公开(公告)号：US08642745B2

公开(公告)日：2014-02-04

申请号：US11608673

申请日：2006-12-08

Applicant: W. Robert Arathoon ,  Paul J. Carter ,  Anne M. Merchant ,  Leonard G. Presta

Inventor： W. Robert Arathoon ,  Paul J. Carter ,  Anne M. Merchant ,  Leonard G. Presta

IPC: C07K1/22 ,  C07K16/46 ,  C12P21/08

CPC classification number: C07K16/2863 ,  A61K38/00 ,  C07K1/22 ,  C07K16/2809 ,  C07K16/2812 ,  C07K16/46 ,  C07K16/468 ,  C07K2317/732 ,  Y10S435/972

Abstract: The invention relates to a method of preparing heteromultimeric polypeptides such as bispecific antibodies, bispecific immunoadhesins and antibody-immunoadhesin chimeras. The invention also relates to the heteromultimers prepared using the method. Generally, the method provides a multispecific antibody having a common light chain associated with each heteromeric polypeptide having an antibody binding domain. Additionally the method further involves introducing into the multispecific antibody a specific and complementary interaction at the interface of a first polypeptide and the interface of a second polypeptide, so as to promote heteromultimer formation and hinder homomultimer formation; and/or a free thiol-containing residue at the interface of a first polypeptide and a corresponding free thiol-containing residue in the interface of a second polypeptide, such that a non-naturally occurring disulfide bond is formed between the first and second polypeptide. The method allows for the enhanced formation of the desired heteromultimer relative to undesired heteromultimers and homomultimers.

公开(公告)号：US20130089553A1

公开(公告)日：2013-04-11

申请号：US13494870

申请日：2012-06-12

Applicant: Paul J. Carter ,  Leonard G. Presta ,  John B. Ridgway

Inventor： Paul J. Carter ,  Leonard G. Presta ,  John B. Ridgway

IPC: C07K16/46

CPC classification number: C07K16/468 ,  A61K38/00 ,  C07K14/70514 ,  C07K16/2809 ,  C07K16/46 ,  C07K19/00 ,  C07K2317/526 ,  C07K2319/00 ,  C07K2319/30

Abstract: The invention relates to a method of preparing heteromultimeric polypeptides such as bispecific antibodies, bispecific immunoadhesins, heteromultimers and antibody-immunoadhesin chimeras. Generally, the method involves introducing a protuberance at the interface of a first polypeptide and a corresponding cavity in the interface of a second polypeptide, such that the protuberance can be positioned in the cavity so as to promote heteromultimer formation and hinder homomultimer formation. The protuberance and cavity can be made by synthetic means such as altering the nucleic acid encoding the polypeptides or by peptide synthesis.

Abstract translation: 本发明涉及制备异源多聚体多肽的方法，例如双特异性抗体，双特异性免疫粘附素，异源多聚体和抗体免疫粘附素嵌合体。 通常，该方法包括在第二多肽的界面中的第一多肽和相应空腔的界面处引入突起，使得突起可以位于空腔中，以促进异源多聚体形成并阻止同源多聚体形成。 突起和空腔可以通过合成方式制备，例如改变编码多肽的核酸或通过肽合成。

公开(公告)号：US20100254986A1

公开(公告)日：2010-10-07

申请号：US12700618

申请日：2010-02-04

Applicant: PAUL J. CARTER ,  LEONARD G. PRESTA ,  JOHN B. RIDGWAY

Inventor： PAUL J. CARTER ,  LEONARD G. PRESTA ,  JOHN B. RIDGWAY

IPC: A61K39/395 ,  C12P21/06 ,  C07K16/00 ,  C12N5/10

CPC classification number: C07K16/468 ,  A61K38/00 ,  C07K14/70514 ,  C07K16/2809 ,  C07K16/46 ,  C07K19/00 ,  C07K2317/526 ,  C07K2319/00 ,  C07K2319/30

Abstract: The invention relates to a method of preparing heteromultimeric polypeptides such as bispecific antibodies, bispecific immunoadhesins and antibody-immunoadhesin chimeras. The invention also relates to the heteromultimers prepared using the method. Generally, the method involves introducing a protuberance at the interface of a first polypeptide and a corresponding cavity in the interface of a second polypeptide, such that the protuberance can be positioned in the cavity so as to promote heteromultimer formation and hinder homomultimer formation. “Protuberances” are constructed by replacing small amino acid side chains from the interface of the first polypeptide with larger side chains (e.g. tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the protuberances are created in the interface of the second polypeptide by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). The protuberance and cavity can be made by synthetic means such as altering the nucleic acid encoding the polypeptides or by peptide synthesis.

