と、を含む、宿主細胞であって、ここで:
(i)前記可変軽鎖フレームワークが、Kabat番号付けスキームに従ったフレームワーク位置1、67および87に非ヒト残基を含み;かつ
(ii)前記可変重鎖フレームワークが、Kabat番号付けスキームに従ったフレームワーク位置24および94に非ヒト残基を含む;
宿主細胞を提供することと、
組み換え抗α4抗体分子またはそのα4結合断片を産生するように、前記細胞を培養することと、
を含む、方法。 - 請求項1〜4のいずれか一項に記載の組み換え抗体またはそのα4結合断片を含む、患者を治療するための組成物。
- 前記患者は、癌を有する、請求項10に記載の組成物。
- 前記患者は、固形腫瘍を有する、請求項11に記載の組成物。
- 前記患者は、血液悪性腫瘍を有する、請求項11に記載の組成物。
- 前記患者は、多発性骨髄腫または急性骨髄性白血病(AML)を有する、請求項11に記載の組成物。
- 前記患者は、炎症性障害を有する、請求項10に記載の組成物。
- 前記患者は、多発性硬化症、喘息、関節リウマチ、糖尿病、視神経炎、またはクローン病を有する、請求項10に記載の組成物。
- 前記患者は、急性障害を有する、請求項10に記載の組成物。
- 前記患者は、脊髄損傷または外傷性脳損傷を有する、請求項10に記載の組成物。
- 前記組成物は、第2の治療薬と組み合わせて投与されることを特徴とする、請求項10に記載の組成物。
- 前記第2の治療薬は、血栓溶解剤、化学療法剤、神経保護剤、抗炎症剤、ステロイド、サイトカイン、または成長因子である、請求項19に記載の組成物。
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