JP6784724B2 - 改善された二重特異性ポリペプチド分子 - Google Patents
改善された二重特異性ポリペプチド分子 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1036—Retroviridae, e.g. leukemia viruses
- C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2833—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
- C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
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- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
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- C07K2317/32—Immunoglobulins specific features characterized by aspects of specificity or valency specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
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- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/626—Diabody or triabody
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- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
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- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Description
第1のポリペプチド鎖は、ヒト免疫エフェクター細胞の細胞表面抗原に特異的に結合する抗体の可変ドメイン(VD1)の第1の結合領域を含んでなり、TCRの可変ドメイン(VR1)の第1の結合領域は、MHC関連ペプチドエピトープに特異的に結合し、第1のリンカー(LINK1)は前記ドメインを連結し;
第2のポリペプチド鎖は、MHC関連ペプチドエピトープに特異的に結合するTCRの可変ドメイン(VR2)の第2の結合領域を含んでなり、抗体の可変ドメイン(VD2)の第2の結合領域は、ヒト免疫エフェクター細胞の細胞表面抗原に特異的に結合し、第2のリンカー(LINK2)は前記ドメインを連結し;
前記第1の結合領域(VD1)および前記第2の結合領域(VD2)は結合して、細胞表面分子のエピトープに結合する第1の結合部位(VD1)(VD2)を形成し;
前記第1の結合領域(VR1)および前記第2の結合領域(VR2)は結合して、前記MHC関連ペプチドエピトープに結合する第2の結合部位(VR1)(VR2)を形成し;
前記2つのポリペプチド鎖は、ヒトIgGヒンジドメインおよび/またはヒトIgGFcドメインまたはその二量体化部分に融合し;前記2つのポリペプチド鎖は、前記ヒンジドメインおよび/またはFcドメイン間の共有結合および/または非共有結合によって連結され;
前記二重特異性ポリペプチド分子は、細胞表面分子およびMHC関連ペプチドエピトープに同時に結合でき、二重特異性ポリペプチド分子中では、ポリペプチド鎖中の結合領域の順序が、VD1−VR1;VD1−VR2;VD2−VR1;VD2−VR2;VR1−VD1;VR1−VD2;VR2−VD1;VR2−VD2から選択され、ドメインはLINK1またはLINK2のどちらかによって連結される。
IgG1:E216PKSCDKTHTCPPCPAPELLG(配列番号1)
IgG2:E216RKCCVECPPCPAPPVAGP(配列番号2)
IgG3:ELKTPLGDTTHTCPRCPEPKSCDTPPPCPRCPE216PKSCDTPPPCPRCPAPELLG(配列番号3)
IgG4:E216SKYGPPCPSCPAPEFLG(配列番号4)。
コアヒンジ領域は、通常、2つの重鎖を連結する少なくとも1つのシステイン架橋を含有する。さらに、望ましくない抗体依存性細胞媒介性細胞傷害(ADCC)を改善するために、下部ヒンジ領域に変異を作製し得る。
231−APPVA−GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEK−334(配列番号5);
および
231−APPVA−GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEK−334(配列番号6)、変化は下線で強調され、297位に、N(グリコシル化変異型)が、またはA、G、およびQ(脱グリコシル化変異型)の群から選択される残基がある。
一態様では、VD1は、配列番号28のアミノ酸配列と、少なくとも50%、少なくとも55%、少なくとも60%、少なくとも65%、少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも91%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%の同一性を有してもよい。
