BRPI0720924A2 - TREATMENT METHODS - Google Patents

Description

Report of the Invention Patent for "TREATMENT METHODS".

This application claims the benefit of United States Provisional Patent Application No. 60 / 874,589, filed December 13, 2006; United States Provisional Patent Application 60 / 870,937, filed December 20, 2006; United States Provisional Patent Application No. 60 / 946,011, filed June 25, 2007, and United States Provisional Patent Application No. 60 / 979,274, filed October 11, 2007; each of which is incorporated herein by reference 10 in its entirety.

Field of the Invention

The present invention relates to compositions and methods for treating or preventing cancer.

Background of the Invention Insulin-like growth factors, also known as

Somatomedins include insulin-like growth factor-1 (IGF-I) and insulin-like growth factor-11 (IGF-II) (Klapper, et al., (1983) Endocrinol. 112: 2215 and Rinderknecht1 et al. al. (1978) Feb. Letts 89: 283). These growth factors exert mitogenic activity on various cell types, including tumor cells (Macaulay, (1992) Br. J. Cancer 65: 311), by binding to a common receptor called the similar growth factor receptor. to insulin-1 (IGF1R or IGFR1) (Sepp-Lorenzino, (1998) Breast Cancer Research and Treatment 47: 235). The interaction of IGFs with IGF1R activates the receptor by triggering receptor autophosphorylation on tyrosine residues (Butler, et al., (1998) Comparative Biochemistry and Physiology 121: 19). Once activated, IGF1R, in turn, phosphorylates intracellular targets to activate cellular signaling pathways. This receptor activation is critical for tumor cell growth stimulation and survival. Therefore, inhibition of IGF1R activity represents a potentially valuable method for treating or preventing the growth of human cancers and other proliferative diseases.

Accordingly, therapies that inhibit IGF1R are useful for treating or preventing certain cancers. Anti-IGF1R antibodies are useful therapies for cancer treatment or prevention. There are several anti-IGF1R antibodies that are known in the art (see, for example, WO 03/100008; WO 2002/53596; WO 04/71529; WO 03/106621;

5 US2003 / 235582; WO 04/83248; WO 03/59951; WO 04/87756 or WO 2005/16970). Other small molecule IGF1R inhibitors are also known in the art.

Although there are known IGF1R inhibitors in the art that can be used to treat or prevent some cancers, there remains a need in the art for therapeutic compositions and methods for treating or preventing other cancers, such as head and neck cancer, squamous cell carcinoma, solitary plasmacitoma, multiple myeloma and renal cell cancer.

Summary of the Invention The present invention provides this need, in part, for

by providing IGF1R inhibitors and combinations thereof that are effective in the treatment or prevention of head and neck cancer, squamous cell carcinoma, multiple myeloma, solitary plasmacitoma, renal cell cancer, retinoblastoma, germ cell tumors, hepatoblastoma , 20 hepatocellular carcinoma, melanoma, rhabidoid kidney tumor, Ewing's sarcoma, chondrosarcoma, any haemotological malignancy (eg chronic lymphoblastic leukemia, chronic myelomonocytic leukemia, acute T-cell lineage, precursor lineage). B-cell sera), acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, chronic myeloblastic leukemia, Hodgkin's disease, non-Hodgekin's lymphoma, chronic myelogenous leukemia, myelodysplastic syndrome , hair cell leukemia, c leukemia mast squid, mast cell neoplasm, follicular lymphoma, diffuse large cell lymphoma, lining cell lymphoma, marginal zone 30 lymphoma, Burkitt lymphoma, mycosis fungoides, seyary syndrome, cell-lymphoma T skin, Peripheral T-cell lymphoma, Chronic myeloproliferative disorders, Myelofibrosis, Myeloid metaplasia, Systemic mastocytosis, and Central nervous system tumors (eg, brain cancer, glioblastoma, non-glioblastoma of brain cancer, meningioma, adenoma pituitary, vestibular schwanoma, a primitive neurotodermal tumor, medulloblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma and choroidal plexus papilloma), myeloproliferative disorders (eg, polycythemia vera, mammothiopathy, thrombocythemia, thrombocythemia, thrombocythemia, soft tissue, thyroid cancer, endometrial cancer, carcinoid cancer, tumor germ cell diseases, or liver cancer.

The present invention provides a method for treating or preventing a medical condition in an individual selected from the group consisting of head and neck cancer, squamous cell carcinoma, multiple myeloma, solitary plasmacitoma, renal cell cancer, retinoblastoma, germ cell tumors, hepatoblastoma, hepatocellular carcinoma, melanoma, rhabidoid kidney tumor, Ewing's sarcoma, chondrosarcoma, any haemotological malignancies (eg chronic lymphoblastic leukemia, chronic lymphoblastic leukemia (eg, acute lymphoblastic leukemia). T-cell line, B-cell precursor line), acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, chronic myeloblastic leukemia, Hodgekin's disease, non-Hodgekin's lymphoma, chronic lymphocytic leukemia , chronic myelogenous leukemia, myelodysplastic syndrome, hair cell leukemia, mast cell leukemia (mast cell neoplasm, Follicular lymphoma, Diffuse large cell lymphoma, Coating cell lymphoma, Burkitt lymphoma, Mycosis fungoides, Seary syndrome, Cutaneous T-cell lymphoma, Chronic myeloproliferative disorders), and central nervous system tumors (eg, brain cancer, glioblastoma, non-glioblastoma of brain cancer, meningioma, pituitary adenoma, vestibular schwanoma, a primitive neurotodermal tumor, medulloblastoma, astrocytoma, aplastic astrocytoma, oligodendroglioma, ependymoma and choroid plexus papilloma), myeloproliferative disorders (eg, polycythemia vera, thrombocythemia, idiopathic myelfibrosis), soft tissue sarcoma, thyroid cancer, endometrial cancer, carcinoid cancer, germ cell tumors, and liver cancer, including administer a therapeutically effective amount of one or more IGF1R inhibitors, or pharmaceutical compositions designed to to the individual. In one embodiment of the invention, the IGF1R inhibitor is selected from the group consisting of

5 and an isolated antibody that specifically binds IGF1R (e.g., human IGF1R), or an antigen binding fragment thereof. In one embodiment of the invention, the antibody comprises: (a) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 2 and a heavy chain variable region comprising amino acids 20-137 of 10 SEQ ID NO: 10 or 12; (b) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 4, and a heavy chain variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 12; (c) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 6 and a heavy chain variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 12; (d) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 8 and a heavy chain variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 12; or any other IGF1R inhibitor placed herein, for example under the "IGF1R inhibitors" section below. In one embodiment of the invention, the IGF1R inhibitor is administered in combination with one or more additional anticancer chemotherapeutic agents, or a pharmaceutical composition thereof. In one embodiment of the invention, the additional anti-cancer chemotherapeutic agent is a member selected from the group consisting of OH

H2N-

tin,

carboplatin>.

(

), any formulation

such as Caelyx or Doxil, „o

/ Va OH2

I xN, NH

Cl

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acid

NH,

I 2

Pt-Cl

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etoposide

doxorrubicin

Hypososomal cyclophosphamide

13-retinoic H0C CH, CH3

gemcitabine (

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OH F

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HQ 'GH2CH-J

), vincristine (),

ο

dactinomicin

methotrexate (0Η) and any other chemotherapeutic agent placed herein, for example as placed under the "Additional Chemotherapy" section below. In one embodiment of the invention, the dosage of any anti-IGF1R antibody placed herein is in the range of about 0.3-20 mg / kg body weight, or about 40-1200 mg / m2. In one embodiment of the invention, the IGF1R inhibitor and additional anti-cancer therapeutic agent are administered simultaneously. In one embodiment of the invention, the IGF1R inhibitor and the additional anticancer therapeutic agent are administered non - simultaneously. In one embodiment of the invention, the antibody comprises an IgG constant region. In one embodiment of the invention, the individual is a human (e.g., a child). In one embodiment of the invention, the IGF1R inhibitor is administered in combination with an anticancer therapeutic procedure. In one embodiment of the invention, the anticancer therapeutic procedure is surgical tumorectomy and / or anticancer radiation treatment.

Brief Description of the Figures

Figure 1. IGF1R mRNA expression in head and neck primary tumor samples as measured using Taqman. Each dot represents the normalized expression level of IGF1R in a single tissue sample. The stage of head and neck cancer in the patient from which each sample was obtained is marked I, II, Ill or IV. Values corresponding to normal tissue samples are labeled "normal", and values corresponding to normal adjacent tissue located adjacent to tumor cells, but otherwise displaying normal characteristics, are labeled "NAT".

Figure 2. Western blot analysis of protein expression level of total IGF1R, IGF-I, and IGF-II in various cell lines (upper panel). The amount of IGF1 and IGF2 is secreted from several cell lines into the surrounding growth medium (ng IGF1 or IGF2 protein / 10 6 cells) (bottom panel). Figures 3 (a) -3 (c). Inhibition of squamous cell carcinoma in cell lines in vitro at various concentrations of anti-IGF1R LCF / HCA antibody. (a): SCC cell line 15; (b): SCC cell line 25; (c): SCC cell line 9.

Figure 4. IGF2 expression level in tumoral tissue from

primary stomach denocarcinoma as compared to that of normal tissue.

Figure 5. Expression levels of various proteins in various gastric and ovarian cancer cell lines as measured by western blot analysis.

Figure 6. In vitro growth inhibition of squamous cell carcinoma cancer cells (SNU-16 cell line) at various concentrations of anti-IGF1R LCF / HCA antibody.

Figure 7. Renal cell carcinoma tumor growth in a mouse xenograft model over time after exposure to anti-IGF1R LCF / HCA antibody or a control immunoglobulin.

Figure 8. In vitro growth inhibition of A375-SM melanoma cell line when exposed to various concentrations of anti-IGF1 R LCF / HCA antibody.

Figure 9. In vivo growth inhibition of

SCC15 squamous cell carcinoma in mice when exposed to anti-IGF1R LCF / HCA antibody.

Figure 10. Tumor volume assessment over time in EW5 (Ewins sarcoma), OS-1 (osteosarcoma) and OS-9 (osteosarcoma) xenograft tumor models.

Detailed Description of the Invention

The present invention comprises compositions and methods for treating or preventing non-cancerous medical disorders and cancer including head and neck cancer, squamous cell carcinoma, multiple myoma, solitary plasmacitoma, renal cell cancer, retinoblastoma, cell tumors. germ cell, hepatoblastoma, hepatocellular carcinoma, melanoma, rhabidoid tumor of the kidney, Ewing's sarcoma, chondrosarcoma, any haemotological malignancy (eg chronic lymphoblastic leukemia, acute lymphoblastic leukemia (eg lineage) T cell, B-cell precursor lineage), acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, 5 chronic myeloblastic leukemia, Hodgekin's disease, chronic non-Hodgekin's lymphoma, chronic myelogenous leukemia, myelodysplastic syndrome, l hair cell eucemia, mast cell leukemia, mast cell neoplasm, follicular lymphoma, diffuse large cell lymphoma, lining cell lymphoma, Burkitt lymphoma, mycosis fungoides 10, seary syndrome, Cutaneous T-cell lymphoma, chronic myeloproliferative disorders), and central nervous system tumors (eg, brain cancer, glioblastoma, non-glioblastoma of brain cancer, meningioma, pituitary adenoma, vestibular schwanoma, a neurotumor primitive dermal, medulloblastoma, astrocytoma, anaplastic astrocytoma, oligendroglioma, choroid plexus papilloma and ependymoma), myeloproliferative disorder (eg, polycythemia vera, thrombocythemia, idiopathic myelibrosis), soft tissue sarcoma, thyroid cancer endometrial cancer carcinoid cancer germ cell tumors liver cancer gastric cancer gigantism ad pituitary enoma, psoriasis and rhabidoid tumor of the kidney. Cancer can be treated or prevented by administering an IGF1R inhibitor, such as an anti-IGF1R antibody. The antibody may be associated with an additional chemotherapeutic agent such as an anticancer chemotherapeutic agent such as any of those set forth herein.

