JP2021530511A - 抗pd−1抗体、投薬量、およびその使用 - Google Patents
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Abstract
Description
本出願は、2018年7月19日に出願されたPCT出願第PCT/CN2018/096206号の優先権の恩典および優先権を主張する。本出願の内容は、その全体が参照により本明細書に組み込まれている。
ASCIIテキストファイルでの以下の提出物の内容は、その全体が参照により本明細書に組み込まれている:コンピューター読み取り可能な形態(CRF)の配列表(ファイル名:792572000940SEQLIST.TXT、記録日:2019年7月17日、サイズ:36KB)。
抗PD治療は、ヒトがん、特に固形腫瘍に対する免疫療法において中心的な位置を占めている。この治療は、全身免疫応答をブーストすること、またはがんに対するde novo免疫を生成することを主にねらいとするこれまでの免疫療法剤とは異なる;その代わりに、抗PD治療は腫瘍部位での免疫応答を調節し、腫瘍誘導性の免疫欠損を標的とし、進行中の免疫応答を修復する。多様なヒトがんの処置に関して抗PD治療が臨床で成功していることからこのアプローチが確証されているが、本発明者らはなおもこの経路および関連する免疫応答を研究中であり、これは、がん免疫療法における新規の臨床応用可能なアプローチの発見および設計を助けるであろう。
用語「1つの(a)」または「1つの(an)」実体は、その実体の1つまたは複数を指すことに注意すべきである;例えば「1つの抗体」は、1つまたは複数の抗体を表すと理解される。そのため、用語「1つの(または1つの(an))」、「1つまたは複数」、および「少なくとも1つ」は、本明細書において互換的に使用することができる。
本開示は、ヒトPD−1タンパク質に対して高い親和性を有する抗PD−1抗体を提供する。試験される抗体は、強力な結合活性および阻害活性を示し、治療的使用および診断的使用にとって有用である。さらに、試験したヒト化抗体の1つ(TY101)は、FDAが承認した2つの抗hPD−1抗体より有意に高い結合親和性を示した。
PD−1は、免疫チェックポイント分子であり、腫瘍抗原でもある。腫瘍抗原標的化分子として、PD−1に特異的な抗体または抗原結合性断片を、免疫細胞に特異的な第2の抗原結合性断片と組み合わせて、二特異性抗体を生成することができる。
一部の実施形態では、本開示は、本明細書に記載される抗体またはその断片をコードするヌクレオチド配列を含むポリヌクレオチドを提供する。
本明細書に記載されるように、本開示の抗体、バリアント、または誘導体は、ある特定の処置および診断方法において使用することができる。
実験例において実証するように、本開示の抗体は、感染症を処置するために有用であり得る免疫応答を活性化することができる。
PD−1の過剰発現は、ある特定の腫瘍試料において観察され、PD−1過剰発現細胞を有する患者は、本開示の抗PD−1抗体による処置に応答する可能性が高い。したがって、本開示の抗体はまた、診断目的および予後判定目的のために使用することもできる。
本開示はまた、医薬組成物も提供する。そのような組成物は、有効量の抗体および許容される担体を含む。一部の実施形態では、組成物は、第2の抗がん剤(例えば、免疫チェックポイント阻害剤)をさらに含む。
全長のヒトPD−1 cDNAのクローニング
ヒトTリンパ球を、ヒト末梢血リンパ球(PBMC)からMACSビーズ(MiltenyiBiotec)によって単離した。総RNAを、RNeasy Mini Kit(QIAGEN)によってヒトT細胞から抽出し、cDNAを、逆転写PCR(SuperScript First−Strand Synthesis System、Invitrogen)によって得た。hPD−1をコードする全長のcDNAを、ヒトT細胞mRNAからのセンスプライマー(5’−CTGTCTAGAATGCAGATCCCACAGGCGCC、配列番号47)およびアンチセンスプライマー(5’−GGATCCTCAGAGGGGCCAAGAGCAGT、配列番号48)を使用してRT−PCRによって生成した。配列を、DNAシークエンシング、およびNCBIデータベース(NM−005018.2)との比較によって確認した。