一態様では、Fc領域は、配列番号26または配列番号6のアミノ酸配列と、少なくとも50%、少なくとも55%、少なくとも60%、少なくとも65%、少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも91%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%の同一性を有してもよい。
一態様では、本明細書で開示されるようなポリペプチドまたは二重特異性ポリペプチド分子は、ポリペプチド鎖内の異なる、場合により選択的な部位における、1つまたは複数の残基の置換によって修飾され得る。このような置換は、保存的性質であってもよく、例えば、疎水性アミノ酸が別の疎水性アミノ酸によって置換されるなど、構造および特徴の類似したアミノ酸によってアミノ酸が置換される。さらにより保存的な置換は、ロイシンのイソロイシンによる置換などの、同一または類似サイズおよび化学的性質のアミノ酸の置換である。天然起源相同タンパク質ファミリーの配列多様性の研究では、特定のアミノ酸置換は、他よりも耐容されることが多く、これらは、元のアミノ酸とその置換物との間のサイズ、電荷、極性、および疎水性の類似性との相関を示すことが多く、これが「保存的置換」の定義の基礎である。
Fc含有二重特異性TCR/mAb二特異性抗体および対照分子の設計
Fc含有二重特異性TCR/mAb二特異性抗体および対照分子(図2に示される)は、ヒトTCR−CD3複合体と、HLA−A2*01に結合したHIV由来ペプチドSLYNTVATL(配列番号7)を含んでなるペプチド:MHC複合体とに、特異的に結合するように設計した。TCR−CD3複合体を標的化するために、Zhu et al.(Identification of heavy chain residues in a humanized anti−CD3 antibody important for efficient antigen binding and T cell activation.J Immunol,1995,155,1903−1910)によって記載された、CD3特異的ヒト化抗体hUCHT1(V9)に由来するVHおよびVLドメイン、またはShearman et al.(Construction,expression and characterization of humanized antibodies directed against the human alpha/beta T cell receptor.J Immunol,1991,147,4366−73)に記載され、ヒト化バージョン変異型10で用いられた(自社内データ)、α/βTCR−特異的抗体BMA031に由来するVHおよびVLドメインを使用した。ペプチド:MHC複合体を標的化するために、Aggen et al.(Identification and engineering of human variable regions that allow expression of stable single−chain T cell receptors.PEDS,2011,24,361−372)によって開示された、前述の安定性および親和性成熟ヒト一本鎖T細胞受容体868Z11のVαおよびVβドメインを使用した。
Fc含有二重特異性TCR/mAb二特異性抗体の製造および精製
組換えタンパク質の発現のためのベクターは、HCMV由来のプロモーター要素であるpUC19誘導体によって制御される単シストロン性として設計した。プラスミドDNAは、標準的な培養法に従って大腸菌(E.coli)において増幅し、引き続いて商業的に入手できるキット(Macherey & Nagel)を用いて精製した。精製されたプラスミドDNAは、製造業者の取扱説明書(ExpiCHO(商標)システム;Thermo Fisher Scientific)に従って、CHO−S細胞の一過性形質移入に使用した。形質移入されたCHO細胞を32℃〜37℃で6〜14日間培養し、ExpiCHO(商標)供給液を1〜2回与えた。
Fc含有TCR/mAb二重特異性抗体によって誘導される特異的かつ標的細胞依存性のT細胞活性化
T細胞活性化に対するFc含有TCR/mAb二特異性抗体の効力は、細胞活性化生物検定(Promega)を用いて評価した。アッセイは、NFAT応答要素(NFAT−RE)によって駆動されるルシフェラーゼレポーターを発現する、遺伝子操作されたジャーカット細胞株からなる。アッセイは、製造業者に従って実施した。簡潔に述べると、HIV特異的ペプチドSLYNTVATL(配列番号7)が負荷されたT2細胞、またはペプチド負荷のないT2細胞(未負荷対照)を、漸増する濃度の二重特異性TCR/mAb分子の存在下で、Promegaの改変ジャーカット細胞と共に引き続いて共培養した。ジャーカットレポーターT細胞の活性化は、ルミネセンス強度を測定することによって16〜20時間後に分析した。
分子プラットフォームとしてのFc含有二重特異性TCR/mAb二特異性抗体の開発
