JP6267689B2 - 多重特異性モノクローナル抗体 - Google Patents
多重特異性モノクローナル抗体 Download PDFInfo
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Description
この出願の発明に関連する先行技術文献情報としては、以下のものがある(国際出願日以降国際段階で引用された文献及び他国に国内移行した際に引用された文献を含む)。
(先行技術文献)
(特許文献)
(特許文献1) 米国特許第8,765,412号明細書
(特許文献2) 米国特許第8,642,745号明細書
(特許文献3) 米国特許第8,637,258号明細書
(特許文献4) 米国特許第8,597,911号明細書
(特許文献5) 米国特許第8,597,652号明細書
(特許文献6) 米国特許第8,586,039号明細書
(特許文献7) 米国特許第8,580,265号明細書
(特許文献8) 米国特許第8,420,783号明細書
(特許文献9) 米国特許第8,350,010号明細書
(特許文献10) 米国特許第8,337,841号明細書
(特許文献11) 米国特許第8,303,953号明細書
(特許文献12) 米国特許第8,034,903号明細書
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(特許文献31) 米国特許第5,677,149号明細書
(特許文献32) 米国特許出願公開第2011/0159007号明細書
(特許文献33) 米国特許出願公開第2011/0130324号明細書
(特許文献34) 米国特許出願公開第2009/0074780号明細書
(特許文献35) 米国特許出願公開第2005/0266425号明細書
(特許文献36) 米国特許出願公開第2014/0242076号明細書
(特許文献37) 米国特許出願公開第2014/0242075号明細書
(特許文献38) 米国特許出願公開第2014/0081002号明細書
(特許文献39) 米国特許出願公開第2014/0037621号明細書
(特許文献40) 米国特許出願公開第2014/0045725号明細書
(特許文献41) 米国特許出願公開第2013/0330345号明細書
(特許文献42) 米国特許出願公開第2013/0243775号明細書
(特許文献43) 米国特許出願公開第2013/0089554号明細書
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(特許文献45) 米国特許出願公開第2013/0017200号明細書
(特許文献46) 米国特許出願公開第2012/0321626号明細書
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(特許文献48) 米国特許出願公開第2012/0184718号明細書
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(特許文献52) 米国特許出願公開第2011/0152173号明細書
(特許文献53) 米国特許出願公開第2010/0015133号明細書
(特許文献54) 米国特許出願公開第2010/0256338号明細書
(特許文献55) 米国特許出願公開第2010/0233173号明細書
(特許文献56) 米国特許出願公開第2009/0298195号明細書
(特許文献57) 米国特許出願公開第2009/0162380号明細書
(特許文献58) 米国特許出願公開第2008/0069820号明細書
(特許文献59) 米国特許出願公開第2007/0072225号明細書
(特許文献60) 米国特許出願公開第2002/0168343号明細書
(特許文献61) 国際公開第2011/109726号
(特許文献62) 国際公開第2012/009026号
(特許文献63) 国際公開第2013/174873号
(特許文献64) 国際公開第2013/170168号
(特許文献65) 国際公開第2013/142255号
(特許文献66) 国際公開第2013/003652号
(特許文献67) 国際公開第2010/014629号
(特許文献68) 国際公開第2010/003118号
(特許文献69) 国際公開第2014/096390号
(特許文献70) 国際公開第2010/003101号
(特許文献71) 米国特許出願公開第2002/0062010号明細書
(特許文献72) 米国特許出願公開第2007/0184523号明細書
(特許文献73) 国際公開第2011/133886号
(特許文献74) 国際公開第2012/023053号
(特許文献75) 豪国特許出願公開第2013200009号明細書
(特許文献76) 米国特許出願公開第2005/0142539号明細書
(特許文献77) 米国特許出願公開第2003/0078385号明細書
(非特許文献)
(非特許文献1) Int’l Search Report issued 29 July 2013 in co−pending Int’l Appln.No.PCT/US2013/040575.
(非特許文献2) Merus presentation "Approaches to Cancer Therapy Using Bispecific Human Antibodies," June,2012
(非特許文献3) Bio 2012 Boston,Merus presentation," Building a Unique Pipeline 01 Bispecific Antibodies to Treat Cancer," June 18−21,2012.