Abstract translation: 本发明涉及制备异源多聚体多肽如双特异性抗体，双特异性免疫粘附素和抗体免疫粘附素嵌合体的方法。 本发明还涉及使用该方法制备的异源多聚体。 通常，该方法包括在第二多肽的界面中的第一多肽和相应空腔的界面处引入突起，使得突起可以位于空腔中，以促进异源多聚体形成并阻止同源多聚体形成。 通过用较大侧链（例如酪氨酸或色氨酸）从第一多肽的界面替代小的氨基酸侧链构建“突起”。 通过用较小的（例如丙氨酸或苏氨酸）代替大的氨基酸侧链，在第二多肽的界面中产生与突起相同或相似大小的补偿性“空腔”。 突起和空腔可以通过合成方式制备，例如改变编码多肽的核酸或通过肽合成。

公开(公告)号：US20100016556A1

公开(公告)日：2010-01-21

申请号：US11969430

申请日：2008-01-04

Applicant: PAUL J. CARTER ,  Leonard G. Presta

Inventor： PAUL J. CARTER ,  Leonard G. Presta

IPC: C07K16/00 ,  C12N5/00 ,  C12P21/06

CPC classification number: C07K16/2845 ,  A61K38/00 ,  C07K16/00 ,  C07K16/28 ,  C07K16/2809 ,  C07K16/32 ,  C07K16/465 ,  C07K2317/24 ,  C07K2317/31 ,  C07K2317/54 ,  C07K2317/55 ,  C07K2317/73 ,  C07K2317/732 ,  C07K2319/00 ,  G06F15/00

Abstract: Variant immunoglobulins, particularly humanized antibody polypeptides are provided, along with methods for their preparation and use. Consensus immunoglobulin sequences and structural models are also provided.

Abstract translation: 提供了变体免疫球蛋白，特别是人源化抗体多肽，以及其制备和使用方法。 还提供了共同的免疫球蛋白序列和结构模型。

公开(公告)号：US07288249B2

公开(公告)日：2007-10-30

申请号：US10447331

申请日：2003-05-28

Applicant: Paul J. Carter ,  John B. Ridgway

Inventor： Paul J. Carter ,  John B. Ridgway

IPC: A61K39/395 ,  C07K16/00

CPC classification number: A61K39/39541 ,  A61K38/00 ,  A61K2039/505 ,  C07K16/2896 ,  C07K2317/21 ,  C07K2317/622 ,  A61K2300/00

Abstract: The present application describes a method for making antibodies which can be used for cancer diagnosis or therapy. The application also discloses a method for identifying an antigen which is differentially expressed on the surface of two or more distinct cell populations. The application additionally describes human antibodies directed against decay accelerating factor (DAF), as well as therapeutic compositions comprising such antibodies. Moreover, the application discloses a method of treating lung cancer with antibodies directed against DAF.

Abstract translation: 本申请描述了可用于癌症诊断或治疗的制备抗体的方法。 本申请还公开了一种用于鉴定在两个或多个不同细胞群体的表面上差异表达的抗原的方法。 该应用另外描述了针对衰变加速因子（DAF）的人类抗体以及包含此类抗体的治疗组合物。 此外，本申请公开了一种用针对DAF的抗体治疗肺癌的方法。

公开(公告)号：US06342220B1

公开(公告)日：2002-01-29

申请号：US08918148

申请日：1997-08-25

Applicant: Camellia W. Adams ,  Paul J. Carter ,  Brian M. Fendly ,  Austin L. Gurney

Inventor： Camellia W. Adams ,  Paul J. Carter ,  Brian M. Fendly ,  Austin L. Gurney

IPC: A61K39395

CPC classification number: C40B40/02 ,  A61K38/00 ,  C07K16/286 ,  C12N15/1037

Abstract: Various forms of c-mpl agonist antibodies are shown to influence the replication, differentiation or maturation of blood cells, especially megakaryocytes and megakaryocyte progenitor cells. Accordingly, these compounds may be used for treatment of thrombocytopenia.

Abstract translation: 显示各种形式的c-mpl激动剂抗体影响血细胞，特别是巨核细胞和巨核细胞祖细胞的复制，分化或成熟。 因此，这些化合物可用于治疗血小板减少症。

公开(公告)号：US6054297A

公开(公告)日：2000-04-25

申请号：US437642

申请日：1995-05-09

Applicant: Paul J. Carter ,  Leonard G. Presta

Inventor： Paul J. Carter ,  Leonard G. Presta

IPC: A61K38/00 ,  A61P35/00 ,  A61P37/02 ,  C07K16/28 ,  C07K16/32 ,  C07K16/46 ,  C12N15/13 ,  C12P21/08 ,  G06F15/00 ,  A61K39/395 ,  C07K16/00 ,  C07K16/30

CPC classification number: C07K16/28 ,  C07K16/2809 ,  C07K16/32 ,  C07K16/465 ,  G06F15/00 ,  A61K38/00 ,  C07K2317/24 ,  C07K2317/31 ,  C07K2317/54 ,  C07K2317/55 ,  C07K2317/732 ,  C07K2319/30 ,  C07K2319/55

Abstract: Variant immunoglobulins, particularly humanized antibody polypeptides are provided, along with methods for their preparation and use. Consensus immunoglobulin sequences and structural models are also provided.