MAbのアイソタイプ:マウス免疫グロブリンアイソタイピングキット(BD Biosciences)を使用してmAbのアイソタイプを同定した。5つ全てのPD−1 mAbが、IgG1アイソタイプおよびκ鎖であることが同定された。
抗PD−1抗体産生ハイブリドーマのシークエンシング:1×107個のハイブリドーマ細胞を回収してPBSによって洗浄した。メッセンジャーRNAを、RAeasy Mini Kit(Qiagen)を使用してハイブリドーマから抽出した。RACE−Ready第1鎖cDNAを、SMARTer RACE cDNA増幅キット(Clontech)を使用して合成した。逆転写後、5’RACE PCR反応を、鋳型としてのready cDNA、ならびにキットによって供給された5’ユニバーサルプライマー(UPM)、ならびにマウスIgG重鎖可変領域およびκ軽鎖遺伝子配列によって設計された3’遺伝子特異的プライマー(GSP1)によって実施した。RACE産物を、ゲル電気泳動分析によって決定した(図6)。PCR産生物を、Zero Blunt TOPO PCRクローニングキット(Invitrogen)を使用してTベクターにクローニングした。形質転換後、プラスミドをシークエンシング分析によって確認した。抗体遺伝子断片を、VBASE2(http://www.vbase2.org)を使用して分析した。配列を(表2)に開示する。
表2.マウス抗体の配列
表3A.キメラ抗体(ヒトIgG4-S228P骨格)
表3B.ヒト化重鎖および軽鎖可変領域
表3C.様々なCDR定義での例示的な抗PD-1 CDR
ヒト化抗体の結合活性:CHO/hPD−1細胞を、連続希釈したmAbと共にインキュベートした。9つのヒト化抗体のPD−1タンパク質に対する結合効果を、フローサイトメトリー分析を使用して評価し、キメラ親抗体と比較した。
表4.ヒト化抗体の結合親和性および動態の決定
PBMCにおけるサイトカイン増強混合リンパ球反応(MRL)。健康な個体からのヒト末梢血単核細胞(PBMC)を、Ficoll−Hypaqueを使用する密度勾配遠心分離によって単離した。健康なドナー1からのPBMCに、40Gyの線量のX線を照射し、スティミュレーター細胞とした。Tリンパ球を、ヒト汎T細胞単離キット(MiltenylBiotec)によって健康なドナー2から単離し、レスポンダー細胞とした。レスポンダー細胞およびスティミュレーター細胞を、10%FCSを含有する完全RPMI培地に再懸濁し、TY101またはhIgG対照の連続希釈物の存在下で、96ウェルプレートにウェルあたり2.5×105個のレスポンダー細胞および1.25×105個のスティミュレーター細胞(R/S=2)を播種した。細胞を、5%CO2の湿潤インキュベーター内で、37℃で5日間培養した。T細胞の増殖活性を、5日目に細胞計数キット−8(Dojindo Molecular Technologies、Inc)によって評価した。サイトカインを検出するために、培養上清を3日目および5日目に収集した。サイトカイン分析を、ヒトTh1/Th2/Th17細胞測定ビーズアレイキット(CBA;BD Biosciences)を使用して実施した。
本実施例は、TY101と比較するために、がん患者の臨床的処置のために現在承認されている2つの抗hPD−1抗体を選択した:MerckのKeytruda(ペンブロリズマブ)およびBristol−Myers SquibbのOpdivo(ニボルマブ)。
TY101の配列を、専売の発現ベクターにクローニングし、CHO細胞にトランスフェクトした。単クローン性の細胞株を、ClonePixおよび/または限界希釈を使用して樹立した。複数のクローンを樹立し、そのような3つのクローンによって産生された抗体(TY101−01−09、TY101−04−T3−05、およびTY101−4G1)を特徴付けした。
抗体のhPD−1に対する結合およびmPD−1タンパク質に対する交差反応性を、ELISAによって試験した。試験抗体の連続希釈物を、1μg/ml hPD−1またはmPD−1を予めコーティングしたELISAプレートに添加した。次いで、HRPコンジュゲートヤギ抗ヒトIgGまたはヤギ抗マウスIgG抗体を添加した後、基質テトラメチルベンジジン(TMB)を添加し、SpectraMax Plus 384マイクロプレートリーダー(Molecular Device,LLC.、Sunnyvale、CA)によって450nmの波長で定量した。試験したTY101クローン、TY101−01−09、TY101−04−T3−05、およびTY101−4G1は、0.01〜0.15nMの範囲のEC50でhPD−1タンパク質に対して良好な結合を示した。抗体は、mPD−1タンパク質に対する結合を示さなかった(図19)。
