HK1103020A - Uses of anti-ctla-4 antibodies - Google Patents

Description

Use of anti-CTLA-4 antibodies

Technical Field

The present invention relates to compositions comprising anti-CTLA-4 antibodies having amino acid sequences derived from human genes and their use in the treatment of cancer in combination with stem cell transplantation.

Background

CTLA-4 (cytotoxic T lymphocyte antigen-4) is a member of the immunoglobulin (Ig) superfamily, which plays a role in downregulating T cell activation and maintaining immune stability. In particular, it is believed that CD28 and CTLA-4 transmit opposing signals that T cells integrate to determine the response to an antigen. The CD28 co-stimulatory signal and the CTLA-4 derived inhibitory signal modulate the outcome of T cell receptor stimulation by antigen. It is determined by the interaction between CD28 or CTLA-4 on T cells and the B7 molecule expressed on antigen presenting cells.

Kwon et al PNAS USA 94: 8099-103(1997) demonstrated that antibody-mediated blockade of CTLA-4 in vivo enhances the immune response against prostate cancer. Based on in vitro and in vivo results, Yang et al Cancer Res 57: 4036-41(1997) found that blockade of CTLA-4 in tumor-bearing animals enhances their ability to generate anti-tumor T cell responses; in this model, the potentiating effect is limited to the early stages of tumor growth. Hurwitz et al Proc Natl Acad Sci USA 95: 10067-71(1998) use a combination of CTLA-4 blocking and vaccine (consisting of granulocyte-macrophage colony stimulating factor expressing SM1 cells) to induce regression of parental SM1 tumors, but neither treatment works alone.

U.S. patent 5,811,097 to Allison et al relates to administering a CTLA-4 blocking agent to reduce tumor cell growth. WO00/37504 (published 6/29/2000) relates to human anti-CTLA-4 antibodies and the use of these antibodies in the treatment of cancer. WO01/14424 (published 3/1 2001) relates to other human anti-CTLA-4 antibodies and the use of these antibodies in the treatment of cancer. WO93/00431 (published on 7/1/1993) relates to the modulation of cellular interactions with monoclonal antibodies reactive with CTLA4Ig fusion proteins. WO00/32231 (published 6/8/2000) relates to the stimulation of T cells with a combination of a tumor vaccine and a CTLA-4 blocking agent. WO03/086459 relates to methods of using CTLA-4 antibodies to improve memory responses.

Summary of The Invention

The present invention relates to methods of treating cancer using anti-CTLA-4 antibodies.

In one embodiment, the invention relates to methods of treating cancer in a mammal by administering more than 10mg/kg of an anti-CTLA-4 antibody in a single dose or multiple doses.

In another aspect, the invention relates to a method for treating cancer in a mammal that has received a stem cell transplant, comprising administering to the mammal an effective amount of a human anti-CTLA-4 antibody.

In another aspect, the invention relates to a method of treating cancer in a mammal comprising the steps of (i) performing stem cell transplantation in the mammal, and (ii) administering an effective amount of a human anti-CTLA-4 antibody. Preferably, the mammal is a human. The stem cell transplantation may be allogeneic stem cell transplantation (allogeneic stem cell transplantation) or autologous stem cell transplantation.

In other aspects, the invention relates to a method for treating cancer in a mammal comprising the steps of (i) administering chemotherapy to the mammal; (ii) (ii) performing a stem cell transplant, and (iii) administering an effective amount of a human anti-TLA-4 antibody. The stem cell transplantation may be a allogeneic stem cell transplantation or an autologous stem cell transplantation, and the chemotherapy may be a high-dose chemotherapy.

Brief Description of Drawings

FIGS. 1A-W show the full length nucleotide and amino acid sequences of anti-CTLA-4 antibodies 4.1.1, 4.8.1, 4.13.1, 6.1.1 and 11.2.1.

FIGS. 2A-C show the predicted amino acid sequence alignment between heavy chain clones 4.1.1, 4.8.1, 4.14.3, 6.1.1, 3.1.1, 4.10.2, 4.13.1, 11.2.1, 11.6.1, 11.7.1, 12.3.1 and 12.9.1.1 and germline (germline) DP-50(3-33) amino acid sequences. The changes produced compared to the germline are shown in bold.

FIG. 3 shows the amino acid sequence alignment between the predicted heavy chain sequence of clone 2.1.3 and the germline DP-65(4-31) amino acid sequence. Changes occurring compared to the germline are indicated in bold and the CDRs are underlined.

Fig. 4A-B show amino acid sequence alignments between the predicted kappa light chain sequences of clones 4.1.1, 4.8.1, 4.14.3, 6.1.1, 4.10.2 and 4.13.1 and germline a27 amino acid sequence. Changes occurring compared to the germline are indicated in bold and the CDRs are underlined.

Figure 5 shows the amino acid sequence alignment between the predicted kappa light chain sequence and germline 012 amino acid sequence for clones 3.1.1, 11.2.1, 11.6.1, and 11.7.1. Changes occurring compared to the germline are indicated in bold and the CDRs are underlined.

FIG. 6 shows the amino acid sequence alignment between the predicted kappa light chain sequence of clone 2.1.3 and the germline A10/A26 amino acid sequence. Changes occurring compared to the germline are indicated in bold and the CDRs are underlined.

Figure 7 shows an amino acid sequence alignment between the predicted kappa light chain sequence of clone 12.3.1 and the germline a17 amino acid sequence. Changes occurring compared to the germline are indicated in bold and the CDRs are underlined.

FIG. 8 shows the amino acid sequence alignment between the predicted kappa light chain sequence of clone 12.9.1 and the germline A3/A19 amino acid sequence. Changes occurring compared to the germline are indicated in bold and the CDRs are underlined.

Figures 9A-L show the full length nucleotide and amino acid sequences of anti-CTLA-4 antibodies 4.1.1 (figure 9A), 4.8.1 (figure 9B), 4.14.3 (figure 9C), 6.1.1 (figure 9D), 3.1.1 (figure 9E), 4.10.2 (figure 9F), 2.1.3 (figure 9G), 4.13.1 (figure 9H), 11.6.1 (figure 9I), 11.7.1 (figure 9J), 12.3.1.1 (figure 9K), and 12.9.1.1 (figure 9L).

Detailed Description

All patents, patent applications, publications, and other references cited herein are hereby incorporated by reference in their entirety.

In one aspect, the invention relates to a method of treating cancer in a mammal comprising administering to the mammal more than 10mg/kg of a human anti-CTLA-4 antibody. Preferably, the mammal is a human. Examples of cancers to be treated are breast cancer (including metastatic breast cancer), lung cancer (including small cell lung cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, melanoma (including cutaneous or intraocular melanoma), uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, non-hodgkin's lymphoma, carcinoma of the esophagus, cancer of the small intestine, cancer of the endocrine system, carcinoma of the thyroid gland, carcinoma of the parathyroid gland, carcinoma of the adrenal gland, sarcoma of soft tissue, carcinoma of the urethra, carcinoma of the penis, carcinoma of the prostate, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia (chronic myoledleukemia), acute lymphocytic leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, cervical cancer, Chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphomas, cutaneous T-cell lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, carcinoma of the renal pelvis, Central Nervous System (CNS) tumors, primary central nervous system lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced carcinomas including asbestos-induced carcinomas, myelomas, neuroblastoma, childhood sarcoma, and combinations of said cancers. In certain embodiments, solid tumors are treated, such as breast cancer (including metastatic breast cancer), testicular cancer, ovarian cancer, small cell lung cancer, neuroblastoma, and childhood sarcoma. In another embodiment, the cancer is melanoma and the mammal is a human. In additional embodiments, the cancer is prostate cancer and the mammal is a human.

As used herein, the term "treatment" refers to reversing, slowing, inhibiting the progression of the disease or disorder to which the term refers, or inhibiting one or more symptoms of the disease or disorder, unless otherwise indicated. The term "treating", as used herein, refers to the act of treating as "treating" defined immediately above, unless otherwise indicated. The effectiveness of cancer therapy can be monitored by observing disease endpoints (endings), such as long-term survival, disease-free survival (time to no recurrence), response rate, duration of response, and/or time to progression.

For the treatment of cancer, the antibodies described herein can be administered as described below, e.g., in an amount of more than 10 mg/kg. In some embodiments, the amount of antibody may be from more than 10mg/kg to 21mg/kg, such as 10.5mg/kg to 21mg/kg or 11mg/kg to 21mg/kg, or such as more than 10mg/kg to 18mg/kg, such as 10.5mg/kg to 18mg/kg or 11mg/kg to 18 mg/kg. In other embodiments, the amount of antibody is at least 15mg/kg, such as 15 mg/kg. In other embodiments, the amount of antibody is about 20 mg/kg. Single or multiple doses of the antibody may be administered. For example, at least 1 dose, or at least 3, 6, or 12 doses may be administered. The dose may be administered, for example, 1 time every 2 weeks, 1 time every month, 1 time every 3 months, 1 time every 6 months, or 1 time per year.

The methods of the invention also relate to the treatment of cancer in a mammal that has received a stem cell transplant, the method comprising administering to the mammal an amount of human anti-CTLA-4 antibody that, in combination with the stem cell transplant, has an effect on treating cancer. Examples of cancers to be treated are breast cancer, including metastatic breast cancer, lung cancer, including small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, melanoma, including cutaneous or intraocular malignant melanoma (intraepithelial melanoma), uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, non-hodgkin's lymphoma, carcinoma of the esophagus, cancer of the small intestine, cancer of the endocrine system, carcinoma of the thyroid gland, carcinoma of the parathyroid gland, carcinoma of the adrenal gland, sarcoma of soft tissue, carcinoma of the urethra, carcinoma of the penis, prostate cancer, chronic or acute leukemias, including acute myeloid leukemia, chronic myeloid leukemia (chronoid myoid leukemia), acute lymphocytic leukemia, Chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphomas, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvis cancer, Central Nervous System (CNS) tumors, primary central nervous system lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced carcinomas including asbestos-induced carcinomas, myelomas, neuroblastomas, childhood sarcomas, and combinations of said cancers. Preferably, solid tumors are treated, such as breast cancer (including metastatic breast cancer), testicular cancer, ovarian cancer, small cell lung cancer, neuroblastoma, and childhood sarcoma. Preferably, the mammal is a human.

In combination therapy, the antibodies described herein can be administered, for example, in an amount of at least 1mg/kg, in an amount of at least 5mg/kg, at least 10mg/kg, or at least 15mg/kg, as described further below. Single or multiple doses of the antibody may be administered. For example, at least 1 dose, or at least 3, 6, or 12 doses may be administered. The dose may be administered, for example, 1 time every 2 weeks, 1 time every month, 1 time every 3 months, 1 time every 6 months, or 1 time per year. The first dose may be administered after the immune system of the mammal has recovered from the transplant, for example, within 1 to 12 months after the transplant. In certain embodiments, the first dose is administered within a period of 1 to 3 months, or 1 to 4 months after transplantation. The patient may receive a stem cell transplant and a preparatory treatment (preparation treatment) as described below.

The present invention also relates to a method of treating cancer in a mammal comprising the steps of (i) stem cell transplantation in the mammal, and (ii) administering an effective amount of a human anti-CTLA-4 antibody. Preferably, the mammal is a human. The stem cell transplantation may be a allogeneic stem cell transplantation or an autologous stem cell transplantation.

The term "stem cell transplantation" as used herein refers to the infusion of hematopoietic stem cells into a mammal, which may be derived from any suitable source of stem cells within the body. Thus, stem cells may be derived from, for example, bone marrow, the peripheral circulation after bone marrow mobilization (e.g., blood), or fetal sources such as fetal tissue, fetal circulation, and umbilical cord blood.

As used herein, "bone marrow transplantation" is a form of stem cell transplantation.

A "allogeneic stem cell transplant" refers to donors and recipients that are not immunologically identical.

"autologous stem cell transplantation" involves the removal and preservation of the patient's own stem cells, which are then reinfused with them. This method is generally performed after a high dose of myeloablative therapy (myeloablative therapy).

The stem cell transplantation can be performed according to methods known in the art. Some such methods are described in F.R. Appelbaum, Bone Marrow and Stem Cell Transplantation, Chapter 14, Harrison's springletters of Internal Medicine, Eugene Braunwald et al, eds (McGraw-Hill Professional; 15 th edition, February 16, 2001), which is incorporated herein by reference.

Thus, bone marrow may be collected from the donor's posterior and sometimes anterior iliac crest under general or spinal anesthesia. Typically, 10 to 15mL/kg bone marrow is aspirated, placed in heparinized media, and filtered through 0.3-and 0.2-mm sieves to remove fat and ossicle pieces. For example, for allogeneic transplantation, about 1.5 to 5X 10 per kilogram can be collected⁸And nucleated bone marrow cells. The collected bone marrow may be further processed depending on clinical conditions, for example, to remove red blood cells to prevent hemolysis of ABO incompatible transplants, to remove donor T cells to prevent Graft Versus Host Disease (GVHD), or by attempting to remove potentially contaminating tumor cells in an autologous transplant.

In one embodiment, stem cells may be mobilized from the bone marrow by treating the donor with granulocyte colony stimulating factor (G-CSF) or other factors, such as IL-8, which may induce movement of the stem cells from the bone marrow into the peripheral circulation. In some embodiments, peripheral blood stem cells are collected after treatment of the donor with hematopoietic growth factors, or in the case of autologous transplantation, sometimes after treatment with a combination of chemotherapeutic agents and growth factors.

After mobilization, stem cells can be collected from peripheral blood by any suitable cell separation technique (leukapheresis), for example, using a commercially available blood collection device such as a CS3000 blood cell separator (Baxter Healthcare Corporation, Deerfield, IL). In Williamset et al, Bone Marrowtransplantation 5: 129-33(1990) and Hillyer et al, transfer 33: 316-21(1993), both of which are incorporated herein by reference, describes a method of plasmapheresis (apheresis) using a CS3000 blood cell separator.

The stem cell transplant may be administered according to methods known in the art, for example, by intravenous injection. The stem cells for transplantation can be infused through a large-diameter central venous catheter.

In certain embodiments, the preparatory therapy is performed prior to stem cell transplantation. The preparatory treatment regimen administered to the mammal prior to transplantation can be designed to eradicate the latent disease of the mammal, or, in the setting up of allogeneic transplants, to sufficiently immunosuppress the mammal to prevent rejection of the transplanted stem cells. Thus, suitable protocols depend on the disease condition and the source of the bone marrow. These protocols may include providing chemotherapy and/or systemic irradiation to the mammal.

Accordingly, the present invention also relates to a method for treating cancer in a mammal comprising the steps of (i) providing chemotherapy to the mammal; (ii) (ii) performing a stem cell transplant, and (iii) administering an effective amount of a human anti-CTLA-4 antibody. Preferably, the mammal is a human. The stem cell transplantation may be a allogeneic stem cell transplantation or an autologous stem cell transplantation.

The chemotherapeutic agent can be, for example, any cytotoxic drug, e.g., doxorubicin, bleomycin, busulfan, capecitabine, carboplatin, carmustine, cisplatin, cyclophosphamide, docetaxel, epirubicin, etoposide, fludarabine, gemcitabine, ifosfamide, irinotecan, melphalan, methotrexate, paclitaxel, teniposide, topotecan, thiotepa, or a combination thereof. Generally, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, cell cycle inhibitors, enzymes, and topoisomerase inhibitors. Silky hair inhibitors such as docetaxel, paclitaxel and vinblastine; alkylating agents, for example, busulfan, carboplatin, cisplatin, cyclophosphamide, ifosfamide and thiotepa; antimetabolites, for example, 5-fluorouracil, capecitabine, cytarabine, fludarabine, gemcitabine, methotrexate and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European patent application 239362, for example, N- (5- [ N- (3, 4-dihydroxy-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino ] -2-thenoyl) -L-glutamic acid; intercalating antibiotics, such as doxorubicin, bleomycin and epirubicin.

The chemotherapy may be high dose chemotherapy; for example, high doses of any of the above chemotherapeutic agents may be administered. Preferably, a high dose of busulfan, cyclophosphamide, melphalan, thiotepa, carmustine, etoposide, cisplatin, epirubicin, fludarabine, or a combination thereof may be administered.