The terms IGF1R, IGFR1 and IGF-1R are synonymous and refer to insulin-like growth factor receptor 1.

IGF1R Inhibitors

The terms "IGF1R inhibitor" or "IGF1R antagonist" or the like include any expression-enhancing, ligand-binding (eg, IGF-1 and / or IGF-2 binding) substance, kinase activity (eg autophosphorylation activity), or any other biological activity of IGF1R (eg anchorage-independent cell growth mediation) and the level of phospho-IRS-1 that will induce a biological or medical response of a tissue. , system, individual, or patient being sought by the administrator (such as a researcher, physician, or veterinarian) that includes any measurable relief of signs, symptoms, and / or clinical evidence of both noncancerous and cancer disorders (eg. tumor growth) and / or the prevention, lowering, or arrest of cancer progression or metastasis (eg, head and neck cancer, left-sided cell carcinoma mosa, multiple myeloma, solitary plasmacytoma, renal cell cancer, retinoblastoma, germ cell tumors, hepatosblastoma, hepatocellular carcinoma, melanoma, rhabidoid kidney tumor, Ewing's sarcoma, chondrosarcoma, any hemotological malignancy (eg , chronic lymphoblastic leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia (eg, T-cell line, B-cell precursor lineage), acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, 15 Hodgekin's disease, Non-Hodgekin's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Myelodysplastic syndrome, Capillary cell leukemia, Ballast cell leukemia, Follicular lymphoma, Fuzzy large cell lymphoma Coating Cell Iymphoma, Burkitt Lymphoma, fungoides d and ringworm, seary syndrome, cutaneous T-cell lymphoma, chronic myeloproliferative disorders, and central nervous system tumors (eg, brain cancer, glioblastoma, non-glioblastoma, brain cancer, meningioma, pituitary adenoma, vestibular schwannoma, a primitive neuroctodermal tumor, medulloblastoma, astro-cytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma and papilloma 25 of choroid plexus), myeloproliferative disorders (eg, polycythemia vera, myocardial thrombocytosis, thrombocytosis, thrombocytosis, thrombocytosis, thrombocytosis). soft tissue, thyroid cancer, endometrial cancer, carcinoid cancer, germ cell tumors, liver cancer, gastric cancer, gigantism, pituitary adenoma, psoriasis, and kidney rabidoid tumor to any degree.

In one embodiment of the invention, an IGF1R inhibitor that is

administered to a patient in a method according to the invention is any isolated antibody or antigen-binding fragment thereof that specifically binds to an insulin-like growth factor receptor (e.g., human IGF1R) (e.g. monoclonal antibodies (e.g. fully human monoclonal antibodies), polyclonal antibodies, bispecific antibodies, Fab antibody fragments, F (ab) 2 antibody fragments, gFv antibody fragments (e.g. VH or VL), single chain Fv antibody fragments, dsFv antibody fragments, humanized antibodies, chimeric antibodies or anti-idiotypic antibodies), such as any of those described in any of Burtrum et. al Cancer Research 63: 8912-8921 (2003); French Patent Applications FR2834990, FR2834991 and FR2834900, and PCT Application Publication Nos. WO 03/100008; WO 03/59951; WO 2006/13472; WO 04/71529; WO 03/106621; WO 04/83248; WO 04/87756, WO 05/16970; and WO 02/53596.

In one embodiment of the invention, an IGF1R inhibitor that is administered to a patient in a method according to the invention is an isolated anti-insulin-like growth factor receptor (IGF1R) antibody isolated comprising a C-Light Chain. , D, E or F 19D12 / 15H12 maturity (LCC, LCD, LCE or LCF) and a mature A or B 19D12 / 15H12 heavy chain (HCA or HCB). In one embodiment of the invention, the antibody comprises mature LCF and mature HCA (LCF / HCA). In one embodiment of the invention, an IGF1R inhibitor that is administered to a patient in a method according to the invention is an isolated antibody that specifically binds IGF1R comprising one or more Light Chain Complementarity Determination Regions (CDRs) -C, D, E or F 19D12 / 15H12 and / or heavy chain-A or B 19D12 / 15H12 (e.g. all 3 light chain CDRs and all 3 heavy chain CDRs).

The amino acid and nucleotide sequences of the antibody chains of the invention are shown below. Dotted underline indicates the signal peptide. Underline full type indicates the CDRs. Flat type indicates the frame regions. Mature fragments lack signal peptide. Modified Light Chain-C 19D12 / 15H12 (SEQ ID NO: 1)

ATG TCG .CCA.TCA..Ç ^ .. ÇTC _ATT GGG TTT CTG CTG CTG CTC TGG GTT CCA GCC TCC AGG GGT GAA ATT GTG ACT CAG AGC CCA GAC TCT CTG TCT GTG ACT CCA GGC GAG AGA GTC ACC ATC ACC TGC CGG GCC AGT CAG AGC ATT GGT AGT AGC TTA CAC TGG TAC CAG CAG AAA CCA GGT CAG TCT CCA AAG CTT CTC ATC AAG

TAT GCA TCC CAG TCC CTC TCA GGG GTC CCC TCG AGG TTC AGT GGC AGT GGA TCT GGG ACA GAT TTC ACC CTC ACC AGC CTC GAG GAA GAT GCT GCA GCG TAT TAC TGT CAT CAG AGT AGT CGT TTA CCT GTA CAA GGG ACC AAG GTG GAG ATC AAA CGT ACG

(SEQ ID NO: 2)

MI P S Q L I G FLLLWVPAS

R G E I V L T Q S P D S L S V T P G E R V T I C C A S Q S I S S L H W Y Q Q K K P Q L K K A S Q S L S G S P S F S G S F S L E S D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D E D L E S

ATG TCG CCA TCA CAA CTC ATT GGG TTT CTG CTG CTC CTC TGG GTT CCA GCC TCC

AGG GGT GAA ATT GTG CTG ACT CAG AGC CCA GAC TCT CTG TCT GTG ACT CCA GGC GAG AGA GTC ACC ATC TGC CGG GCC AGT CAG AGT ATC GGT AGC TTA CAC TGA TAG CAG AAA CCA GGT CAG TCT CCA CTC AAG TAT GCA TCC CAG TCC CTC TCA GGG GTC CCC TCG AGG TTC AGT GGC AGT GGA

TCT GGG ACA GAT TTC ACC CTC ACC ATC AGT AGC CTC GAG GCT GAA GAT TTC

GCA GTG TAT TAC TGT CAT CAG AGT AGT CGT TTA CCT CAC ACT TTC GGC CAA GGG ACC AAG GTG GAG ATC AAA CGT ACG

(SEQ ID NO: 4)

Ms P..S.Q.l.J..G..F.k.L.k.W.y.P.A.S

R .G EIVLTQSPDSLSVTP

G E R V T I T C RASQSIGSS LHWYQQKPGQSPKLLIK YASQSLS gvpsrfsgsg

SGTDFTLTISSLEAEDF AVYYC HQSSRLPHT FGQ GTKVEIKRT Modified Light Chain E 19D12 / 15H12 (SEQ ID NO: 5)

ATG TCG..CCA TCA CAA CTC ATT GGG TTT CTG CTG CTG CTC TGG GTT CCA GCC TCC AGG GGT GAA ATT GTG CTG ACC CAG GGT ACC CTG TCT GTG TCT CCA GGC GAG AGC ACC CTC TCC TGC CGC GT AGT CAG GGT AGT AGC TTA CAC TGG TAC CAG CAG AAA CCA GGT CAG GCT CCA AGG CTT CTC ATC AAG TAT GCA TCC CAG TCC CTC TCA GGG ATC CCC GAT AGG TTC AGT GGC AGT GGA

TCT GGG ACA GAT TTC ACC CTC ACC ATC AGT AGA CTG GAG CCT GAA GAT GCT GCA GCG TAT TAC TGT CAT CAG AGT AGT CGT TTA CCT ACC TTC GGC CAA GGG ACC AAG GTG GAG ATC AAA CGT ACA

(SEQ ID NO: 6)

M S P S Q L I G F L L L W V P O R L E I V L T Q S P L L S V S P L E R A T E S C R S Q S I G S S L H W Y Q Q K P G Q A Q A L L I K Y S Q S L S L I P D R F S G S G S L D F T U T I O R L E P E D A A A Y Y C H F S R L P H T F G Q G T K V E I K R T Light Chain-F Modified 19D12 / 15H12 (SEQ ID N0: 7)

AT? .J.CG.CCA.TCA CAA CTC ATT GGG TTT CTG CTG CTC TGG GTT CCA GCC TCC

AGG..GGT GAA ATT GTG CTG ACT CAG AGA CCA GGT ACC CTG TCT GTG TCT CCA

GGC GAG AGA GCC ACC CTC TCC TGC CGG GCC AGT CAG AGC ATT GGT AGT AGC

TTA CAC TGG TAC CAG CAG AAA CCA GGT CAG GCT CCA AGG CTT CTC ATC AAG

TCA GCA TCC CAG TCC CTC TCA GGG ATC CCC GAT AGG TTC AGT GGC AGT GGA

TCT GGG ACA GAT TTC ACC CTC ACC ATC AGT AGA CTG GAG CCT GAA GAT TTC

GCA GTG TAT TAC TGT CAT CAG AGT AGT CGT TTA CCT CAC ACT TTC GGC CAA

GGG ACC AAG GTG GAG ATC AAA CGT ACA (SEQ ID NO: 8)

M S P S Q L I G F L L L W V P O R L E I V L T Q S P L L S V S P L E R A T E S C R S Q S I G S S L H W Y Q Q K P G Q A Q A L L I K Y S Q S L S L I P D R F S G S G S L D F T U T I O R L E P E D F A V Y Y C H F S R L P H T F G Q G T K V E I K R T Chain Heavy-A Modified 19D12 / 15H12 (SEQ ID N0: 9)

AT? .. GAG .TTT GGG. CTG_ AGC TGG GTT TTC CTT GTT GCT ATA TTA AAA GGT GTC CAG TGT GAG GTT CAG CTG GTG CAG TCT GGG GGA TTG GTA AAG CCT GGG GGG TCC CTG AGA CTC TCC TGT GCA GCC TCT GGA TTC AGC TTC AGC TTC TGT GTT CGC CAG GCT CCA GGA AAA GGT CTG GAG TGG ATA TCA GTT ATT GAT ACT CGT GGT GCC ACA TAC TAT GCA TAC GTG AAG GGC CGA

TTC ACC ATC TCC AGA GAC AAT GCC AAG AAC TCC TTG TAT CTT CAA ATG AAC AGC CTG AGA GCC GAG GAC ACT GCT GTG TAT TAC TAC GAC AGA CTG GAC TTC TAC TAC GGT ATG GAC TAG GGC ACC GGG ACC GAT TCC TCA

(SEQ ID NO: 10)

Met .__ Glju Phe _G1 and Read SEC. Trp. Val Phe_ Read Val Wing He Read Lys Gly Val Gin. Cys Glu Val Gln Leu Val Gln Be Gly Gly Gly Leu Val Lys Pro Gly Gly Be Leu Arg Leu Be Cys Wing Ala Be Gly Phe Thr Phe Be Ser Phe Ala Met His Trp Val Arg Gln Pro Gly Lys Gly Leu Glu Trp He Ser Val He Asp Thr Arg Gly Wing Thr Tyr Tyr Wing Asp Ser Val Lys Gly Arg

Phe Thr He Be Arg Asp Asn Wing Alys Lys Asn Be Read Tyr Leu Gln Met Asn Be Read Arg Wing Glu Asp Thr Wing Val Tyr Tyr Cys Arg Wing Leu Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Val Val Ser Being Modified Heavy Chain-B 19D12 / 15H12 (SEQ ID NO: 11) ATG GAG TTT GGG ÇTG.AGC TGG GTT TXT CTT GTT GTA ATA TTAAAfVGGTGTC CAG TGT GAG GTT CAG TCT GGG GGA GG GG CCG GG TCC CTG AGA CTC TCC TGT GCA GCC TCT GGA TTC ACC TTC AGT AGTTT GCT ATG CAC TGG GTT CGC CAG GCT CCA GGA AAA GGT CTG GAG ATA TCA GTT ATT GAT ACT CGT GGT GCC ACA TAC TAT GCA GCC TGC TGA ACC ATC TCC AGA GAC AAT GCC AAG AAC TCC TTG TAT CTT CAA ATG AAC AGC CTG AGA GCC GAG GAC ACT GCT GTG TAT TAC TGT GCA AGA CTG GGG AAC TTC TAC TAC GGT ATG GAC GTC TGA GAC ACC GTC ACC GTC TCA

(SEQ ID NO: 12)

yal Phe Leu Val Vala He Leu Lys Gly Val Gln__Cy_s Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ser Gly Phe Thr Be Phe Ala Met His Trp Val Arg Gln Pro Wing Gly Lys Gly Leu Glu Trp He Be Val He Asp Thr Arq Gly Wing Thr Tyr Tyr Wing Asp Be Val Lys Gly Arg Phe Thr He Be Arg Asp Asn Wing Lys Asn Be Leu Tyr Leu Gln Met Asn Be Read Arg Wing Ala Glu Asp Thr Wing Val Tyr Tyr Cys Wing Arg Read Le Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser

The present invention includes embodiments in which the antibody chains placed herein are conservatively substituted with one or more mutations that do not significantly affect antibody binding activity.