抗体のhPD−1に対する結合およびカニクイザルPD−1(cPD−1)に対する交差反応性を、フローサイトメトリーによって、hPD−1またはcPD−1発現CHOK1細胞を使用して試験した。CHOK1−hPD−1、CHOK1−cPD−1、およびCHOK1ブランク細胞を、試験物質の連続希釈物と共にインキュベートし、その後にAlexa Fluor(登録商標)488コンジュゲートヤギ抗ヒトIgG(H+L)抗体と共にインキュベートし、FACSCanto II(BD Biosciences、San Jose、CA)を使用して分析した。試験したTY101クローン、TY101−01−09、TY101−04−T3−05、およびTY101−4G1は、CHOK1−hPD−1に対してナノモル濃度より低いEC50で良好な結合を示し、CHOK1−cPD−1細胞に対して一桁のナノモル濃度EC50で良好な結合を示した(図20)。
これらの抗体を、がん患者の処置における潜在的有効性の鍵となる、hPD−1/hPD−L1ならびにhPD−1/hPD−L2結合を遮断する能力に関してさらに試験した。CHOK1−hPD−1細胞を、ビオチン−hPD−L1またはビオチン−hPD−L2と混合した試験物質の連続希釈物と共にインキュベートした。次いで、細胞をAlexa 488標識ストレプトアビジンと共にインキュベートし、FACSCanto IIを使用して分析した。抗hPD−1抗体TY101−01−09、TY101−04−T3−05、およびTY101−4G1は、hPD−L1のhPD−1発現CHOK1細胞に対する結合を1.15〜1.47nMのIC50で遮断した。それらはまた、hPD−L2のhPD−1発現CHOK1細胞に対する結合を1.52〜2.33nMのIC50で遮断した(図21)。
これらの抗体がT細胞機能に及ぼす効果を、2人のドナーから単離されたT細胞によるヒトMLRアッセイにおいて試験した。接着PBMC(ほとんどが単球;ドナー1から単離され、細胞培養皿に播種して接着させたもの)を、100ng/mLの組換えヒト(rh)GM−CSFおよび50ng/mLのrhIL−4の存在下で5日間培養し、培地の半分の体積を3日後に新しくし、1μg/mL LPSを6日目に添加した。7日目に、得られた細胞(ほとんどが成熟DC)を回収し、マイトマイシンCによって処置した。CD3+ T細胞を、ドナー2および3からEasySep(商標)ヒトT細胞単離キット(ネガティブセレクション、STEMCELL Technologies)によって単離した。DCおよびT細胞を、試験抗体の3つの濃度(5、0.5、0.05μg/ml)の存在下で5日間同時培養した。上清を3日後に回収して、IL−2レベルを決定し、5日後(100μL)にIFN−γレベルを決定した。抗hPD−1抗体TY101−01−09、TY101−04−T3−05、およびTY101−4G1は、アイソタイプ対照hIgG4と比較した場合に、用量依存的に両方のドナーからの細胞によるIL−2およびIFN−γの分泌を促進した(図22)。
これらの抗体がT細胞機能に及ぼす効果もまた、4人の異なるドナーから単離したT細胞を使用して、操作された腫瘍細胞−ヒトT細胞同時培養アッセイにおいて試験した。CD3+ T細胞を、4人のドナーのPBMCからEasySep(商標)ヒトT細胞単離キットによって単離した。OS8(抗CD3一本鎖可変断片(scFv))ならびにhPD−L1を安定に発現するように操作されたHep3B細胞(KCLB、カタログ番号:88064)である操作された腫瘍細胞Hep3B−OS8−hPDL1を、マイトマイシンCによって処置し、試験抗体の3つの濃度(5、0.5、0.05μg/ml)の存在下でCD3+ T細胞と共に3日間同時培養し、培養上清を回収してIFN−γレベルを決定した。抗hPD−1抗体TY101−01−09、TY101−04−T3−05、およびTY101−4G1は、アイソタイプ対照hIgG4と比較した場合に4人全てのドナーからの細胞によるIFN−γの分泌を用量依存的に促進した(図23)。