(非特許文献4) European Search Report; Mailed 2016−04−21 for EP Application No.EP13788439.1
(非特許文献5) European Office Action; Mailed 2017−01−19 for EP Application No.EP13788439.1
(非特許文献6) Chinese Office Action; Mailed 2016−08−01 for CN Application No.CN 201380035170
本明細書に提供される例を理解するのを容易にするために、ある頻度で生じる方法および/または用語が、説明されるであろう。
本発明の多重特異性抗体の生成
種々の特性(例えば、改善された親和性、結合活性および薬物動態)および構造を有する抗体、例えば、完全なヒト抗体、ヒトおよび非ヒトの要素を含むキメラ抗体、Fab抗体ならびに他の抗体構造は、分子生物学的技術、例えば、クローニング、ファージディスプレイ、トランスジェニックマウスおよび変異誘発を使用して、研究室において構築されてきた。本発明の多重特異性抗体は、開始分子またはテンプレートとして使用される抗体から生成され得る。親抗体は、完全なヒト抗体、げっ歯類、ウサギ、イヌ、ウシ、偶蹄類、魚類、軟骨魚類、キメラ抗体、ヒト化抗体、部分的にヒト抗体または他の抗体であり得る。このような抗体を生成するための方法は、当該分野において周知である。かなりの情報が公開されており、モノクローナル抗体ならびに、研究、診断および複数の疾患、例えば、ガンの処置におけるその有用性について知られている。例えば、12個以上のモノクローナル抗体が、患者における治療的使用についての政府規制承認を有する。
開始親抗体は、種々の抗原に対する公知のバインダー(例えば、抗体1を有するLC1/HC1対および抗体2を有するLC2/HC2対)であることができ(例えば、抗体1は抗原1と結合し、抗体2は抗原2と結合する)、非ヒト、ヒト化または完全にヒト抗体であることができる。
Claims (17)
- 軽鎖LC1及び重鎖HC1を有する抗原1に結合する抗体と、軽鎖LC2及び重鎖HC2を有する抗原2に結合する他の抗体とから、多重特異性抗体を産生する方法であって、
(a)前記重鎖HC1及びHC2の免疫グロブリン重鎖(HC)可変抗体領域を機能的に補完する1つの免疫グロブリン軽鎖(LC)可変抗体領域を特定する工程であって、
(i)前記抗原1に結合する抗体のために、前記重鎖HC1の免疫グロブリン重鎖可変抗体領域と、前記軽鎖LC1を進化させることによって生成されたヒトLC1ライブラリとを共発現させることによって生成された抗体ライブラリをスクリーニングする工程と、
(ii)前記抗原2に結合する抗体のために、前記重鎖HC2の免疫グロブリン重鎖可変抗体領域と、前記軽鎖LC2を進化させることによって生成されたヒトLC2ライブラリとを共発現させることによって生成された他の抗体ライブラリをスクリーニングする工程と、
(iii)
(1)前記抗原2に結合する抗体のために、前記抗原1に結合する工程(i)由来の抗体の軽鎖と、前記重鎖HC2の免疫グロブリン重鎖可変抗体領域とを共発現させ、かつ選択する工程、または
(2)前記抗原1に結合する抗体のために、前記抗原2に結合する工程(ii)由来の抗体の軽鎖と、前記重鎖HC1の免疫グロブリン重鎖可変抗体領域とを共発現させ、かつ選択する工程、
を介して抗体を選択する工程と
によって行われ、工程(1)または(2)で選択された抗体の軽鎖可変抗体領域は、前記重鎖HC1及びHC2の2種類の免疫グロブリン重鎖可変抗体領域を機能的に補完する免疫グロブリン軽鎖可変抗体領域である、前記特定する工程と、
(b)免疫グロブリン重鎖のホモ二量体をアッセンブリして形成し得ないように修飾されたIgG定常領域を有するフレームにおいて、前記重鎖HC1及びHC2の2種類の免疫グロブリン重鎖(HC)可変抗体領域をクローニングする工程と、
(c)工程(a)で特定された免疫グロブリン軽鎖(LC)可変抗体領域と、前記重鎖HC1及びHC2の2種類の免疫グロブリン重鎖(HC)可変抗体領域とを、宿主細胞において共発現させて、抗原1及び抗原2の両方に結合する多重特異性抗体を産生する工程と
を有する方法。 - 請求項1記載の方法において、工程(b)における修飾は、他方の免疫グロブリン重鎖のCH3ドメインにおいて適切に設計された空洞内にフィットする、一方の免疫グロブリン重鎖のCH3ドメイン内へのアミノ酸側鎖の導入である方法。
- 請求項1記載の方法であって、さらに、前記多重特異性抗体の1若しくはそれ以上の特徴を改善するために前記軽鎖可変抗体領域または重鎖可変抗体領域を進化させる追加の工程を有する方法。
- 請求項3記載の方法において、前記1若しくはそれ以上の特徴は、平衡解離定数(KD);安定性;融点(Tm);pI;溶解性;発現レベル;低下した免疫原性および改善したエフェクター機能から成る群から選択される方法。
- 請求項3記載の方法において、前記進化させる追加の工程は、包括的位置進化(CPE);包括的位置挿入進化(CPI);包括的位置欠失進化(CPD);包括的位置進化(CPE)後のコンビナトリアルタンパク質合成(CPS);包括的位置欠失進化(CPD)後のコンビナトリアルタンパク質合成(CPS);及び包括的位置欠失進化(CPD)後のコンビナトリアルタンパク質合成(CPS)の1つを有する方法。
- 請求項1記載の方法であって、さらに、コンジュゲートした多重特異性抗体を生成するために、前記多重特異性抗体を有機部分にコンジュゲートさせる工程を有する方法。
- 請求項1記載の方法において、前記重鎖可変抗体領域は両方とも、同じ親抗体由来である方法。
- 請求項1記載の方法において、前記多重特異性抗体は、3つのエピトープと、または4つのエピトープと、または5つ以上のエピトープと特異的に結合する方法。
- 請求項1記載の方法において、前記宿主細胞は、3T3マウス繊維芽細胞;BHK21シリアンハムスター繊維芽細胞;MDCK、イヌ上皮細胞;Helaヒト上皮細胞;PtK1ネズミカンガルー上皮細胞;SP2/0マウス形質細胞;およびNS0マウス形質細胞:HEK 293ヒト胚腎臓細胞;COSサル腎臓細胞;CHO、CHO−Sチャイニーズハムスター卵巣細胞:Rlマウス胚細胞;E14.1マウス胚細胞:H1ヒト胚細胞;H9ヒト胚細胞;PER C.6、ヒト胚細胞;S.cerevisiae酵母細胞;およびpicchia酵母細胞から成る群のメンバーから選択される真核性宿主細胞株から選択される方法。
- 請求項1記載の方法において、前記宿主細胞は原核性宿主細胞である方法。
- 請求項1記載の方法であって、さらに、
d.前記多重特異性抗体を、前記多重特異性抗体が有機部分を有するように修飾する工程
を有する方法。 - 請求項1記載の方法であって、さらに、前記多重特異性抗体を製造する工程を有する方法。
- 請求項1記載の方法であって、さらに、
a.請求項1記載の多重特異性抗体を進化させて、製造宿主において、進化した多重特異性抗体のセットを産生する工程と、
b.前記進化した多重特異性抗体のセットをスクリーニングする工程であって、最適化された特徴を有する進化した多重特異性抗体を選択する、前記スクリーニングする工程と、