Plasmids comprising a CMV promoter operably linked to the 15H12 / 19D12 light chains and heavy chains were deposited in the American Type Culture Collection (ATCC); 10801 University Boulevard; Manassas, Virginia 20110-2209, May 21, 2003. The deposit name and ATCC accession numbers for the plasmids are given below:

(i) CMV-15H12 / 19D12 HCA promoter (γ4) - Deposit name: "15H12 / 19D12 HCA (γ4)"; ATCC Access No: PTA-5214;

(ii) CMV-15H12 / 19D12 HCB promoter (γ4) -

Deposit name: "15H12 / 19D12 HCB (γ4)";

ATCC Access No: PTA-5215;

(iii) CMV-15H12 / 19D12 HCA promoter (γ1) -

Deposit name: "15H12 / 19D12 HCA (γ1)";

ATCC Access No: PTA-5216;

(iv) CMV-15H12 / 19D12 LCC promoter (k) -

Deposit name: "15H12 / 19D12 LCC (/ c)";

ATCC Access No: PTA-5217;

(v) CMV-15H12 / 19D12 LCD promoter (k) -

Deposit name: "15H12 / 19D12 LCD (/ c)";

ATCC Access No: PTA-5218;

(vi) CMV-15H12 / 19D12 LCE promoter (k) -

Deposit name: "15H12 / 19D12 LCE (/ c)";

ATCC Access No: PTA-5219; and

(vii) CMV-15H12 / 19D12 LCF promoter (k) -

Deposit Name: "15H12 / 19D12 LCF (/ c)";

ATCC Access No: PTA-5220.

The present invention includes methods and compositions (e.g.

such as any described herein) comprising anti-IGF1R antibodies and antigen binding fragments thereof comprising any of the light and / or heavy immunoglobulin chains or mature fragments thereof located on any of the preceding ATCC deposited plasmids.

In one embodiment of the invention, an antibody that binds

"specifically" human IGF1R binds with a Kd of about 10 8 M or 10 7 M, or a smaller number; or, in one embodiment of the invention, with a Kd of about 1.28X10'10 M, or a smaller number by Biacore measurement, or with a Kd of about 2.05X10'12 M, or a lower number by

KinExA measurement. In another embodiment, an antibody that "specifically" binds human IGF1R binds exclusively to human IGF1R and no other protein in any specific amount. In one embodiment of the invention, an IGF1R inhibitor that is administered to a patient in a method according to the invention comprises any light chain immunoglobulin and / or a heavy chain immunoglobulin as placed in International Published Application No. WO 5 2002/53596, which is incorporated herein by reference in its entirety. For example, in one embodiment of the invention, the antibody comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID Nos: 2, 6, 10, 14, 18, 22, 47 and 51, as set forth in WO 2002/53596, and / or a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID Nos: 4, 8, 12, 16, 20, 24, 45 and 49, as placed in WO 2002/53596. In one embodiment of the invention, the antibody comprises a heavy and / or light chain selected from that of antibody 2.12.1; 2.13.2; 2.14.3; 3.1.1; 4.9.2; and 4.17.3 in WO 2002/53596.

In one embodiment of the invention, an IGF1R inhibitor that

may be administered to a patient in a method according to the invention comprises any light chain immunoglobulin and / or a heavy chain immunoglobulin as placed in International Published Application No. WO 2003/59951, which is incorporated herein by reference. in its entirety. For example, in one embodiment of the invention, the antibody comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NoS: 54, 61 and 65, as set forth in WO 2003/59951, and / or a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID Nos: 69, 75, 79 and 83, as set forth in WO 2003/59951.

In one embodiment of the invention, an IGF1R inhibitor that may be administered to a patient in a method according to the invention comprises any light chain immunoglobulin and / or a heavy chain immunoglobulin as placed in the International Application. Published No. WO 2004/83248, which is incorporated herein by reference in its entirety. For example, in one embodiment of the invention, the antibody comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID Nos: 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141 and 143, as set forth in WO 2004/83248, and / or a heavy chain variable region comprising a selected amino acid sequence from the group consisting of SEQ ID NOs: 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140 and 142 as placed in WO 2004/83248. In one embodiment of the invention, the antibody comprises a light and / or heavy chain selected from that of PINT-6A1; PINT-7A2; PINT-7A4; PINT-7A5; PINT-7A6; PINT-8A1; PINT-9A2; PINT-11A1; PINT-11A2; PINT-11A3; PINT-11A4; PINT-11A5; PINT-11A7; PINT-12A1; PINT-12A2; PINT-12A3; PINT-12A4 and PINT-12A5 in WO 2004/83248.

In one embodiment of the invention, an IGF1R inhibitor that may be administered to a patient in a method according to the invention comprises any light chain immunoglobulin and / or a heavy chain immunoglobulin as placed in the International Published Application. WO 2003/106621, which is incorporated herein by reference in its entirety. For example, in one embodiment of the invention, the antibody comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID Nos: 8-12, 58-69, 82-86, 90, 94, 96, 98 as placed in WO 2003/106621 and / or a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID Nos: 7, 13, 70-81, 87, 88, 92, as set forth in WO 2003/106621.

In one embodiment of the invention, an IGF1R inhibitor that may be administered to a patient in a method according to the invention comprises any light chain immunoglobulin and / or a heavy chain immunoglobulin as placed in the International Application. Published No. WO 2004/87756, which is incorporated herein by reference in its entirety. For example, in one embodiment of the invention, the antibody comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 2, as set forth in WO 2004/87756, and / or a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 1 as placed in WO 5 2004/87756.

In one embodiment of the invention, an IGF1R inhibitor that may be administered to a patient in a method according to the invention comprises any light chain immunoglobulin and / or a heavy chain immunoglobulin as placed in International Application 10. Published No. WO 2005/16970, which is incorporated herein by reference in its entirety. For example, in one embodiment of the invention, the antibody comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 6 or 10, as set forth in WO 2005/16970, and / or a chain variable region. comprising an amino acid sequence of SEQ ID NO: 2 as placed in WO 2005/16970.

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises an immunoglobulin heavy chain variable region comprising an amino acid sequence selected from the group consisting of:

1 grlgqawrsl rlscaasgft fsdyymswir qapgkglewv syisssgstr 51 dyadsvkgrf tisrdnakns Iylqmnslra edtavyycvr dgvettfyyy 101 yygmdvwgqg ttvtvssast csvsvstsfpspclsvcl

1 vqllesgggl vqpggslrls ctasgftfss yamnwvrqap gkglewvsai 51 sgsggttfya dsvkgrftis rdnsrttlyl qmnslraedt avyycakdlg 101 wsdsyyyyyg mdvwgqgttv tvss: SEQ

1 gpglvkpset Isltctvsgg sisnyywswi rqpagkglew igriytsgsp

51 nynpslksrv tmsvdtsknq fslklnsvta adtavyycav tifgvviifd 101 ywgqgtlvtvss (SEQ ID NO: 15)

1 evqllesggg Ivqpggslrl scaasgftfs syamswvrqa pgkglewvsa 51 isgsggityy adsvkgrfti srdnskntly Iqmnslraed tavyycakdl 101 gygdfyyyyy gmdvwgqgtt vtvss

1 pglvkpsetl sltctvsggs issyywswir qppgkglewi gyiyysgstn 51 ynpslksrvt isvdtsknqf slklssvtaa dtavyycart ysssfyyygm 101 dvwgqgttvt vss (SEQ ID N0: 17)

1 evqllesggg Ivqpggslrl scaasgftfs syamswvrqa pgkglewvsg

51 itgsggstyy adsvkgrfti srdnskntly Iqmnslraed tavyycakdp 101 gttvimswfd pwgqgtlvtv ss (SEQ IDN0: 18)

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises an immunoglobulin light chain variable region comprising an amino acid sequence selected from the group consisting of:

1 asvgdrvtft crasqdirrd Igwyqqkpgk apkrliyaas rlqsgvpsrf 51 sgsgsgteft Itisslqped fatyyclqhn nyprtfgqgt eveiirtvaa 101 psvfifppsd eqlksgtasv vcllnnfypr eakvqw

(SEQ ID NO: 19)

1 diqmtqfpss Isasvgdrvt itcrasqgir ndlgwyqqkp gkapkrliya 51 asrlhrgvps rfsgsgsgte ftltisslqp edfatyyclq hnsypcsfgq 101 gtkleik (SEQ ID N0: 20)

1 sslsasvgdr vtftcrasqd irrdlgwyqq kpgkapkrli yaasrlqsgv 51 psrfsgsgsg teftltissl qpedfatyyc Iqhnnyprtf gqgteveiir (SEQ ID NO: 21)

1 diqmtqspss Isasvgdrvt itcrasqgir sdlgwfqqkp gkapkrliya 51 asklhrgvps rfsgsgsgte ftltisrlqp edfatyyclq hnsypltfgg

101 gtkveik (SEQ ID NO: 22)

1 gdrvtitcra sqsistflnw yqqkpgkapk Ilihvasslq ggvpsrfsgs 51 gsgtdftlti sslqpedfat yycqqsynap Itfgggtkve ik (SEQ ID NO: 23)

1 ratlscrasq svrgrylawy qqkpgqaprl Iiygassrat gipdrfsgsg

51 sgtdftltis rlepedfavf ycqqygsspr tfgqgtkvei k (SEQ ID NO: 24)

In one embodiment of the invention, the anti-IGF1R antibody comprises a light chain immunoglobulin, or a mature fragment thereof (i.e. lacking signal sequence), or variable region thereof, comprising the amino acid sequence of:

1 mdmrvpaqll gllllwfpga rcdiqmtasp sslsasvqdr vtitcrasgg 51 irndlawvQQ kpqkapkrli vaass / qsqv psrfsqsqsq teftltissl 101 qpedfatwc lahnsvpwtí qqqtkveikr tvaapsvsqsqvqsqsqvqsqsqvqs

201 Itlskadyek hkvyacevth qglsspvtks fnrgec;

(SEQ ID NO: 25)

1 mdmrvpaqll gllllwfpga rcdiqmtqsp sslsasvqdr vtftcrasad 51 irrdlawvQQ kpqkapkrli vaasr / gsqv psrfsqsqsq teftltissl 101 qpedfatwc Iahnnvprtf qqqteveiif pva

151 taswcllnn fypreakvqw kvdnalqsgn sqesvteqds kdstyslsst 201 Itlskadyek hkvyacevth qglsspvtks fnrgec;

(SEQ ID NO: 26)

1 mdmrvpaqll gllllwfpga rcdiqmtqsp sslsasvqdr vtitcrasqg 51 / md / qwyqq kpqkapkrli vaass / qsqv psrfsqsqsq teftltissl

101 qpedfatwc lahnsvpytf qqqtkleikr tvaapsvfif ppsdeqlksg 151 taswcllnn fypreakvqw kvdnalqsgn sqesvteqds kdstyslsst 201 Itlskadyek hkvyacevth qglsspvtks fnrgec;

(SEQ ID NO: 27)

or

1 mdmrvpaqll gllllwfpga rcdiqmtqfp sslsasvqdr vtitcrasqg 51 imdlamaa kpqkapkrli vaasrlhrav psrfsqsqsq teftltissl 101 qpedfatwc lahnsypcsf aaatkleikr tvaapsvfif ppsdeqlksg 151 taswcllnn fypreakvqw kvdnalqsgn sqesvteqds kdstyslsst 201 Itlskadyek hkvyacevth qglsspvtks fnrgec (SEQ ID N0: 28).