抗体エピトープ重複を試験するための競合的ELISA
これらの抗体がFDA承認抗hPD−1抗体であるニボルマブまたはペンブロリズマブと同じエピトープに結合するか否かを、競合的ELISAアッセイにおいて試験した。競合抗体の連続希釈物およびビオチン−hPD−1を、1μg/mlの試験抗体によって予めコーティングしたELISAプレートに添加した。次いで、HRPコンジュゲートストレプトアビジンを添加し、その後、基質TMBを添加し、SpectraMax Plus 384マイクロプレートリーダーによって波長450nmで定量した。抗hPD−1抗体TY101−01−09、TY101−04−T3−05、およびTY101−4G1は、hPD−1に対する互いの結合をほぼ完全に遮断し、それらが類似のエピトープを共有することを示唆する。3つの抗体はまた、ニボルマブおよびペンブロリズマブのhPD−1に対する結合もほぼ完全に(93%〜94%)遮断したが、ニボルマブおよびペンブロリズマブは、これらの抗体のhPD−1に対する結合をごく部分的に遮断した(ニボルマブに関して77%〜78%、ペンブロリズマブに関して46%〜49%)。これらのデータは、TY101−01−09、TY101−04−T3−05、およびTY101−4G1抗体が、ニボルマブおよびペンブロリズマブとは異なるエピトープに結合し、それらがhPD−1に対してニボルマブおよびペンブロリズマブより高い親和性を有し得ることを示唆している(図24)。
hPD−1に対する結合親和性の正確な測定を得るために、抗体TY101−01−09、TY101−04−T3−05およびTY101−4G1、ならびにニボルマブおよびペンブロリズマブを、SPRによって分析した。ヒトPD−1 ECDタンパク質を、フローセル3において低い固定レベル(60RU)およびフローセル4において高い固定レベル(960RU)を達成するために異なる長さの時間、CM5センサーチップ上に固定した。連続希釈した(0、1.5625、3.125、6.25、12.5、25、および50nM)抗体を、フローセルに注入した。結合時間は180秒であり、解離時間は600秒(ニボルマブおよびペンブロリズマブに関して)または1500秒(TY101−01−09、TY101−04−T3−05、およびTY101−4G1に関して)であった。参照(フローセル1)およびゼロ濃度の両方のシグナルを試料のシグナルから差し引いた後、結合動態を、Biacore T200評価ソフトウェアバージョン1.0およびカーブフィッティングのために1:1結合モデルを使用して計算した。対照ヒトIgG4のhPD−1に対する結合は認められなかった。hPD−1の低い固定レベル(約60RU;表3;図23)からのデータに基づき、抗hPD−1抗体TY101−01−09、TY101−04−T3−05、およびTY101−4G1によるヒトPD−1に対する結合速度は、ニボルマブおよびペンブロリズマブの結合速度よりわずかに低かった(1/2〜1/4)。これら3つの抗体のヒトPD−1からの解離速度は、ニボルマブおよびペンブロリズマブの1/12〜1/30であり、ニボルマブおよびペンブロリズマブの親和性より4〜8倍良好な親和性をもたらした(より低いKDは、より良好な親和性に対応し、その逆も同様である;表3)。抗hPD−1抗体TY101−01−09、TY101−04−T3−05、およびTY101−4G1のhPD−1に対する結合親和性をまた、hPD−1の高い固定レベルでも試験した。抗体TY101−01−09、TY101−04−T3−05、およびTY101−4G1は、非常に遅い解離速度を示し、最小の解離は、1500秒の解離時間後でさえ観察された(図23)。データは、TY101−01−09、TY101−04−T3−05、およびTY101−4G1の結合親和性が、主に遅い解離速度によりニボルマブおよびペンブロリズマブの結合親和性より良好であったことを示唆した(図25)。
TY101の薬物動態を評価するために、全体で18匹のカニクイザルを、3匹/性別/群で3つの群に割付した。TY101をそれぞれ、1、3、および10mg/kgの用量レベルで静脈内注入によって注射した。各投薬は、注射ポンプを使用して右後肢を通して投与した。注入速度は、30mL/kg/hであった。用量体積は10mL/kgであった。確証されたELISA法を、動物血漿中でのTY101の定量のために使用した。薬物動態分析のためにEDTA−K2抗凝固剤を有するおよそ1mLの血液試料を、群1〜3において、投与前、注入終了の直前直後(±1分)、ならびに注入開始後2、6、24(D2)、48(D3)、72(D4)、96(D5)、120(D6)、168(D8)、240(D11)、336(D15)、408(D18)、504(D22)、576(D25)、および672(D29)時間に左後肢の皮下静脈から収集した。血液試料を、薬物動態分析のための血漿の調製のために使用した。
