公开(公告)号：US07541034B1

公开(公告)日：2009-06-02

申请号：US09381497

申请日：1998-03-19

申请人： David J. Fitzgerald ,  Ira Pastan ,  Elizabeth Mansfield ,  Robert Kreitman

发明人： David J. Fitzgerald ,  Ira Pastan ,  Elizabeth Mansfield ,  Robert Kreitman

IPC分类号： A61K39/00

CPC分类号： A61K47/48561 ,  A61K38/00 ,  A61K47/6849 ,  C07K16/2803 ,  C07K2319/00

摘要： Methods and compositions relating to recombinant anti-CD22 antibodies with high binding affinity, and immunoconjugates comprising the anti-CD22 antibody linked to a therapeutic agent such as a Pseudomonas exotoxin or a detectable label. The invention provides diagnostic methods, and means to inhibit the growth of malignant B cells.

摘要翻译： 与具有高结合亲和力的重组抗CD22抗体相关的方法和组合物，以及包含与治疗剂如假单胞菌外毒素或可检测标记物连接的抗CD22抗体的免疫偶联物。 本发明提供诊断方法和抑制恶性B细胞生长的手段。

公开(公告)号：US20080292632A1

公开(公告)日：2008-11-27

申请号：US11664211

申请日：2005-09-22

申请人： Ira Pastan ,  Tomoko Ise ,  Laiman Xiang ,  Satoshi Nagata

发明人： Ira Pastan ,  Tomoko Ise ,  Laiman Xiang ,  Satoshi Nagata

IPC分类号： A61K39/395 ,  C07K16/18 ,  C07H21/00 ,  C12N15/00 ,  G01N33/574 ,  G01N33/566 ,  A61K39/44 ,  C12N5/00 ,  C12N5/02

CPC分类号： G01N33/57407 ,  A61K2039/505 ,  C07K16/2803 ,  G01N33/57426

摘要： Antibodies that specifically bind the extracellular domain of IRTA2 are disclosed herein. In one embodiment, these antibodies do not specifically bind IRTA1, IRTA3, IRTA4, or IRTA5. In one example, the antibodies are humanized antibodies. The antibodies can be conjugated to effector molecules, including detectable labels, radionucleotides, toxins and chemotherapeutic agents. The antibodies that specifically bind IRTA2 are of use to detect B cell malignancies, such as hairy cell leukemia and non-Hodgkin's lymphoma. These antibodies that specifically bind IRTA2 are also of use to treat B cell malignancies that express IRTA2, such as hairy cell leukemia and non-Hodgkin's lymphoma.

摘要翻译： 本文公开了特异性结合IRTA2细胞外结构域的抗体。 在一个实施方案中，这些抗体不特异性结合IRTA1，IRTA3，IRTA4或IRTA5。 在一个实例中，抗体是人源化抗体。 抗体可以与效应分子结合，包括可检测标记，放射性核苷酸，毒素和化学治疗剂。 特异性结合IRTA2的抗体可用于检测B细胞恶性肿瘤，如毛细胞白血病和非霍奇金淋巴瘤。 特异性结合IRTA2的这些抗体也可用于治疗表达IRTA2的B细胞恶性肿瘤，例如毛细胞白血病和非霍奇金淋巴瘤。

公开(公告)号：US07399827B1

公开(公告)日：2008-07-15

申请号：US09763393

申请日：1999-08-31

申请人： Ira Pastan ,  Ulrich Brinkmann ,  George Vasmatzis ,  Byungkook Lee

发明人： Ira Pastan ,  Ulrich Brinkmann ,  George Vasmatzis ,  Byungkook Lee

IPC分类号： C07K14/00

CPC分类号： C07K14/4748 ,  A61K39/00

摘要： PAGE-4 is a gene preferentially expressed in normal male and female reproductive tissues, prostate, testis, fallopian tube, uterus and placenta, as well as in prostate cancer, testicular cancer and uterine cancer. This expression pattern makes it a target for diagnosis and for vaccine based therapy of neoplasms of prostate, testis and uterus. The invention provides immunogenic compositions comprising PAGE-4 protein or immunogenic peptides thereof, methods of inhibiting the growth of malignant cells expressing PAGE-4, and methods of inducing an enhanced immune response to PAGE-4-expressing cancers.