c.前記選択された多重特異性抗体を、前記選択された多重特異性抗体が有機部分を有するように修飾する工程と、
d.前記修飾した多重特異性抗体を、同一の製造宿主において産生する工程と
を有する方法。 - 請求項13記載の方法において、前記製造宿主は、3T3マウス繊維芽細胞;BHK21シリアンハムスター繊維芽細胞;MDCK、イヌ上皮細胞;Helaヒト上皮細胞;PtK1ネズミカンガルー上皮細胞;SP2/0マウス形質細胞;およびNS0マウス形質細胞:HEK 293ヒト胚腎臓細胞;COSサル腎臓細胞;CHO、CHO−Sチャイニーズハムスター卵巣細胞:R1マウス胚細胞;E14.1マウス胚細胞:H1ヒト胚細胞;H9ヒト胚細胞;PER C.6、ヒト胚細胞;S.cerevisiae酵母細胞;およびpicchia酵母細胞から成る群のメンバーから選択される方法。
- 請求項13記載の方法において、前記スクリーニングする工程は、蛍光活性化細胞ソーティング(FACS)を有する方法。
- 請求項1記載の方法において、前記軽鎖可変抗体領域または重鎖可変抗体領域は、認可された治療用抗体由来である方法。
- 請求項13記載の方法において、前記スクリーニングする工程は、定量ELISA;親和性ELISA;ELISPOT;フローサイトメトリー、免疫細胞学.Biacore(登録商標)表面プラズモン共鳴分析、Sapidyne KinExA(商標)動的排除アッセイ;SDS−PAGE;ウェスタンブロットおよびHPLCから成る群から選択される方法。
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CN108690132B (zh) | 2012-05-10 | 2022-10-14 | 生物蛋白有限公司 | 多特异单克隆抗体 |
CN111593414A (zh) | 2013-08-05 | 2020-08-28 | 特韦斯特生物科学公司 | 从头合成的基因文库 |
WO2015175375A1 (en) | 2014-05-13 | 2015-11-19 | Short Jay M | Conditionally active biological proteins |
KR102615681B1 (ko) | 2014-08-28 | 2023-12-18 | 바이오아트라, 인코퍼레이티드 | 변형된 t 세포에 대한 조건부 활성 키메라 항원 수용체 |
US11111288B2 (en) | 2014-08-28 | 2021-09-07 | Bioatla, Inc. | Conditionally active chimeric antigen receptors for modified t-cells |
CA2975852A1 (en) | 2015-02-04 | 2016-08-11 | Twist Bioscience Corporation | Methods and devices for de novo oligonucleic acid assembly |
US9981239B2 (en) | 2015-04-21 | 2018-05-29 | Twist Bioscience Corporation | Devices and methods for oligonucleic acid library synthesis |
CA2998169A1 (en) * | 2015-09-18 | 2017-03-23 | Twist Bioscience Corporation | Oligonucleic acid variant libraries and synthesis thereof |
US11512347B2 (en) | 2015-09-22 | 2022-11-29 | Twist Bioscience Corporation | Flexible substrates for nucleic acid synthesis |
CN108780094B (zh) | 2016-01-12 | 2022-09-13 | 生物蛋白有限公司 | 使用条件活性抗体的诊断方法 |
US10697972B2 (en) | 2016-01-12 | 2020-06-30 | Bioatla, Llc | Diagnostics using conditionally active antibodies |
AU2017238172B2 (en) | 2016-03-21 | 2024-06-27 | Marengo Therapeutics, Inc. | Multispecific and multifunctional molecules and uses thereof |
MX2018013306A (es) | 2016-05-13 | 2019-01-30 | Bioatla Llc | Anticuerpos anti-ror2, fragmentos de anticuerpos, sus inmunoconjugados y usos de los mismos. |
CN110248724B (zh) | 2016-09-21 | 2022-11-18 | 特韦斯特生物科学公司 | 基于核酸的数据存储 |
US20200291089A1 (en) | 2017-02-16 | 2020-09-17 | Elstar Therapeutics, Inc. | Multifunctional molecules comprising a trimeric ligand and uses thereof |
WO2018156792A1 (en) | 2017-02-22 | 2018-08-30 | Twist Bioscience Corporation | Nucleic acid based data storage |
WO2018222901A1 (en) | 2017-05-31 | 2018-12-06 | Elstar Therapeutics, Inc. | Multispecific molecules that bind to myeloproliferative leukemia (mpl) protein and uses thereof |
CN111566209B (zh) | 2017-06-12 | 2024-08-30 | 特韦斯特生物科学公司 | 无缝核酸装配方法 |
WO2018231864A1 (en) | 2017-06-12 | 2018-12-20 | Twist Bioscience Corporation | Methods for seamless nucleic acid assembly |
CN111356477B (zh) * | 2017-08-01 | 2024-08-30 | Ab工作室有限公司 | 双特异性抗体及其用途 |
GB2581620A (en) | 2017-09-11 | 2020-08-26 | Twist Bioscience Corp | GPCR binding proteins and synthesis thereof |
JP7066840B2 (ja) | 2017-10-20 | 2022-05-13 | ツイスト バイオサイエンス コーポレーション | ポリヌクレオチド合成のための加熱されたナノウェル |