AUC比=TY101の平均AUC(0-672h)/OPDIVO(登録商標)の平均AUC(0-672h)
Claims (21)
- がん、感染症、または免疫障害の処置を必要とする患者におけるがん、感染症、または免疫障害を処置する方法であって、1つまたは複数の用量の、ヒトプログラム細胞死タンパク質1(PD−1)に対して特異性を有する単離された抗体またはその断片を前記患者に投与するステップを含み、各用量が約1mg/kg〜約10mg/kgである、方法。
- 各用量が、約1mg/kg、約3mg/kg、または約10mg/kgである、請求項1に記載の方法。
- 各用量が3mg/kgである、請求項2に記載の方法。
- 前記抗体またはその断片が、
重鎖相補性決定領域HCDR1、HCDR2、およびHCDR3を含む重鎖可変領域、ならびに軽鎖相補性決定領域LCDR1、LCDR2、およびLCDR3を含む軽鎖可変領域を含み、前記HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、およびLCDR3が、
(a)HCDR1:GFTFSSYT(配列番号1)、HCDR2:ISHGGGDT(配列番号2)、HCDR3:ARHSGYERGYYYVMDY(配列番号3)、LCDR1:ESVDYYGFSF(配列番号4)、LCDR2:AAS(配列番号5)、LCDR3:QQSKEVPW(配列番号6);
(b)HCDR1:GYTFTSYT(配列番号7)、HCDR2:INPTTGYT(配列番号8)、HCDR3:ARDDAYYSGY(配列番号9)、LCDR1:ENIYSNL(配列番号10)、LCDR2:AAK(配列番号11)、LCDR3:QHFWGTPWT(配列番号12);および
(c)HCDR1:GFAFSSYD(配列番号13)、HCDR2:ITIGGGTT(配列番号14)、HCDR3:ARHRYDYFAMDN(配列番号15)、LCDR1:ENVDNYGINF(配列番号16)、LCDR2:VSS(配列番号17)、LCDR3:QQSKDVPW(配列番号18)
からなる群より選択される、請求項1〜3のいずれか一項に記載の方法。 - 前記抗体またはその断片が、重鎖定常領域、軽鎖定常領域、Fc領域、またはその組合せをさらに含む、請求項4に記載の方法。
- 前記抗体またはその断片が、軽鎖定常領域を含み、前記軽鎖定常領域がカッパまたはラムダ鎖定常領域である、請求項5または6に記載の方法。
- 前記抗体またはその断片が、IgG、IgM、IgA、IgE、またはIgDのアイソタイプのものである、請求項1〜6のいずれか一項に記載の方法。
- 前記アイソタイプが、IgG1、IgG2、IgG3、またはIgG4である、請求項7に記載の方法。
- 前記抗体またはその断片が、キメラ抗体、ヒト化抗体、または完全なヒト抗体である、請求項1〜8のいずれか一項に記載の方法。
- 前記抗体またはその断片が、ヒト化抗体である、請求項9に記載の方法。
- 前記抗体またはその断片が、配列番号35、配列番号37、配列番号39のアミノ酸配列、または配列番号35、配列番号37、もしくは配列番号39と少なくとも95%の配列同一性を有するアミノ酸配列を含む重鎖可変領域を含む、請求項1〜10のいずれか一項に記載の方法。
- 前記抗体またはその断片が、配列番号41、配列番号43、配列番号45のアミノ酸配列、または配列番号41、配列番号43、もしくは配列番号45と少なくとも95%の配列同一性を有するアミノ酸配列を含む、請求項1〜10のいずれか一項に記載の方法。
- 前記抗体またはその断片が、
重鎖相補性決定領域HCDR1、HCDR2、およびHCDR3を含む重鎖可変領域、ならびに軽鎖相補性決定領域LCDR1、LCDR2、およびLCDR3を含む軽鎖可変領域を含み、前記HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、およびLCDR3が、