In one embodiment of the invention, the signal sequence is

acids 1-22 of SEQ ID NoS: 25-28. In one embodiment of the invention, the mature variable region is underlined. In one embodiment of the invention, the CDRs are in bold / italic font. In one embodiment of the invention,

The anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises one or more CDRs (e.g., 3 light chain CDRSs) as set forth above.

In one embodiment of the invention, the anti-IGF1R antibody comprises a heavy chain immunoglobulin or a mature segment thereof (i.e. lacking signal sequence), or a variable region thereof, comprising the amino acid sequence of:

1 mefglswvfl vaiikgvqcq vqlvesggql vkpqqslrls caasaftfsd 51 yymswirgap gkgIewvsw sssastivva dsvkgrítis rdnaknslvl 101 gmnslraedt aWvcarWr fIewllvvvv vvamd \> WGGG ttvtvssast 151 kgpsvfplap csrstsesta algclvkdyf pepvtvswns galtsgvhtf 201 pavlqssgly slsswtvps snfgtqtytc nvdhkpsntk vdktverkcc

251 vecppcpapp vagpsvflfp pkpkdtlmis rtpevtcvvv dvshedpevq 301 fnwyvdgvev hnaktkpree qfnstfrws vltwhqdwl ngkeykckvs 351 nkglpapiek tisktkgqpr epqvytlpps reemtknqvs Itclvkgfyp 401 sdiavewesn gqpennyktt ppmldsdgsf flyskltvdk srwqqgnvfs 451 csvmhealhn hytqkslsls pgk;

(SEQ ID NO: 29)

1 mefglswvfl vaiikgvgcg aglvesgggl vkpggslrls caas aftfsd 51 wmswirgap gkglewvsw sssastrdva dsvkarftis rdnaknslvl 101 gmnslraedt awvcvrdav ettfvvvvva mdvwgggttv svfsvsvsvgvg

201 Iqssglyslssvvtvpssnfgtqtytcnvd hkpsntkvdk tverkccvec 251 psvflfppkp kdtlmisrtp ppcpappvag evtcvvvdvs hedpevqfnw 301 yvdgvevhna ktkpreeqfn stfrvvsvlt vvhqdwlngk eykckvsnkg 351 mtknqvsltc Ipapiektis ktkgqprepq vytlppsree Ivkgfypsdi 401 avewesngqp ennykttppm skltvdksrw qqgnvfscsv 451 mhealhnhyt Idsdgsffly qkslslspgk;

(SEQ ID NO: 30)

1 mefglswlfl vailkqvqce vqllesqqql vgpqqslrls caasqfffss 51 uamswvrqap qkqlewvsa / sasaastvva dsvkgríüs rdnskntlvl 101 gmnslraedt avvvcakqys sgwvvvvvva mdvw qqqttv tvssastkqp 151 svfplapcsr stsestaalg clvkdyfpep vtvswnsgal tsgvhtfpav 201 Iqssglysls svvtvpssnf gtqtytcnvd hkpsntkvdk tverkccvec

251 psvflfppkp kdtlmisrtp ppcpappvag evtcvvvdvs hedpevqfnw 301 yvdgvevhna ktkpreeqfn stfrvvsvlt vvhqdwlngk eykckvsnkg 351 mtknqvsltc Ipapiektis ktkgqprepq vytlppsree Ivkgfypsdi 401 avewesngqp ennykttppm skltvdksrw qqgnvfscsv 451 mhealhnhyt Idsdgsffly qkslslspgk;

(SEQ ID NO: 31) or

1 mefglswlfl vailkqvqce vqllesqqql vgpqqslrls ctasgftfss 51 yamnwvrqap qkqlewvsa / sgsggttfva dsvkgrftis rdnsrttlvl 101 gmnslraedt awvcakdlg wsdsdqvv tv>

151 svfplapcsr stsestaalg clvkdyfpep vtvswnsgal tsgvhtfpav 201 Iqssglyslssvvtvpssnfgtqtytcnvd hkpsntkvdk tverkccvec 251 psvflfppkp kdtlmisrtp ppcpappvag evtcvvvdvs hedpevqfnw 301 yvdgvevhna ktkpreeqfn stfrvvsvlt vvhqdwlngk eykckvsnkg 351 mtknqvsltc Ipapiektis ktkgqprepq vytlppsree Ivkgfypsdi

401 avewesngqp ennykttppm Idsdgsffly skltvdksrw qqgnvfscsv 451 mhealhnhyt qkslslspgk (SEQ ID NO: 32).

In one embodiment of the invention, the signal sequence is amino acids 1-19 of SEQ ID NoS: 29-32. In one embodiment of the invention, the natural variable region is underlined. In one embodiment of the invention, the anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises one or more CDRs (e.g., 3 light chain CDRs) as set forth above.

In one embodiment of the invention, the anti-IGF1R antibody comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID Nos: 19-24 shared with a heavy chain variable region comprising an amino acid sequence of any one. of SEQ ID Nos: 13-18, respectively. In one embodiment of the invention, the anti-IGF1R antibody comprises a mature light chain variable region comprising an amino acid sequence of any of SEQ ID Nos: 25 or 26 shared with a heavy chain variable region comprising an amino acid sequence of any of In one embodiment of the invention, the anti-IGF1 R antibody comprises a mature light chain variable region comprising an amino acid sequence of either SEQ ID Nos: 27 or 28 shared with a variable region. heavy chain comprising an amino acid sequence of any of SEQ ID Nos: 31 or 32.

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises an immunoglobulin heavy chain, or mature 2.12.1 fx fragment or variable region (SEQ ID NO: 33) (in one embodiment of the invention, the conductive sequence is underlined; in one embodiment of the invention, the CDRs are bold / italicized fonts):

1 mefglswvfl vaiikqvqcq vqlvesgggl vkpggslrls caasgftfsd 51 yymswirqap gkglewvsy / 'sssgstrdya dsvkgrftis rdnaknslyl 101 qmnslraedt avyycardgv ettfyyyyyg mdv tvv

151 svfplapcsr stsestaalg clvkdyfpep vtvswnsgal tsgvhtfpav 201 Iqssglyslssvvtvpssnfgtqtytcnvd hkpsntkvdk tverkccvec 251 psvflfppkp kdtlmisrtp ppcpappvag evtcvvvdvs hedpevqfnw 301 yvdgvevhna ktkpreeqfn stfrvvsvlt vvhqdwlngk eykckvsnkg 351 mtknqvsltc Ipapiektis ktkgqprepq vytlppsree Ivkgfypsdi

401 avewesngqp ennykttppm Idsdgsffly skltvdksrw qqgnvfscsv 451 mhealhnhyt qkslslspgk In one embodiment of the invention, the anti-IGF1R antibody or antigen binding fragment of this invention comprises amino acids 20-470 of 2.12.1 fx (SEQ ID NO: 33)

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises mature 2.12.1 fx heavy chain variable region (amino acids 20-144 or SEQ ID NO: 33; SEQ ID NO: 34):

qqlvesgggl vkpggslrls caasgftfsd yymswirqap gkglewvsyi sssgstrd- ya dsvkgrftis rdnaknslyl qmnslraedt avyycardgv ettfyyyyyg mdvwgqgttv tvss In an antibody-IG embodiment, an anti-IGR

or antigen-binding fragment thereof of the invention comprises an immunoglobulin light chain, or mature 2.12.1 fx fragment or variable region (SEQ ID NO: 35) (in one embodiment of the invention, the leader sequence is underlined; in one embodiment of the invention). CDRs are in bold / italic fonts):

1 mdmrvpaqll gllllwfpga rcdiqmtqsp sslsasvgdr vtitcrasqd 51 / DRR / gwyqq kpgkapkrli yaasrlqsgv psrfsgsgsg teftltissl 101 qpedfatyyc Iqhnnyprtt gqgtkveikr tvaapsvfif ppsdeqlksg 151 taswcllnn fypreakvqw kvdnalqsgn sqesvteqds kdstyslsst 201 Itlskadyek hkvyacevth qglsspvtks fnrgec

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises 2.12.1 fx amino acids 23-236 (SEQ ID NO: 35).

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises mature 2.12.1 fx light chain variable region (amino acids 23-130 of SEQ ID NO: 35; SEQ ID NO: 36):

diqmtqsp sslsasvgdr vtitcrasqd irrdlgwyqq kpgkapkrli yaasrlqsgv psrfsgsgsg teftltissl qpedfatyyc Iqhnnyprtf gqgtkveikr In one embodiment of the invention, an anti-IGF1R antibody,

or antigen-binding fragment thereof, comprises or consists of a light chain immunoglobulin chain comprising or consisting of 2.12.1 fx amino acids 23-236 (SEQ ID NO: 35) and a heavy chain immunoglobulin chain comprising or consisting of 2.12.1 fx 20-470 amino acids (SEQ ID NO: 33).

In one embodiment of the invention, the anti-IGF1R antibody, or antigen binding fragment thereof, comprises one or more 2.12.1 fx CDRs (e.g., 3 light chain CDRs and / or 3 heavy chain CDRs), as stated above.

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof, or antigen binding fragment thereof, comprises a humanized 7C10 immunoglobulin light chain variable region; version 1 (SEQ ID NO: 37):

1 dvvmtqspls Ipvtpgepas iscrssqsiv hsngntylqw ylqkpgqspq 51 Iliykvsnrl ygvpdrfsgs gsgtdftlki srveaedvgv yycfqgshvp 101 wtfgqgtkve ik

In one embodiment of the invention, an anti-IGF1R antibody,

or antigen binding fragment thereof of the invention comprises a humanized immunoglobulin 7C10 light chain variable region; version

2 (SEQ ID NO: 38):

1 divmtqspls Ipvtpgepas iscrssqsiv hsngntylqw ylqkpgqspq 51 Iliykvsnrl ygvpdrfsgs gsgtdftlki srveaedvgv yycfqgshvp

101 wtfgqgtkve ik

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises a humanized 7C10 immunoglobulin heavy chain variable region; version 1 (SEQ ID NO: 39):

1 qvqlqesgpg Ivkpsetlsl tctvsgysit ggylwnwirq ppgkglewmg 51 yisydgtnny kpslkdriti srdtsknqfs Iklssvtaad tavyycaryg 101 rvffdywgqg tlvtvss

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises the humanized immunoglobulin 7C10 heavy chain variable region; version 2 (SEQ ID N0: 40): 1 qvqlqesgpg Ivkpsetlsl tctvsgysit ggylwnwirq ppgkglewig 51 yisydgtnny kpslkdrvti srdtsknqfs Iklssvtaad tavyycaryg 101 rvffdywgqg tlvtvss

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises the humanized immunoglobulin 7C10 heavy chain variable region; version 3 (SEQ ID NO: 41):

1 qvqlqesgpg Ivkpsetlsl tctvsgysis ggylwnwirq ppgkglewig 51 yisydgtnny kpslkdrvti svdtsknqfs Iklssvtaad tavyycaryg 101 rvffdywgqg tlvtvss

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises immunoglobulin A12 heavy chain variable region (SEQ ID NO: 42):

1 evqlvqsgae vkkpgssvkv sckasggtfs syaiswvrqa pgqglewmgg 51 iipifgtany aqkfqgrvti tadkststay melsslrsed tavyycarap

101 Irflewstqd hyyyyymdvw gkgttvtvss

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises immunoglobulin A12 light chain variable region (SEQ ID NO: 43):

1 sseltqdpav svalgqtvri tcqgdslrsy yaswyqqkpg qapvlviygk

51 nnrpsgipdr fsgsssgnta sltitgaqae deadyycnsr dnsdnrlifg 101 ggtkltvls or

(SEQ ID NO: 105):

1 sseltqdpav svalgqtvri tcqgdslrsy yatwyqqkpg qapilviyge

51 nkrpsgipdr fsgsssgnta sltitgaqae deadyycksr dgsgqhlvfg 101 ggtkltvlg

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises immunoglobulin 1A heavy chain variable region (SEQ ID NO: 44):

1 evqlvqsggg Ivhpggslrl scagsgftfr nyamywvrqa pgkglewvsa 51 igsgggtyya dsvkgrftis rdnaknslyl qmnslraedm avyycarapn 101 wgsdafdiwg qgtmvtvss

optionally including one or more of the following mutations: R30, S30, N31, S31, Y94, H94, D104, E104.