摘要翻译： PAGE-4是在正常男性和女性生殖组织，前列腺，睾丸，输卵管，子宫和胎盘以及前列腺癌，睾丸癌和子宫癌中优先表达的基因。 这种表达模式使其成为诊断和基于疫苗的前列腺，睾丸和子宫肿瘤的治疗的目标。 本发明提供包含PAGE-4蛋白或其免疫原性肽的免疫原性组合物，抑制表达PAGE-4的恶性细胞生长的方法，以及诱导对表达PAGE-4的癌症增强的免疫应答的方法。

公开(公告)号：US20070189962A1

公开(公告)日：2007-08-16

申请号：US10580635

申请日：2004-11-24

申请人： Ira Pastan ,  Mitchell Ho ,  Sookhee Bang

发明人： Ira Pastan ,  Mitchell Ho ,  Sookhee Bang

IPC分类号： A61K51/00 ,  A61K39/395 ,  C07H21/04 ,  C12P21/06 ,  C12N1/21 ,  C12N5/06 ,  C07K16/46 ,  C07K14/21 ,  A61K9/127

CPC分类号： C07K16/2803 ,  A61K47/6829 ,  A61K47/6849 ,  C07K14/70503 ,  C07K2317/565 ,  C07K2317/622 ,  C07K2317/624 ,  C07K2317/92 ,  C07K2319/00 ,  C07K2319/30

摘要： Recombinant immunotoxins are fusion proteins composed of the Fv domains of antibodies fused to bacterial or plant toxins. RFB4 (Fv)-PE38 is an immunotoxin that targets CD22 expressed on B cells and B cell malignancies. The present invention provides antibodies and antibody fragments that have improved ability to bind the CD22 antigen compared to RFB4. Immunotoxins made with the antibodies and antibody fragments of the invention have improved cytotoxicity to CD22-expressing cancer cells. Compositions that incorporate these antibodies into chimeric immunotoxin molecules that can be used in medicaments and methods for inhibiting the growth and proliferation of such cancers. Additionally, the invention provides a method of increasing the cytotoxicity of forms of Pseudomonas exotoxin A (“PE”) with the mutation of a single amino acid, as well as compositions of such mutated PEs, nucleic acids encoding them, and methods for using the mutated PEs.

摘要翻译： 重组免疫毒素是由与细菌或植物毒素融合的抗体的Fv结构域组成的融合蛋白。 RFB4（Fv）-PE38是靶向在B细胞和B细胞恶性肿瘤上表达的CD22的免疫毒素。 本发明提供与RFB4相比具有改善的结合CD22抗原的能力的抗体和抗体片段。 用本发明的抗体和抗体片段制备的免疫毒素对表达CD22的癌细胞具有改善的细胞毒性。 将这些抗体并入可用于药物的嵌合免疫毒素分子中的组合物和用于抑制这些癌症的生长和增殖的方法。 此外，本发明提供了增加单一氨基酸突变的假单胞菌外毒素A（“PE”）形式的细胞毒性的方法，以及这些突变的PE的组成，编码它们的核酸，以及使用 突变PE。

公开(公告)号：US20060051359A1

公开(公告)日：2006-03-09

申请号：US10537061

申请日：2003-12-01

申请人： Ira Pastan ,  Masanori Onda ,  Nai-Kong Cheung

发明人： Ira Pastan ,  Masanori Onda ,  Nai-Kong Cheung

IPC分类号： A61K39/00 ,  C07K14/82

CPC分类号： C07K16/30 ,  A61K47/6851 ,  A61K2039/505 ,  C07K14/21 ,  C07K2317/622 ,  C07K2317/624 ,  C07K2319/00

摘要： Immunotoxins are disclosed that include a toxin, a variable region of a heavy chain of a monoclonal antibody that binds the antigen specifically bound by monoclonal antibody 8H9, and a variable region of a light chain of the monoclonal antibody that binds the antigen specifically bound by monoclonal antibody 8H9 and effector molecule. These immunotoxins include scFv and dsFv of monoclonal antibody 8H9. The immunotoxins are of use for the treatment of tumors.