(a)HCDR1:GFTFSSYT(配列番号1)、HCDR2:ISHGGGDT(配列番号2)、HCDR3:ARHSGYERGYYYVMDY(配列番号3)、LCDR1:ESVDYYGFSF(配列番号4)、LCDR2:AAS(配列番号5)、LCDR3:QQSKEVPW(配列番号6);
(b)HCDR1:GYTFTSYT(配列番号7)、HCDR2:INPTTGYT(配列番号8)、HCDR3:ARDDAYYSGY(配列番号9)、LCDR1:ENIYSNL(配列番号10)、LCDR2:AAK(配列番号11)、LCDR3:QHFWGTPWT(配列番号12);
(c)HCDR1:GFAFSSYD(配列番号13)、HCDR2:ITIGGGTT(配列番号14)、HCDR3:ARHRYDYFAMDN(配列番号15)、LCDR1:ENVDNYGINF(配列番号16)、LCDR2:VSS(配列番号17)、LCDR3:QQSKDVPW(配列番号18);および
(d)(a)〜(c)に示されるHCDR1、HCDR2、HCDR3、LCDR1、LCDR2、およびLCDR3であって、ただしそのうちの少なくとも1つが、1つ、2つ、または3つのアミノ酸付加、欠失、保存的アミノ酸置換、またはその組合せを含む、HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、およびLCDR3
からなる群より選択される、請求項1〜3のいずれか一項に記載の方法。 - 前記HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、およびLCDR3が、(a)〜(c)のいずれか1つに示されるとおりであるが、そのうちの1つが保存的アミノ酸置換を含む、請求項13に記載の方法。
- 前記HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、およびLCDR3が、(a)〜(c)のいずれか1つに示されるとおりであるが、そのうちの2つが、各々保存的アミノ酸置換を含む、請求項13に記載の方法。
- 前記HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、およびLCDR3が、(a)〜(c)のいずれか1つに示されるとおりであるが、そのうちの3つが各々保存的アミノ酸置換を含む、請求項13に記載の方法。
- 前記方法ががんを処置するためであり、前記がんが、膀胱がん、肝臓がん、結腸がん、直腸がん、子宮内膜がん、白血病、リンパ腫、膵臓がん、小細胞肺がん、非小細胞肺がん、乳がん、尿道がん、頭頸部がん、消化器がん、胃がん、食道がん、卵巣がん、腎臓がん、黒色腫、前立腺がん、および甲状腺がんからなる群より選択される、請求項1〜16のいずれか一項に記載の方法。
- 前記方法が感染症を処置するためであり、前記感染症が、ウイルス感染症、細菌感染症、真菌感染症、または寄生生物による感染症である、請求項1〜16のいずれか一項に記載の方法。
- 前記方法が免疫障害を処置するためであり、前記免疫障害が、感染症、感染症に関連するエンドトキシンショック、関節炎、関節リウマチ、喘息、COPD、骨盤腹膜炎、アルツハイマー病、炎症性腸疾患、クローン病、潰瘍性大腸炎、ペロニー病、セリアック病、胆嚢疾患、毛巣病、腹膜炎、乾癬、血管炎、外科的癒着、卒中、I型糖尿病、ライム病、関節炎、髄膜脳炎、自己免疫性ぶどう膜炎、中枢および末梢神経系の免疫媒介性炎症障害、多発性硬化症、狼瘡およびギラン・バレー症候群、アトピー性皮膚炎、自己免疫性肝炎、線維化肺胞炎、グレーヴス病、IgA腎症、特発性血小板減少性紫斑病、メニエール病、天疱瘡、原発性胆汁性肝硬変、サルコイドーシス、強皮症、ウェゲナー肉芽腫症、膵炎、外傷、移植片対宿主病、移植片の拒絶、虚血疾患、心筋梗塞、アテローム性動脈硬化症、血管内凝固、骨吸収、骨粗鬆症、変形性関節炎、歯周炎、低塩酸症、および母子間免疫寛容の欠如に関連する不妊症からなる群より選択される、請求項1〜16のいずれか一項に記載の方法。
- 前記方法が感染症を処置するためであり、前記感染症が肝炎である、請求項1〜16のいずれか一項に記載の方法。
- 前記肝炎が、A型肝炎、B型肝炎、C型肝炎、D型肝炎、およびE型肝炎から選択される、請求項21に記載の方法。
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