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises immunoglobulin light chain variable region 1A (SEQ ID NO: 45):

1 diqmtqspss Isasvgdrvt itcrasqgis swlawyqqkp ekapksliya 51 asslqsgvps rfsgsgsgtd ftltisslqp edfatyycqq ynsypptfgp 101 gtkvdik

optionally including one or more of the following mutations:

P96, I96, P100, Q100, R103, K103, V104, L104, D105, E105

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises single chain antibody (fv) 8A1 (SEQ ID NO: 46):

1 evqlvqsgae vkkpgeslti sckgpgynff nywigwvrqm pgkglewmgi

51 iyptdsdtry spsfqgqvti svdksistay Iqwsslkasd tamyycarsi 101 rycpggrcys gyygmdvwgq gtmvtvssgg ggsggggsgg ggs-

seltqdp

151 avsvalgqtv ritcqgdslr syyaswyqqk pgqapvlviy gknnrpsgip 201 drfsgsssgn tasltitgaq aedeadyycn srdssgnhvv fgggtkltvl

251g

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises single chain (fv) 9A2 antibody (SEQ ID NO: 47):

1 qvqlvqsgae vrkpgasvkv scktsgytfr nydinwvrqa pgqglewmgr

51 isghygntdh aqkfqgrftm tkdtststay melrsltfdd tavyycarsq 101 wnvdywgrgt Ivtvssgggg sggggsgggg salnfmltqp hsvsespgkt 151 siasnyvqwy qqrpgssptt vifednrrps vtisctrssg gvpdrfsgsi 201 dtssnsaslt isglktedea dyycqsfdst nlwfgggtk vtvlg In one embodiment of the invention, an anti-IGF1R antibody,

or fragment of this invention comprising antigen-binding single chain anti body (fv) 11A4 (SEQ ID N0: 48): 1 evqllesggg Ivqpggslrl scaasgftfs syamswvrqa pgkglewvsa 51 isgsggstyy adsvkgrfti srdnskntly Iqmnslraed tavyycassp 101 yssrwysfdp wgqgtmvtvs sggggsgggg sggggsalsy eltqppsvsv 151 spgqtatitc sgddlgnkyv swyqqkpgqs pvlviyqdtk rpsgiperfs 201 gsnsgniatl tisgtqavde adyycqvwdt gtvvfgggtk Itvlg

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises single chain antibody (fv) 7A4 (SEQ ID NO: 49):

1 evqlvqsgae vkkpgeslti sckgsgynff nywigwvrqm pgkdlewmgi 51 iyptdsdtry spsfqgqvti svdksistay Iqwsslkasd tamyycarsi

101 rycpggrcys gyygmdvwgq gtmvtvssgg gssggggsgg ggs-

seltqdp

151 avsvalgqtv ritcrgdslr nyyaswyqqk pgqapvlviy gknnrpsgip 201 drfsgsssgn tasltitgaq aedeadyycn srdssgnhmv fgggtkltvl 251 g

In one embodiment of the invention, an anti-IGF1R antibody, or antigen binding fragment thereof of the invention comprises single chain (fv) 11A1 antibody (SEQ ID NO: 50):

1 evqlvesggg vvqpgrslrl scaasgftfs dfamhwvrqi pgkglewlsg 51 Irhdgstayy agsvkgrfti srdnsrntvy Iqmnslraed tatyycvtgs

101 gssgphafpv wgkgtlvtvs sggggsgggg sggggsalsy vltqppsasg 151 sgsnsnigty tvnwfqqlpg tapklliysn tpgqrvtisc nqrpsgvpdr 201 fsgsksgtsa slaisglqse deadyycaaw ddslngpvfg ggtkvtvlg In one embodiment of the invention, an anti-IGF1R antibody or antigen-binding fragment thereof of the invention comprises single chain antibody (fv) 7A6 (SEQ ID NO: 51)

1 evqlvqsgae vkkpgeslti sckgsgynff nywigwvrqm pgkglewmgi 51 iyptdsdtry spsfqgqvti svdksistay Iqwsslkasd tamyycarsi 101 rycpggrcys gyygmdvwgq gtlvtvssgg ggsggggsgg ggsseltqdp 151 avsvalgqtv ritcqgdslr syytnwfqqk pgqapllvvy aknkrpsgip

In one embodiment of the invention, an anti-IGF1R antibody, or an antigen binding fragment thereof (for example, a heavy chain or light chain immunoglobulin) of the invention comprises one or more complementarity determining regions (CDRs) selected from the group consisting of: sywmh (SEQ ID NO: 52); einpsngrtnynekfkr (SEQ ID NO: 53); grpdyygsskwyfdv (SEQ ID NO: 54); rssqsivhsnvntyle (SEQ ID NO: 55);

kvsnrfs (SEQ ID NO: 56); and

fqgshvppt (SEQ ID NO: 57).

In one embodiment of the invention, an anti-IGF1R antibody, or an antigen binding fragment thereof of the invention comprises a heavy chain immunoglobulin variable region selected from the group consisting of:

1 qvqlvqsgae vvkpgasvkl sckasgytft sywmhwvkqr pgqglewige 51 inpsngrtny nqkfqgkatl tvdkssstay mqlssltsed savyyfargr 101 pdyygsskwy fdvwgqgttv tvs (SEQ) ID: 0

1 qvqfqqsgae Ivkpgasvkl sckasgytft sylmhwikqr pgrglewigr

51 idpnnwtkf nekfkskatl tvdkpsstay melssltsed savyycarya 101 ycrpmdywgq gttvtvss (SEQ ID NO: 59);

1 qvqlqqsgae Ivkpgasvkl sckasgytft sywmhwvkqr pgqglewige 51 inpsngrtny nekfkrkatl tvdkssstay mqlssltsed savyyfargr

101 pdyygsskwy fdvwgagttv tvs (SEQ ID NO: 60);

1 qvqlqqsgae Imkpgasvki sckatgytfs sfwiewvkqr pghglewige 51 ilpgsggthy nekfkgkatf tadkssntay mqlssltsed savyycargh 101 syyfydgdyw gqgtsvtvss (SEQ ID N0: 61);

1 qvqlqqpgsv Ivrpgasvkl sckasgytft sswihwakqr pgqglewige 51 ihpnsgntny nekfkgkatl tvdtssstay vdlssltsed savyycarwr 101 ygspyyfdyw gqgttltvss (SEQ ID N0: 62);

1 qvqlqqpgae Ivkpgasvkl sckasgytft sywmhwvkqr pgrglewigr 51 idpnsggtky nekfkskatl tvdkpsstay mqlssltsed savyycaryd 101 yygssyfdyw gqgttltvss (SEQ ID N0: 63);

1 qvqlvqsgae vvkpgasvkl sckasgytft sywmhwvkqr pgqglewige

51 inpsngrtny nqkfqgkatl tvdkssstay mqlssltsed savyyfargr 101 pdyygsskwy fdvwgqgttv tvs (SEQ ID NO: 64);

1 qvqlqqsgae Ivkpgasvkl sckasgytft sywmhwvkqr pgqglewige 51 inpsngrtny nekfkrkatl tvdkssstay mqlssltsed savyyfargr

101 pdyygsskwy fdvwgagttv tvss (SEQ ID NO: 65);

1 qvqlvqsgae vvkpgasvkl sckasgytft sywmhwvkqr pgqglewige 51 inpsngrtny nqkfqgkatl tvdkssstay mqlssltsed savyyfargr 101 pdyygsskwy fdvwgqgttv tvss

(SEQ ID NO: 66);

1 qvqlqqsgae Ivkpgasvkl sckasgytft sywmhwvkqr pgrglewigr 51 idpnsggtky nekfkskatl tvdkpsstay mqlssltsed savyycaryd 101 yygssyfdyw gqgttvtvss (SEQ ID N0: 67)

1 qiqlqqsgpe Ivrpgasvki sckasgytft dyyihwvkqr pgeglewigw 51 iypgsgntky nekfkgkatl tvdtssstay mqlssltsed savyfcargg 101 kfamdywgqg tsvtvss (SEQ ID NO: 68);

1 qvqlqqsgae Ivkpgasvkl sckasgytft sywmhwvkqr pgqglewige

51 inpsngrtny nekfkrkatl tvdkssstay mqlssltsed savyyfargr 101 pdyygsskwy fdvwgagttv tvss (SEQ ID NO: 69);

1 qiqlqqsgpe Ivkpgasvki sckasgytft dyyinwmkqk pgqglewigw 51 idpgsgntky nekfkgkatl tvdtssstay mqlssltsed tavyfcarek 101 ttyyyamdyw gqgtsvtvsa (SEQ ID N0: 70);

1 vqlqqsgael mkpgasvkis ckasgytfsd ywiewvkqrp ghglewigei 51 Ipgsgstnyh erfkgkatft adtssstaym qlnsltseds gvyyclhgny 101 dfdgwgqgtt Itvss (SEQ ID N0: 71); and

1 qvqllesgae Imkpgasvki sckatgytfs sfwiewvkqr pghglewige

51 ilpgsggthy nekfkgkatf tadkssntay mqlssltsed savyycargh 101 syyfydgdyw gqgtsvtvss (SEQ ID NO: 72);

and / or a light chain immunoglobulin variable region selected from the group consisting of:

1 dvlmtqipvs Ipvslgdqas iscrssqiiv hnngntylew ylqkpgqspq 51 Iliykvsnrf sgvpdrfsgs gsgtdftlki srveaedlgv yycfqgshvp 101 ftfgsgtkle ikr (SEQ ID N0: 73)

1 dvlmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspk

51 Iliykvsnrfsgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID NO: 74);

1 dvlmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspr 51 Iliykvsnrf sgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp

Ptfgggtkle ikr (SEQ ID NO: 75);

1 dvlmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspk 51 Iliykvsnrf sgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID N0: 76)

1 dvlmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspr 51 Iliykvsnrfsgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID N0: 77)

1 dvlmtqtpls Ipvslgdqas iscrssqxiv hsngntylew ylqkpgqspk 51 Iliykvsnrf sgvpdrfsgs gsgtdftlki srveaedlgv yycfqgshvp 101 xtfgggtkle ikr (SEQ ID N0: 78

1 dwmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspk

51 Iliykvsnrf sgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID NO: 79);

1 dwmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspr 51 Iliykvsnrfsgvpdrfsgsgagtdftlrisrveaedlgiyycfqgshvp

Ptfgggtkle ikr (SEQ ID NO: 80);

1 dvlmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspr 51 Iliykvsnrf sgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr

(SEQ ID NO: 81);

1 dvlmtqipvs Ipvslgdqas iscrssqiiv hnngntylew ylqkpgqspq 51 Iliykvsnrf sgvpdrfsgs gsgtdftlki srveaedlgv yycfqgshvp 101 ftfgsgtkle ikr (SEQ ID NO: 82)