Examples of chemotherapy may be Childs R, et al, Regression of metabolic product-cell cardio-cellular metabolic functional-blood-stem-cell transplantation, N EnglJ Med.2000 Sep 14; 343(11): 750-8; basser RL, et al, multicycle high-dose chemotherapy and profiling-mobilizedproperiter-blood reagent cells in women with high-rise stage11 or III Breast cancer: five-year follow-up, J Clin Oncol.1999Jan; 17(1): 82-92; socie G, et al, Busulfan Plurecycling cyclophosphospamide shared with total-body irradation multiplying cycloprophopsphoamide before migration for myelo-idi-leukaemia: long-term follow-up of 4 random students, Blood2001 Dec 15; 98(13): 3569-74, each of which is incorporated herein by reference.

Thus, chemotherapy may include a combination of cyclophosphamide and fludarabine followed by stem cell transplantation. For example, 25mg of fludarabine per square meter of body surface area per day may be intravenously infused during the last 5 days before transplantation, after intravenous infusion with 60mg cyclophosphamide per kg body weight on days 7 and 6 before transplantation. Such a protocol may be used, for example, in conjunction with non-myeloablative allogeneic peripheral blood stem cell transplantation.

In other embodiments, high dose chemotherapy may comprise administration of epirubicin, cyclophosphamide, and optionally urinary system protective agent (urocortic agent) mesna (sodium 2-mercaptoethanesulfonate) followed by stem cell transplantation. For example, 200mg/m is administered intravenously over 12 hours on day 4 (day-4) before transplantation²After epirubicin (Pharmacia-Upjohn, Milan, Italy), on day 3 (day-3) prior to transplantation, 1g/m was administered intravenously over 30 minutes in 4 divided doses²By intravenous administration of 4g/m²Cyclophosphamide (Pharmacia-Upjohn). Intravenous bolus infusion (0.8 g/m) may be used prior to administration of the first dose of cyclophosphamide²) Applying mesna (2-mercaptoethanesulfonic acid sodium salt) as urinary system protective agent, then on day-3 (4 g/m)²) And day-2 (2.4 g/m)²) Continuous infusion was performed. Such a protocol may be combined with, for example, autologous peripheral blood stem cell transplantation.

In other embodiments of the invention, chemotherapy and stem cell transplantation may be combined with radiotherapy. Techniques for delivering low or high doses of radiation therapy are known in the art and may be used in the combination therapies described herein. For example, the patient may receive 60mg/kg per day for 2 consecutive days, for a total of 120mg/kg cyclophosphamide. Busulfan may optionally be administered, for example, at 16mg/kg (e.g., 1mg/kg per dose orally every 6 hours for 4 consecutive days). The whole-body irradiation protocol may be very dependent on the condition of the patient, e.g. the patient may receive 12Gy in a grouping scheme. These protocols may be combined with, for example, allogeneic bone marrow transplantation.

Antibodies

Antibodies useful in the present invention and methods for their preparation are described in International application No. PCT/US99/30895, published on 6/29/2000 and European patent application No. EP 1262193A 1, published on 4/12/2002, both of which are incorporated herein by reference. Although sequence information is provided herein, other information can be found in WO00/37504 and EP 1262193; the sequences of these applications are incorporated herein by reference.

Antibodies that bind CTLA-4 can be used to practice the methods described herein. Examples of such antibodies include those described in WO00/37504, which are designated 2.1.3, 3.1.1, 4.1.1, 4.8.1, 4.10.2, 4.13.1, 4.14.3, 6.1.1, 11.2.1, 11.6.1, 11.7.1, 12.3.1.1 and 12.9.1.1. Also included are antibodies described in International patent publication Nos. WO01/14424 and WO03/086459 and U.S. patent publication No. 2002/0086014, including, but not limited to, the antibody MDX-010 (formerly known as antibody "10D 1"). These antibodies are typically full length human IgG2 or IgG4 heavy chains with human kappa light chains. In particular, the invention relates to the use of antibodies having the amino acid sequences of these antibodies. The invention also relates to antibodies having the amino acid sequences of the heavy and light chain CDRs of these antibodies, as well as antibodies having variations in the CDR regions, as described herein. The invention also relates to antibodies having the heavy chain light chain variable regions of these antibodies. In other embodiments, the antibody is selected from antibodies having the full length amino acid sequences, variable regions, or amino acid sequences of the CDRs of the heavy and light chains of antibodies 4.1.1, 11.2.1, 4.13.1, 4.14.3, or 6.1.1.

In certain embodiments, the antibodies used in the present invention have the amino acid sequences shown in figures 1-9. If there are any sequence differences between the figures, the disclosure of FIGS. 1-8 controls.

The following subclones were deposited at the American type culture Collection, 10801 Universal Blvd, Manassas, VA20110-2209, 29/4/2003:

clone subcloned ATCC accession number

4.1.1 4.1.1.1 PTA-5166

11.2.1 11.2.1.4 PTA-5169

It will be appreciated that the antibodies of the invention may be derived from a hybridoma, but may also be expressed in cell lines other than hybridomas. Sequences encoding cDNAs or genomic clones of a particular antibody may be used for transformation of a suitable mammalian or non-mammalian host cell. Transformation can be carried out by any known method for introducing a polynucleotide into a host cell, including, for example, packaging the polynucleotide into a virus (or introducing a viral vector) and transducing the host cell with the virus (or vector), or by transfection methods known in the art, such as those exemplified in U.S. Pat. Nos. 4,399,216, 4,912,040, 4,740,461, and 4,959,455. Methods for introducing heterologous polynucleotides into mammalian cells are known in the art and include, but are not limited to, dextran-mediated transfection, calcium phosphate precipitation, polycation-mediated transfection, protoplast fusion, electroporation, biolistics, encapsulation of polynucleotides in liposomes, peptide conjugates, dendrimers, and direct microinjection of DNA into the nucleus of cells.

Available mammalian cell lines for use as expression hosts are known in the art and include a number of immortalized cell lines available from the American Type Culture Collection (ATCC), including but not limited to Chinese Hamster Ovary (CHO) cells, NSO, HeLa cells, Baby Hamster Kidney (BHK) cells, monkey kidney Cells (COS), and human hepatocellular carcinoma cells (e.g., Hep G2). Non-mammalian cells, including cells of bacteria, yeast, insects, and plants, may also be used. To prevent alterations in immunogenicity, pharmacokinetics and/or effector function due to non-human glycosylation, it is preferred to subject the antibody CH2 domain to site-directed mutagenesis to remove glycosylation. The expression systems for glutamine synthase are described in whole or in part in european patents 216846, 256055 and 323997 and european patent application 89303964.4. In addition, dihydrofolate reductase (DHFR) expression systems, including those known in the art, can be used to produce the antibodies.

Antibodies useful in the invention can also be produced by transgenic methods, by producing mammals or plants which have the immunoglobulin heavy and light chain sequences of interest and producing recoverable forms of the antibodies therefrom. Transgenic antibodies can be produced and recovered from goat, cow or other mammalian milk. See, for example, U.S. patents 5,827,690, 5,756,687, 5,750,172 and 5,741,957.

The antibodies used in the present invention preferably have very high affinity, typically from about 10 when measured by solid or liquid phase^-9To about 10^-11Kd of M.

In one embodiment, the antibody that binds CTLA-4 has the following properties:

binding affinity to CTLA-4 is about 10^-9Or higher;

inhibition of binding between CTLA-4 and B7-1 has an IC of about 100nM or less₅₀(ii) a And

inhibition of binding between CTLA-4 and B7-2 has an IC of about 100nM or less₅₀。

Preferably, the antibody comprises a heavy chain amino acid sequence comprising a sequence derived from V_H3-30 or 3-33 gene or conservative substitutions or somatic mutations contained therein. The antibody may also comprise CDR regions derived from the a27 or 012 genes on its light chain.

In other embodiments of the invention, the antibody inhibits binding between CTLA-4 and B7-1 with an IC of about 10nM or less₅₀IC of, e.g., about 5nM or less, or, e.g., about 1nM₅₀。

Alternatively, the anti-CTLA-4 antibody and the antibody having the heavy and light chain amino acid sequences of the antibody selected from among 4.1.1, 6.1.1, 11.2.1, 4.13.1, and 4.14.3 compete for binding. In another embodiment, the antibody cross-competes with an antibody having such heavy and light chain sequences or with the deposited antibody 4.1.1 or 11.2.1. For example, the antibody can bind to an epitope bound by an antibody having the amino acid sequences of the heavy and light chains of an antibody selected from among 4.1.1, 6.1.1, 11.2.1, 4.13.1, and 4.14.3.

In another embodiment, the invention is practiced by using an antibody comprising a heavy chain comprising the CDR-1, CDR-2 and CDR-3 amino acid sequences of an antibody selected from the group consisting of 3.1.1, 4.1.1, 4.8.1, 4.10.2, 4.13.1, 4.14.3, 6.1.1, 11.2.1, 11.6.1, 11.7.1, 12.3.1.1 and 12.9.1.1 or a sequence having conservative changes, conservative substitutions, additions or deletions of residues as compared to the CDR sequences and a light chain comprising the amino acid sequences of a CDR-1, CDR-2 and CDR-3 amino acid sequence of an antibody selected from the group consisting of 3.1, 4.1.1, 4.8.1, 4.10.2, 4.13.1, 4.14.3, 6.1.1, 11.2.1, 11.6.1, 11.7.1, 12.3.1.1.1 and 12.9.1.1, or a conservative change, conservative changes, conservative substitutions of residues as compared to the CDR-1, residues of the amino acid sequences of the other amino acid sequences of the conservative changes, or substitutions of residues of the amino acid sequences of the CDR-1, conservative changes, CDR-1, or of residues of the residues of residues, Substitution of polar charged residues with other polar uncharged residues, substitution of polar charged residues with other polar charged residues and substitution of structurally similar residues; wherein the non-conservative substitutions are selected from the group consisting of substitutions of polar charged residues for polar uncharged residues and substitutions of non-polar residues for polar residues. In other embodiments of the invention, the antibody contains less than 10, 7, 5, or 3 amino acid changes in the framework or CDR regions compared to the germline sequences. In another embodiment, the antibody contains less than 5 amino acid changes in the framework regions and less than 10 amino acid changes in the CDR regions. In a preferred embodiment, the antibody contains less than 3 amino acid changes in the framework regions and less than 7 amino acid changes in the CDR regions. In a preferred embodiment, the changes in the framework regions are conservative and the changes in the CDR regions are somatic mutations.

The following table shows the number of amino acid changes in the H and L chain FR and CDR regions of certain antibodies of the invention compared to the germline.

	4.1.1	4.8.1	6.1.1	11.2.1
					H-FR	1	0	1	0
H-CDR	3	4	3	1
					L-FR	1	0	1	0
L-CDR	3	4 (including 2 deletions)	2 (including 1 deletion)	3
					Total FR/CDR	2/6	0/8	2/5	0/4

In another embodiment, the antibody comprises a heavy chain comprising the CDR-1, CDR-2, and CDR-3 amino acid sequences of an antibody selected from among 3.1.1, 4.1.1, 4.8.1, 4.10.2, 4.13.1, 4.14.3, 6.1.1, 11.2.1, 11.6.1, 11.7.1, 12.3.1.1, and 12.9.1.1 and a light chain comprising the CDR-1, CDR-2, and CDR-3 amino acid sequences of an antibody selected from among 3.1.1, 4.1.1, 4.8.1, 4.10.2, 4.13.1, 4.14.3, 6.1.1, 11.2.1, 11.6.1, 11.7.1, 12.3.1.1, and 12.9.1.1. In another embodiment, the antibody has the same amino acid sequence of the heavy and light chain variable regions as an antibody selected from the group consisting of 4.1.1, 4.8.1, 6.1.1, and 11.2.1, 11.6.1, 11.7.1, 12.3.1.1, and 12.9.1.1. In other embodiments, the antibody comprises the heavy chain amino acid sequence of human gene 3-33 and the light chain sequence of human gene a27 or 012.

As used herein, the term "epitope" includes any protein determinant capable of specifically binding to an immunoglobulin or T cell receptor. Epitopic determinants generally consist of chemically active surface groupings in the molecule, such as amino acids or sugar side chains, and generally have specific three-dimensional structural characteristics as well as specific charge characteristics.

An antibody is said to specifically bind to an antigen when the dissociation constant is ≦ 1M, preferably ≦ 100nM, most preferably ≦ 10 nM.

The term "antibody" as used herein refers to an intact antibody, or a binding fragment thereof that competes for specific binding with the intact antibody. The binding fragments are generated by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab ', F (ab') 2, Fv and single chain antibodies. It is understood that the binding sites are identical except for antibodies that are "bispecific" or "bifunctional" antibodies. An antibody substantially inhibits the binding of a receptor to a counterreceptor when an excess of antibody reduces the amount of receptor bound to the counterreceptor by at least about 20%, 40%, 60%, or 80%, and more typically more than about 80% (as measured in an in vitro competitive binding assay).

The basic antibody structural unit is known to consist of a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25kDs) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain comprises a variable region of about 100 to 110 or more amino acids, which is primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as μ, δ, γ, α or ε, and define the antibody isotype as IgM, IgD, IgG, IgA and IgE, respectively. Within the light and heavy chains, the variable and constant regions are connected by a "J" region of about 12 or more amino acids, and the heavy chain also contains a "D" region of about 10 more amino acids. See generally, Fundamental Immunology Ch.7(Paul, W., ed., 2 nd edition Raven Press, N.Y. (1989)). The variable regions of each light/heavy chain pair form the antibody binding site.

Thus, an intact IgG antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are identical. All chains exhibit the same overall structure, i.e., relatively conserved Framework Regions (FR) are connected by three hypervariable regions (also known as complementarity determining regions or CDRs). The CDRs from both chains of each pair are aligned by the framework regions and are thus able to bind a specific epitope. From N-terminus to C-terminus, both light and heavy chains comprise domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR 4. Amino acid assignments to each domain and either Kabat Sequences of Proteins of Immunological Interest (national institutes of Health, Bethesda, Md. (1987 and 1991)) or Chothia & Lesk J.mol.biol.196: 901-917 (1987); chothia et al Nature 342: 878-883 (1989).

The term "human antibody" refers to an antibody having an amino acid sequence derived from a human gene, including human genes present in transgenic mice or elsewhere, and also including sequences resulting from somatic mutations or other changes made when the antibody sequence is generated from a human gene. The invention includes variations in the amino acid sequence of the type described below.

The antibodies used in the present invention are preferably derived from cells expressing human immunoglobulin genes. The use of transgenic mice in the art is known to produce these "human" antibodies. In Mendez et al Nature Genetics 15: 146-: 483-495(1998) and U.S. patent application Ser. No. 08/759,620 (filed 12/3 1996) describe one such approach. In U.S. patent applications 07/466,008 (filed 1/12.1990), 07/610,515 (filed 11/8.1990), 07/919,297 (filed 7/24.1992), 07/922,649 (filed 7/30.1992), 08/031,801 (filed 3/15.1993), 08/112,848 (filed 8/27.1993), 08/234,145 (filed 4/28.1994), 08/376,279 (filed 1/20.1995), 08/430,938 (filed 4/27.1995), 08/464,584 (filed 6/5.1995), 08/464,582 (filed 6/5.1995), 08/463,191 (filed 6/5.1995), 08/462,837 (filed 6/5.1995), 08/486,853 (filed 6/5.1995), 08/486,857 (filed 6/5.1995), 08/486,859 (filed 6/5.1995), 08/462,513 (f. filed 6.5.1995), 08/724,752 (filed 10.2.1996) and 08/759,620 (filed 12.3.1996) also describe the use of such mice to obtain human antibodies. See also Mendez et al Naturegenetics 15: 146-: 483-495(1998). See also European patent EP 0463151 (published as granted at 12.6.1996), International patent application WO 94/02602 (published at 3.2.1994), International patent application WO 96/34096 (published at 31.10.1996) and WO 98/24893 (published at 11.6.1998).

