JP2022512646A - スタフィロコッカス・アウレウス(Staphylococcus aureus)ロイコトキシンに対して向けられた抗体 - Google Patents
スタフィロコッカス・アウレウス(Staphylococcus aureus)ロイコトキシンに対して向けられた抗体 Download PDFInfo
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Abstract
Description
本明細書で使用される場合、「ロイコトキシン」という用語は、細菌のロイコトキシンポリペプチド(例えば、限定されないが、天然のロイコトキシンポリペプチド及びロイコトキシンポリペプチドのアイソフォーム)を指す。「ロイコトキシン」には、完全長の未処理ロイコトキシンポリペプチド及び細胞内での処理により生じるロイコトキシンポリペプチドの形態が包含される。ロイコトキシンとして、LukSF、ロイコトキシンED(LukED)、HlgAB、HlgCB)及びロイコトキシンAB(LukAB、LukGHとしても既知である)が挙げられる。本明細書で使用される場合、「S.アウレウス(S.aureus)LukF」という用語は、配列番号25のアミノ酸配列を含むポリペプチドを指す。本明細書で使用される場合、「S.アウレウス(S.aureus)LukD」という用語は、配列番号26のアミノ酸配列を含むポリペプチドを指す。本明細書で使用される場合、「S.アウレウス(S.aureus)HIgB」という用語は、配列番号27のアミノ酸配列を含むポリペプチドを指す。(図3を参照されたい)。「ロイコトキシンポリヌクレオチド」、「ロイコトキシンヌクレオチド」又は「ロイコトキシン核酸」は、ロイコトキシンをコードするポリヌクレオチドを指す。
本明細書で提供されるのは、少なくとも1種のS.アウレウス(S.aureus)ロイコトキシンに結合する抗体及びその抗原結合断片である。
同様に本明細書で提供されるのは、少なくとも1種のロイコトキシンに結合する抗体又はその抗原結合断片(任意選択的に、この抗体又はその抗原結合断片は、モノクローナル抗体又は断片である)をコードする1種又は複数の単離された核酸配列である。
本開示は、本明細書で説明されている抗体又はその抗原結合断片と、薬学的に許容される担体とを含む組成物を提供する。
抗ロイコトキシン抗体SAN481は、配列番号9のアミノ酸配列を有する重鎖と、配列番号10のアミノ酸配列を有する軽鎖とを含む。これらの配列では、いくつかの配列障害を特定した。例えば、重鎖W100a(VH-CDR3中)及びM256(Fcドメイン中)の酸化を観察した。加えて、可変重鎖中のグリコシル化部位(NFS)は、70%グリコシル化されていた。VL-CDR1中に2箇所のNS脱アミド化部位を特定し、VH-CDR2中にDG/DS異性化部位を特定した。更に、光感受性により、1週間CWL-2kLuxでSAN481の凝集が3.5%増加した。
この実施例では、他のSAN481バリアントと異なり、SAN481-SYT-YTE抗体は、SAN481のインビトロでの活性を維持することが実証される。
この実施例では、SAN481-SYT-YTE抗体は、SAN481抗体と同様のインビトロでのロイコトキシン中和を有することが実証される。
この実施例では、SAN481-SYT-YTEは、優れた光安定性を示すことが実証される。
Claims (58)
- 少なくとも1種のS.アウレウス(S.aureus)ロイコトキシンに特異的に結合する抗体又はその抗原結合断片であって、可変重鎖(VH)相補性決定領域(CDR)1、VH CDR2、VH CDR3、可変軽鎖(VL)CDR1、VL CDR2及びVL CDR3を含み、前記VH CDR1、VH CDR2、VH CDR3、VL CDR1、VL CDR2及びVL CDR3は、(a)それぞれ配列番号1、2、3、12、5及び6;(b)それぞれ配列番号1~6;(c)それぞれ配列番号1、2、17、4、5及び6;(d)それぞれ配列番号1、2、17、12、5及び6;並びに(e)それぞれ配列番号1、20、3、4、5及び6からなる群から選択される配列を含む、抗体又はその抗原結合断片。
- 少なくとも1種のS.アウレウス(S.aureus)ロイコトキシンに特異的に結合する抗体又はその抗原結合断片であって、SAN481-SYT-YTEのVH CDR1、VH CDR2、VH CDR3、VL CDR1、VL CDR2及びVL CDR3を含む抗体又はその抗原結合断片。
- 前記CDRは、Kabat定義CDR、Chothia定義CDR又はAbM定義CDRである、請求項2に記載の抗体又はその抗原結合断片。