1 dvlmtqtpls Ipvslgdqas iscrfsqsiv hsngntylew ylqksgqspk 51 Iliykvsnrf sgvpdrfsgs gsgtdftlki srveaedlgv yycfqgshvp 101 rtfgggtkle ikr (SEQ ID N0: 83)

1 dvlmtqtpls Ipvslgdqas iscrssqsiv hsnvntylew ylqkpgqspk

51 Iliykvsnrf sgvpdrfsgs gsgtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID NO: 84);

1 dwmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspk 51 Iliykvsnrfsgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID N0: 85);

1 elvmtqtpls Ipvslgdqas iscrssqtiv hsngdtyldw flqkpgqspk 51 Iliykvsnrf sgvpdrfsgs gsgtdftlki srveaedlgv yycfqgshvp 101 ptfgggtkle ikr (SEQ ID N0: 86)

1 dvlmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspk

51 Iliykvsnrf sgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID NO: 87);

1 dwmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspr 51 Iliykvsnrf sgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp

Ptfgggtkle ikr (SEQ ID NO: 88);

1 dvlmtqtpvs Isvslgdqas iscrssqsiv hstgntylew ylqkpgqspk 51 Iliykisnrf sgvpdrfsgs gsgtdftlki srveaedlgv yycfqashap 101 rtfgggtkle ikr

(SEQ ID NO: 89);

1 dvlmtqtpls Ipvslgdqas isckssqsiv hssgntyfew ylqkpgqspk 51 Iliykvsnrfsgvpdrfsgs gsgtdftlki srveaedlgv yycfqgship 101 ftfgsgtkle ikr (SEQ ID N0: 90);

1 dieltqtpls Ipvslgdqas iscrssqsiv hsngntylew ylqkpgqspk 51 Iliykvsnrf sgvpdrfsgs gsgtdftlki srveaedlgv yycfqgshvp 101 ytfggggtkle ikr (SEQ ID N0: 91)

1 dvlmtqtpls Ipvslgdqas iscrssqsiv hsnvntylew ylqkpgqspk

51 Iliykvsnrf sgvpdrfsgs gsgtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID NO: 92);

1 dwmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspr 51 Iliykvsnrf sgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID N0: 93);

1 dvlmtqtpls Ipvslgdqas iscrssqsiv hsnvntylew ylqkpgqspk 51 Iliykvsnrfsgvpdrfsgs gsgtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID N0: 94)

1 dwmtqtpls Ipvslgdpas iscrssqsiv hsnvntylew ylqkpgqspk

51 Iliykvsnrf sgvpdrfsgs gagtdftlri srveaedlgi yycfqgshvp 101 ptfgggtkle ikr (SEQ ID NO: 95);

1 dvlmtqtpls Ipvslgdqas iscrsnqtil Isdgdtylew ylqkpgqspk 51 Iliykvsnrf sgvpdrfsgs gsgtdftlki srveaedlgv yycfqgshvp

Ptfgggtkle ikr (SEQ ID NO: 96);

1 dvlmtqtpls Ipvslgdqas iscrssqtiv hsngntylew ylqkpgqspk 51 Iliykvtnrfsgvpdrfsgs gsgtdftlki srveaedlgv yycfqgthap 101 ytfgggtkle ikr

(SEQ ID NO: 97); and

1 dvlmtqtpls Ipvslgdqas iscrssqsiv hsngntylew ylqkpgqspk 51 Iliysissrf sgvpdrfsgs gsgtdftlki srvqaedlgv yycfqgshvp 101 ytfgggtkle ikr (SEQ ID N0: 98)

The scope of the present invention includes methods in which a patient is administered an insulin-1 receptor antibody-like growth factor (IGF1R) anti-growth factor in which the antibody variable region is linked to an immunoglobulin constant region. In one embodiment of the invention, the light chain variable region is linked to a constant chain region k. In one embodiment of the invention, the heavy chain variable region is linked to a constant region γ1, γ2, γ3 or γ4. Any of the immunoglobulin variable regions set forth herein in embodiments of the invention may be linked to any of the preceding constant regions.

In addition, the scope of the present invention comprises any antibody or antibody fragment comprising one or more 5 CDRs (3 light chain CDRs and / or 3 heavy chain CDRs) and / or framework regions of any of the chain immunoglobulin. light chain or heavy chain immunoglobulin as placed herein as identified by any of the methods employed in Chothia et al., J. Mol. Biol. 186: 651-663 (1985); Novotny and Haber, Proc. Natl. Acad. Know. USA 82: 4592-4596 (1985) 10 or Kabat, E.A. et al., Sequences of Proteins of Immunoloaical Interest. National Institutes of Health, Bethesda, Md., (1987)).

In one embodiment of the invention, the term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous antibody population, that is, individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in smaller quantities. As mentioned above, monoclonal antibodies to be used according to the present invention may be produced by the first hybridoma method described by Kohler, et al. (1975) Nature 20 256: 495.

In one embodiment of the invention, a bispecific or bifunctional antibody is a hybrid artificial antibody having two different heavy / light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods, including fusion of hybridomas or binding of Fab 'fragments. See, for example, Songsivilai, et al. (1990) Clin. Exp. Immunol. 79: 315-321, Kostelny, et al. (1992) J Immunol. 148: 1547-1553. In addition, bispecific antibodies may be formed as "diabodies" (Holliger, et al., (1993) PNAS USA 90: 6444-6448), or as "Janusins" (Traunecker, et al., (1991) EMBO J. 30 10: 3655-3659 and Traunecker, et al. (1992) Int. J. Cancer Suppl. 7: 51-52).

In one embodiment of the invention, the term "fully human antibody" refers to an antibody that comprises human immunoglobulin protein sequences only. An all-human antibody may contain nonhuman, for example, murine, carbohydrate chains if produced in a mouse, a mouse cell, or a hybridoma derived from a mouse cell. Similarly, "mouse antibody" refers to an antibody that comprises mouse immunoglobulin protein sequences only.

The present invention includes "chimeric antibodies" means an antibody comprising a variable region of the present invention fused to or chimerized with an antibody region (e.g., constant region) of another human or non-human species (e.g., mouse, horse, rabbit, dog, cow, chicken). Antibodies can be used to modulate IGF1R expression or activity in non-human species.

"Single stranded Fv" or "sFv" antibody fragments have the Vh and Vl domains of an antibody, in which these domains are present in a single polypeptide chain. Generally, the sFv polypeptide additionally comprises a polypeptide linker between the Vh and Vl domains that enable the sFv to form the desired antigen binding structure. Techniques described for the production of single chain antibodies (United States Patent Nos. 5,476,786; 5,132,405 and 4,946,778) can be adapted to produce anti-IGF1R-specific single chain antibodies. For a review of sFv see Pluckthun in The Pharmacology of Monoclonal Antibodies. vol. 113, Rosenburg and Moore eds. Springer-Verlag, N.Y., pp. 269-315 (1994).

In one embodiment of the invention, "disulfide stabilized Fv fragments" and "dsFv" refer to immunoglobulins comprising a heavy chain variable (Vh) and a light chain variable (V1) that are linked by a disulfide bridge.

Antigen binding fragments within the scope of the present invention also include F (ab) 2 fragments which may be produced by enzymatic cleavage of an IgG by, for example, pepsin. Fab fragments may be produced by, for example, reducing F (ab) 2 with dithiothreitol or mercaptoethylamine. A Fab fragment is a V1-Cl chain attached to a Vh-Chi chain by a disulfide bridge. An F (ab) 2 fragment is two Fab fragments which, in turn, are attached by two disulfide bridges. The Fab portion of an F (ab> 2) molecule includes a portion of the Fc region between which the disulfide bridges are located.

An Fv fragment is a region of Vl or Vh.

Depending on the amino acid sequences of the constant domain of their heavy chains, immunoglobulins may be transferred to different classes. There are at least five major classes of immunoglobulin: IgA, IgD, IgE, IgG and IgM, and several of these can be further divided into subclasses (isotypes), for example, lgG-1, lgG-2, lgG- 3 and IgG-4; IgA-1 and IgA-2. As discussed herein, any such antibody or antigen binding fragment thereof is within the scope of the present invention.

Anti-IGF1R antibodies and fragments of the invention may

also conjugate to a chemical moiety. The chemical moiety may be, among others, a polymer, radionuclide or cytotoxic factor. In one embodiment of the invention, the chemical moiety is a polymer that increases the half-life of the antibody molecule in an individual's body. Suitable polymers include, but are not limited to, polyethylene glycol (PEG) (e.g., PEG with a molecular weight of 2kDa, 5kDa, 10kDa, 12kDa, 20kDa, 30kDa or 40kDa), dextran and monomethoxypolyethylene glycol (mPEG). Lee, et al. (1999) (Bioconj. Chem. 10: 973-981) describe PEG conjugated single chain antibodies. Wen, et al. (2001) (Bioconj. 25 Chem. 12: 545-553) describe PEG-conjugating antibodies that are attached to a radiometal chelator (diethylenetriaminpentaacetic acid (DT-PA)).

Antibodies and antibody fragments of the invention may also be conjugated to labels such as 99Tc190Y, 111In, 32P, 14C, 125I, 3H, 131I, 11C, 15O, 13N, 18F, 35S, 51Cr, 57To, 226Ra, 60Co, 59Fe, 57Se, 152Eu, 67CU, 217Ci, 211At, 212Pb, 47Sc, 109Pd, 234Th, and 40K, 157Gd, 55Mn, 52Tr and 56Fe.

Antibodies and antibody fragments of the invention may also be conjugated to fluorescent or chromiluminescent labels, including fluorophores such as rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanate, phycoitrin, phycocyanin, allophycocyanin, o-phthalaldehyde, fluorescamine, 152I, dansil, umbellferone, 5 luciferin, luminal label, isoluminal label, an aromatic acridinium ester label, an imidazole label, an acridimine salt label, an oxalate ester label, an aequorin tag, 2,3-dihydrophthalazinedione, biotin / avidin, spin tags and stable free radicals.

Antibodies and antibody fragments may also be

conjugated to a cytotoxic factor such as dipteria toxin, Pseudomonas aeruginosa A chain exotoxin, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins and compounds (e.g. fatty acids), diantin proteins, Phytoiacca americas cane proteins PAPI, PAPII, and PAP-S, momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, mitogellin, restrictocin, fenomycin, and enomycin.

Any method known in the art for conjugating antibody molecules and fragments of the invention to the various moieties may be employed, including those methods described by Hunter, et al. (1962) Nature 144: 945; David, et al. (1974) Biochemistry 13: 1014; Pain, et al. (1981) J. Immunol. Meth 40: 219; and Nygren, J. (1982) Histochem. and Cythem. 30: 407. Methods for antibody conjugation are conventional and well known in the art.

In one embodiment of the invention, an IGF1R inhibitor is

BMS-577098

H \ -NH

HN HO '· "/

(W /) or AEW-541 (

) or

Methods of treating or preventing any medical condition set forth herein by administering these agents are within the scope of the present invention.

In one embodiment of the invention, an IGF1R inhibitor is any of the pyrimidine derivatives placed on WO 03/48133, for example, comprising the core structure:

HN K

4 H

N R

\ Q

Methods of treating or preventing any medical disorder posed herein by administering these agents are within the scope of the present invention.

In one embodiment of the invention, an IGFTR inhibitor is any of the tyrosine kinase inhibitors placed on WO 03/35614, for example, comprising the core structure:

H

(for example) ■

Methods of treating or preventing any medical disorder posed herein by administering these agents are within the scope of the present invention.

In one embodiment of the invention, an IGF1R inhibitor is any of the tyrosine kinase inhibitors placed on WO 03/35615, for example, comprising the core structure:

10

Methods of treating or preventing any medical disorder posed herein by administering these agents are within the scope of the present invention.

In one embodiment of the invention, an IGF1R inhibitor is any of the tyrosine kinase inhibitors placed on WO 03/35616, for example, comprising the core structure:

B

(per

example or

) ·

Methods of treating or preventing any medical disorder posed herein by administering these agents are within the scope of the present invention.