CA3079793A1 (en) | 2017-12-22 | 2019-06-27 | Argenx Bvba | Bispecific antigen binding construct |
JP7191448B2 (ja) | 2018-01-04 | 2022-12-19 | ツイスト バイオサイエンス コーポレーション | Dnaベースのデジタル情報ストレージ |
GB201802487D0 (en) | 2018-02-15 | 2018-04-04 | Argenx Bvba | Cytokine combination therapy |
EP3765517A1 (en) | 2018-03-14 | 2021-01-20 | Elstar Therapeutics, Inc. | Multifunctional molecules that bind to calreticulin and uses thereof |
EP3765516A2 (en) | 2018-03-14 | 2021-01-20 | Elstar Therapeutics, Inc. | Multifunctional molecules and uses thereof |
SG11202011467RA (en) | 2018-05-18 | 2020-12-30 | Twist Bioscience Corp | Polynucleotides, reagents, and methods for nucleic acid hybridization |
WO2019241315A1 (en) | 2018-06-12 | 2019-12-19 | Obsidian Therapeutics, Inc. | Pde5 derived regulatory constructs and methods of use in immunotherapy |
EP3807318A4 (en) * | 2018-06-14 | 2022-03-02 | BioAtla, Inc. | MULTISPECIFIC ANTIBODY CONSTRUCTS |
AU2019297451A1 (en) | 2018-07-03 | 2021-01-28 | Marengo Therapeutics, Inc. | Anti-TCR antibody molecules and uses thereof |
CN112566929A (zh) * | 2018-08-21 | 2021-03-26 | 生物蛋白有限公司 | 具pH选择性的条件活性蛋白质 |
US20210386788A1 (en) | 2018-10-24 | 2021-12-16 | Obsidian Therapeutics, Inc. | Er tunable protein regulation |
EP3927744A1 (en) | 2019-02-21 | 2021-12-29 | Marengo Therapeutics, Inc. | Multifunctional molecules that bind to t cell related cancer cells and uses thereof |
GB2599227B (en) | 2019-02-21 | 2024-05-01 | Marengo Therapeutics Inc | Multifunctional molecules that bind to T cells and uses thereof to treat autoimmune disorders |
EP3927746A1 (en) | 2019-02-21 | 2021-12-29 | Marengo Therapeutics, Inc. | Multifunctional molecules that bind to calreticulin and uses thereof |
CA3131014A1 (en) | 2019-02-21 | 2020-08-27 | Andreas Loew | Anti-tcr antibody molecules and uses thereof |
WO2020172605A1 (en) | 2019-02-21 | 2020-08-27 | Elstar Therapeutics, Inc. | Antibody molecules that bind to nkp30 and uses thereof |
JP2022522668A (ja) | 2019-02-26 | 2022-04-20 | ツイスト バイオサイエンス コーポレーション | 抗体を最適化するための変異体核酸ライブラリ |
SG11202109172TA (en) | 2019-03-08 | 2021-09-29 | Obsidian Therapeutics Inc | Human carbonic anhydrase 2 compositions and methods for tunable regulation |
WO2020227515A1 (en) | 2019-05-07 | 2020-11-12 | Voyager Therapeutics, Inc. | Compositions and methods for the vectored augmentation of protein destruction, expression and/or regulation |
AU2020298294A1 (en) | 2019-06-21 | 2022-02-17 | Twist Bioscience Corporation | Barcode-based nucleic acid sequence assembly |
US20220348937A1 (en) | 2019-09-06 | 2022-11-03 | Obsidian Therapeutics, Inc. | Compositions and methods for dhfr tunable protein regulation |
KR20220066151A (ko) | 2019-09-23 | 2022-05-23 | 트위스트 바이오사이언스 코포레이션 | Crth2에 대한 변이체 핵산 라이브러리 |
WO2021084104A1 (en) | 2019-10-30 | 2021-05-06 | Bioinvent International Ab | Tetravalent antibody molecules |
WO2021138407A2 (en) | 2020-01-03 | 2021-07-08 | Marengo Therapeutics, Inc. | Multifunctional molecules that bind to cd33 and uses thereof |
JP2023523011A (ja) | 2020-04-24 | 2023-06-01 | マレンゴ・セラピューティクス,インコーポレーテッド | T細胞関連のがん細胞に結合する多機能性分子およびその使用 |
KR20230074487A (ko) | 2020-08-26 | 2023-05-30 | 마렝고 테라퓨틱스, 인크. | Trbc1 또는 trbc2를 검출하는 방법 |