An alternative method for making human antibody-producing transgenic mice is the "minilocus" method, in which the foreign Ig locus is mimicked by the inclusion of fragments (single genes) from the Ig locus. One or more VH genes, one or more DH genes, one or more JH genes, a mu constant region, and a second constant region (preferably a gamma constant region) are formed into a construct for insertion into an animal. See U.S. Pat. No. 5,545,807 to Surani et al and U.S. Pat. Nos. 5,545,806, 5,625,825, 5,625,126, 5,633,425, 5,661,016, 5,770,429, 5,789,650, and 5,814,318, both to Lonberg and Kay, U.S. Pat. No. 5,591,669 to Krimpen and Berns, U.S. Pat. Nos. 5,612,205, 5,721,367, 5,789,215 to Berns et al, and U.S. Pat. No. 5,643,763 to Choi and Dunn, and Genpharm International U.S. patent application 07/574,748(1990 8.29), 07/575,962(1990 8.31.d.), 07/810,279(1991 12.17.16.d.), 07/853,408(1992 3.18.d.), 07/904,068 (1992.6.23.d.), 07/990,860(1992 12.16.d.), 08/053,131 (1993), 08/096,762 (1993), 08/155,301 (1993), 1993 (1993) 4612.18.16.16.1993), 4612.16.16.1993 (1993), 4612.16.16.16.1993), 08/209,741 (filed 3/9 of 1994). See also European patent 546073B 1, International patent applications WO 92/03918, WO92/22645, WO 92/22647, WO 92/22670, WO 93/12227, WO 94/00569, WO 94/25585, WO 96/14436, WO 97/13852 and WO 98/24884.

Antibodies having changes in amino acid sequence compared to the specific antibodies exemplified herein can be used in the methods of the invention. For example, the sequences may have "substantial identity," meaning that the original and altered sequences have at least 80% sequence identity, preferably at least 90% sequence identity, more preferably at least 95% sequence identity, most preferably at least 99% sequence identity over the sequence of the entire antibody, variable region, framework region or CDR region, when optimally aligned, for example, by the programs GAP or BESTFIT using default GAP weights. Preferably, non-identical residue positions differ by conservative amino acid substitutions. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, the group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; the group of amino acids having aliphatic hydroxyl side chains is serine and threonine; the group of amino acids having amide-containing side chains is asparagine and glutamine; the group of amino acids having aromatic side chains are phenylalanine, tyrosine and tryptophan; the group of amino acids having basic side chains is lysine, arginine and histidine; and the group of amino acids having sulfur-containing side chains are cysteine and methionine. Preferred conservative amino acid substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid and asparagine-glutamine. For example, isolated substitutions of leucine with isoleucine or valine, aspartic acid with glutamic acid, threonine with serine, or similar substitutions of amino acids with structurally related amino acids can reasonably be expected to have no significant effect on the binding or properties of the resulting molecule, particularly when the substitutions do not include amino acids within the framework sites. Whether a change in amino acid results in a functional peptide can be readily determined by determining the specific activity of the polypeptide derivative.

Fragments or analogs of antibodies or immunoglobulin molecules can be readily prepared by those skilled in the art. Preferred fragments or analogs occur near the boundaries of the functional domain at the amino and carboxy termini. Structural and functional domains can be identified by comparing nucleotide and/or amino acid sequences to public or private sequence databases. Preferably, computerized comparison methods are used to identify sequence motifs or predicted protein conformation domains present in other proteins of known structure and/or function. Methods for identifying protein sequences that fold into known three-dimensional structures are known. Bowie et al Science 253: 164(1991). Thus, one skilled in the art can identify sequence motifs and structural conformations that can be used to determine the structural and functional domains of the present invention.

Preferred amino acid substitutions are those which: (1) reduced susceptibility to proteolysis, (2) reduced susceptibility to oxidation, (3) altered binding affinity associated with formation of protein complexes, (4) altered binding affinity, and (4) provision or modification of other physicochemical or functional properties of these analogs. Analogs can include various sequence muteins in addition to the naturally occurring peptide sequence. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in a naturally occurring sequence (preferably in the part of the polypeptide outside the domains forming intermolecular contacts). Conservative amino acid substitutions should not significantly alter the structural characteristics of the parent sequence (e.g., a substituted amino acid should not disrupt the helix present in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). In Proteins, Structures and Molecular Principles (Creighton, Ed., W.H.Freeman and Company, New York (1984)); examples of art-recognized secondary and tertiary structures of polypeptides are described in Introduction to protein Structure (C.Branden and J.Tooze, eds., Garland Publishing, New York, N.Y. (1991); and Thornton et al Nature 354: 105 (1991)).

The antibodies used in the methods of the invention may be labeled. Labeling can be achieved by incorporating a detectable label, e.g., a radiolabeled amino acid, into or attached to a polypeptide of biotinylated moieties detectable by labeled avidin (e.g., streptavidin containing a fluorescent label or enzymatic activity that can be detected optically or colorimetrically). In certain instances, the marker or marker may also be therapeutic. Methods for labeling polypeptides and glycoproteinsMethods are known in the art and may be used. Examples of polypeptide markers include, but are not limited to, the following: a radioisotope or radionuclide (e.g.,³H、¹⁴C、¹⁵N、³⁵S、⁹⁰Y、⁹⁹Tc、¹¹¹In、¹²⁵I、¹³¹I) a fluorescent label (e.g., FITC, rhodamine, lanthanide phosphors), an enzymatic label (e.g., horseradish peroxidase, β -galactosidase, luciferase, alkaline phosphatase), a chemiluminescent agent, a biotinylated group, a predetermined polypeptide epitope recognized by another reporter (e.g., leucine zipper pair sequence, binding site for a second antibody, metal binding domain, epitope tag). In some embodiments, the labels are attached by spacer arms of various lengths to reduce potential steric hindrance.

In another embodiment, the antibodies used in the methods of the invention are not fully human, but are "humanized". In particular, murine antibodies or antibodies from other species may be humanized or primatized (primatized) by techniques well known in the art. See, e.g., Winter and Harris immunological Today 14: 43-46(1993) and Wright et al crit. reviews in immunol.12125-168 (1992). Antibodies can be genetically engineered by recombinant DNA techniques to replace CH1, CH2, CH3, the hinge region, and/or the framework domain with the corresponding human sequences (see, WO 92/02190 and U.S. Pat. nos. 5,530,101, 5,585,089, 5,693,761, 5,693,792, 5,714,350, and 5,777,085). Furthermore, the use of Ig cDNA to construct chimeric immunoglobulin genes is known in the art (Liu et al P.N.A.S.84: 3439(1987) and J.Immunol.139: 3521 (1987)). mRNA is isolated from hybridomas or other cells that produce antibodies and used to produce cDNA. The cDNA of interest can be amplified by polymerase chain reaction using specific primers (U.S. Pat. nos. 4,683,195 and 4,683,202). Alternatively, libraries can be prepared and screened to isolate sequences of interest. The DNA sequence encoding the variable region of the antibody is then fused to the human constant region sequence. The sequence of the human constant region gene can be found in Kabat et al (1991) Sequences of Proteins of immunological interest, N.I.H.publication No. 91-3242. The human C region gene can be easily obtained from a known clone. The isotype may be selected for the desired effector function, e.g., activity in complement fixation or antibody-dependent cellular cytotoxicity. Preferred isotypes are IgG1, IgG2, IgG3 and IgG 4. Particularly preferred isotypes of the antibodies of the invention are IgG2 and IgG 4. The constant region of a human light chain (kappa or lambda) may be used. The chimeric, humanized antibody can be expressed by conventional methods.

As mentioned above, the invention includes the use of antibody fragments (encompassed herein within the definition of "antibody"). Antibody fragments, such as Fv, F (ab') 2 and Fab, can be prepared by cleavage of the intact protein, for example by protease or chemical cleavage. Alternatively, truncated genes are designed. For example, a chimeric gene encoding a portion of a F (ab') 2 fragment may comprise a DNA sequence encoding a H chain CH1 domain and a hinge region, followed by a translation stop codon to produce a truncated molecule.

In one approach, oligonucleotides encoding the consensus sequences of the heavy and light chain J regions can be used to design primers for introducing useful restriction sites into the J region for subsequent ligation of V region fragments to human C region fragments to modify the cDNA of the C region by site-directed mutagenesis to place the restriction sites at similar sites in the human sequence.

Expression vectors for obtaining the antibodies used in the present invention include plasmids, retroviruses, cosmids, YACs, EBV-derived episomes, and the like. Convenient vectors are generally those which encode fully functional human CH or CL immunoglobulin sequences, with appropriate restriction sites created by genetic engineering so that any VH or VL sequence can be readily inserted and expressed. In these vectors, splicing typically occurs between the splice donor site in the inserted J region and the splice acceptor site preceding the human C region, as well as in the splice region present within the human CH exon. Polyadenylation and transcription termination occur at native chromatin sites downstream of the coding region. The resulting chimeric antibody can be ligated to any strong promoter, including retroviral LTRs, such as the SV-40 early promoter, (Okayama et al mol. Cell. Bio.3: 280(1983)), Rous sarcoma virus LTR (Gorman et al P.N.A.S.79: 6777(1982)), and murine leukemia virus LTR (Grosschedl et al Cell 41: 885(1985)), the native Ig promoter, and the like.

Human antibodies or antibodies from other species useful in the practice of the present invention can also be generated by display-type techniques, including but not limited to: phage display, retrovirus display, ribosome display. The resulting molecule may be subjected to further maturation, such as affinity maturation, techniques which are well known in the art. Wright and Harris, immunological Today 14: 43-46(1993), Hanes and Plucthau PNAS USA 94: 4937-4942(1997) (ribosome display), Parmley and Smith Gene 73: 305-318(1988) (phage display), Scott TIBS 17: 241-: 6378-6382(1990), Russel et al nucleic acids Research 21: 1081-: 43-68(1992), Chiswell and McCafferty TIBTECH 10: 80-84(1992) and U.S. Pat. No. 5,733,743. If display technology is used to produce non-human antibodies, these antibodies can be humanized as described above.

By using these techniques, antibodies can be raised against CTLA-4-expressing cells, CTLA-4 itself, various forms of CTLA-4, epitopes or peptides thereof and expression libraries thereof (see, U.S. Pat. No. 5,703,057), which can then be screened for the above-described activities.

Antibodies prepared for use in the present invention need not initially have a defined desired isotype. Of course, the antibodies produced may have any isotype and may be those which are later converted using conventional techniques. These techniques include targeted recombinant techniques (see, e.g., U.S. Pat. No. 4,816,397) and cell-cell fusion techniques (see, e.g., U.S. patent application 08/730,639 (filed 10/11/1996).

The effector function of the antibodies of the invention can be altered by isotype switching to IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE or IgM for various therapeutic uses. Furthermore, the dependence on complement for cell killing can be avoided, for example, by using bispecific, immunotoxins or radioactive labels.

Bispecific antibodies can be generated comprising (i) two antibodies: one antibody has specificity for CTLA-4 and the other antibody has specificity for a second molecule, (ii) a single antibody having one chain specific for CTLA-4 and a second chain specific for the second molecule, or (iii) a single chain antibody having specificity for CTLA-4 and the other molecule. These bispecific antibodies can be produced using well known techniques (e.g., Fanger et al Immunol methods 4: 72-81(1994), Wright and Harris, supra and Trunecker et al int. J. cancer (Suppl.) 7: 51-52 (1992)).

Antibodies useful in the present invention also include "kappa antibodies" (III et al, "Design and construction of a carbohydrate domain with properties of bouth heav and light chain derivatives" Protein Eng 10: 949-57(1997), "miniantibodies" (Martin et al, "therapy-selection of a minor polypeptide inhibitor of human interferon-6" EMBO J13: 5303-9), (1994), "Diabodies" (Holliger et al, "' diabetes additives": bivalent and biological additives "PNAS fragment AS 6490: 6444 (1993)) and" calcium ligand J "(1992) HIV ligand J3655, and" calcium ligand J "(19951, Jappn et al," molecular Protein J1: 3-52. for biological samples and biological samples "3: 3651. for biological samples".

The antibody used may be modified by conventional methods to be used as an immunotoxin. See, e.g., Vitetta immunological Today 14: 252(1993). See also U.S. Pat. No. 5,194,594. Radiolabeled antibodies may also be prepared using well-known techniques. See, for example, Junghans et al Cancer chemothermal and Biotherapy 655-. See also U.S. patents 4,681,581, 4,735,210, 5,101,827, 5,102,990(RE35,500), 5,648,471 and 5,697,902.

Pharmaceutical compositions and administration

The antibodies for use in the present invention may be incorporated into a pharmaceutical composition suitable for administration to a subject. Generally, the pharmaceutical composition comprises an antibody and a pharmaceutically acceptable vehicle. As used herein, "pharmaceutically acceptable vehicle" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are physiologically compatible. Examples of pharmaceutically acceptable vehicles include one or more of water, saline, phosphate buffered saline, glucose, glycerol, ethanol, and the like, and combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. A pharmaceutically acceptable substance such as a wetting agent or a small amount of an auxiliary substance such as a wetting or emulsifying agent, a preservative or a buffer, which increases the shelf life or effectiveness of the antibody or antibody portion.

The antibodies may exist in various forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. Generally preferred compositions are in the form of injectable or infusible solutions, e.g., compositions similar to those used for passive immunization of humans with other antibodies. Preferred modes of administration are parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular) modes. In a preferred embodiment, the antibody is administered by intravenous infusion or injection. In other preferred embodiments, the antibody is administered by intramuscular or subcutaneous injection.

Therapeutic compositions must generally be sterile and stable under the conditions of manufacture and storage. The compositions may be formulated as solutions, microemulsions, dispersions, liposomes or other ordered structures suitable for high drug concentrations. Sterile injectable solutions can be prepared by incorporating the antibody in the required amount in an appropriate solvent with one or a combination of the ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Suitable fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by incorporating into the compositions an agent which delays absorption, for example, a monostearate salt or gelatin.

The antibody can be administered by a variety of methods known in the art including, but not limited to, oral, parenteral, transmucosal, inhalation, topical, oral, nasal, and rectal. For many therapeutic applications, the preferred route/mode of administration is subcutaneous, intramuscular, intravenous or infusion. Needle-free injection (Non-needle injection) may be used if desired. As will be appreciated by those skilled in the art, the route and/or mode of administration will vary depending on the desired result.

In certain embodiments, antibodies can be prepared with vehicles that prevent rapid release of the compounds, such as controlled release formulations, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers may be used, such as ethylene-vinyl acetate copolymers, polyanhydrides, polyglycolic acid (polyglycolic acid), collagen, polyorthoesters, and polylactic acid. Many methods for preparing these formulations have been patented or are generally known to those skilled in the art. See, for example, Sustained and Controlled Release Drug delivery systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

The dosage regimen may be adjusted to provide the most appropriate desired response. For example, a single bolus dose may be administered, several divided doses may be administered over a period of time, or the dose may be reduced or increased proportionally according to the exigencies of the therapeutic condition. It is particularly advantageous to formulate compositions for parenteral administration in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the mammalian subjects being treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The specification for the dosage unit of the invention is dictated by and directly dependent on (a) the unique properties of the antibody and the particular therapeutic or prophylactic effect to be achieved, and (b) limitations inherent in the art of formulating such active compounds for use in the treatment of sensitivity in an individual.

An exemplary, non-limiting range of therapeutically effective amounts of the antibodies administered in combination according to the invention is at least 1mg/kg, at least 5mg/kg, at least 10mg/kg, more than 10mg/kg or at least 15mg/kg, such as 1-21mg/kg, or such as 5-18mg/kg, or such as 10-18mg/kg, or such as 15 mg/kg. The high dose embodiments of the present invention relate to doses in excess of 10 mg/kg. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, which may include single or multiple doses. It is further understood that the specific dosage regimen for a particular subject should be adjusted over a period of time according to the individual need and the professional judgment of the person administering or monitoring the administration of the composition, and that the dosage ranges provided herein are exemplary only and do not limit the scope or practice of the composition.

In one embodiment, the antibody is administered as an intravenous formulation as a sterile aqueous solution containing 5 or 10mg/ml of the antibody, 20mM sodium acetate, 0.2mg/ml polysorbate 80 and 140mM sodium chloride, pH 5.5.