In one embodiment of the invention, an IGF1R inhibitor is any of the tyrosine kinase inhibitors placed on WO 03/35619, for example, comprising the core structure:

Methods of treating or preventing any medical disorder posed herein by administering these agents are within the scope of the present invention.

In one embodiment of the invention, an IGF1R inhibitor is a

multi-target kinase inhibitor which also inhibits, for example, VEGF-2R, Kit, FLT3 and / or PDGFR, for example, SU-11248 (eg, sunitinib malate) or Bay43-9006 (sorafenib). Methods of treatment or any medical disorder posed herein by the administration of these agents are within the scope of the present invention.

In one embodiment of the invention, an IGF1R inhibitor is any of the compounds set forth in WO 03/24967, for example, comprising the core structure: Methods of treating or preventing any medical disorder posed herein by the administration of these agents are within the scope of the present invention.

In one embodiment of the invention, an IGF1R inhibitor is any of the compounds placed on WO 04/30625, for example, comprising the core structure:

10

Methods of treating or preventing any medical disorder posed herein by administering these agents are within the scope of the present invention.

In one embodiment of the invention, an IGF1R inhibitor is any of the compounds placed on WO 04/30627, for example, comprising the core structure:

Methods of treating or preventing any medical disorder posed herein by the administration of these agents are within the scope of the present invention.

In one embodiment of the invention, an IGF1R inhibitor is any of the heteroaryl aryl ureas as placed in WO 00/35455, for example, comprising the core structure: Methods of treating or preventing any medical disorder posed herein by administration of these agents are within the scope of the present invention.

In one embodiment of the invention, a GF1R inhibitor is any of the peptides placed on WO 03/27246. Methods of treating or preventing any medical disorder posed herein by administering these agents are within the scope of the present invention.

^ i ^ uai ^ uci ucnvauu Je 4-

amino-5-phenyl-7-cyclobutyl-pyrrolo [2,3-d] pyrimidine described in PCT International Publication No. WO 02/92599. Methods of treating or preventing any medical disorder posed herein by administering these agents are within the scope of the present invention.

Antibody Generation Any suitable method can be used to induce an antibody.

antibody with the desired biological properties to inhibit IGF1R. It is desirable to prepare monoclonal antibodies (mAbs) from various mammalian hosts, such as mice, rodents, primates, humans, etc. Descriptions of techniques for preparing such monoclonal antibodies can be found in, for example, Stites, et al. (eds.) BASIC AND CLINICAL IMMUNOLOGY (4th ed.) Lange Medical Publications, Los Altos, CA, and references cited herein; Harlow and Lane (1988) ANTIBODIES: A LABORATORY MANUAL CSH Press; Goding (1986) M0N0Cl0NAL ANTIBODIES: PRINCIPLES AND PRACTICE (2nd ed.) Academic Press, New York, NY. Thus, monoclonal antibodies can be obtained by a variety of techniques familiar to those skilled in the art. Typically, spleen cells from an animal immunized with a desired antigen are immortalized, commonly by fusion with a myeloma cell. See, Kohler and Milstein (1976) Eur. J. Immunol. 6: 511-519. Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods known in the art. See, for example, Doyle, et al (eds. 1994 and periodic supplements) CELL AND TISSUE CULTURE: LABORATORY PROCEDURES, John Wiley and Sons, New York, NY. Colonies from single immortalized cells are classified for antibody production of the desired antigen specificity and affinity, and production of monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, DNA sequences encoding a monoclonal antibody or binding fragment can be isolated by classifying a human B cell DNA library according to, for example, the general protocol outlined by Huse, et al. (1989) Science 246: 1275-1281.

Other suitable techniques involve selection of antibody libraries on phage or similar vectors. See, for example, Huse et al., Science 246: 1275-1281 (1989); and Ward et al., Nature 341: 544-546 (1989). The polypeptides and antibodies of the present invention may be used with or without modification, including chimeric or humanized antibodies. Frequently, polypeptides will be labeled by the union, either covalently or non-covalently, of a substance that provides a detectable signal. A wide variety of labels and conjugation techniques are known and are reported extensively in both scientific and patent literature. As discussed above, suitable labels include radionuclides, enzymes, substrates, cofactors, inhibitors, fluorescent moieties, chemiluminescent moieties, magnetic particles, and the like. Patents teaching the use of such labels include United States Patent Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241. Also, recombinant immunoglobulins may be produced, see Cabilly United States Patent No. 4,816,567; and Queen et al. (1989) 5 Proc. Nat'l Acad. Know. USA 86: 10029-10033; or produced in transgenic mice, see Mendez et al. (1997) Nature Genetics 15: 146-156. Additional methods for producing humanized chimeric antibodies and human antibodies are well known in the art. See, for example, United States Patent No. 5,530,101, published to Queen et al, United States Patent No. 5,225,539, published to Winter et al, United States Patent No. 4,816,397, published to Boss et al, all of which are incorporated by reference in their entirety.

Mammalian cell lines available as hosts for antibody expression of the invention are well known in the art, and include many available American Type Culture Collection (ATCC) immortalized cell lines. These include, but are not limited to, Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, Newborn hamster kidney cells (BHK), Monkey kidney cells (COS), Hepatocellular human carcinoma (e.g., Hep G2), A549 cells, 3T3 cells, HEK-293 cells, and a number of other cell lines. Mammalian host cells include human, mouse, rat, dog, monkey, pig, goat, bovine, horse, and hamster cells. Particularly preferred cell lines are selected by determining which cell lines have high levels of expression. Other cell lines that can be used are insect cell lines, such as Sf9 cells, amphibian cells, bacterial cells, plant cells, and fungal cells. When recombinant expression vectors encoding the heavy chain or antigen binding portion thereof, light chain and / or antigen binding portion thereof are introduced into mammalian host cells, antibodies are produced by culturing the host cells for a period of time sufficient to allow expression of the antibody in the host cells, or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown.

Antibodies may be recovered from the culture medium using standard protein purification methods. Additionally, the expression of antibodies of the invention (or other portions thereof) of production cell lines can be enhanced using a number of known techniques. For example, the glutamine synthetase gene expression system (the GS system) is a common approach for enhancing expression under certain conditions. The GS system is discussed in whole or in part in conjunction with European Patents Nos. 216 846, 0 256 055, and 0 10 323 997, and European Patent Application No. 89303964.4.

It is similarly that antibodies expressed by different cell lines or in transgenic animals will have different glycosylation from each other. However, all antibodies encoded by the nucleic acid molecules provided herein, or comprising the amino acid sequence provided herein, are part of the present invention, regardless of the glycosylation of antibodies.

A convenient plasmid system useful for producing an anti-IGF1R antibody, or antigen binding fragment thereof, is placed in United States Published Application No. US2005 / 0176099 (see also W02005 / 47512).

Other Chemotherapy

The present invention provides methods for treating or preventing any of the medical disorders posed herein by administering a therapeutically acceptable dosage or amount of an anti-IGF1R antibody, or antigen binding fragment thereof, for example. as placed herein in combination with an additional chemotherapeutic agent (e.g., an anticancer chemotherapeutic agent, and / or an antiemetic chemotherapeutic agent). For example, additional chemotherapeutic agents include erlotinib, dasatanib, nilotinib, decatanib, panitu-mumab, amrubicin, oregovomab, lep-etu ("paclitaxel arrested in Ioposome-Easy To Use"), nolatrexed, azd2171, batumab, ofum, zanolimumab, edotecarin, tetrandrina, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilin

15

mumab, gossypol, Bio 111, 131-Ι-ΤΜ-601, ALT-110, ΒΙΟ 140, CC 8490, cyclengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR, KRX-0402, Iucanthine, LY 317615 neuradiab, vitespan, Rta 744, Sdx 102, thalampanel, delay, Xr 311, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, or AT-9263.

Abraxane is an injectable suspension of paclitaxel protein binding particles comprising a bound form of paclitaxel albumin with an average particle size of approximately 130 nanometers. Abraxane is supplied as a sterile white to yellow lyophilized powder for reconstitution with 20 mL 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single use vial contains 100 mg paclitaxel and approximately 900 mg human albumin. Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. Abraxane is solvent free and free of chromophore (polyoxyethylated castor oil).

In one embodiment of the invention, an antibody or antigen-binding fragment thereof of the invention is provided in association with ro-

midepsin

(FK-228;

ADS-100380,

CG-781

CG-1521 SB-556629

JNJ-16241199) or vorinostat (SAHA;

OH

) ■

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with etoposide (VP-16;

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with In one embodiment of the invention an antibody or antigen binding fragment thereof of the invention is provided in association with any compound described in the application. United States Patent No. US 2004 / 0209878A1 (for example, comprising a structure

of core represented by

) or doxorubicin

‘Cm

H

(om o) including Caelyx or Doxil® (injection

liposome doxorubicin HC; Ortho Biotech Products L.P; Raritan, NJ). Doxyl® comprises doxorubicin in STEALTH® liposome carriers which are composed of sodium N- (carbonyl methoxypolyethylene glycol 2000) -1,2-distearoyl-sn-glycero-3-phosphoethaneamine (MPEG-DSPE); fully hydrogenated phosphatidylcholine (HSPC), and cholesterol.

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with 5-deoxy-5-fluorouridine ().

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with vincrine (

) ·

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with proteins.

/

V N.

mozolomide (

) any CDK1 inhibitor such as ZK-

Hn

Selicycl (R-roscovitine) from MEK, such as PD0325901 (p), AZD-

6244; capecitabine (5'-deoxy-5-fluoro-N - [(pentyloxy) carbonyl] cytidine); or L-Glutamic acid, N - [4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-2-one

5-yl) ethyl] benzoyl] -,

dislike,

GO-r Na +

; Pemetrexed disodium heptahydrate).

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with

Stork et al., J. Am. Chem. Soc. 93 (16): 4074-4075 (1971); Beisler et al., J. Med. Chem. 14 (11): 1116-1117 (1962)), irinotecan (

Pharmacia & Upjohn Co .; Kalamazoo, M1); a combination of irinotecan, 5-fluorouracil and leucovorin; or PEG-labeled irinotecan.

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with the FOLFOX (oxaliplatin (

THE

xp, 2V

/ Y / o '-.> 0

H

), together with fluorouracil

Hn

in

H..N

infusion

acid

folinic

"W-1 -

(un (Chaouche et al., Am. J. Clin.

Oncol. 23 (3): 288-289 (2000); de Gramont et al., J. Clin. Oncol. 18 (16): 2938-2947 (2000)).

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with a

antiestrogen such as ^ (tamoxifen;

sold as Nolvadex® by AstraZeneca Pharmaceuticals LP; Wilmington,

, CH3 OCH2CH2N

// \ / Í CH3

/ G cN_

GH2

CH2CI

CH2COOH HO-C — COOH

I

CH2COOH

CH2CI \ _ /

DE), or - (toremifene citrate;

referred to as Fareston® by Shire US, Inc .; Florence, KY).

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with a:

aromatase inhibitor such as

XH3 -CH3

(anas-

zole; sold as Arimidex® by AstraZeneca Pharmaceutieals LP; Wil-

CH3o

mington, DE),

Aromasin® by Pharmacia

(exemestane; sold as Corporation; Kalamazoo, M1), or

(letrozole; sold as Femara by Novartis Pharmaceuticals Corporation; East Hanover, NJ).

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with an estrogen such as DES (diethylstilbestrol),

Warner Chilcott, Inc .; Rockaway, NJ), or conjugated estrogen (sold 10

as Premarin® by Wyeth Pharmaceuticals Inc .; Philadelphia1 PA).