- VH及びVLを含み、前記VHは、配列番号7、15、18、21又は23のアミノ酸配列を含む、請求項1~3のいずれか一項に記載の抗体又はその抗原結合断片。
- VH及びVLを含み、前記VLは、配列番号8又は13のアミノ酸配列を含む、請求項1~4のいずれか一項に記載の抗体又はその抗原結合断片。
- VH及びVLを含み、前記VH及びVLは、(a)それぞれ配列番号15及び13;(b)それぞれ配列番号7及び8;(c)それぞれ配列番号7及び13;(d)それぞれ配列番号15及び8;(e)それぞれ配列番号18及び8;(f)それぞれ配列番号18及び13;(g)それぞれ配列番号21及び8;並びに(h)それぞれ配列番号23及び13からなる群から選択される配列を含む、請求項1~5のいずれか一項に記載の抗体又はその抗原結合断片。
- 配列番号15の配列を含むVHと、配列番号13の配列を含むVLとを含む、請求項1~5のいずれか一項に記載の抗体又はその抗原結合断片。
- 配列番号16、9、11、22又は24の配列を含む重鎖を含む、請求項1~7のいずれか一項に記載の抗体又はその抗原結合断片。
- 配列番号14又は10の配列を含む軽鎖を含む、請求項1~8のいずれか一項に記載の抗体又はその抗原結合断片。
- 前記抗体は、重鎖及び軽鎖を含み、前記重鎖及び軽鎖は、(a)それぞれ配列番号16及び14;(b)それぞれ配列番号9及び10;(c)それぞれ配列番号11及び10;(d)それぞれ配列番号11及び14;(e)それぞれ配列番号16及び10;(f)それぞれ配列番号19及び10;(g)それぞれ配列番号19及び14;(h)それぞれ配列番号22及び10;並びに(i)それぞれ配列番号24及び14からなる群から選択される配列を含む、請求項1~9のいずれか一項に記載の抗体又はその抗原結合断片。
- 前記抗体は、配列番号16の配列を含む重鎖と、配列番号14の配列を含む軽鎖とを含む、請求項1~9のいずれか一項に記載の抗体又はその抗原結合断片。
- 配列番号15のアミノ酸配列を含むVHと、配列番号13のアミノ酸配列を含むVLとを含む抗体と同じS.アウレウス(S.aureus)ロイコトキシンエピトープに結合する抗体又はその抗原結合断片。
- S.アウレウス(S.aureus)ロイコトキシンへの、配列番号15のアミノ酸配列を含むVHと、配列番号13のアミノ酸配列を含むVLとを含む抗体の結合を競合的に阻害する抗体又はその抗原結合断片。
- (a)LukF、LukD若しくはHlgBに結合し、且つ/又は(b)LukF、LukD若しくはHlgBを中和する、請求項1~13のいずれか一項に記載の抗体又はその抗原結合断片。
- (a)LukF、LukD及びHlgBに結合し、且つ/又は(b)LukF、LukD及びHlgBを中和する、請求項1~14のいずれか一項に記載の抗体又はその抗原結合断片。
- 重鎖定常領域を更に含む、請求項1~15のいずれか一項に記載の抗体又はその抗原結合断片。
- 前記重鎖定常領域は、ヒト免疫グロブリンIgG1、IgG2、IgG3、IgG4、IgA1及びIgA2重鎖定常領域からなる群から選択される、請求項16に記載の抗体又はその抗原結合断片。
- 前記重鎖定常領域は、ヒトIgG1定常領域である、請求項17に記載の抗体又はその抗原結合断片。
- 軽鎖定常領域を更に含む、請求項1~18のいずれか一項に記載の抗体又はその抗原結合断片。
- 前記軽鎖定常領域は、ヒト免疫グロブリンIgGκ及びIgGλ軽鎖定常領域からなる群から選択される、請求項19に記載の抗体又はその抗原結合断片。
- 前記軽鎖定常領域は、ヒトIgGκ軽鎖定常領域である、請求項20に記載の抗体又はその抗原結合断片。
- IgG抗体又はその抗原結合断片である、請求項1~21のいずれか一項に記載の抗体又はその抗原結合断片。
- 半減期を改善するように操作されているFc領域を含む、請求項1~22のいずれか一項に記載の抗体又はその抗原結合断片。
- YTE変異を有するFc領域を含む、請求項1~23のいずれか一項に記載の抗体又はその抗原結合断片。
- モノクローナル抗体又は抗原結合断片である、請求項1~24のいずれか一項に記載の抗体又はその抗原結合断片。
- 完全長の抗体である、請求項1~25のいずれか一項に記載の抗体又はその抗原結合断片。
- 抗原結合断片である、請求項1~9又は12~26のいずれか一項に記載の抗体又はその抗原結合断片。
- Fab、Fab’、F(ab’)2、一本鎖Fv(scFv)、ジスルフィド連結Fv、イントラボディ、IgGΔCH2、ミニボディ、F(ab’)3、テトラボディ、トリアボディ、ダイアボディ、DVD-Ig、Fcab、mAb2、(scFv)2又はscFv-Fcを含む、請求項27に記載の抗原結合断片。