摘要翻译： 公开了免疫毒素，其包括毒素，结合由单克隆抗体8H9特异性结合的抗原的单克隆抗体的重链可变区，以及单克隆抗体的轻链可变区，其与单克隆抗体特异性结合的抗原结合 抗体8H9和效应分子。 这些免疫毒素包括单克隆抗体8H9的scFv和dsFv。 免疫毒素可用于治疗肿瘤。

公开(公告)号：US20050244828A1

公开(公告)日：2005-11-03

申请号：US10514910

申请日：2003-05-20

申请人： Robert Kreitman ,  Kakushi Matsushita ,  Wyndham Wilson ,  Ira Pastan

发明人： Robert Kreitman ,  Kakushi Matsushita ,  Wyndham Wilson ,  Ira Pastan

IPC分类号： A61B20060101 ,  A61K39/395 ,  C07K16/00 ,  C07K16/28 ,  C12Q1/68 ,  G01N33/50 ,  G01N33/53 ,  G01N33/574

CPC分类号： C07K16/2803 ,  A61K2039/505 ,  G01N33/5052 ,  G01N33/57426 ,  G01N2333/70596

摘要： Disclosed herein are methods of using previously unknown soluble forms of CD22 (sCD22) present in the serum of subjects with B-cell leukemias and lymphomas to assess tumor burden in the subjects. Also disclosed are methods of diagnosing or prognosing development or progression of a B-cell lymphoma or leukemia in a subject, including detecting sCD22 in a body fluid sample taken or derived from the subject, for instance serum.

摘要翻译： 本文公开了使用存在于患有B细胞白血病和淋巴瘤的受试者血清中的先前未知的可溶形式的CD22（sCD22）的方法来评估受试者的肿瘤负担。 还公开了诊断或预测受试者中B细胞淋巴瘤或白血病的发展或进展的方法，包括检测取自或衍生自受试者的体液样品中的sCD22，例如血清。

公开(公告)号：US20050181494A1

公开(公告)日：2005-08-18

申请号：US10515150

申请日：2003-05-20

申请人： Vijay Chaudhary ,  Amita Gupta ,  Sankar Adhya ,  Ira Pastan

发明人： Vijay Chaudhary ,  Amita Gupta ,  Sankar Adhya ,  Ira Pastan

IPC分类号： A61K20060101 ,  C07H21/04 ,  C12N1/20 ,  C12N7/00 ,  C12N15/00 ,  C12N15/10 ,  C12N15/74 ,  C12N15/86 ,  C12P21/04 ,  C12P21/06 ,  C12Q1/68 ,  C40B40/02

CPC分类号： C40B40/02 ,  C07H21/04 ,  C12N15/1037

摘要： The present invention relates to a process of obtaining recombinant lambdoid bacteriophage with high density display of functional peptides and proteins on surface of said phage comprising of: constructing a donor plasmid having a nucleotide sequence that defines the elements for replication of the vector in bacteria, a selectable marker, a nucleotide sequence flanked by two non-compatible recombination sequences, and an inducible cistron for expression of a capsid protein and a fusion protein; constructing a recipient phage having a nucleotide sequence that defines the lambdoid elements for replication and packaging of the vector into an assembled bacteriophage and encodes an inducible cistron for expression of a selectable marker flanked by two non-compatible recombination sequences; transferring the said donor plasmid to said recipient plasmid to obtain cointegrates; growing said cointegrates in selective liquid medium; harvesting phages displaying protein encoded by the foreign DNA encapsulated in said harvested phage particle.