Fc含有二重特異性TCR/mAb二特異性抗体コンストラクトは、分子プラットフォームの役割を果たして、異なるペプチド:MHC複合体およびエフェクター細胞表面抗原をそれぞれ標的化する、異なるTCR由来およびmAb由来可変ドメインにスキャフォールドを提供するように、設計された。プラットフォームとしての適合性を検証するために、mAb由来可変ドメインを第1の分子セットで交換した。hUCHT1(V9)抗CD3抗体の可変ドメインは、同一ドメイン配向(コンストラクトID_4およびID_5)または異なる配向(IC_4、IC_5)を用いて、hBMA031(var10)抗TCR抗体のドメインで交換した。これらの分子の発現、精製、および特性決定は、上述したように実施した。HPLC−SEC分析によれば、最終調製物の純度および完全性は92%を超えた。
Fc含有二重特異性TCR/mAb二特異性抗体の安定性
二重特異性TCR/mAb分子の安定性は、最初に、ProteinThermal Shift Assay(Thermo Fisher Scientific)を使用して、7500リアルタイムPCRシステム(Applied Biosciences)を用いて、製造業者の取扱説明書に従って評価した。簡潔に述べると、精製された分子をPTS緩衝液およびPTS色素と混合し、サンプルの蛍光を絶えずモニタリングしながら、上昇する温度勾配に供した。記録された蛍光シグナルをPTSソフトウェア(Thermo Fisher Scientific)を用いて分析し、融解温度(TM)を微分法によって計算した。
がん標的化二重特異性TCR/mAb二特異性抗体分子の作製
二重特異性TCR/mAb二特異性抗体コンストラクトのプラットフォーム能力をさらに検証するために、TCR由来可変ドメインを、以前に記載されている方法(Smith et al,2015,T Cell Receptor Engineering and Analysis Using the Yeast Display Platform.Methods Mol Biol.1319:95−141)に従って、酵母ディスプレイによって安定性/親和性成熟された、TCRの可変ドメインで交換した。HLA−A*02の文脈で、HIV由来ペプチドSLYNTVATL(配列番号7)に特異的に結合するTCR可変ドメインを、HLA−A*02に結合した腫瘍関連ペプチドPRAME−004(配列番号49)に特異的に結合するTCR可変ドメインで交換した。さらに、ヒト化T細胞動員抗体hUCHT1(V9)の可変ドメインを、UCHT1抗体の新規ヒト化バージョンであるhUCHT1(Var17)の可変ドメインで交換し、PRAME−004−標的化TCR/mAb二特異性抗体分子IA_5(配列番号43および配列番号44を含んでなる)を得た。この分子の発現、精製、および特性決定は、実施例2に記載したように実施した。HPLC−SEC分析によれば、最終調製物の純度および完全性は96%を超えた。
TCR/mAb二特異性抗体コンストラクトの操作性
コンストラクトIA_5で使用された可変TCRドメインを、PRAME−004に対する親和性およびTCR安定性に関してさらに増強して使用し、TCR/mAb二特異性抗体スキャフォールドに操作して、コンストラクトIA_6(配列番号45および配列番号46を含んでなる)をもたらした。TCR/mAb二特異性抗体分子IA_5およびIA_6の発現、精製、および特性決定は、実施例2に記載のように行った。HPLC−SEC分析によれば、最終調製物の純度および完全性は97%を超えた。
好ましいコンストラクトの例
本明細書に記載のHIV特異的TCR二重特異性コンストラクト(配列番号16および配列ID番号17、Dの配向)に加えて、本発明は、試験されたいくつかのその他の例示的なHIV特異的コンストラクトをさらに提供する。これらのコンストラクトは、4つの可能な配向の全て(配列番号51〜配列番号58、配向A〜D)で、本明細書で開示されるようなHIV特異的TCR868と融合された、基礎となるCD3(UCHT1)に対する抗体の改良されたヒト化変異型に基づいている。
Claims (15)
- 第1のポリペプチド鎖および第2のポリペプチド鎖を含んでなる二重特異性ポリペプチド分子であって、
a)前記第1のポリペプチド鎖が、
a1)抗体の第1の可変ドメイン(VD1)、
a2)T細胞受容体(TCR)の第1の可変ドメイン(VR1)、および
a3)前記2つのドメインを連結する第1のリンカー(LINK1)
を含み、
b)前記第2のポリペプチド鎖が、
b1)TCRの第2の可変ドメイン(VR2)、
b2)抗体の第2の可変ドメイン(VD2)、および
b3)前記2つのドメインを連結する第2のリンカー(LINK2)
を含み、
前記第1の可変ドメイン(VD1)および前記第2の可変ドメイン(VD2)が結合して、ヒト免疫エフェクター細胞の細胞表面抗原に特異的に結合する第1の結合部位(VD1)(VD2)を形成し;
前記第1の可変ドメイン(VR1)がTCR由来VαドメインまたはTCR由来Vβドメインのいずれか一方であり、および前記第2の可変ドメイン(VR2)が第1の可変ドメイン(VR1)で選択されない他方のTCR由来VαドメインまたはTCR由来Vβドメインのいずれかであり、
前記第1の可変ドメイン(VR1)および前記第2の可変ドメイン(VR2)が結合して、前記MHC関連ペプチドエピトープに特異的に結合する第2の結合部位(VR1)(VR2)を形成し;
前記2つのポリペプチド鎖が、ヒトIgGヒンジドメインおよび/またはヒトIgG Fcドメインまたはその二量体化部分に融合し;
前記2つのポリペプチド鎖が、前記ヒンジドメインおよび/またはFc−ドメイン間の共有結合および/または非共有結合によって連結され;