- S.アウレウス(S.aureus)のLukF、LukD及びHlgBに対する75pM未満の親和性を有する、請求項1~28のいずれか一項に記載の抗体又はその抗原結合断片。
- LukF、LukD及びHIgBに対する類似した結合親和性を有する、請求項1~29のいずれか一項に記載の抗体又はその抗原結合断片。
- 検出可能な標識を更に含む、請求項1~30のいずれか一項に記載の抗体又はその抗原結合断片。
- 請求項1~31のいずれか一項に記載の抗体又はその抗原結合断片と、任意選択的に、薬学的に許容される担体とを含む組成物。
- 対象においてスタフィロコッカス・アウレウス(Staphylococcus aureus)(S.アウレウス(S.aureus))感染症を処置又は予防する方法であって、請求項1~31のいずれか一項に記載の抗体若しくは抗原結合断片又は請求項32に記載の組成物を前記対象に投与することを含む方法。
- 前記S.アウレウス(S.aureus)感染症は、敗血症である、請求項33に記載の方法。
- 前記S.アウレウス(S.aureus)感染症は、菌血症である、請求項33に記載の方法。
- 前記S.アウレウス(S.aureus)感染症は、肺炎である、請求項33に記載の方法。
- 前記S.アウレウス(S.aureus)感染症は、ICU肺炎である、請求項33に記載の方法。
- 前記S.アウレウス(S.aureus)感染症は、皮膚又は軟組織感染症(SSTI)である、請求項33に記載の方法。
- 前記S.アウレウス(S.aureus)感染症は、下肢の糖尿病性感染症である、請求項33に記載の方法。
- 前記S.アウレウス(S.aureus)感染症は、糖尿病性足部潰瘍(DFU)である、請求項33に記載の方法。
- 前記DFUは、非感染である、請求項40に記載の方法。
- 前記DFUは、感染である、請求項40に記載の方法。
- 前記DFUは、グレード1、2又は3のDFUである、請求項40に記載の方法。
- 前記S.アウレウス(S.aureus)感染症は、骨又は関節の感染症である、請求項33に記載の方法。
- 前記S.アウレウス(S.aureus)感染症は、関節感染症、器具感染症、創傷感染症、手術部位感染症又は骨髄炎である、請求項33に記載の方法。
- 前記対象は、手術対象である、請求項33~45のいずれか一項に記載の方法。
- 前記S.アウレウス(S.aureus)感染症は、抗生物質耐性S.アウレウス(S.aureus)を含む、請求項33~46のいずれか一項に記載の方法。
- 前記対象は、糖尿病を有する、請求項33~47のいずれか一項に記載の方法。
- 前記対象は、ヒトである、請求項33~48のいずれか一項に記載の方法。
- S.アウレウス(S.aureus)感染症を前記処置又は予防することは、毒素の中和、細胞溶解を阻害すること、多臓器不全を阻害すること、S.アウレウス(S.aureus)関連敗血症を阻害すること又は前述のものの任意の組み合わせを含む、請求項33~49のいずれか一項に記載の方法。
- 請求項1~30のいずれか一項に記載の抗体又はその抗原結合断片の前記VH又は重鎖をコードする核酸分子を含む、単離されたポリヌクレオチド。
- 請求項1~30のいずれか一項に記載の抗体又はその抗原結合断片の前記VL又は軽鎖をコードする核酸分子を含む、単離されたポリヌクレオチド。
- 請求項51及び/又は52に記載のポリヌクレオチドを含む、単離されたベクター。
- 請求項51及び/若しくは52に記載のポリヌクレオチド、請求項53に記載のベクター又は請求項51に記載のポリヌクレオチドを含む第1のベクター及び請求項52に記載のポリヌクレオチドを含む第2のベクターを含む宿主細胞。
- CHO、NS0、PER-C6、HEK-293及びHeLa細胞からなる群から選択される、請求項54に記載の宿主細胞。
- 単離されている、請求項54又は55に記載の宿主細胞。
- 抗体又はその抗原結合断片を作製する方法であって、前記抗体又はその抗原結合断片が産生されるように、請求項54~56のいずれか一項に記載の宿主細胞を培養することを含む方法。
- サンプル中のS.アウレウス(S.aureus)又はS.アウレウス(S.aureus)ロイコトキシンを検出する方法であって、前記サンプルを、請求項1~31のいずれか一項に記載の抗体又はその抗原結合断片と接触させることを含む方法。
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