JP7341259B2 - Tl1aに特異的に結合する抗体 - Google Patents
Tl1aに特異的に結合する抗体 Download PDFInfo
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- JP7341259B2 JP7341259B2 JP2022005039A JP2022005039A JP7341259B2 JP 7341259 B2 JP7341259 B2 JP 7341259B2 JP 2022005039 A JP2022005039 A JP 2022005039A JP 2022005039 A JP2022005039 A JP 2022005039A JP 7341259 B2 JP7341259 B2 JP 7341259B2
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Description
本願は、2015年9月18日に出願された米国仮出願第62/220,442号の優先権を主張し、その内容は、あらゆる目的のためにその全体を参照として本明細書に援用する。
本願は、2015年9月18日に89,000バイトのサイズで作成したファイル名TL1A_ST25のテキストファイルとして電子的に提出した配列表を含む。この配列表は参照として本明細書に援用する。
本開示は、一般に、抗体工学の分野に関する。より具体的には、本開示は、TL1Aに特異的に結合し、TL1Aと細胞死受容体3(DR3)との間の相互作用を阻害する変異型抗体に関する。いくつかの態様では、抗体はまた、TL1Aとデコイ受容体3(DcR3)との間の相互作用を阻害する。抗体は、変異体の由来元の親抗体に比べて力価が向上している。
TNF様リガンド1A(TL1A、syn.TNFスーパーファミリーメンバー15(TNFSF15);TL1及びVEGI)は、抗原提示細胞(樹状細胞、B細胞及びマクロファージを含む)、CD4+及びCD8+T細胞、ならびに内皮細胞が発現する腫瘍壊死因子スーパーファミリーのメンバーである。TL1Aは、細胞表面上に発現するか、または可溶性サイトカインとして分泌され得る。CD4+及びCD8+T細胞、NK細胞、NKT細胞及びFOXP3+調節性T(Treg)細胞ならびに2型及び3型自然リンパ球系細胞(ILC2及びILC3)を含む様々な細胞が、TL1Aの受容体である細胞死受容体3(DR3)を発現する。
本明細書及び特許請求の範囲全体を通じて、開示の態様に関する様々な用語を使用する。そのような用語は、他に特段の指示がない限り、当該分野における通常の意味を有するものとする。他の特別に定義する用語は、本明細書で提供する定義と一致するように解釈すべきである。
材料及び方法
これらの実施例のアミノ酸位置は、Kabatナンバリングシステムに従って番号付けしている。CDRは、本明細書を通してCDR定義システムのAbM法に従って定義している。
実験結果
2.1. C320‐179に比べて解離速度が同等または向上したTL1A結合変異体の選択。抗体320‐179の変異体を構築し、上記のように発現させた。各変異体のEXPI293(登録商標)(Life Technologies Corp.)上清をBIACORE(登録商標)(GE Healthcare)により評価し、得られたデータを親抗体320‐179のデータと比較した。いくつかの実験では、抗体を、プロテインAクロマトグラフィー(1.4参照)を用いて精製し、精製抗体をBIACORE(登録商標)(GE Healthcare)実験で使用した。表3~11は、各変異体の発現レベルを、早期及び後期の時点でのTL1Aへの結合とともに示す。後の実験(表10及び11)では、2つ以上のアミノ酸置換を含む抗体変異体を試験した。
喘息:アレルゲン誘発喘息―げっ歯類(マウス、ラットまたはモルモット)をオボアルブミン(OVA)、特にニワトリ卵由来のOVA、及びミョウバンを皮内注射により感作し、次いで少なくとも2週間後に、エアロゾル化したOVAによりチャレンジし、気道過敏、好酸球の流入及びサイトカイン産生の増加を含む喘息様症状を引き起こす(例えば、Hylkema et al.,2002,Clin.Exp.Immunol.129:390‐96)。そのようなモデルは、チャレンジを反復することで改変することができ、気道リモデリング及び線維化誘導の増加を伴う、より慢性の疾患特性を提示する(例えば、Bos et al.,2007,Eur.Respir.J.30:653‐661)。チリダニのような別のアレルゲンもまた、使用してもよい(例えば、Lambert et al.,1998,Am.J.Respir.Crit.Care Med.157:1991‐9)。あるいは、非ヒト霊長類(例えば、カニクイザル)を、Ascaris suumなどの環境抗原で感作し、チャレンジして、気道過敏、好酸球の流入及びサイトカイン産生の増加を誘導してもよい(例えば、Wegner et al.,1991,J.Allergy Clin.Immunol.87:835‐41)。