In one embodiment, a portion of the dose is administered in the form of an intravenous bolus and the remainder is administered by infusion of the antibody formulation. For example, 0.01mg/kg of antibody may be injected intravenously in a bolus dose, and the remainder of the intended antibody dose may be administered by intravenous injection. For example, a predetermined dose of antibody may be administered over a period of one-half to two-hours to two-half hours.

The invention also relates to an article of manufacture (e.g., a dosage form suitable for intravenous administration) comprising "a cancer-treating effective amount (e.g., greater than 10mg/kg, at least 15mg/kg, or 20mg/kg) of a human anti-CTLA-4 antibody. In certain embodiments, the article of manufacture comprises a container loaded with human anti-CTLA-4 antibody and a label and/or instructions for treating cancer.

Other treatment regimens

The above-described treatment regimens can be further combined with other cancer therapeutic agents and/or regimens (e.g., other chemotherapeutics, cancer vaccines, signal transduction inhibitors, agents useful for treating abnormal cell growth or cancer, antibodies or other ligands that inhibit tumor growth by binding IGF-1R, and cytokines).

When the mammal is receiving other chemotherapy, the chemotherapeutic agents described above may be used. In addition, growth factor inhibitors, biological response modifiers (biological responses), anti-hormone therapeutics, Selective Estrogen Receptor Modulators (SERMs), angiogenesis inhibitors and anti-androgens may be used. For example, anti-hormonal agents may be used, for example anti-estrogens such as Nolvadex^TM(tamoxifen) or antiestrogens such as Casodex^TM(4 '-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3' - (trifluoromethyl) propionylaniline).

In certain embodiments of the invention, the methods described above may be combined with a cancer vaccine. Useful vaccines can be, but are not limited to, vaccines composed of cancer-associated antigens (e.g., BAGE, carcinoembryonic antigen (CEA), EBV, GAGE, gp100 (including gp 100: 209-217 and gp 100: 280-288, etc.), HBV, HER-2/neu, HPV, HCV, MAGE, mammaglobulin (mammaglobin), MART-1/Melan-A, Mucin-1, NY-ESO-1, protease-3, PSA, RAGE, TRP-1, TRP-2, tyrosinase (e.g., tyrosinase: 368-376), WT-1), GM-CSF DNA and cell-based vaccines, dendritic cell vaccines, recombinant virus (e.g., vaccinia virus) vaccines and Heat Shock Protein (HSP) vaccines. Useful vaccines also include tumor vaccines, such as those formed from melanoma cells, which may be autologous or heterologous. The vaccine may be, for example, a peptide, DNA and cell based vaccine. These various agents can be combined such that a combination comprising gp100 peptide, tyrosinase and MART-1 can be administered with the antibody.

The vaccine can be administered before or after stem cell transplantation, and when chemotherapy is part of a treatment regimen, the vaccine can be administered before chemotherapy. In certain embodiments, the antibodies of the invention may also be administered prior to chemotherapy. The vaccine may also be administered after stem cell transplantation, and in certain embodiments, the vaccine may be administered with the antibody.

The above therapies may be used with signal transduction inhibitors, e.g., agents that inhibit EGFR (epidermal growth factor receptor) responses, e.g., EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors, such as VEGF receptors and molecules that inhibit VEGF; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, such as Herceptin  (Genentech, inc. of South San Francisco, California).

EGFR inhibitors are described, for example, in WO 95/19970 (published at 27.7.1995), WO 98/14451 (published at 9.4.1998), WO 98/02434 (published at 22.1.1998), and U.S. Pat. No. 5,747,498 (granted 5.5.1998), which are useful in the present invention as described herein. EGFR inhibitors include, but are not limited to, the monoclonal antibodies ERBITOX (Imclone Systems Incorporated of New York, New York), and ABX-EGF (Abgenix Inc. of Fremont, California), the compounds ZD-1839(AstraZeneca), BIBX-1382(Boehringer Ingelheim), MDX-447 (Mearex Inc. of Annandale, New Jersey), and OLX-103(Merck & Co. of Whitehouse State, New Jersey), VRCTC-310(Ventech Research), and EGF fusion toxins (Seragen Inc. of Hopkinsetts). These and other EGFR inhibitors are useful in the present invention.

VEGF inhibitors, such as SU-5416 and SU-6668(Sugen Inc. of South san Francisco, Calif.), may also be used with the antibodies. VEGF inhibitors are described, for example, in WO 99/24440 (published 5/4/1999), PCT International application PCT/IB99/00797 (filed 5/3/1999), WO 95/21613 (published 8/17/1995), WO 99/61422 (published 12/2/1999), US 5,834,504 (published 11/10/1998), WO 98/50356 (published 12/1998), US 5,883,113 (published 3/16/1999), US 5,886,020 (published 3/23/1999), US 5,792,783 (published 11/8/1998), WO 99/10349 (published 3/4/1999), WO 97/32856 (published 12/1997), WO 97/22596 (published 26/6/1998), WO 98/54093 (published 3/1998), WO 98/02438 (published 1/22/1998), WO 99/16755 (published on 8.4.1999) and WO 98/02437 (published on 22.1.1998). Other examples of some specific VEGF inhibitors that may be used in the present invention are IM862(Cytran Inc. of Kirkland, Washington), IMC-1C 11Imclone antibody, AVASTIN (Genentech, Inc., San Francisco, Calif.); and angiozyme, synthetic ribozymes from Ribozyme (Boulder, CO) and Chiron (Emeryville, CA).

ErbB2 receptor inhibitors, such as GW-282974(Glaxo Wellcome plc), and monoclonal antibodies AR-209(Aronex Pharmaceuticals Inc. of the Woodlands, Texas) and 2B-1(Chiron), may further be used with antibodies such as those disclosed in WO 98/02434 (published 22/1 1998), WO 99/35146 (published 15/7 1999), WO 99/35132 (published 15/7 1999), WO 98/02437 (published 22/1/1998), WO 97/13760 (published 17/4/1997), WO 95/19970 (published 27/7/1995), U.S. Pat. No. 5,587,458 (published 24/12/1996) and U.S. Pat. 5,877,305 (published 2/3/1999). Inhibitors of the ErbB2 receptor useful in the present invention are also described in EP1029853 (published 8/23/2000) and WO 00/44728 (published 8/3/2000). ErbB2 receptor inhibitor compounds and substances described in the aforementioned PCT applications, U.S. patents, and U.S. provisional applications, as well as other compounds and substances that inhibit the ErbB2 receptor, may be used with the antibodies of the present invention.

The therapeutics of the invention can also be used with other agents for treating abnormal cell growth or cancer, including, but not limited to, other agents that can enhance the anti-tumor immune response, such as other different CTLA4 antibodies, and other agents that can also block CTLA 4; antiproliferative agents such as farnesyl protein transferase inhibitors and α v β 3 inhibitors, such as the α v β 3 antibody Vitaxin, α v β 35 inhibitors, p53 inhibitors, and the like.

When the antibodies of the invention are used with other immunomodulators, the immunomodulators can be selected from, for example, dendritic cell activators such as CD40 ligand and anti-CD 40 agonist antibodies, as well as enhancers of antigen presentation, T cell tropism enhancers, inhibitors of tumor-associated immunosuppressive factors such as TGF-beta (transforming growth factor beta) and IL-10.

The present treatment regimen may also be combined with an antibody or other ligand that inhibits tumor growth by binding to IGF-1R (insulin-like growth factor 1 receptor). Specific anti-IGF-1R antibodies useful in the present invention include those described in PCT application PCT/US01/51113, published as WO02/053596, filed 12/20/2001.

The antibodies of the invention may also be administered with cytokines such as IL-2, IFN-g, GM-CSF, IL-12, IL-18, and FLT-3L.

The treatment regimens described herein can be combined with anti-angiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9)The inhibitor and COX-II (cyclooxygenase II) inhibitor combination may be used with the antibody in the methods of the invention. Examples of useful COX-II inhibitors include CELEBREX^TM(celecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published 24.10.1996), WO 96/27583 (published 7.3.1996), European patent application 97304971.1 (published 8.7.1997), European patent application 99308617.2 (published 29.10.1999), WO 98/07697 (published 26.2.1998), WO 98/03516 (published 29.1.1998), WO 98/34918 (published 13.8.1998), WO 98/34915 (published 13.8.1998), WO 98/33768 (published 6.8.1998), WO 98/30566 (published 16.7.1998), European patent publication No. 606046 (published 13.7.1994), European patent application 931788 (published 28.7.1999), WO 90/05719 (published 31.5.31), WO 99/52910 (published 21.10.1999), WO 99/52889 (published 1021 in 1999), WO99/29667 (published 17/6/1999), PCT International application PCT/IB98/01113 (filed 21/7/1998), European patent application 99302232.1 (filed 25/3/1999), british patent application No. 9912961.1 (filed 3/6/1999), U.S. provisional application No. 60/148,464 (filed 12/8/1999), U.S. patent 5,863,949 (granted 26/1/1999), U.S. patent 5,861,510 (granted 19/1999), and European patent publication No. 780386 (published 25/6/1997). Preferred MMP-2 and MMP-9 inhibitors are those that have little and/or no activity for inhibiting MMP-1. More preferred are inhibitors that selectively inhibit MMP-2 and/or MMP-9 relative to other matrix metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO32-3555, RS13-0830, and the compounds cited in the following list:

3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-cyclopentyl) -amino ] -propionic acid;

3-exo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;

(2R, 3R)1- [4- (2-chloro-4-fluoro-benzyloxy) -benzenesulfonyl ] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;

4- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;

3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-cyclobutyl) -amino ] -propionic acid;

4- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;

(R)3- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-3-carboxylic acid hydroxyamide;

(2R, 3R)1- [4- (4-fluoro-2-methyl-benzyloxy) -benzenesulfonyl ] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;

3- [ [4- (4-fluoro-phenoxy) -phenyliodoyl ] - (1-hydroxycarbamoyl-1-methyl-ethyl) -amino ] -propionic acid;

3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino ] -propionic acid;

3-exo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;

3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; and

(R)3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -tetrahydro-furan-3-carboxylic acid hydroxyamide;

and pharmaceutically acceptable salts and solvates of said compounds.

The invention is further described in the following non-limiting examples.

Examples

Example 1

Human anti-CTLA-4 antibody designated 11.2.1 was used for the study. A single dose of antibody is administered intravenously in a bolus (0.01 and 0.1mg/kg dose levels) or over one hour (1 to 10mg/kg dose levels) or over two and a half hours (15mg/kg dose levels) as a sterile aqueous solution containing 5 or 10mg/ml antibody, 20mM sodium acetate, 0.2mg/ml polysorbate 80 and 140mM sodium chloride, pH 5.5. Objective tumor response was observed.

The following doses (in mg/kg) were administered: 0.01, 0.1, 1.0, 3.0, 6.0, 10.0 and 15.0. Most patients suffer from melanoma, a highly developed metastatic disease; two patients had stage iii melanoma; four patients had renal cell carcinoma and one patient had colon cancer. Three patients received 0.01 mg/kg; three patients received 0.1 mg/kg; three patients received 1 mg/kg; eight patients received 3 mg/kg; five patients received 6 mg/kg; eleven patients received 10 mg/kg; six patients received 15 mg/kg.

The antibody was surprisingly effective at 15 mg/kg. At this dose, three objective tumor responses (two complete responses, one partial response) were observed.

The results of patients showing that certain clinically beneficial aspects have been achieved are provided in the following table, wherein the following abbreviations are used: AWD: survival with tumor group (alive with disease); CR: complete reaction; and (4) docet: docetaxel (docetaxel); LN: lymph nodes; NE: not measurable; NED: no evidence of disease (not evidence of disease); PD: progression of the disease; post-Tx: after treatment; PR; partial reaction; RFA: radiofrequency ablation; SC: subcutaneous injection; SD: stabilization of the disease; SX: performing surgery; tem: temozolomide (temozolamide); thal: thalidomide; XRT: and (4) radioactive treatment.

Pt	Diseased site	Dosage (mg/kg)	Reaction of	Current state of the art	After Tx	OS (number of months)
							1	LN lung	0.01	SD	NED	CTLA4, vaccine, SX (brain)	25+
2	Lung (lung)	1	SD	AWD (PD to brain)	CTAL4, vaccine, tem + thal, XRT	23+
							3	Bone	1	PD	NED	CTLA4，SX(LN)	23+
4	LN，SC	3	SD	NED	Vaccine, SX (LN, SC)	22+
							5	Lung (lung)	3	CR	NED	CTLA4	21+
6	Bone	10	SD	AWD (sustained SD)	Docet，tem+thal	17+
							7	Lung, abdominal, omentum, SC	10	SD	AWD (sustained PR)	Revimid	12+
8	LN	10	SD	AWD (sustained SD)	Revimid	7+
							9	Liver disease	15	PD	NED	SX (lever), adjuvanted vaccine	12+
10	Lung (lung)	15	PR	AWD (sustained PR)	CTLA4	11+
							11	Lung (lung)	15	CR	NED (continuous CR)	Is free of	10+
12	Lung (lung)	15	NE	NED	Is free of	10+
							13	Liver disease	15	PD	NED	RFA, SX (Small intestine)	10+
14	Lung (lung)	15	CR	NED (continuous CR)	Is free of	10+

Example 2:

patients with solid tumors, such as breast cancer (including metastatic breast cancer), testicular cancer, ovarian cancer, small cell lung cancer, neuroblastoma, and childhood sarcoma (pediatric sarcomas) are treated with a combination of chemotherapy, stem cell transplantation, and human anti-CTLA-4 antibody 11.2.1.

Patients received an intravenous infusion of 60mg cyclophosphamide per kg body weight daily on days 7 and 6 prior to transplantation and then 25mg fludarabine per square meter body surface area daily for the last 5 days prior to transplantation.

Stem cell transplants were prepared by treating donors with granulocyte colony stimulating factor (G-CSF), mobilizing bone marrow-derived stem cells. After mobilization, as in Williams et al, Bonemarro transfer 5: 129-33(1990) and Hillyer et al, transfer 33: 316-21(1993), stem cells were collected from peripheral blood of donors using a CS3000 blood cell separator (Baxter Healthcare Corporation, Deerfield, IL). Stem cell transplants were administered by large-bore central venous catheter infusion.

Alternatively, bone marrow is collected from the posterior or anterior iliac crest of the donor, with the donor under general or spinal anesthesia. Approximately 10 to 15mL/kg bone marrow was aspirated, placed in heparinized media, and filtered through 0.3 and 0.2mm sieves to remove fat and small bone mass. Depending on the clinical situation, the collected bone marrow may be further processed by removing red blood cells to prevent hemolysis in ABO incompatible transplants, or to remove donor T cells to prevent Graft Versus Host Disease (GVHD).

30 days after transplantation, 15mg/kg of antibody 11.2.1 was administered to the patient by infusion over a period of two and a half hours. Patient groups designated for treatment with multiple antibody doses received an additional 15mg/kg dose at 3 or 6 months post-transplantation.

The effect of the treatment is monitored by observing disease endpoints such as long-term survival, disease-free survival (time to relapse), response rate, duration of response and/or time to progression.

While the invention has been disclosed with respect to specific embodiments, it is apparent that other embodiments and variations of the invention may be devised by others skilled in the art without departing from the spirit and scope of the invention. It is intended that the following claims be interpreted to embrace all such embodiments and equivalent variations.

Sequence listing

<110>PFIZER PRODUCTS INC.

Gomez-Navarro，Jesus

Hanson，Douglas C.

Eileen，Mueller Elliott

Noe，Dennis A.