摘要翻译： 本发明涉及一种在所述噬菌体的表面上获得功能性肽和蛋白质的高密度显示的重组羔羊噬菌体的方法，包括：构建具有限定用于细菌中载体复制的元件的核苷酸序列的供体质粒， 选择性标记，侧翼为两个不相容的重组序列的核苷酸序列，以及用于表达衣壳蛋白和融合蛋白的诱导性顺反子; 构建具有限定用于复制载体的载体噬菌体的载体噬菌体并将载体包装到组装的噬菌体中，并编码可诱导的顺反子，用于表达两侧不对称重组序列的选择性标记; 将所述供体质粒转移到所述受体质粒以获得协整体; 在选择性液体培养基中生长表示协整; 收获展示由封装在所述收获的噬菌体颗粒中的外源DNA编码的蛋白质的噬菌体。

公开(公告)号：US20050053988A1

公开(公告)日：2005-03-10

申请号：US10913196

申请日：2004-08-05

申请人： Ira Pastan ,  Kristi Egland ,  Byungkook Lee ,  James Vincent

发明人： Ira Pastan ,  Kristi Egland ,  Byungkook Lee ,  James Vincent

IPC分类号： A61K38/00 ,  A61K39/00 ,  C07K14/47 ,  C07K14/705 ,  C12Q1/00 ,  C12Q1/68 ,  G01N33/574

CPC分类号： C07K14/47 ,  A61K38/00 ,  A61K39/00 ,  C07K14/705

摘要： A polypeptide is disclosed that is detected in the breast cancer cells termed 68h05. Polynucleotides encoding 68h05 are also disclosed, as are vectors including these polynucleotides. Host cells transformed with these polynucleotides are also disclosed. Antibodies and immunoconjugates are disclosed that specifically bind 68h05. Methods are disclosed for using a 68h05 polypeptide, an antibody that specifically binds 68h05, or a polynucleotide encoding 68h05, such as in the treatment of breast cancer or prostate cancer. Assays are disclosed for the detection breast or prostate cancer. Pharmaceutical compositions including a 68h05 polypeptide, an antibody that specifically binds 68h05, or a polynucleotide encoding 68h05 are also disclosed. These pharmaceutical compositions are of use in the treatment of breast or prostate cancer.

摘要翻译： 公开了在称为68h05的乳腺癌细胞中检测到的多肽。 还公开了编码68h05的多核苷酸，以及包括这些多核苷酸的载体也是公开的。 还公开了用这些多核苷酸转化的宿主细胞。 公开了特异性结合68h05的抗体和免疫偶联物。 公开了使用68h05多肽，特异性结合68h05的抗体或编码68h05的多核苷酸的方法，例如用于治疗乳腺癌或前列腺癌。 公开了检测乳腺癌或前列腺癌的检测。 还公开了包含68h05多肽，特异性结合68h05的抗体或编码68h05的多核苷酸的药物组合物。 这些药物组合物可用于治疗乳腺癌或前列腺癌。

公开(公告)号：US06426075B1

公开(公告)日：2002-07-30

申请号：US09297851

申请日：1999-07-30

申请人： David J. Fitzgerald ,  Yoram Reiter ,  Ira Pastan

发明人： David J. Fitzgerald ,  Yoram Reiter ,  Ira Pastan

IPC分类号： A61K39108

CPC分类号： C07K14/21 ,  A61K38/00 ,  A61K47/6829 ,  C07K16/3069 ,  C07K2319/00

摘要： This invention provides protease-activatable Pseudomonas exotoxin A-like (“PE-like”) proproteins. The proproteins comprise (1) a cell recognition domain of between 10 and 1500 amino acids that binds to a cell surface receptor; (2) a modified PE translocation domain comprising an amino acid sequence sufficiently homologous to domain II of PE to effect translocation to a cell cytosol upon proteolytic cleavage, wherein the translocation domain comprises a cysteine-cysteine loop that comprises a protease activatable sequence cleavable by a protease and wherein the cysteine-cysteine loop is substantially un-activatable by furin; (3) optionally, a PE Ib-like domain comprising an amino acid sequence up to 1500 amino acids; (4) a cytotoxicity domain comprising an amino acid sequence substantially homologous to domain III of PE, the cytotoxicity domain having ADP-ribosylating activity; and (5) an endoplasmic reticulum (“ER”) retention sequence. The invention also provides methods of using these proproteins for killing target cells.