前記二重特異性ポリペプチド分子が、前記細胞表面分子および前記MHC関連ペプチドエピトープに同時に結合でき、
前記2つのポリペプチド鎖中の前記可変ドメインの順序が、VD1−VR1およびVR2−VD2またはVD2−VR2およびVR1−VD1から選択される、二重特異性ポリペプチド分子。 - 前記リンカー配列LINK1および/またはLINK2が、GGGS、GGGGS、TVLRT、TVSSAS、およびTVLSSASから選択される、少なくとも1つの配列モチーフを含有する、請求項1に記載の二重特異性ポリペプチド分子。
- 前記第1および第2のポリペプチド鎖が、ヒトIgG1、IgG2またはIgG4由来のヒンジドメインおよびFcドメインまたはその部分を少なくともさらに含んでなる、または、前記Fcドメインが、233、234、235、236、297、および331位から選択される残基に少なくとも1つのエフェクター機能サイレンシング変異を含んでなり、好ましくは前記エフェクター機能サイレンシング変異が、233、234、235、236、および331位の少なくとも1つの残基をIgG2またはIgG4由来の対応する残基で置換することによって生成される、請求項1または2に記載の二重特異性ポリペプチド分子。
- 前記Fcドメインが、ヘテロ二量体の形成を促進する少なくとも1つの変異を含んでなるCH3ドメインを含んでなる、または、前記変異が366、368、405、および407から選択される任意の位置にあり、好ましくは前記変異がノブ・イン・ホール変異としてT366WおよびT366S、L368AおよびY407Vを含んでなる、請求項3に記載の二重特異性ポリペプチド分子。
- 前記Fcドメインが、例えば、S354CおよびY349CまたはL242CおよびK334Cなどの少なくとも2つの追加的なシステイン残基を含んでなるCH2およびCH3ドメインを含んでなる、請求項3または4に記載の二重特異性ポリペプチド分子。
- 前記抗体由来ドメインVD1およびVD2が、VD1およびVD2の間に共有結合を導入する操作されたジスルフィド架橋を提示し、システインが、VLの場合はフレームワーク領域(FR)4に、VHの場合はフレームワーク領域2に導入される、請求項1〜5のいずれか一項に記載の二重特異性ポリペプチド分子。
- 前記細胞表面分子が、免疫細胞の活性化を誘導することが知られており、またはCD3γ、CD3δ、およびCD3ε鎖などのCD3、CD4、CD7、CD8、CD10、CD11b、CD11c、CD14、CD16、CD18、CD22、CD25、CD28、CD32a、CD32b、CD33、CD41、CD41b、CD42a、CD42b、CD44、CD45RA、CD49、CD55、CD56、CD61、CD64、CD68、CD94、CD90、CD117、CD123、CD125、CD134、CD137、CD152、CD163、CD193、CD203c、CD235a、CD278、CD279、CD287、Nkp46、NKG2D、GITR、FcεRI、TCRα/βおよびTCRγ/δ、HLA−DRなどの免疫応答関連分子からなる群から選択される少なくとも1つである、請求項1〜6のいずれか一項に記載の二重特異性ポリペプチド分子。
- 前記第1のポリペプチド鎖が、配列番号28、配列番号29、配列番号30を含んでなり;および、前記第2のポリペプチド鎖が、配列番号31、配列番号32、配列番号30を含んでなる、請求項1〜7のいずれか一項に記載の二重特異性ポリペプチド分子。
- 前記第1のポリペプチド鎖中のFc領域が、配列番号26または配列番号47を含んでなり(Fc1)、前記第2のポリペプチド鎖中のFc領域が、配列番号27または配列番号48を含んでなる(Fc2)、請求項3〜8のいずれか一項に記載の二重特異性ポリペプチド分子。
- 前記第1のポリペプチド鎖が配列番号16または配列番号43または配列番号45または配列番号51、53、55、または57を含んでなり、および、前記第2のポリペプチド鎖が配列番号17または配列番号44または配列番号46または配列番号52、54、56、または58を含んでなる、請求項1に記載の二重特異性ポリペプチド分子。
- 前記免疫細胞の細胞表面抗原に結合する前記第1の結合部位(VD1)(VD2)がヒト化され;および/または前記MHC関連ペプチドエピトープに結合する前記第2の結合部位(VR1)(VR2)が親和性成熟および/または安定性成熟である、請求項1〜10のいずれか一項に記載の二重特異性ポリペプチド分子。
- 請求項1〜11のいずれか一項に記載の前記第1のポリペプチド鎖および前記第2のポリペプチド鎖をコードする核酸、または前記核酸を含んでなる発現ベクター。
- 請求項12に記載のベクターを含んでなり、任意選択的にそれを発現する、宿主細胞。
- 1つまたは複数の薬学的に許容可能な担体または賦形剤と共に、請求項1〜11のいずれか一項に記載の二重特異性ポリペプチド分子、請求項12に記載の核酸または発現ベクター、または請求項13に記載の細胞を含んでなる、医薬組成物。
- 疾患または障害の予防または治療で使用するための、または、がん、感染性疾患、および免疫学的障害から選択される疾患または障害の予防または治療で使用するための、請求項1〜11のいずれか一項に記載の二重特異性ポリペプチド分子、請求項12に記載の核酸または発現ベクター、請求項13に記載の細胞、または請求項14に記載の医薬品組成物。
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