<120> use of anti-CTLA-4 antibodies

<130>PC32177A

<150>US 60/556，801

<151>2004-03-26

<160>91

<170>PatentIn version 3.3

<210>1

<211>1392

<212>DNA

<213> human (Homo sapiens)

<400>1

atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60

gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120

tgtgtagcgt ctggattcac cttcagtagc catggcatgc actgggtccg ccaggctcca 180

ggcaaggggc tggagtgggt ggcagttata tggtatgatg gaagaaataa atactatgca 240

gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtttctg 300

caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag aggaggtcac 360

ttcggtcctt ttgactactg gggccaggga accctggtca ccgtctcctc agcctccacc 420

aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480

gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540

ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600

tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660

aacgtagatc acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720

gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780

ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840

gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg cgtggaggtg 900

cataatgcca agacaaagcc acgggaggag cagttcaaca gcacgttccg tgtggtcagc 960

gtcctcaccg ttgtgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020

aacaaaggcc tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080

gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140

ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200

gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga cggctccttc 1260

ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320

tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380

ccgggtaaat ga 1392

<210>2

<211>1999

<212>DNA

<213> human

<400>2

atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60

gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120

tgtgtagcgt ctggattcac cttcagtagc catggcatgc actgggtccg ccaggctcca 180

ggcaaggggc tggagtgggt ggcagttata tggtatgatg gaagaaataa atactatgca 240

gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtttctg 300

caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag aggaggtcac 360

ttcggtcctt ttgactactg gggccaggga accctggtca ccgtctcctc agctagcacc 420

aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480

gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540

ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600

tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660

aacgtagatc acaagcccag caacaccaag gtggacaaga cagttggtga gaggccagct 720

cagggaggga gggtgtctgc tggaagccag gctcagccct cctgcctgga cgcaccccgg 780

ctgtgcagcc ccagcccagg gcagcaaggc aggccccatc tgtctcctca cccggaggcc 840

tctgcccgcc ccactcatgc tcagggagag ggtcttctgg ctttttccac caggctccag 900

gcaggcacag gctgggtgcc cctaccccag gcccttcaca cacaggggca ggtgcttggc 960

tcagacctgc caaaagccat atccgggagg accctgcccc tgacctaagc cgaccccaaa 1020

ggccaaactg tccactccct cagctcggac accttctctc ctcccagatc cgagtaactc 1080

ccaatcttct ctctgcagag cgcaaatgtt gtgtcgagtg cccaccgtgc ccaggtaagc 1140

cagcccaggc ctcgccctcc agctcaaggc gggacaggtg ccctagagta gcctgcatcc 1200

agggacaggc cccagctggg tgctgacacg tccacctcca tctcttcctc agcaccacct 1260

gtggcaggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 1320

cggacccctg aggtcacgtg cgtggtggtg gacgtgagcc acgaagaccc cgaggtccag 1380

ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc acgggaggag 1440

cagttcaaca gcacgttccg tgtggtcagc gtcctcaccg ttgtgcacca ggactggctg 1500

aacggcaagg agtacaagtg caaggtctcc aacaaaggcc tcccagcccc catcgagaaa 1560

accatctcca aaaccaaagg tgggacccgc ggggtatgag ggccacatgg acagaggccg 1620

gctcggccca ccctctgccc tgggagtgac cgctgtgcca acctctgtcc ctacagggca 1680

gccccgagaa ccacaggtgt acaccctgcc cccatcccgg gaggagatga ccaagaacca 1740

ggtcagcctg acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga 1800

gagcaatggg cagccggaga acaactacaa gaccacacct cccatgctgg actccgacgg 1860

ctccttcttc ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt 1920

cttctcatgc tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc 1980

cctgtctccg ggtaaatga 1999

<210>3

<211>463

<212>PRT

<213> human

<400>3

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

20 25 30

Pro Gly Arg Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe

35 40 45

Ser Ser His Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Arg Asn Lys Tyr Tyr Ala

65 70 75 80

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

85 90 95

Thr Leu Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

100 105 110

Tyr Tyr Cys Ala Arg Gly Gly His Phe Gly Pro Phe Asp Tyr Trp Gly

115 120 125

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

130 135 140

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala

145 150 155 160

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

165 170 175

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

180 185 190

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

195 200 205

Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His

210 215 220

Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys

225 230 235 240

Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val

245 250 255

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

260 265 270

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

275 280 285

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

290 295 300

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser

305 310 315 320

Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

325 330 335

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile

340 345 350

Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

355 360 365

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

370 375 380

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

385 390 395 400

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser

405 410 415

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

420 425 430

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

435 440 445

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

450 455 460

<210>4

<211>1392

<212>DNA

<213> human

<400>4

atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60

gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120

tgtgtagcgt ctggattcac cttcagtagc catggcatgc actgggtccg ccaggctcca 180

ggcaaggggc tggagtgggt ggcagttata tggtatgatg gaagaaataa atactatgca 240

gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtttctg 300

caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag aggaggtcac 360

ttcggtcctt ttgactactg gggccaggga accctggtca ccgtctcctc agcctccacc 420

aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480

gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540

ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600

tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660

aacgtagatc acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720

gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780

ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840

gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg cgtggaggtg 900

cataatgcca agacaaagcc acgggaggag cagttccaaa gcacgttccg tgtggtcagc 960

gtcctcaccg ttgtgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020

aacaaaggcc tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080

gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140

ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200

gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga cggctccttc 1260

ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320

tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380

ccgggtaaat ga 1392

<210>5

<211>463

<212>PRT

<213> human

<400>5

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

20 25 30

Pro Gly Arg Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe

35 40 45

Ser Ser His Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Arg Asn Lys Tyr Tyr Ala

65 70 75 80

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

85 90 95

Thr Leu Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

100 105 110

Tyr Tyr Cys Ala Arg Gly Gly His Phe Gly Pro Phe Asp Tyr Trp Gly

115 120 125

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

130 135 140

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala

145 150 155 160

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

165 170 175

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

180 185 190

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

195 200 205

Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His

210 215 220

Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys

225 230 235 240

Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val

245 250 255

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

260 265 270

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

275 280 285

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

290 295 300

Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Phe Arg Val Val Ser

305 310 315 320

Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

325 330 335

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile

340 345 350

Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

355 360 365

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

370 375 380

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

385 390 395 400

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser

405 410 415

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

420 425 430

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

435 440 445

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

450 455 460

<210>6

<211>708

<212>DNA

<213> human

<400>6

atggaaaccc cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60

gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120

ctctcctgca gggccagtca gagtattagc agcagcttct tagcctggta ccagcagaga 180

cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 240

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 300

cctgaagatt ttgcagtgta ttactgtcag cagtatggta cctcaccctg gacgttcggc 360

caagggacca aggtggaaat caaacgaact gtggctgcac catctgtctt catcttcccg 420

ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480

tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540

caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600

acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660

ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgttag 708

<210>7

<211>235

<212>PRT

<213> human

<400>7

Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro

1 5 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser

20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser

35 40 45

Ile Ser Ser Ser Phe Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala

50 55 60

Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro

65 70 75 80

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

85 90 95

Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr

100 105 110

Gly Thr Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

115 120 125

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

130 135 140

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

145 150 155 160

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

165 170 175

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

180 185 190

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

195 200 205

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

210 215 220

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

225 230 235

<210>8

<211>1395

<212>DNA

<213> human

<400>8

atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60

gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120

tgtacagcgt ctggattcac cttcagtaac tatggcatgc actgggtccg ccaggctcca 180

ggcaaggggc tggagtgggt ggcagttata tggtatgatg gaagtaataa acactatgga 240

gactccgtga agggccgatt caccatctcc agtgacaatt ccaagaacac gctgtatctg 300

caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag aggagagaga 360

ctggggtcct actttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagcctcc 420

accaagggcc catcggtctt ccccctggcg ccctgctcca ggagcacctc cgagagcaca 480

gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 540

tcaggcgctc tgaccagcgg cgtgcacacc ttcccagctg tcctacagtc ctcaggactc 600

tactccctca gcagcgtggt gaccgtgccc tccagcaact tcggcaccca gacctacacc 660

tgcaacgtag atcacaagcc cagcaacacc aaggtggaca agacagttga gcgcaaatgt 720

tgtgtcgagt gcccaccgtg cccagcacca cctgtggcag gaccgtcagt cttcctcttc 780

cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac gtgcgtggtg 840

gtggacgtga gccacgaaga ccccgaggtc cagttcaact ggtacgtgga cggcgtggag 900

gtgcataatg ccaagacaaa gccacgggag gagcagttca acagcacgtt ccgtgtggtc 960

agcgtcctca ccgttgtgca ccaggactgg ctgaacggca aggagtacaa gtgcaaggtc 1020

tccaacaaag gcctcccagc ccccatcgag aaaaccatct ccaaaaccaa agggcagccc 1080

cgagaaccac aggtgtacac cctgccccca tcccgggagg agatgaccaa gaaccaggtc 1140

agcctgacct gcctggtcaa aggcttctac cccagcgaca tcgccgtgga gtgggagagc 1200

aatgggcagc cggagaacaa ctacaagacc acacctccca tgctggactc cgacggctcc 1260

ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1320

tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 1380

tctccgggta aatga 1395

<210>9

<211>464

<212>PRT

<213> human

<400>9

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

20 25 30

Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe

35 40 45

Ser Asn Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys His Tyr Gly

65 70 75 80

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn

85 90 95

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

100 105 110

Tyr Tyr Cys Ala Arg Gly Glu Arg Leu Gly Ser Tyr Phe Asp Tyr Trp

115 120 125

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

130 135 140

Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr

145 150 155 160

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

165 170 175

Val Ser Trp Ash Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

180 185 190

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

195 200 205

Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp

210 215 220

His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys

225 230 235 240

Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser

245 250 255

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

260 265 270

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

275 280 285

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

290 295 300

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val

305 310 315 320

Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

325 330 335

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr

340 345 350

Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

355 360 365

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

370 375 380

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

385 390 395 400

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp

405 410 415

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

420 425 430

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

435 440 445

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

450 455 460

<210>10

<211>702

<212>DNA

<213> human

<400>10

atggaaaccc cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60

gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120

ctctcctgca ggaccagtgt tagcagcagt tacttagcct ggtaccagca gaaacctggc 180

caggctccca ggctcctcat ctatggtgca tccagcaggg ccactggcat cccagacagg 240

ttcagtggca gtgggtctgg gacagacttc actctcacca tcagcagact ggagcctgaa 300

gattttgcag tctattactg tcagcagtat ggcatctcac ccttcacttt cggcggaggg 360

accaaggtgg agatcaagcg aactgtggct gcaccatctg tcttcatctt cccgccatct 420

gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 480

agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 540

agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 600

agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 660

agctcgcccg tcacaaagag cttcaacagg ggagagtgtt ag 702

<210>11

<211>233

<212>PRT

<213> human

<400>11

Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro

1 5 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser

20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Val Ser

35 40 45

Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg

50 55 60

Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg

65 70 75 80

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg

85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ile

100 105 110

Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr

115 120 125

Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu

130 135 140

Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro

145 150 155 160

Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly

165 170 175

Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr

180 185 190

Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His

195 200 205

Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val

210 215 220

Thr Lys Ser Phe Ash Arg Gly Glu Cys

225 230

<210>12

<211>1392

<212>DNA

<213> human

<400>12

atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60

gtgcagctgg tggagtctgg gggaggcgtg gtcgagcctg ggaggtccct gagactctcc 120

tgtacagcgt ctggattcac cttcagtagt tatggcatgc actgggtccg ccaggctcca 180

ggcaaggggc tggagtgggt ggcagttata tggtatgatg gaagcaataa acactatgca 240

gactccgcga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctg 300

caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agccggactg 360

ctgggttact ttgactactg gggccaggga accctggtca ccgtctcctc agcctccacc 420

aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480

gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540

ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600

tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660

aacgtagatc acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720

gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780

ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840

gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg cgtggaggtg 900

cataatgcca agacaaagcc acgggaggag cagttcaaca gcacgttccg tgtggtcagc 960

gtcctcaccg ttgtgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020

aacaaaggcc tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080

gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140

ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200

gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga cggctccttc 1260

ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320

tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380

ccgggtaaat ga 1392

<210>13

<211>463

<212>PRT

<213> human

<400>13

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Glu

20 25 30

Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe

35 40 45

Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly hys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys His Tyr Ala

65 70 75 80

Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

85 90 95

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

100 105 110

Tyr Tyr Cys Ala Arg Ala Gly Leu Leu Gly Tyr Phe Asp Tyr Trp Gly

115 120 125

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

130 135 140

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala

145 150 155 160

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

165 170 175

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

180 185 190

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

195 200 205

Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His

210 215 220

Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys

225 230 235 240

Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val

245 250 255

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

260 265 270

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

275 280 285

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

290 295 300

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser

305 310 315 320

Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

325 330 335

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile

340 345 350

Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

355 360 365

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

370 375 380

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

385 390 395 400

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser

405 410 415

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

420 425 430

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

435 440 445

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

450 455 460

<210>14

<211>705

<212>DNA

<213> human

<400>14

atggaaaccc cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60

gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120

ctctcctgta gggccagtca aagtgttagc agctacttag cctggtacca acagaaacct 180

ggccaggctc ccaggcccct catctatggt gtatccagca gggccactgg catcccagac 240

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag actggagcct 300

gaagattttg cagtgtatta ctgtcagcag tatggtatct caccattcac tttcggccct 360

gggaccaaag tggatatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 420

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600

ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660

ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 705

<210>15

<211>234

<212>PRT

<213> human

<400>15

Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro

1 5 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser

20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser

35 40 45

Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

50 55 60

Arg Pro Leu Ile Tyr Gly Val Ser Ser Arg Ala Thr Gly Ile Pro Asp

65 70 75 80

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

85 90 95

Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly

100 105 110

Ile Ser Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg

115 120 125

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

130 135 140

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

145 150 155 160

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

165 170 175

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

180 185 190

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

195 200 205

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

210 215 220

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

225 230

<210>16

<211>1413

<212>DNA

<213> human

<400>16

atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60

gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120

tgtgcagcgt ctggattcac cttcagtagc tatggcatgc actgggtccg ccaggctcca 180

ggcaaggggc tggagtgggt ggcagttata tggtatgatg gaagtaataa atactatgca 240

gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctg 300

caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agatccgagg 360

ggagctaccc tttactacta ctactacggt atggacgtct ggggccaagg gaccacggtc 420

accgtctcct cagcctccac caagggccca tcggtcttcc ccctggcgcc ctgctccagg 480

agcacctccg agagcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 540

gtgacggtgt cgtggaactc aggcgctctg accagcggcg tgcacacctt cccagctgtc 600

ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcaacttc 660

ggcacccaga cctacacctg caacgtagat cacaagccca gcaacaccaa ggtggacaag 720

acagttgagc gcaaatgttg tgtcgagtgc ccaccgtgcc cagcaccacc tgtggcagga 780

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 840

gaggtcacgt gcgtggtggt ggacgtgagc cacgaagacc ccgaggtcca gttcaactgg 900

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cacgggagga gcagttcaac 960

agcacgttcc gtgtggtcag cgtcctcacc gttgtgcacc aggactggct gaacggcaag 1020

gagtacaagt gcaaggtctc caacaaaggc ctcccagccc ccatcgagaa aaccatctcc 1080

aaaaccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1140

atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctaccc cagcgacatc 1200

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac acctcccatg 1260

ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1320

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1380

cagaagagcc tctccctgtc tccgggtaaa tga 1413

<210>17

<211>451

<212>PRT

<213> human

<400>17

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Pro Arg Gly Ala Thr Leu Tyr Tyr Tyr Tyr Tyr Gly Met