Abstract translation: 提供了变体免疫球蛋白，特别是人源化抗体多肽，以及其制备和使用方法。 还提供了共同的免疫球蛋白序列和结构模型。

公开(公告)号：US5807706A

公开(公告)日：1998-09-15

申请号：US433105

申请日：1995-05-03

Applicant: Paul J. Carter ,  Leonard G. Presta ,  John B. Ridgway

Inventor： Paul J. Carter ,  Leonard G. Presta ,  John B. Ridgway

IPC: C12N15/09 ,  A61K38/00 ,  A61K39/395 ,  A61P31/04 ,  A61P31/12 ,  C07K14/73 ,  C07K16/28 ,  C07K16/46 ,  C07K19/00 ,  C12N5/10 ,  C12N15/13 ,  C12P21/08 ,  C12R1/91 ,  C12P21/06

CPC classification number: C07K16/468 ,  C07K14/70514 ,  C07K16/2809 ,  C07K16/46 ,  C07K19/00 ,  A61K38/00 ,  C07K2317/526 ,  C07K2319/00 ,  C07K2319/30

Abstract: The invention relates to a method of preparing heteromultimeric polypeptides such as bispecific antibodies, bispecific immunoadhesins and antibody-immunoadhesin chimeras. The invention also relates to the heteromultimers prepared using the method. Generally, the method involves introducing a protuberance at the interface of a first polypeptide and a corresponding cavity in the interface of a second polypeptide, such that the protuberance can be positioned in the cavity so as to promote heteromultimer formation and hinder homomultimer formation. "Protuberances" are constructed by replacing small amino acid side chains from the interface of the first polypeptide with larger side chains (e.g. tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the protuberances are created in the interface of the second polypeptide by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). The protuberance and cavity can be made by synthetic means such as altering the nucleic acid encoding the polypeptides or by peptide synthesis.

公开(公告)号：US5648237A

公开(公告)日：1997-07-15

申请号：US433781

申请日：1995-05-03

Applicant: Paul J. Carter

Inventor： Paul J. Carter

IPC: C12N15/09 ,  C07K16/00 ,  C07K16/06 ,  C07K16/32 ,  C07K16/46 ,  C12N15/13 ,  C12P21/08 ,  C12R1/19 ,  C12P21/06 ,  C12P21/04

CPC classification number: C07K16/00 ,  C07K16/065 ,  C07K16/32 ,  C07K16/468 ,  C07K2317/10 ,  C07K2317/24 ,  C07K2317/73 ,  C07K2317/732 ,  C07K2317/77 ,  C07K2319/00 ,  C07K2319/034 ,  Y10S435/972

Abstract: Methods for the high yield production of antibody Fv-containing polypeptides, especially Fab' and F(ab').sub.2 antibody fragments are provided. Expression of heavy and light chain Fv in a microbial secretory system is followed by recovery of Fv from the periplasm under conditions that maintain a cysteine residue as a free thiol. The free thiol is reacted with free thiol of an antibody fragment of the same or differing specificity, or with agents such as diagnostic labels or therapeutic moieties. The products offer advantages of homogeneity and purity not available through the use of known methods for preparing such derivatives.

Abstract translation: 提供了高产量产生含抗体Fv的多肽，特别是Fab'和F（ab'）2抗体片段的方法。 重链和轻链Fv在微生物分泌系统中的表达之后，在维持半胱氨酸残基作为游离硫醇的条件下，从周质中回收Fv。 游离硫醇与相同或不同特异性的抗体片段的游离硫醇反应，或与试剂如诊断标记或治疗部分反应。 该产品通过使用已知的制备这种衍生物的方法提供了均匀性和纯度的优点。

公开(公告)号：US5371190A

公开(公告)日：1994-12-06

申请号：US90902

申请日：1993-07-12

Applicant: Paul J. Carter ,  James A. Wells

Inventor： Paul J. Carter ,  James A. Wells

IPC: C11D3/386 ,  C12N9/54 ,  C12N9/56 ,  C12N15/10 ,  C12N15/31 ,  C12N15/52 ,  C12N15/75 ,  C07K15/00

CPC classification number: C12N15/52 ,  C11D3/386 ,  C12N15/102 ,  C12N15/75 ,  C12N9/54 ,  C12R1/07

Abstract: Novel enzyme mutants are disclosed which are derived from a precursor enzyme by replacing or modifying at least one catalytic functional group of an amino acid residue in a precursor enzyme. Such mutant enzymes have a catalytic preference for substrates which provide the replaced or modified catalytic group or its equivalent such that the substrate together with the enzyme mutant assists in its own catalysis.

Abstract translation: 公开了通过置换或修饰前体酶中氨基酸残基的至少一个催化官能团而衍生自前体酶的新型酶突变体。 这样的突变酶对提供替代或修饰的催化基团或其等同物的底物具有催化倾向，使得底物与酶突变体一起有助于其自身的催化。