3.0.1. 喘息
ラットの急性オボアルブミン誘発性喘息。Brown‐Norwayラットを、OVAを用いて0日目に腹腔内注射で感作し、次いで35~42日目にOVAエアロゾルを用いて毎日チャレンジした。抗体320‐587またはビヒクルを用いて、14、21、28及び35日目にラットを静脈内注射で処置した。43日目の全細胞及び差分の細胞について、気管支肺胞洗浄液(BALF)を評価した。処置により、BALFの好酸球が有意に減少することが判明した(図15)。
ラットにおけるTNBS誘発性大腸炎:エタノール中のトリニトロベンゼンスルホン酸の直腸内注入量の単回投与により、ラットを処置した。対照動物には等量のエタノールのみを与えた。7日間の間隔にわたって、動物は、炎症性浸潤及び様々な程度の線維症を伴う結腸の潰瘍形成を特徴とする局所性大腸炎を発症した(例えばWirtz et al.(2007)Nat.Protoc.2:541‐546)。320‐587を投与することにより、結腸の厚さ(図12A)、癒着の数及び重症度(図12B)、ならびに狭窄の数及び重症度(図12C)を含む多発性疾患の指標が有意に低下し、ビヒクル、またはアイソタイプが一致する無関係の抗体のいずれかで処置した動物に比べて、疾患の発症は有意に軽度であった(図12D)。結腸線維症の軽減(図19)も、320.587処置動物において観察された。
Claims (16)
- 配列番号3のアミノ酸配列を有する重鎖可変領域と、配列番号4のアミノ酸配列を有する軽鎖可変領域とを含む、TNF様リガンド1A(TL1A)に特異的に結合する組換え抗体を含む、皮下に投与することを含む、被験体における呼吸器疾患、胃腸疾患、関節炎、または皮膚疾患の治療における使用のための医薬組成物であって、配列番号1のアミノ酸配列を有する重鎖可変領域及び配列番号2のアミノ酸配列を有する軽鎖可変領域を有する抗体に比べて、少なくとも10倍高い力価の向上した力価を有し、前記力価は、TF‐1細胞(7.5×104個/ウェル)を、100ng/mlのヒトTL1A及び10μg/mlのシクロヘキシミドと共にインキュベートする、TF‐1細胞におけるTL1A誘導性カスパーゼ力価アッセイによって測定される、医薬組成物。
- 配列番号1のアミノ酸配列を有する重鎖可変領域及び配列番号2のアミノ酸配列を有する軽鎖可変領域を有する抗体に比べて、少なくとも約40倍高い力価の向上した力価を有し、前記力価は、TF‐1細胞におけるTL1A誘導性カスパーゼ力価アッセイによって測定される、請求項1に記載の医薬組成物。
- 前記抗体がヒトIgG1重鎖定常領域を含む、請求項1または2に記載の医薬組成物。
- 前記ヒトIgG1重鎖定常領域が、配列番号42、配列番号43、配列番号44、配列番号62、配列番号63、配列番号64、配列番号65、または配列番号66を有する、請求項3に記載の医薬組成物。
- 前記抗体がヒト重鎖IgG4定常領域を含む、請求項1または2に記載の医薬組成物。
- 前記ヒト重鎖IgG4定常領域が、配列番号45、配列番号46、配列番号47、または配列番号69を有する、請求項5記載の医薬組成物。
- 前記抗体がヒト重鎖IgG2定常領域を含む、請求項1または2に記載の医薬組成物。
- 前記ヒト重鎖IgG2定常領域が、配列番号67、配列番号68、配列番号70、または配列番号71を有する、請求項7に記載の医薬組成物。
- 前記抗体が、ヒト軽鎖λ定常領域を含む、請求項1から8のいずれか一項に記載の医薬組成物。
- 前記ヒト軽鎖λ定常領域が、配列番号48を有する、請求項9に記載の医薬組成物。
- 前記組換え抗体が、配列番号60のアミノ酸配列を有する重鎖を含む、請求項1または2に記載の医薬組成物。
- 前記抗体が、配列番号61のアミノ酸配列を有する軽鎖を含む、請求項1、2または11に記載の医薬組成物。
- 結合平衡除外法によって測定する前記TL1AのKDが、約30pMから約60pMである、請求項1から10のいずれか一項に記載の医薬組成物。
- 結合平衡除外法によって測定する前記TL1AのKDが、約35pMから約50pMである、請求項1から10のいずれか一項に記載の医薬組成物。
- 結合平衡除外法によって測定する前記TL1AのKDが、約35pMから約42pMである、請求項1から10のいずれか一項に記載の医薬組成物。
- 呼吸器疾患、喘息、COPD、肺サルコイドーシス、アレルギー性鼻炎、肺線維症、嚢胞性線維症、胃腸疾患、炎症性腸疾患、大腸炎、潰瘍性大腸炎、好酸球性食道炎、嚢胞性線維症に関連する胃腸疾患、過敏性腸症候群、クローン病、関節炎、関節リウマチ、皮膚疾患、アトピー性皮膚炎、湿疹、または強皮症の治療における使用のための、請求項1から10のいずれか一項に記載の医薬組成物。
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