100 105 110

Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr

115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

180 185 190

Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys

195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu

210 215 220

Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe

290 295 300

Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210>18

<211>714

<212>DNA

<213> human

<400>18

atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60

agatgtgaca tccagatgac ccagtctcca tcctccctgt ctgcatctgt aggagacaga 120

gtcaccatca cttgccgggc aagtcagagc attaacagct atttagattg gtatcagcag 180

aaaccaggga aagcccctaa actcctgatc tatgctgcat ccagtttgca aagtggggtc 240

ccatcaaggt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagtctg 300

caacctgaag attttgcaac ttactactgt caacagtatt acagtactcc attcactttc 360

ggccctggga ccaaagtgga aatcaaacga actgtggctg caccatctgt cttcatcttc 420

ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480

ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540

tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 600

ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660

cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgtta gtga 714

<210>19

<211>214

<212>PRT

<213> human

<400>19

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr

20 25 30

Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210>20

<211>76

<212>PRT

<213> human

<400>20

Val Ser Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr Trp Ser Trp Ile

1 5 10 15

Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr

20 25 30

Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile

35 40 45

Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val

50 55 60

Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg

65 70 75

<210>21

<211>172

<212>PRT

<213> human

<400>21

Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ile Leu Ser Leu Thr Cys

1 5 10 15

Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Gly His Tyr Trp Ser Trp

20 25 30

Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr

35 40 45

Tyr Ile Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr

50 55 60

Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser

65 70 75 80

Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Gly

85 90 95

Asp Tyr Tyr Gly Ile Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val

100 105 110

Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys

115 120 125

Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys

130 135 140

Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu

145 150 155 160

Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170

<210>22

<211>96

<212>PRT

<213> human

<400>22

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

<210>23

<211>141

<212>PRT

<213> human

<400>23

Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu

1 5 10 15

Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser Phe Leu Ala Trp Tyr

20 25 30

Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser

35 40 45

Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly

50 55 60

Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala

65 70 75 80

Val Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro Trp Thr Phe Gly Gln

85 90 95

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

100 105 110

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

115 120 125

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

<210>24

<211>141

<212>PRT

<213> human

<400>24

Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu

1 5 10 15

Ser Cys Arg Thr Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln

20 25 30

Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg

35 40 45

Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

50 55 60

Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr

65 70 75 80

Tyr Cys Gln Gln Tyr Gly Ile Ser Pro Phe Thr Phe Gly Gly Gly Thr

85 90 95

Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe

100 105 110

Pro Pro Ser Aso Glu Gln Leu Lvs Ser Gly Thr Ala Ser Val Val Cys

115 120 125

Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln

130 135 140

<210>25

<211>139

<212>PRT

<213> human

<400>25

Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg

1 5 10 15

Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro

20 25 30

Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr

35 40 45

Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr

50 55 60

Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys

65 70 75 80

Gln Gln Tyr Gly Arg Ser Pro Phe Thr Phe Gly Pro Gly Thr Lys Val

85 90 95

Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro

100 105 110

Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

115 120 125

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln

130 135

<210>26

<211>142

<212>PRT

<213> human

<400>26

Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu

1 5 10 15

Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln

20 25 30

Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile Tyr Gly Val Ser Ser

35 40 45

Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr

50 55 60

Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val

65 70 75 80

Tyr Tyr Cys Gln Gln Tyr Gly Ile Ser Pro Phe Thr Phe Gly Pro Gly

85 90 95

Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile

100 105 110

Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val

115 120 125

Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln

130 135 140

<210>27

<211>142

<212>PRT

<213> human

<400>27

Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser

1 5 10 15

Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn Phe Leu Ala Trp Tyr Gln

20 25 30

Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Arg Pro Ser Ser

35 40 45

Arg Ala Thr Gly Ile Pro Asp Ser Phe Ser Gly Ser Gly Ser Gly Thr

50 55 60

Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Leu

65 70 75 80

Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro Phe Thr Phe Gly Pro Gly

85 90 95

Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile

100 105 110

Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val

115 120 125

Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln

130 135 140

<210>28

<211>146

<212>PRT

<213> human

<400>28

Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu

1 5 10 15

Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln

20 25 30

Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser

35 40 45

Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr

50 55 60

Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val

65 70 75 80

Tyr Tyr Cys Gln Gln Tyr Gly Arg Ser Pro Phe Thr Phe Gly Pro Gly

85 90 95

Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile

100 105 110

Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val

115 120 125

Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys

130 135 140

Val Asp

145

<210>29

<211>95

<212>PRT

<213> human

<400>29

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro

85 90 95

<210>30

<211>152

<212>PRT

<213> human

<400>30

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

1 5 10 15

Thr Cys Arg Ala Ser Gln Ser Ile Asn Thr Tyr Leu Ile Trp Tyr Gln

20 25 30

Gln Lys Pro Gly Lys Ala Pro Asn Phe Leu Ile Ser Ala Thr Ser Ile

35 40 45

Leu Gln Ser Gly Val Pro Ser Arg Phe Arg Gly Ser Gly Ser Gly Thr

50 55 60

Asn Phe Thr Leu Thr Ile Asn Ser Leu His Pro Glu Asp Phe Ala Thr

65 70 75 80

Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe Thr Phe Gly Pro Gly

85 90 95

Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile

100 105 110

Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val

115 120 125

Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys

130 135 140

Val Asp Asn Ala Leu Gln Ser Gly

145 150

<210>31

<211>139

<212>PRT

<213> human

<400>31

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

1 5 10 15

Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asp Trp Tyr Gln Gln Lys

20 25 30

Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln

35 40 45

Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

50 55 60

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr

65 70 75 80

Cys Gln Gln Tyr Tyr Ser Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys

85 90 95

Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro

100 105 110

Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu

115 120 125

Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val

130 135

<210>32

<211>134

<212>PRT

<213> human

<400>32

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

1 5 10 15

Ile Thr Cys Arg Ala Ser Gln Asn Ile Ser Arg Tyr Leu Asn Trp Tyr

20 25 30

Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile Tyr Val Ala Ser

35 40 45

Ile Leu Gln Ser Gly Val Pro Ser Gly Phe Ser Ala Ser Gly Ser Gly

50 55 60

Pro Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

65 70 75 80

Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe Thr Phe Gly Pro

85 90 95

Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

100 105 110

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

115 120 125

Val Cys Leu Leu Asn Asn

130

<210>33

<211>150

<212>PRT

<213> human

<400>33

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

1 5 10 15

Ile Thr Cys Arg Ala Ser Gln Ser Ile Cys Asn Tyr Leu Asn Trp Tyr

20 25 30

Gln Gln Lys Pro Gly Lys Ala Pro Arg Val Leu Ile Tyr Ala Ala Ser

35 40 45

Ser Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

50 55 60

Ile Asp Cys Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

65 70 75 80

Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Thr Pro Phe Thr Phe Gly Pro

85 90 95

Gly Thr Arg Val Asp Ile Glu Arg Thr Val Ala Ala Pro Ser Val Phe

100 105 110

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

115 120 125

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

130 135 140

Lys Val Asp Asn Ala Tyr

145 150

<210>34

<211>96

<212>PRT

<213> human

<400>34

Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys

1 5 10 15

Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser

20 25 30

Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile

35 40 45

Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala

65 70 75 80

Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Ser Ser Ser Leu Pro Gln

85 90 95

<210>35

<211>155

<212>PRT

<213> human

<400>35

Ser Pro Asp Phe Gln Ser Val Thr Pro Lys Glu Lys Val Thr Ile Thr

1 5 10 15

Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser Leu His Trp Tyr Gln Gln

20 25 30

Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile Lys Tyr Ala Ser Gln Ser

35 40 45

Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

50 55 60

Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr

65 70 75 80

Tyr Cys His Gln Ser Ser Ser Leu Pro Leu Thr Phe Gly Gly Gly Thr

85 90 95

Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe

100 105 110

Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys

115 120 125

Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val

130 135 140

Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155

<210>36

<211>100

<212>PRT

<213> human

<400>36

Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Mer Gln Gly

85 90 95

Thr His Trp Pro

100

<210>37

<211>139

<212>PRT

<213> human

<400>37

Pro Leu Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys

1 5 10 15

Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr Leu Asn

20 25 30

Trp Phe Gln Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr Lys

35 40 45

Val Ser Asn Trp Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly

50 55 60

Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp

65 70 75 80

Val Gly Val Tyr Tyr Cys Met Gln Gly Ser His Trp Pro Pro Thr Phe

85 90 95

Gly Gln Gly Thr Lys Val Glu1 Ile Lys Arg Thr Val Ala Ala Pro Ser

100 105 110

Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala

115 120 125

Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro

130 135

<210>38

<211>100

<212>PRT

<213> human

<400>38

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser

20 25 30

Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

Leu Gln Thr Pro

100

<210>39

<211>133

<212>PRT

<213> human

<400>39

Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu

1 5 10 15

His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly

20 25 30

Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly

35 40 45

Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu

50 55 60

Lys Leu Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met

65 70 75 80

Gln Ala Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu

85 90 95

Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser

100 105 110

Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn

115 120 125

Asn Phe Tyr Pro Arg

130

<210>40

<211>1392

<212>DNA

<213> human

<400>40

atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60

gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120

tgtgtagcgt ctggattcac cttcagtagc catggcatgc actgggtccg ccaggctcca 180

ggcaaggggc tggagtgggt ggcagttata tggtatgatg gaagaaataa atactatgca 240

gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtttctg 300

caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag aggaggtcac 360

ttcggtcctt ttgactactg gggccaggga accctggtca ccgtctcctc agcctccacc 420

aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480

gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540

ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600

tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660

aacgtagatc acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720

gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780

ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840

gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg cgtggaggtg 900

cataatgcca agacaaagcc acgggaggag cagttcaaca gcacgttccg tgtggtcagc 960

gtcctcaccg ttgtgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020

aacaaaggcc tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080

gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140

ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200

gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga cggctccttc 1260

ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320

tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380

ccgggtaaat ga 1392

<210>41

<211>463

<212>PRT

<213> human

<400>41

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

20 25 30

Pro Gly Arg Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe

35 40 45

Ser Ser His Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Arg Asn Lys Tyr Tyr Ala