GB2616128A (en) | 2020-08-26 | 2023-08-30 | Marengo Therapeutics Inc | Antibody molecules that bind to NKp30 and uses thereof |
EP4204450A4 (en) | 2020-08-26 | 2024-11-13 | Marengo Therapeutics Inc | MULTIFUNCTIONAL MOLECULES BINDING TO CALRETICULIN AND USES THEREOF |
WO2022076474A2 (en) * | 2020-10-07 | 2022-04-14 | Amgen Inc. | Rational selection of building blocks for the assembly of multispecific antibodies |
AU2022255506A1 (en) | 2021-04-08 | 2023-11-09 | Marengo Therapeutics, Inc. | Multifunctional molecules binding to tcr and uses thereof |
WO2023023055A1 (en) | 2021-08-16 | 2023-02-23 | Renagade Therapeutics Management Inc. | Compositions and methods for optimizing tropism of delivery systems for rna |
WO2023044343A1 (en) | 2021-09-14 | 2023-03-23 | Renagade Therapeutics Management Inc. | Acyclic lipids and methods of use thereof |
JP2024533865A (ja) | 2021-09-14 | 2024-09-12 | レナゲード セラピューティクス マネージメント インコーポレイテッド | 環状脂質及びその使用方法 |
WO2023122752A1 (en) | 2021-12-23 | 2023-06-29 | Renagade Therapeutics Management Inc. | Constrained lipids and methods of use thereof |
WO2023196931A1 (en) | 2022-04-07 | 2023-10-12 | Renagade Therapeutics Management Inc. | Cyclic lipids and lipid nanoparticles (lnp) for the delivery of nucleic acids or peptides for use in vaccinating against infectious agents |
Family Cites Families (92)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL154598B (nl) | 1970-11-10 | 1977-09-15 | Organon Nv | Werkwijze voor het aantonen en bepalen van laagmoleculire verbindingen en van eiwitten die deze verbindingen specifiek kunnen binden, alsmede testverpakking. |
US3817837A (en) | 1971-05-14 | 1974-06-18 | Syva Corp | Enzyme amplification assay |
US3939350A (en) | 1974-04-29 | 1976-02-17 | Board Of Trustees Of The Leland Stanford Junior University | Fluorescent immunoassay employing total reflection for activation |
US3996345A (en) | 1974-08-12 | 1976-12-07 | Syva Company | Fluorescence quenching with immunological pairs in immunoassays |
US4196265A (en) | 1977-06-15 | 1980-04-01 | The Wistar Institute | Method of producing antibodies |
US4704362A (en) | 1977-11-08 | 1987-11-03 | Genentech, Inc. | Recombinant cloning vehicle microbial polypeptide expression |
US4275149A (en) | 1978-11-24 | 1981-06-23 | Syva Company | Macromolecular environment control in specific receptor assays |
US4277437A (en) | 1978-04-05 | 1981-07-07 | Syva Company | Kit for carrying out chemically induced fluorescence immunoassay |
US4361549A (en) | 1979-04-26 | 1982-11-30 | Ortho Pharmaceutical Corporation | Complement-fixing monoclonal antibody to human T cells, and methods of preparing same |
US4366241A (en) | 1980-08-07 | 1982-12-28 | Syva Company | Concentrating zone method in heterogeneous immunoassays |
US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
US4800159A (en) | 1986-02-07 | 1989-01-24 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences |
SG47099A1 (en) | 1991-03-15 | 1998-03-20 | Amgen Boulder Inc | Pegylation of polypeptides |
EP0746609A4 (en) | 1991-12-17 | 1997-12-17 | Genpharm Int | NON-HUMAN TRANSGENIC ANIMALS CAPABLE OF PRODUCING HETEROLOGOUS ANTIBODIES |