摘要翻译： 本发明提供蛋白酶活化的假单胞菌外毒素A样（“PE样”）前蛋白。 所述蛋白质包含（1）结合细胞表面受体的10至1500个氨基酸的细胞识别结构域; （2）修饰的PE易位结构域，其包含与PE的结构域II充分同源的氨基酸序列，以在蛋白水解切割时实现对细胞溶质的移位，其中所述易位结构域包含半胱氨酸 - 半胱氨酸环，其包含可被 蛋白酶，其中半胱氨酸 - 半胱氨酸环基因不被弗林蛋白酶激活; （3）任选地，包含至多1500个氨基酸的氨基酸序列的PE 1b样结构域; （4）细胞毒性结构域，其包含与PE的结构域III基本上同源的氨基酸序列，细胞毒性结构域具有ADP-核糖基化活性; 和（5）内质网（“ER”）保留序列。 本发明还提供了使用这些蛋白质杀死靶细胞的方法。

公开(公告)号：US06287562B1

公开(公告)日：2001-09-11

申请号：US09227693

申请日：1999-01-08

申请人： Ira Pastan ,  Itai Benhar ,  Eduardo A. Padlan ,  Sun-Hee Jung ,  Byungkook Lee

发明人： Ira Pastan ,  Itai Benhar ,  Eduardo A. Padlan ,  Sun-Hee Jung ,  Byungkook Lee

IPC分类号： A61K39395

CPC分类号： G01N33/57419 ,  A61K38/00 ,  A61K47/6851 ,  C07K14/21 ,  C07K16/18 ,  C07K16/30 ,  C07K16/34 ,  C07K19/00 ,  C07K2317/24 ,  C07K2317/56 ,  C07K2317/622 ,  C07K2319/00 ,  G01N33/57446 ,  G01N33/57449 ,  G01N33/57492

摘要： The invention provides methods for inhibiting the growth of a cell bearing a LewisY antigen. The methods involve contacting the cell with a composition comprising an Fv region of a light chain of a monoclonal antibody selected from B1, B3, and B5, and the Fv region of a humanized heavy chain of a monoclonal antibody independently selected from B1, B3, and B5, provided that if the heavy and the light chains are from the same antibody, the residue at position 95 of the heavy chain is a serine, and, if the antibody chain is from B3, the residue at position 4 of the light chain can be a leucine and the residue at position 82b of the heavy chain can be an arginine. The Fv regions are joined to an effector molecule selected from a chemotherapeutic agent, a toxin, a radioisotope, and a liposome loaded with a chemotherapeutic agent. In preferred embodiments, the heavy chain and the light chain are recombinantly fused, and the Fv regions are recombinantly fused to a toxin.

摘要翻译： 本发明提供了抑制携带LewisY抗原的细胞生长的方法。 所述方法包括使细胞与包含选自B1，B3和B5的单克隆抗体的轻链的Fv区和单独抗体的人源化重链的Fv区的组合物接触，所述单克隆抗体独立地选自B1，B3， 和B5，条件是如果重链和轻链来自相同的抗体，则重链位置95处的残基是丝氨酸，并且如果抗体链来自B3，则轻链第4位的残基 可以是亮氨酸，重链位置82b处的残基可以是精氨酸。 Fv区连接到选自化疗剂，毒素，放射性同位素和装载有化学治疗剂的脂质体的效应分子。 在优选的实施方案中，将重链和轻链重组融合，并将Fv区重组融合至毒素。