65 70 75 80

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

85 90 95

Thr Leu Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

100 105 110

Tyr Tyr Cys Ala Arg Gly Gly His Phe Gly Pro Phe Asp Tyr Trp Gly

115 120 125

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

130 135 140

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala

145 150 155 160

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

165 170 175

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

180 185 190

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

195 200 205

Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His

210 215 220

Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys

225 230 235 240

Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val

245 250 255

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

260 265 270

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

275 280 285

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

290 295 300

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser

305 310 315 320

Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

325 330 335

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile

340 345 350

Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

355 360 365

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

370 375 380

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

385 390 395 400

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser

405 410 415

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

420 425 430

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

435 440 445

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

450 455 460

<210>42

<211>708

<212>DNA

<213> human

<400>42

atggaaaccc cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60

gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120

ctctcctgca gggccagtca gagtattagc agcagcttct tagcctggta ccagcagaga 180

cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 240

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 300

cctgaagatt ttgcagtgta ttactgtcag cagtatggta cctcaccctg gacgttcggc 360

caagggacca aggtggaaat caaacgaact gtggctgcac catctgtctt catcttcccg 420

ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480

tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540

caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600

acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660

ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgttag 708

<210>43

<211>235

<212>PRT

<213> human

<400>43

Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro

1 5 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser

20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser

35 40 45

Ile Ser Ser Ser Phe Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala

50 55 60

Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro

65 70 75 80

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

85 90 95

Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr

100 105 110

Gly Thr Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

115 120 125

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

130 135 140

Gln Leu Lys Ser Gly Thr Ala Ser Val Val cys Leu Leu Asn Asn Phe

145 150 155 160

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

165 170 175

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

180 185 190

Thr Tyr Ser Leu Sar Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

195 200 205

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

210 215 220

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

225 230 235

<210>44

<211>1395

<212>DNA

<213> human

<400>44

atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60

gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120

tgtacagcgt ctggattcac cttcagtaac tatggcatgc actgggtccg ccaggctcca 180

ggcaaggggc tggagtgggt ggcagttata tggtatgatg gaagtaataa acactatgga 240

gactccgtga agggccgatt caccatctcc agtgacaatt ccaagaacac gctgtatctg 300

caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag aggagagaga 360

ctggggtcct actttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagcctcc 420

accaagggcc catcggtctt ccccctggcg ccctgctcca ggagcacctc cgagagcaca 480

gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 540

tcaggcgctc tgaccagcgg cgtgcacacc ttcccagctg tcctacagtc ctcaggactc 600

tactccctca gcagcgtggt gaccgtgccc tccagcaact tcggcaccca gacctacacc 660

tgcaacgtag atcacaagcc cagcaacacc aaggtggaca agacagttga gcgcaaatgt 720

tgtgtcgagt gcccaccgtg cccagcacca cctgtggcag gaccgtcagt cttcctcttc 780

cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac gtgcgtggtg 840

gtggacgtga gccacgaaga ccccgaggtc cagttcaact ggtacgtgga cggcgtggag 900

gtgcataatg ccaagacaaa gccacgggag gagcagttca acagcacgtt ccgtgtggtc 960

agcgtcctca ccgttgtgca ccaggactgg ctgaacggca aggagtacaa gtgcaaggtc 1020

tccaacaaag gcctcccagc ccccatcgag aaaaccatct ccaaaaccaa agggcagccc 1080

cgagaaccac aggtgtacac cctgccccca tcccgggagg agatgaccaa gaaccaggtc 1140

agcctgacct gcctggtcaa aggcttctac cccagcgaca tcgccgtgga gtgggagagc 1200

aatgggcagc cggagaacaa ctacaagacc acacctccca tgctggactc cgacggctcc 1260

ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1320

tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 1380

tctccgggta aatga 1395

<210>45

<211>464

<212>PRT

<213> human

<400>45

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

20 25 30

Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe

35 40 45

Ser Asn Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys His Tyr Gly

65 70 75 80

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn

85 90 95

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

100 105 110

Tyr Tyr Cys Ala Arg Gly Glu Arg Leu Gly Ser Tyr Phe Asp Tyr Trp

115 120 125

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

130 135 140

Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr

145 150 155 160

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

165 170 175

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

180 185 190

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

195 200 205

Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp

210 215 220

His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys

225 230 235 240

Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser

245 250 255

Val Phe Leu Phe Pro pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

260 265 270

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

275 280 285

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

290 295 300

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val

305 310 315 320

Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

325 330 335

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr

340 345 350

Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

355 360 365

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

370 375 380

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

385 390 395 400

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp

405 410 415

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

420 425 430

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

435 440 445

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 5er Pro Gly Lys

450 455 460

<210>46

<211>702

<212>DNA

<213> human

<400>46

atggaaaccc cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60

gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120

ctctcctgca ggaccagtgt tagcagcagt tacttagcct ggtaccagca gaaacctggc 180

caggctccca ggctcctcat ctatggtgca tccagcaggg ccactggcat cccagacagg 240

ttcagtggca gtgggtctgg gacagacttc actctcacca tcagcagact ggagcctgaa 300

gattttgcag tctattactg tcagcagtat ggcatctcac ccttcacttt cggcggaggg 360

accaaggtgg agatcaagcg aactgtggct gcaccatctg tcttcatctt cccgccatct 420

gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 480

agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 540

agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 600

agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 660

agctcgcccg tcacaaagag cttcaacagg ggagagtgtt ag 702

<210>47

<211>233

<212>PRT

<213> human

<400>47

Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro

1 5 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser

20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Val Ser

35 40 45

Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg

50 55 60

Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg

65 70 75 80

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg

85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ile

100 105 110

Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr

115 120 125

Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu

130 135 140

Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro

145 150 155 160

Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly

165 170 175

Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr

180 185 190

Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His

195 200 205

Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val

210 215 220

Thr Lys Ser Phe Asn Arg Gly Glu Cys

225 230

<210>48

<211>489

<212>DNA

<213> human

<400>48

cctgggaggt ccctgagact ctcctgtgca gcgtctggat tcaccttcag tagtcatggc 60

atccactggg tccgccaggc tccaggcaag gggctggagt gggtggcagt tatatggtat 120

gatggaagaa ataaagacta tgcagactcc gtgaagggcc gattcaccat ctccagagac 180

aattccaaga agacgctgta tttgcaaatg aacagcctga gagccgagga cacggctgtg 240

tattactgtg cgagagtggc cccactgggg ccacttgact actggggcca gggaaccctg 300

gtcaccgtct cctcagcctc caccaagggc ccatcggtct tccccctggc gccctgctcc 360

aggagcacct ccgagagcac agcggccctg ggctgcctgg tcaaggacta cttccccgaa 420

ccggtgacgg tgtcgtggaa ctcaggcgct ctgaccagcg gcgtgcacac cttcccagct 480

gtcctacag 489

<210>49

<211>163

<212>PRT

<213> human

<400>49

Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

1 5 10 15

Ser Ser His Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

20 25 30

Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Arg Asn Lys Asp Tyr Ala

35 40 45

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Lys

50 55 60

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

65 70 75 80

Tyr Tyr Cys Ala Arg Val Ala Pro Leu Gly Pro Leu Asp Tyr Trp Gly

85 90 95

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

100 105 110

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala

115 120 125

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

130 135 140

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

145 150 155 160

Val Leu Gln

<210>50

<211>417

<212>DNA

<213> human

<400>50

ggcaccctgt ctttgtctcc aggggaaaga gccaccctct cctgcagggc cagtcagagt 60

gtcagcagct acttagcctg gtaccagcag aaacctggcc aggctcccag actcctcatc 120

tatggtgcat ccagcagggc cactggcatc ccagacaggt tcagtggcag tgggtctggg 180

acagacttca ctctcaccat cagcagactg gagcctgagg attttgcagt gtattactgt 240

cagcagtatg gtaggtcacc attcactttc ggccctggga ccaaagtgga tatcaagcga 300

actgtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 360

actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacag 417

<210>51

<211>139

<212>PRT

<213> human

<400>51

Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg

1 5 10 15

Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro

20 25 30

Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr

35 40 45

Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr

50 55 60

Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys

65 70 75 80

Gln Gln Tyr Gly Arg Ser Pro Phe Thr Phe Gly Pro Gly Thr Lys Val

85 90 95

Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro

100 105 110

Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val cys Leu Leu

115 120 125

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln

130 135

<210>52

<211>1392

<212>DNA

<213> human

<400>52

atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60

gtgcagctgg tggagtctgg gggaggcgtg gtcgagcctg ggaggtccct gagactctcc 120

tgtacagcgt ctggattcac cttcagtagt tatggcatgc actgggtccg ccaggctcca 180

ggcaaggggc tggagtgggt ggcagttata tggtatgatg gaagcaataa acactatgca 240

gactccgcga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctg 300

caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agccggactg 360

ctgggttact ttgactactg gggccaggga accctggtca ccgtctcctc agcctccacc 420

aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480

gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540

ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600

tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660

aacgtagatc acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720

gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780

ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840

gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg cgtggaggtg 900

cataatgcca agacaaagcc acgggaggag cagttcaaca gcacgttccg tgtggtcagc 960

gtcctcaccg ttgtgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020

aacaaaggcc tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080

gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140

ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200

gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga cggctccttc 1260

ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320

tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380

ccgggtaaat ga 1392

<210>53

<211>463

<212>PRT

<213> human

<400>53

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Glu

20 25 30

Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe

35 40 45

Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys His Tyr Ala

65 70 75 80

Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

85 90 95

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

100 105 110

Tyr Tyr Cys Ala Arg Ala Gly Leu Leu Gly Tyr Phe Asp Tyr Trp Gly

115 120 125

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

130 135 140

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala

145 150 155 160

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

165 170 175

Ser Trp ASn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

180 185 190

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

195 200 205

Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His

210 215 220

Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys

225 230 235 240

Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val

245 250 255

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

260 265 270

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

275 280 285

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

290 295 300

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser

305 310 315 320

Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

325 330 335

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile

340 345 350

Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

355 360 365

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

370 375 380

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

385 390 395 400

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Mer Leu Asp Ser

405 410 415

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

420 425 430

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

435 440 445

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

450 455 460

<210>54

<211>705

<212>DNA

<213> human

<400>54

atggaaaccc cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60

gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120

ctctcctgta gggccagtca aagtgttagc agctacttag cctggtacca acagaaacct 180

ggccaggctc ccaggcccct catctatggt gtatccagca gggccactgg catcccagac 240

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag actggagcct 300

gaagattttg cagtgtatta ctgtcagcag tatggtatct caccattcac tttcggccct 360

gggaccaaag tggatatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 420

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600

ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660

ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 705

<210>55

<211>234

<212>PRT

<213> human

<400>55

Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro

1 5 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser

20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser

35 40 45

Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

50 55 60

Arg Pro Leu Ile Tyr Gly Val Ser Ser Arg Ala Thr Gly Ile Pro Asp

65 70 75 80

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

85 90 95

Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly

100 105 110

Ile Ser Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg

115 120 125

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

130 135 140

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

145 150 155 160

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

165 170 175

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

180 185 190

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

195 200 205

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

210 215 220

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

225 230

<210>56

<211>507

<212>DNA

<213> human

<400>56

ggcgtggtcc agcctgggag gtccctgaga ctctcctgtg cagcgtctgg attcaccttc 60

agtagctatg gcatgcactg ggtccgccag gctccaggca aggggctgga gtgggtggca 120

gttatatggt atgatggaag taataaatac tatgcagact ccgtgaaggg ccgattcacc 180

atctccagag acaattccaa gaacacgctg tatctgcaaa tgaacagcct gagagccgag 240

gacacggctg tgtattactg tgcgagaggg gcccgtataa taaccccttg tatggacgtc 300

tggggccaag ggaccacggt caccgtctcc tcagcctcca ccaagggccc atcggtcttc 360

cccctggcgc cctgctccag gagcacctcc gagagcacag cggccctggg ctgcctggtc 420

aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgctct gaccagcggc 480

gtgcacacct tcccagctgt cctacag 507

<210>57

<211>169

<212>PRT

<213> human

<400>57

Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser

1 5 10 15

Gly Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro

20 25 30

Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn

35 40 45

Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

50 55 60

Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu

65 70 75 80

Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ala Arg Ile Ile Thr Pro

85 90 95

Cys Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala

100 105 110

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser

115 120 125

Thr Ser Glu Ser Thr Ala Ala Leu Gly cys Leu Val Lys Asp Tyr Phe

130 135 140

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly

145 150 155 160

Val His Thr Phe Pro Ala Val Leu Gln

165

<210>58

<211>458

<212>DNA

<213> human

<400>58

cagtctccat cctccctgtc tgcatctgta ggagacagag tcaccatcac ttgccgggca 60

agtcagagca ttaacaccta tttaatttgg tatcagcaga aaccagggaa agcccctaac 120

ttcctgatct ctgctacatc cattttgcaa agtggggtcc catcaaggtt ccgtggcagt 180

ggctctggga caaatttcac tctcaccatc aacagtcttc atcctgaaga ttttgcaact 240

tactactgtc aacagagtta cagtacccca ttcactttcg gccctgggac caaagtggat 300

atcaaacgaa ctgtggctgc accatctgtc ttcatcttcc cgccatctga tgagcagttg 360

aaatctggaa ctgcctctgt tgtgtgcctg ctgaataact tctatcccag agaggccaaa 420

gtacagtgga aggtggataa cgccctccaa tcgggtaa 458

<210>59

<211>152

<212>PRT

<213> human

<400>59

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

1 5 10 15

Thr Cys Arg Ala Ser Gln Ser Ile Asn Thr Tyr Leu Ile Trp Tyr Gln

20 25 30

Gln Lys Pro Gly Lys Ala Pro Asn Phe Leu Ile Ser Ala Thr Ser Ile

35 40 45

Leu Gln Ser Gly Val Pro Ser Arg Phe Arg Gly Ser Gly Ser Gly Thr

50 55 60

Asn Phe Thr Leu Thr Ile Asn Ser Leu His Pro Glu Asp Phe Ala Thr

65 70 75 80

Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe Thr Phe Gly Pro Gly

85 90 95

Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile

100 105 110

Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val

115 120 125

Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys

130 135 140

Val Asp Asn Ala Leu Gln Ser Gly

145 150

<210>60

<211>501

<212>DNA

<213> human

<400>60

ggcgtggtcc agcctgggag gtccctgaga ctctcctgtg tagcgtctgg attcatcttc 60

agtagtcatg gcatccactg ggtccgccag gctccaggca aggggctgga gtgggtggca 120

gttatatggt atgatggaag aaataaagac tatgcagact ccgtgaaggg ccgattcacc 180

atctccagag acaattccaa gaacacgctg tatttgcaaa tgaacagcct gagagccgag 240

gacacggctg tgtattactg tgcgagagtg gccccactgg ggccacttga ctactggggc 300

cagggaaccc tggtcaccgt ctcctcagcc tccaccaagg gcccatcggt cttccccctg 360

gcgccctgct ccaggagcac ctccgagagc acagcggccc tgggctgcct ggtcaaggac 420

tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ctctgaccag cggcgtgcac 480

accttcccag ctgtcctaca g 501

<210>61

<211>167

<212>PRT

<213> human

<400>61

Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Val Ala Ser

1 5 10 15

Gly Phe Ile Phe Ser Ser His Gly Ile His Trp Val Arg Gln Ala Pro

20 25 30

Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Arg Asn

35 40 45

Lys Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

50 55 60

Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu

65 70 75 80

Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val Ala Pro Leu Gly Pro Leu

85 90 95

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr

100 105 110

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

115 120 125

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

130 135 140

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

145 150 155 160

Thr Phe Pro Ala Val Leu Gln

165

<210>62

<211>426

<212>DNA

<213> human

<400>62

tctccaggca ccctgtcttt gtctccaggg gaaagagcca ccctctcctg cagggccagt 60

cagagtatta gcagcaattt cttagcctgg taccagcaga aacctggcca ggctcccagg 120

ctcctcatct atcgtccatc cagcagggcc actggcatcc cagacagttt cagtggcagt 180

gggtctggga cagacttcac tctcaccatc agcagactgg agcctgagga ttttgcatta 240

tattactgtc agcagtatgg tacgtcacca ttcactttcg gccctgggac caaagtggat 300

atcaagcgaa ctgtggctgc accatctgtc ttcatcttcc cgccatctga tgagcagttg 360

aaatctggaa ctgcctctgt tgtgtgcctg ctgaataact tctatcccag agaggccaaa 420

gtacag 426

<210>63

<211>142

<212>PRT

<213> human

<400>63

Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser

1 5 10 15

Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn Phe Leu Ala Trp Tyr Gln

20 25 30

Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Arg Pro Ser Ser

35 40 45

Arg Ala Thr Gly Ile Pro Asp Ser Phe Ser Gly Ser Gly Ser Gly Thr

50 55 60

Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Leu

65 70 75 80

Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro Phe Thr Phe Gly Pro Gly

85 90 95

Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile

100 105 110

Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val

115 120 125

Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln

130 135 140

<210>64

<211>516

<212>DNA

<213> human

<400>64

tcgggcccag gactggtgaa gccttcacag atcctgtccc tcacctgcac tgtctctggt 60

ggctccatca gcagtggtgg tcactactgg agctggatcc gccagcaccc agggaagggc 120

ctggagtgga ttgggtacat ctattacatt gggaacacct actacaaccc gtccctcaag 180

agtcgagtta ccatatcagt agacacgtct aagaaccagt tctccctgaa gctgagctct 240

gtgactgccg cggacacggc cgtgtattat tgtgcgagag atagtgggga ctactacggt 300

atagacgtct ggggccaagg gaccacggtc accgtctcct cagcttccac caagggccca 360

tccgtcttcc ccctggcgcc ctgctccagg agcacctccg agagcacagc cgccctgggc 420

tgcctggtca aggactactt ccccgaaccg gtgacggtgt cgtggaactc aggcgccctg 480

accagcggcg tgcacacctt cccggctgtc ctacaa 516

<210>65

<211>172

<212>PRT

<213> human

<400>65

Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ile Leu Ser Leu Thr Cys

1 5 10 15

Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Gly His Tyr Trp Ser Trp

20 25 30

Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr

35 40 45

Tyr Ile Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr

50 55 60

Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser

65 70 75 80

Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Gly

85 90 95

Asp Tyr Tyr Gly Ile Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val

100 105 110

Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys

115 120 125

Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys

130 135 140

Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu

145 150 155 160

Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170

<210>66

<211>465

<212>DNA

<213> human

<400>66

tctccagact ttcagtctgt gactccaaag gagaaagtca ccatcacctg ccgggccagt 60

cagagcattg gtagtagctt acattggtat cagcagaaac cagatcagtc tccaaagctc 120

ctcatcaagt atgcttccca gtccttctct ggggtcccct cgaggttcag tggcagtgga 180

tctgggacag atttcaccct caccatcaat agcctggaag ctgaagatgc tgcaacgtat 240

tactgtcatc agagtagtag tttaccgctc actttcggcg gagggaccaa ggtggagatc 300

aaacgaactg tggctgcacc atctgtcttc atcttcccgc catctgatga gcagttgaaa 360

tctggaactg cctctgttgt gtgcctgctg aataacttct atcccagaga ggccaaagta 420

cagtggaagg tggataacgc cctccaatcg ggtaactccc aggag 465

<210>67

<211>155

<212>PRT

<213> human

<400>67

Ser Pro Asp Phe Gln Ser Val Thr Pro Lys Glu Lys Val Thr Ile Thr

1 5 10 15

Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser Leu His Trp Tyr Gln Gln

20 25 30

Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile Lys Tyr Ala Ser Gln Ser

35 40 45

Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

50 55 60

Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr

65 70 75 80

Tyr Cys His Gln Ser Ser Ser Leu Pro Leu Thr Phe Gly Gly Gly Thr

85 90 95

Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe

100 105 110

Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys

115 120 125

Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val

130 135 140

Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155

<210>68

<211>459

<212>DNA

<213> human

<400>68

cctgggaggt ccctgagact ctcctgtgca gcgtctggat tcaccttcag tagtcatggc 60

atccactggg tccgccaggc tccaggcaag gggctggagt gggtggcagt tatatggtat 120

gatggaagaa ataaagacta tgcagactcc gtgaagggcc gattcaccat ctccagagac 180

aattccaaga acacgctgta tttgcaaatg aacagcctga gagccgagga cacggctgtg 240

tattactgtg cgagagtggc cccactgggg ccacttgact actggggcca gggaaccctg 300

gtcaccgtct cctcagcctc caccaagggc ccatcggtct tccccctggc gccctgctcc 360

aggagcacct ccgagagcac agcggccctg ggctgcctgg tcaaggacta cttccccgaa 420

ccggtgacgg tgtcgtggaa ctcaggcgct ctgaccagc 459

<210>69

<211>153

<212>PRT

<213> human

<400>69

Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

1 5 10 15

Ser Ser His Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

20 25 30

Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Arg Asn Lys Asp Tyr Ala

35 40 45

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

50 55 60

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

65 70 75 80

Tyr Tyr Cys Ala Arg Val Ala Pro Leu Gly Pro Leu Asp Tyr Trp Gly

85 90 95

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

100 105 110

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala

115 120 125

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

130 135 140

Ser Trp Asn Ser Gly Ala Leu Thr Ser

145 150

<210>70

<211>439

<212>DNA

<213> human

<400>70

cagtctccag gcaccctgtc tttgtctcca ggggaaagag ccaccctctc ctgcagggcc 60

agtcagagtg tcagcagcta cttagcctgg taccagcaga aacctggcca ggctcccagg 120

ctcctcatct atggtgcatc cagcagggcc actggcatcc cagacaggtt cagtggcagt 180

gggtctggga cagacttcac tctcaccatc agcagactgg agcctgagga ttttgcagtg 240

tattactgtc aacagtatgg taggtcacca ttcactttcg gccctgggac caaagtagat 300

atcaagcgaa ctgtggctgc accatctgtc ttcatcttcc cgccatctga tgagcagttg 360

aaatctggaa ctgcctctgt tgtgtgcctg ctgaataact tctatcccag agaggccaaa 420

gtacagtgga aggtggata 439

<210>71

<211>146

<212>PRT

<213> human

<400>71

Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu

1 5 10 15

Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln

20 25 30

Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser

35 40 45

Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr

50 55 60

Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val

65 70 75 80

Tyr Tyr Cys Gln Gln Tyr Gly Arg Ser Pro Phe Thr Phe Gly Pro Gly

85 90 95

Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile

100 105 110

Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala SerVal Val

115 120 125

Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala LVs Val Gln Trp Lys

130 135 140

Val Asp

145

<210>72

<211>451

<212>DNA

<213> human

<400>72

ggcgtggtcc agcctgggag gtccctgaga ctctcctgtg cagcgtctgg attcaccttc 60

agtagctatg gcatgcactg ggtccgccag gctccaggca aggggctgga gtgggtggca 120

gttatatggt atgatggaag tcataaatac tatgcagact ccgtgaaggg ccgattcacc 180

atctccagag acaattccaa gaacacgctg tatctgcaaa tgaacagcct gagagccgag 240

gacacggctg tgtattactg tgcgagaggc gctgtagtag taccagctgc tatggacgtc 300

tggggccaag ggaccacggt caccgtctcc tcagcctcca ccaagggccc atcggtcttc 360

cccctggcgc cctgctccag gagcacctcc gagagcacag cggccctggg ctgcctggtc 420

aaggactact tccccgaacc ggtgacggtg t 451

<210>73

<211>151

<212>PRT

<213> human

<400>73

Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser

1 5 10 15

Gly Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro

20 25 30

Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser His

35 40 45

Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

50 55 60

Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu

65 70 75 80

Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ala Val Val Val Pro Ala

85 90 95

Ala Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala

100 105 110

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser

115 120 125

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe

130 135 140

Pro Glu Pro Val Thr Val Ser

145 150

<210>74

<211>402

<212>DNA

<213> human

<220>

<221>misc_feature

<222>(207)..(207)