EP0670898B1 (en) | 1992-11-24 | 2003-10-08 | G.D. Searle & Co. | Interleukin-3 (il-3) mutant polypeptides |
GB9225453D0 (en) | 1992-12-04 | 1993-01-27 | Medical Res Council | Binding proteins |
JP3720353B2 (ja) | 1992-12-04 | 2005-11-24 | メディカル リサーチ カウンシル | 多価および多重特異性の結合タンパク質、それらの製造および使用 |
EP0720624B1 (en) | 1993-09-22 | 1998-11-25 | Medical Research Council | Retargeting antibodies |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
US6562594B1 (en) | 1999-09-29 | 2003-05-13 | Diversa Corporation | Saturation mutagenesis in directed evolution |
US6171820B1 (en) | 1995-12-07 | 2001-01-09 | Diversa Corporation | Saturation mutagenesis in directed evolution |
US7011812B1 (en) | 1996-05-03 | 2006-03-14 | Immunomedics, Inc. | Targeted combination immunotherapy of cancer and infectious diseases |
ATE365562T1 (de) | 1996-05-03 | 2007-07-15 | Immunomedics Inc | Zielgerichtete kombinations-immuntherapie für krebs |
US5922845A (en) | 1996-07-11 | 1999-07-13 | Medarex, Inc. | Therapeutic multispecific compounds comprised of anti-Fcα receptor antibodies |
DE69830901T2 (de) | 1997-05-02 | 2006-05-24 | Genentech Inc., San Francisco | ein verfahren zur herstellung multispezifischer antikörper die heteromultimere und gemeinsame komponenten besitzen |
US7951917B1 (en) | 1997-05-02 | 2011-05-31 | Genentech, Inc. | Method for making multispecific antibodies having heteromultimeric and common components |
US20030207346A1 (en) | 1997-05-02 | 2003-11-06 | William R. Arathoon | Method for making multispecific antibodies having heteromultimeric and common components |
US20020062010A1 (en) * | 1997-05-02 | 2002-05-23 | Genentech, Inc. | Method for making multispecific antibodies having heteromultimeric and common components |
DE69938923D1 (de) | 1998-03-27 | 2008-07-31 | Genentech Inc | Synergie zwischen apo-2 ligand und antikörper gegen her-2 |
US7833528B2 (en) | 1998-06-22 | 2010-11-16 | Immunomedics, Inc. | Use of multispecific, non-covalent complexes for targeted delivery of therapeutics |
ATE368477T1 (de) | 2000-06-20 | 2007-08-15 | Immunomedics Inc | Zielgerichtete kombinationsimmuntherapie für krebs und infektionskrankheiten |
US6902734B2 (en) * | 2000-08-07 | 2005-06-07 | Centocor, Inc. | Anti-IL-12 antibodies and compositions thereof |
RU2408606C2 (ru) | 2000-10-20 | 2011-01-10 | Тугаи Сейяку Кабусики Кайся | Соединение - агонист тро |
WO2002064746A2 (en) | 2001-02-14 | 2002-08-22 | Uab Research Foundation | Combined transductional and transcriptional targeting system for improved gene delivery |
WO2002066514A2 (en) | 2001-02-19 | 2002-08-29 | Merck Patent Gmbh | Artificial fusion proteins with reduced immunogenicity |
US20050142539A1 (en) * | 2002-01-14 | 2005-06-30 | William Herman | Targeted ligands |
EP1505148B1 (en) | 2002-04-26 | 2009-04-15 | Chugai Seiyaku Kabushiki Kaisha | Methods of screening for agonistic antibodies |
AU2013200009B2 (en) | 2002-07-18 | 2015-05-07 | Merus N.V. | Recombinant production of mixtures of antibodies |
CA2492377C (en) * | 2002-07-18 | 2015-02-03 | Crucell Holland B.V. | Recombinant production of mixtures of antibodies |
EP1605058B1 (en) * | 2003-01-21 | 2009-05-13 | Chugai Seiyaku Kabushiki Kaisha | Method of screening light chain of antibody light chains |