<223>a，c，t，g，other or unknown

<400>74

acccagtctc catcctccct gtctgcatct gtaggagaca gagtcaccat cacttgccgg 60

gcaagtcaga acattagcag gtatttaaat tggtatcaac agaaaccagg gaaagcccct 120

aagttcctga tctatgttgc atctattttg caaagtgggg tcccatcagg gttcagtgcc 180

agtggatctg ggccagattt cactctnacc atcagcagtc tgcaacctga agattttgca 240

acttactact gtcaacagag ttacagtacc ccattcactt tcggccctgg gaccaaagtg 300

gatatcaaac gaactgtggc tgcaccatct gtcttcatct tcccgccatc tgatgagcag 360

ttgaaatctg gaactgcctc tgttgtgtgc ctgctgaata ac 402

<210>75

<211>134

<212>PRT

<213> human

<400>75

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

1 5 10 15

Ile Thr Cys Arg Ala Ser Gln Asn Ile Ser Arg Tyr Leu Asn Trp Tyr

20 25 30

Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile Tyr Val Ala Ser

35 40 45

Ile Leu Gln Ser Gly Val Pro Ser Gly Phe Ser Ala Ser Gly Ser Gly

50 55 60

Pro Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

65 70 75 80

Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe Thr Phe Gly Pro

85 90 95

Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

100 105 110

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

115 120 125

Val Cys Leu Leu Asn Asn

130

<210>76

<211>438

<212>DNA

<213> human

<220>

<221>misc_feature

<222>(64)..(64)

<223>a，c，t，g，other or unknown

<400>76

gtggtccagc ctgggaggtc cctgagactc tcctgtgcag cgtctggatt caccttcagt 60

agcngtggca tgcactgggt ccgccaggct ccaggcaagg ggctggagtg ggtggcagtt 120

atatggtctg atggaagtca taaatactat gcagactccg tgaagggccg attcaccatc 180

tccagagaca attccaagaa cacgctgtat ctgcaaatga acagcctgag agccgaggac 240

acggctgtgt attactgtgc gagaggaact atgatagtag tgggtaccct tgactactgg 300

ggccagggaa ccctggtcac cgtctcctca gcctccacca agggcccatc ggtcttcccc 360

ctggcgccct gctccaggag cacctccgag agcacagcgg ccctgggctg cctggtcaag 420

gactacttcc ccgaaccg 438

<210>77

<211>146

<212>PRT

<213> human

<400>77

Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

1 5 10 15

Phe Thr Phe Ser Ser Cys Gly Met His Trp Val Arg Gln Ala Pro Gly

20 25 30

Lys Gly Leu Glu Trp Val Ala Val Ile Trp Ser Asp Gly Ser His Lys

35 40 45

Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

50 55 60

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

65 70 75 80

Thr Ala Val Tyr Tyr Cys Ala Arg Gly Thr Met Ile Val Val Gly Thr

85 90 95

Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

100 105 110

Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr

115 120 125

Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro

130 135 140

Glu Pro

145

<210>78

<211>451

<212>DNA

<213> human

<400>78

acccagtctc catcctccct gtctgcatct gtaggagaca gagtcaccat cacttgccgg 60

gcaagtcaga gcatttgcaa ctatttaaat tggtatcagc agaaaccagg aaaagcccct 120

agggtcctga tctatgctgc atccagtttg caaggtgggg tcccgtcaag gttcagtggc 180

agtggatctg ggacagattg cactctcacc atcagcagtc tgcaacctga agattttgca 240

acttactact gtcaacagag ttacactacc ccattcactt tcggccctgg gaccagagtg 300

gatatcgaac gaactgtggc tgcaccatct gtcttcatct tcccgccatc tgatgagcag 360

ttgaaatctg gaactgcctc tgttgtgtgc ctgctgaata acttctatcc cagagaggcc 420

aaagtacagt ggaaggtgga taacgcctat t 451

<210>79

<211>150

<212>PRT

<213> human

<400>79

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

1 5 10 15

Ile Thr Cys Arg Ala Ser Gln Ser Ile Cys Asn Tyr Leu Asn Trp Tyr

20 25 30

Gln Gln Lys Pro Gly Lys Ala Pro Arg Val Leu Ile Tyr Ala Ala Ser

35 40 45

Ser Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

50 55 60

Ile Asp Cys Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

65 70 75 80

Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Thr Pro Phe Thr Phe Gly Pro

85 90 95

Gly Thr Arg Val Asp Ile Glu Arg Thr Val Ala Ala Pro Ser Val Phe

100 105 110

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

115 120 125

Val Cys Leu Leu Ash Ash Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

130 135 140

Lys Val Asp Asn Ala Tyr

145 150

<210>80

<211>562

<212>DNA

<213> human

<400>80

tcctgtgcag cgtctggatt caccttcagt tactatggcg tctgggggag gcgtggtcca 60

gcctgggagg tccctgagac tctcctgtgc agcgtctgga ttcaccttca gtagctatgg 120

cgtgcactgg gtccgccagg ctccaggcaa ggggctggag tgggtggcag ttatatggta 180

tgatggaagt aataaatact atgcagactc cgtgaagggc cgattcacca tctccagaga 240

caattccaag agcacgctgt atctgcaaat gaacagcctg agagccgagg acacggctgt 300

gtattattgt gcgagagact cgtattacga tttttggagt ggtcggggcg gtatggacgt 360

ctggggccaa gggaccacgg tcaccgtctc ctcagcctcc accaagggcc catcggtctt 420

ccccctggcg ccctgctcca ggagcacctc cgagagcaca gcggccctgg gctgcctggt 480

caaggactac ttccccgaac cggtgacggt gtcgtggaac tcaggcgctc tgaccagcgg 540

cgtgcacacc ttcccagctg tc 562

<210>81

<211>174

<212>PRT

<213> human

<400>81

Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys

1 5 10 15

Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Val His Trp Val Arg

20 25 30

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp

35 40 45

Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile

50 55 60

Ser Ara Asp Asn Ser Lys Ser Thr Leu Tyr Leu Gln Met Asn Ser Leu

65 70 75 80

Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Tyr Tyr

85 90 95

Asp Phe Trp Ser Gly Arg Gly Gly Met Asp Val Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170

<210>82

<211>419

<212>DNA

<213> human

<400>82

ccactctccc tgcccgtcac ccttggacag ccggcctcca tctcctgcag gtctagtcaa 60

agcctcgtat acagtgatgg aaacacctac ttgaattggt ttcagcagag gccaggccaa 120

tctccaaggc gcctaattta taaggtttct aactgggact ctggggtccc agacagattc 180

agcggcagtg ggtcaggcac tgatttcaca ctgaaaatca gcagggtgga ggctgaggat 240

gttggggttt attactgcat gcaaggttca cactggcctc cgacgttcgg ccaagggacc 300

aaggtggaaa tcaaacgaac tgtggctgca ccatctgtct tcatcttccc gccatctgat 360

gagcagttga aatctggaac tgcctctgtt gtgtgcctgc tgaataactt ctatcccac 419

<210>83

<211>139

<212>PRT

<213> human

<400>83

Pro Leu Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys

1 5 10 15

Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr Leu Asn

20 25 30

Trp Phe Gln Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr Lys

35 40 45

Val Ser Asn Trp Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly

50 55 60

Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp

65 70 75 80

Val Gly Val Tyr Tyr Cys Met Gln Gly Ser His Trp Pro Pro Thr Phe

85 90 95

Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser

100 105 110

Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala

115 120 125

Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro

130 135

<210>84

<211>490

<212>DNA

<213> human

<400>84

gtccagcctg ggaggtccct gagactctcc tgtgcagcgt ctggattcac cttcagtaac 60

tatgccatgc actgggtccg ccaggctcca ggcaaggggc tggagtgggt ggtagttatt 120

tggcatgatg gaaataataa atactatgca gagtccgtga agggccgatt caccatctcc 180

agagacaatt ccaagaacac gctgtatctg caaatgaaca gcctgagagc cgaggacacg 240

gctgtatatt actgtgcgag agatcagggc actggctggt acggaggctt tgacttctgg 300

ggccagggaa ccctggtcac cgtctcctca gcctccacca agggcccatc ggtcttcccc 360

ctggcgccct gctccaggag cacctccgag agcacagcgg ccctgggctg cctggtcaag 420

gactacttcc ccgaaccggt gacggtgtcg tggaactcag gcgctctgac cagcggcgtg 480

cacaccttcc 490

<210>85

<211>163

<212>PRT

<213> human

<400>85

Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

1 5 10 15

Thr Phe Ser Asn Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys

20 25 30

Gly Leu Glu Trp Val Val Val Ile Trp His Asp Gly Asn Asn Lys Tyr

35 40 45

Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

50 55 60

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

65 70 75 80

Ala Val Tyr Tyr Cys Ala Arg Asp Gln Gly Thr Gly Trp Tyr Gly Gly

85 90 95

Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

100 105 110

Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr

115 120 125

Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro

130 135 140

Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val

145 150 155 160

His Thr Phe

<210>86

<211>419

<212>DNA

<213> human

<400>86

cctggagagc cggcttccat ctcttgcagg tctagtcaga gcctcctgca tagtaatgga 60

tacaactatt tggattggta cctgcagaag ccaggacagt ctccacagct cctgatctat 120

ttgggttcta atcgggcctc cggggtccct gacaggttca gtggcagtgg atcaggcaca 180

gattttacac tgaaactcag cagagtggag gctgaggatg ttggggttta ttactgcatg 240

caagctctac aaactcctct cactttcggc ggagggacca aggtggagat caaacgaact 300

gtggctgcac catctgtctt catcttcccg ccatctgatg agcagttgaa atctggaact 360

gcctctgttg tgtgcctgct gaataacttc tatcccagan aggccaaagt acattccat 419

<210>87

<211>133

<212>PRT

<213> human

<400>87

Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu

1 5 10 15

His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly

20 25 30

Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly

35 40 45

Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu

50 55 60

Lys Leu Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met

65 70 75 80

Gln Ala Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu

85 90 95

Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser

100 105 110

Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn

115 120 125

Asn Phe Tyr Pro Arg

130

<210>88

<211>1335

<212>DNA

<213> human

<400>88

caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60

tcctgtgcag cgtctggatt caccttcagt agtcatggca tccactgggt ccgccaggct 120

ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagaaa taaagactat 180

gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240

ttgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagtggcc 300

ccactggggc cacttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagcctcc 360

accaagggcc catcggtctt ccccctggcg ccctgctcca ggagcacctc cgagagcaca 420

gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480

tcaggcgctc tgaccagcgg cgtgcacacc ttcccagctg tcctacagtc ctcaggactc 540

tactccctca gcagcgtggt gaccgtgccc tccagcaact tcggcaccca gacctacacc 600

tgcaacgtag atcacaagcc cagcaacacc aaggtggaca agacagttga gcgcaaatgt 660

tgtgtcgagt gcccaccgtg cccagcacca cctgtggcag gaccgtcagt cttcctcttc 720

cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac gtgcgtggtg 780

gtggacgtga gccacgaaga ccccgaggtc cagttcaact ggtacgtgga cggcgtggag 840

gtgcataatg ccaagacaaa gccacgggag gagcagttca acagcacgtt ccgtgtggtc 900

agcgtcctca ccgttgtgca ccaggactgg ctgaacggca aggagtacaa gtgcaaggtc 960

tccaacaaag gcctcccagc ccccatcgag aaaaccatct ccaaaaccaa agggcagccc 1020

cgagaaccac aggtgtacac cctgccccca tcccgggagg agatgaccaa gaaccaggtc 1080

agcctgacct gcctggtcaa aggcttctac cccagcgaca tcgccgtgga gtgggagagc 1140

aatgggcagc cggagaacaa ctacaagacc acacctccca tgctggactc cgacggctcc 1200

ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1260

tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 1320

tctccgggta aatga 1335

<210>89

<211>444

<212>PRT

<213> human

<400>89

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His

20 25 30

Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Asp Gly Arg Asn Lys Asp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ala Pro Leu Gly Pro Leu Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu cys

210 215 220

Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr

290 295 300

Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ash His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440

<210>90

<211>645

<212>DNA

<213> human

<400>90

gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgtcagc agctacttag cctggtacca gcagaaacct 120

ggccaggctc ccaggctcct catctatggt gcatccagca gggccactgg catcccagac 180

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag actggagcct 240

gaggattttg cagtgtatta ctgtcaacag tatggtaggt caccattcac tttcggccct 300

gggaccaaag tagatatcaa gcgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540

ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600

ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645

<210>91

<211>214

<212>PRT

<213> human

<400>91

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Arg Ser Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Claims (15)

1. A method of treating cancer in a mammal comprising administering to the mammal more than 10mg/kg of a human anti-CTLA-4 antibody.

2. The method of claim 1, comprising administering at least 15mg/kg of human anti-CTLA-4 antibody to the mammal.

3. The method of claim 1, comprising administering 15mg/kg of human anti-CTLA-4 antibody to the mammal.

4. A method for treating cancer in a mammal comprising administering to a mammal that has received a stem cell transplant an effective amount of a human anti-CTLA-4 antibody.

5. The method of claims 1-4, wherein the mammal is a human.

6. The method of claims 4-5, wherein said stem cell transplant is selected from the group consisting of a bone marrow transplant, a peripheral blood stem cell transplant, a allogeneic stem cell transplant, and an autologous stem cell transplant.

7. The method of claims 4-5, wherein the mammal is administered a high dose chemotherapy prior to stem cell transplantation.

8. The method of claim 7, wherein the agent used for said chemotherapy is at least one agent selected from the group consisting of: busulfan, cyclophosphamide, melphalan, thiotepa, carmustine, epirubicin, fludarabine, and etoposide.

9. The method of claims 4-5, wherein the mammal is subjected to systemic irradiation prior to stem cell transplantation.

10. The method of claim 1 or 4, wherein the cancer is selected from the group consisting of: breast cancer including metastatic breast cancer, lung cancer including small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, melanoma, including cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, non-Hodgkin's lymphoma, carcinoma of the esophagus, cancer of the small intestine, cancer of the endocrine system, carcinoma of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphomas, epidermal T cell lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvis cancer, Central Nervous System (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor tunor, brain stem glioma, pituitary adenoma, kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-lymphocyte lymphoma, environmentally induced carcinomas including asbestos-induced carcinomas, myelomas, neuroblastomas and childhood sarcomas.

11. The method of claims 1-10, wherein the human anti-CTLA-4 antibody is an antibody selected from the group consisting of antibodies having the amino acid sequence of antibody 4.1.1, antibody 4.13.1, antibody 4.14.3, antibody 6.1.1, and antibody 11.2.1.

12. The method of claims 1-10, wherein the human anti-CTLA-4 antibody has the amino acid sequence of antibody 10D 1.

13. The method of claims 1-10, wherein the human anti-CTLA-4 antibody has the heavy and light chain CDR amino acid sequences of an antibody selected from among antibody 4.1.1, antibody 4.13.1, antibody 4.14.3, antibody 6.1.1, and antibody 11.2.1.

14. The method of claims 1-10, wherein the human anti-CTLA-4 antibody has the heavy and light chain variable region amino acid sequences of an antibody selected from among antibody 4.1.1, antibody 4.13.1, antibody 4.14.3, antibody 6.1.1, and antibody 11.2.1.

15. The method of claims 1-10, wherein the human anti-CTLA-4 antibody cross-competes with an antibody selected from the group consisting of antibody 4.1.1, antibody 4.13.1, antibody 4.14.3, antibody 6.1.1, and antibody 11.2.1.