JP4794301B2 (ja) | 2003-06-11 | 2011-10-19 | 中外製薬株式会社 | 抗体の製造方法 |
US20090191213A9 (en) | 2003-07-02 | 2009-07-30 | Novo Nordisk A/S | Compositions and methods for regulating NK cell activity |
WO2005030793A2 (en) * | 2003-09-24 | 2005-04-07 | Millennium Pharmaceuticals, Inc. | Antibodies which bind human cxcr3 |
GB0329825D0 (en) | 2003-12-23 | 2004-01-28 | Celltech R&D Ltd | Biological products |
US20050266425A1 (en) * | 2003-12-31 | 2005-12-01 | Vaccinex, Inc. | Methods for producing and identifying multispecific antibodies |
EP1819731A4 (en) | 2004-12-08 | 2013-02-13 | Immunomedics Inc | METHOD AND COMPOSITION FOR IMMUNOTHERAPY AND FOR THE DETECTION OF INFLAMMATORY AND DYSEGRATIVE IMMUNE DISEASES, INFECTION DISEASES, PATHOLOGICAL ANGIOGENESIS AND CANCER |
WO2006072620A1 (en) | 2005-01-05 | 2006-07-13 | F-Star Biotechnologische Forschungs- Und Entwicklungsges.M.B.H. | Synthetic immunoglobulin domains with binding properties engineered in regions of the molecule different from the complementarity determining regions |
WO2006074399A2 (en) | 2005-01-05 | 2006-07-13 | Biogen Idec Ma Inc. | Multispecific binding molecules comprising connecting peptides |
EP1870459B1 (en) | 2005-03-31 | 2016-06-29 | Chugai Seiyaku Kabushiki Kaisha | Methods for producing polypeptides by regulating polypeptide association |
WO2007038392A2 (en) | 2005-09-23 | 2007-04-05 | Walter Reed Army Institute Of Research (Wrair) | Antibodies with simultaneous subsite specificities to protein and lipid epitopes |
UA100969C2 (uk) | 2006-03-21 | 2013-02-25 | Дженентек, Інк. | Антитіло, яке специфічно зв'язує людський альфа5бета1 (alpha5beta1) |
US10118970B2 (en) | 2006-08-30 | 2018-11-06 | Genentech, Inc. | Multispecific antibodies |
GB0620729D0 (en) | 2006-10-18 | 2006-11-29 | Ucb Sa | Biological products |
CN101849001B (zh) | 2007-06-25 | 2014-07-16 | 艾斯巴技术-诺华有限责任公司 | 修饰抗体的方法和具有改善的功能性质的修饰抗体 |
KR20100058509A (ko) | 2007-07-31 | 2010-06-03 | 메디뮨 엘엘씨 | 다중특이적 에피토프 결합 단백질 및 이의 용도 |
KR20100052545A (ko) * | 2007-08-28 | 2010-05-19 | 바이오겐 아이덱 엠에이 인코포레이티드 | Igf―1r의 다중 에피토프에 결합하는 조성물 |
AR066170A1 (es) | 2007-09-26 | 2009-07-29 | Genentech Inc | Anti integrina alfa 5 beta 1 |
EP2113255A1 (en) * | 2008-05-02 | 2009-11-04 | f-star Biotechnologische Forschungs- und Entwicklungsges.m.b.H. | Cytotoxic immunoglobulin |
KR101893010B1 (ko) * | 2008-06-25 | 2018-08-29 | 에스바테크 - 어 노바티스 컴파니 엘엘씨 | TNFα를 저해하는 안정한 가용성 항체 |
CA2729747A1 (en) | 2008-07-02 | 2010-01-07 | Emergent Product Development Seattle, Llc | Il6 immunotherapeutics |
CN102171247A (zh) | 2008-07-02 | 2011-08-31 | 特鲁比昂药品公司 | TNF-α拮抗剂多靶点结合蛋白 |
EA201170031A1 (ru) | 2008-07-02 | 2011-08-30 | Эмерджент Продакт Дивелопмент Сиэтл, Ллс | СВЯЗЫВАЮЩИЕ НЕСКОЛЬКО МИШЕНЕЙ БЕЛКИ, ОБЛАДАЮЩИЕ АНТАГОНИСТИЧЕСКИМ ДЕЙСТВИЕМ ПО ОТНОШЕНИЮ К TGF-β |
US20110130324A1 (en) * | 2008-07-14 | 2011-06-02 | Uchicago Argonne, Llc | Methods for systematic control of protein stability |
EP2321345A1 (en) | 2008-07-28 | 2011-05-18 | Emergent Product Development Seattle, LLC | Multi-specific binding proteins targeting b cell disorders |
EP2344540B1 (en) | 2008-10-02 | 2017-11-29 | Aptevo Research and Development LLC | Cd86 antagonist multi-target binding proteins |
US8597652B2 (en) | 2009-03-20 | 2013-12-03 | Genentech, Inc. | Multispecific anti-HER antibodies |
MX2011010159A (es) | 2009-04-02 | 2011-10-17 | Roche Glycart Ag | Anticuerpos multiespecificos que comprenden anticuerpos de longitud completa y fragmentos fab de cadena sencilla. |
MX2012003598A (es) | 2009-09-29 | 2012-04-20 | Roche Glycart Ag | Anticuerpos biespecificos agonistas de receptores de muerte. |
EP2493920A4 (en) | 2009-10-30 | 2013-05-22 | Bayer Healthcare Llc | MIMETIC SCAFFOLDS OF ANTIBODIES |
US10584181B2 (en) | 2009-12-04 | 2020-03-10 | Genentech, Inc. | Methods of making and using multispecific antibody panels and antibody analog panels |
SG181952A1 (en) | 2009-12-29 | 2012-07-30 | Emergent Product Dev Seattle | Heterodimer binding proteins and uses thereof |
RS54367B2 (sr) * | 2010-02-08 | 2021-08-31 | Regeneron Pharma | Miš sa zajedničkim lakim lancem |
WO2011109726A2 (en) | 2010-03-05 | 2011-09-09 | Bioatla Llc | Homologous multi-specific antibodies |
WO2011133886A2 (en) * | 2010-04-23 | 2011-10-27 | Genentech, Inc. | Production of heteromultimeric proteins |
WO2012009026A2 (en) | 2010-07-16 | 2012-01-19 | Bioatla Llc | Novel methods of protein evolution |
PL2606064T3 (pl) * | 2010-08-16 | 2015-07-31 | Novimmune Sa | Sposoby wytwarzania wieloswoistych i wielowartościowych przeciwciał |
TR201802772T4 (tr) | 2010-11-17 | 2018-03-21 | Chugai Pharmaceutical Co Ltd | Kan pıhtılaşma faktörü VIII in işlevi için alternatif işleve sahip multi-spesifik antijen bağlayıcı molekül. |
SG10201510762YA (en) | 2011-01-14 | 2016-01-28 | Ucb Pharma Sa | Antibody molecules which bind il-17a and il-17f |
EP2500073A1 (en) | 2011-03-17 | 2012-09-19 | ChromaCon AG | Method for identification and purification of multi-specific polypeptides |
US8846042B2 (en) | 2011-05-16 | 2014-09-30 | Fabion Pharmaceuticals, Inc. | Multi-specific FAB fusion proteins and methods of use |
WO2013003647A2 (en) | 2011-06-28 | 2013-01-03 | Sea Lane Biotechnologies, Llc | Multispecific stacked variable domain binding proteins |
UA117901C2 (uk) | 2011-07-06 | 2018-10-25 | Ґенмаб Б.В. | Спосіб посилення ефекторної функції вихідного поліпептиду, його варіанти та їх застосування |
EP2543680A1 (en) | 2011-07-07 | 2013-01-09 | Centre National de la Recherche Scientifique | Multispecific mutated antibody Fab fragments |
WO2013049254A1 (en) | 2011-09-26 | 2013-04-04 | Jn Biosciences Llc | Hybrid constant regions |
US20130243775A1 (en) | 2012-03-14 | 2013-09-19 | Regeneron Pharmaceuticals, Inc. | Multispecific antigen-binding molecules and uses thereof |
WO2013142255A2 (en) | 2012-03-22 | 2013-09-26 | University Of Miami | Multi-specific binding agents |
CN108690132B (zh) * | 2012-05-10 | 2022-10-14 | 生物蛋白有限公司 | 多特异单克隆抗体 |
KR20150013188A (ko) | 2012-05-24 | 2015-02-04 | 에프. 호프만-라 로슈 아게 | 다중특이적 항체 |
IN2015DN01361A (ja) | 2012-08-02 | 2015-07-03 | Jn Biosciences Llc | |
KR20140036905A (ko) | 2012-09-18 | 2014-03-26 | 삼성전자주식회사 | 이중특이 항체를 포함하는 단백질 복합체 |
GB201223276D0 (en) | 2012-12-21 | 2013-02-06 | Ucb Pharma Sa | Antibodies and methods of producing same |
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