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with anti-angiogenesis agents including bevacizumab (Avastin®; Genentech; San Francisco, CA), the anti-VEGFR-2 antibody IMC-1C11. , other inhibitors of

VEGFR such as: CHIR-258 (), any

inhibitors placed on W02004 / 13145 (for example, understanding

giving the core structural formula: * '),

W02004 / 09542 (for example, comprising the structural formula of

2 / -I * N

R X ~ ^ Ju A,

R1

WOOO / 71129 (e.g. comprising

Core structural formula: R), W02004 / 09601

(for example, comprising the structural formula of

R2X-

core:

), W02004 / 01059 (e.g., comprising the core structural formula: B w)

W001 / 29025 (for example, comprising the structural formula of

RF

10

core:

Z 'W á3

), W002 / 32861 (for example, comprising the formula

Core structural:

z h

THE

) or as placed

W003 / 88900 (for example, comprising the structural formula of

M Qt N> HH

core (

); 3- [5- (methylsulfonylpiperadinamethyl) -

HN '

; PTK / ZK; CPG-79787;

); and the VEGF trap (AVE-0005), a soluble decoil receptor comprising portions of VEGF receptors 1 and 2.

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in combination with an LHRH (Lutenization Hormone Release Hormone) agonist, such as the [D-Ser (Bu t) acetate salt. ) 6, Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser (But) -Leu-Arg-Pro-Azgly-NH 2 acetate [CsgH84Ni8O4- (C2H4O2) x,

touch; sold as Zoladex® by AstraZeneca UK Limited; Macclesfield,

sold as Eligard® by Sanofi-Synthelabo Inc .; New York, NY) or

"(triptorelin pamoate; sold with

Trelstar® by Pharmacia Company, Kalamazoo, M1).

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with suninin or sunitinib malate.

where x = 1 to 2.4];

(goserelin accepted)

(leuprolide acetate;

ΓΛ F.

5th

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with a

(fear

xiprogesterone acetate; sold as Provera® by Pharmacia & Upjohn

Co .; Kalamazoo1 Ml), v (hydroxypropyl)

gesterone caproate; 17 - ((1-Oxohexyl) oxy) pregn-4-ene-3,2 () -dione), megestrol acetate or progestins.

In one embodiment of the invention, an antibody or antigen-binding fragment thereof of the invention is provided in association with modulators.

OH

(raloxifene; sold as Evista by Eli Lilly and Company; Indianapolis, IN).

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with an antiandrogen including, but not limited to: (bicalutamide; sold as CA-SODEX® by AstraZeneca Pharmaceuticals LP; Wilmington, DE);

(flutamide; 2-methyl-N- [4-nitro-3- (trifluoromethyl) phenyl] propanamide; sold as Eulexin® by Schering Corporation;

worth, NJ); (nilutamide; sold as

Nilandron® by Aventis Pharmaceuticals Inc .; Kansas City, MO) and

(Megestrol acetate; sold as Megace® by Bristol-Myers Squibb).

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in combination with one or more inhibitors that antagonize the action of the EGF or HER2 Receptor, including, but not limited to, CP-724714 TAK-165.

272 (

); HKI-

); OSI-774 ("° ^ Xi

erlotinib, Hidalgo et al., J. Clin. Oncol. 19 (13): 3267-3279 (2001)), Lapatanib

HLC M

(°. GVV2016; Rusnak et al., Molecu-

Cancer Therapeutics 1: 85-94 (2001); N- {3-Chloro-4 - [(3-fluorobenzyl) oxy] phenyl} -6- [5 - ({[2- (methylsulfonyl) ethyl] amino} methyl) -2-furyl] -4-quinazolinamine; PCT Application No. WO99 / 35146), Canertinib (CI-1033;

; Erliehman et al., Caneer Res. 61 (2): 739-48 (2001); Smaill et al., J. Med. Chem. 43 (7): 1380-97 (2000)), ABX-EGF Antibody (Abgenix, Inc.; Freemont, CA; Yang et al., Cancer Res. 59 (6): 1236-43 (1999); Yang et al Crit Rev Oncol Hematol 38 (1): 17-23

(2001)), erbitux (United States Patent No. 6,217,866; IMC-C225, ketetimab; Imclone; New York, NY), EKB-569 (

Wissner et al., J. Med. Chem. 46 (1): 49-63 (2003)), PKI-166

(à; CGP-75166), GW-572016, any

anti-EGFR antibody and any anti-HER2 antibody.

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with:

(canvasfarnib; Sarasar; Schering-Plow; Kenilworth, NJ). In another embodiment, one of the following FPT inhibitors is provided in association with an antibody or antigen-binding fragment thereof of the invention:

; or Other FPT inhibitors, which may be provided in combination with an antibody or antigen binding fragment thereof of the invention.

CN

43 (20): 3587-95 (2000); Dancey et al., Curr. Pharm. Off 8: 2259-2267 (2002); (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-thienylsulfonyl) -1H-1, 4-benzodiazepine)) and R155777 (tipifarnib; Garner et al., Drug Metab. Dispos. 30 (7): 823-30 (2002); Dancey et al., Curr. Pharm. Des. 8: 2259-2267 (2002). (B) -6- [amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl-1) -1-methyl-2 (1 H ) -quinolinone];

sold as Zarnestra®; Johnson &Johnson; New Brunswick, NJ).

In one embodiment of the invention, an antibody or fragment

includes BMS-214662

Chem.

Cl

The antigen binding number of this invention is provided in association with

OH O-

O L

H2N

'N'

H

> r

HO

, Kk

(Amifostine); m

(NVP-LAQ824; Atadja et al., Cancer Research 64: 689-695 (2004)),

(suberoyl hydroxamic acid analyte),

(Valproic acid; Michaelis et al., Mol. Pharmacol.

.OH

65: 520-527 (2004)),

H

(trichostatin

THE),

(2002)),

(FK-228; Furumai et al., Cancer Research 62: 4916-4921

\

βτ J

- Ç . Ir0

N

H

(SU11248; Mendel et al., Clin. Cancer

Res. 9 (1): 327-37 (2003)), 9006; sorafenib),

(BAY43- (KRN951 $? OvJ- ^ o

CHo

CH,

I 3

0

(Aminoglutethimide);

Hn

Il

ν. THE

(Amsacrine);

dex by AstraZeneea Pharmaceutieals LP; Wilmington1 DE); Asparaginase; Bacillus Calmette-Guerin (BCG) vaccine (Garrido et al., Cytobios.

° y * \! ■.

'ήι

I

«V H CH1 O O

■ ^ ΙΓϊΥΓ · ^: ^

* = CH. HO- CHa * 8

Ihh u>

OH I I

■ IV »

hT>

90 (360): 47-65 (1997));

U0 - »ς -—- JZ, H

obX NH.

r * -H "·

„Air / o ral o r ° O

JyAt Vva-- V -Yi * - VV ^ VJ "Tjv S XjL ü Ts

t.M Il T

(Bleomy-

IlK ^ Mla

cin);

(Buserelin); HsC — Ο

(Busulfan; 1,4-butanediol, dimethanesulfonate; sold as Busulfex® by ESP Pharma, Inc.; Edison, New Jersey);

<

H3N O — k

(Carboplatin; sold as Paraplatin® by Bristol-

Cl '

N "°

N.J.

Cl

Myers Squibb; Princeton, NJ); HO

(Carmustine);

(Chlorambucil);

NH,

I 2

H7N-Pt-CI

I

Cl

(Cisplatin);

-tV'0

I xN, NH

Xl

(Cladribine);

OH,

Cl

(Cyclophosphamide); (Cyproterone); HO OH

(Cytarabine);

ιπ,

carbazine);

(Gives-

(Dactinomycin);

(Daunorrubicin);

CH,

Η0Λ \

OH

Η

(Diethylstilbestrol); OH

(Fludrocortisone);

(Fluoxymesterone);

H_N N 2 H

(Hydroxyurea);

Xl

(Idarrubicin);

Cl

(Ifosfami- CH3SO3H

in);

Pharmaceuticals

H..N. .N

(Imatinib; sold as Gleevec by Novartis Corporation; East Hanover, NJ);

(Leucovorin);

Oji κ.

V

His TrpSer TyrLeuLeuArg

.CH „

THE

Il

N

H I, NJ.

(Leuprolide);

/ CO

Xl

(Levamisole);

(Lomustine);

CH,

Cl

(CKX2CH8JiN- (Cy) -

(Mechorethamine);

NH2

I

CH2 --- C - * - COOH

η (Melpha-

lan; sold as Alkeran® by Celgene Corporation; Warren1 NJ); HS.

At

THE

/

+0 ”

(Mesna);

(Methotrexate); (Mitomicin);

Ck .Cl

Cl

(Mitotane;

(Mitoxantrone;

OH

(Nilutamide;

octreotide

; Katz et al., Clin Pharm. 8 (4): 255-73 (1989); sold as LAR® Depot; by Novartis Pharm. Corp; E. Hanover, NJ); edotreotide (labeled or unlabelled yttrium-90); oxaliplatin (

THE

Pt

/

.0—0

N

O-C

I

THE ; sold as Eloxatin® by Sa-PO3HNa

NH2 -CHa-CH2-C-OH. 5Η20

nofi-Synthelabo Inc .; New York, NY); PO3HNa (Pami-

dronate; sold as Aredia® by Novartis Pharmaceuticals Corporation;

HOCH2

East Hanover, NJ); Nipent®

per

(Pentostatin; sold co-Supergen; Dublin, CA);

(Plicamicin);

(Porfimer; sold as Photofrin® by Axcan Scandipharm Inc .; Birmingham, AL);

CHo

THE

H3Cn

CH,

(Procarbazine); HO ^ .0

HO

s Cfca-

(Raltitrexed); Rituximab (sold

as Rituxan by Genentech1 Inc .; South San Francisco, CA);

OH

CH2OH

HO

OH

HO HN ^

Ύ

N = O

XH,

(Teniposide);

The

(Streptozocin);

(Testosterone);

Hn

-N

>

N

Hzn N 'u

(Thalidomide); (Thioguanine);

H, C CH:

N

(Tiotepa);

(Tretinoin);

(Vindesine) or 13-cis-acid In one embodiment of the invention, an antibody or antigen-binding fragment thereof of the invention is provided in combination with one or more of any of: phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecapto-5 purine, deoxycoformicin, calcitriol, valrubicin, mithramicin, vinblastine, vinorelbine, razoxin, marimastat, COL-3, neovastatine, BMS-27-29 endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, oxyphene, spironolactone, finasteride, trastuzumab, denileukin, diftitox, gefitinib, bortezimel, bortezimel, paclitaxel BMS-247550 (see, for example, Lee et al., Clin. Cancer Res. 7: 1429-1437 (2001)), BMS-310705, droloxifene (3-hydroxy tamoxifen), 4-hydroxy tamoxifen, pipendoxyfen, ERA-923, arz oxyphene, fulvestrant, acolbifene, Iasofoxifene (CP-336156), oxyphene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584 (Thomas et al., Semin On-15 col. 30 (3 Suppl 6): 32-8 (2003)), the humanized anti-VEGF Bevacizumab antibody, VX-745 (Haddad, Curr Opin. Investig. Drugs 2 (8): 1070-6 (2001)), PD 184352 (Sebolt-Leopold, et al. Nature Med. 5: 810-816 (1999)), any hydroxyethyl) -rapamycin, CCI-779 (; temsirolimus;

Sehgal et al., Med. Res. Rev., 14: 1-22 (1994); Elit, Curr. Opin. Investigation

RAD001

(

);

BC-210 LY293646 (VIahos et al., J. Biol. Chem. 269 (7): 5241-5248 (1994)), wortmannin, BAY-43-9006 (Wilhelm et al., Curr. Pharm. Des 8: 2255-2257

(2002)), ZM336372, L-779,450, any Raf inhibitor described in Lowinger et al., Curr. Pharm Des. 8: 2269-2278 (2002); flavopyridol (L86-8275 / HMR 1275; Senderowicz, Oncogene 19 (56): 6600-6606 (2000)) or UCN-01 (7-hydroxy staurosporine; Senderowicz, Oncogene 19 (56): 6600-6606 (2000)).

In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with one or more of any of the compounds set forth in United States Patent 5,656,655, which describes EGFR heteroaryl substituted stiryl inhibitors; United States Patent 5,646,153, which discloses carbocyclic and heterocarbocyclic aryl heteroaryl bis mono and / or bicyclic bis inhibitors EGFR and PDGFR; United States Patent 5,679,683, which discloses EGFR inhibiting tricyclic pyrimidine compounds; United States Patent 5,616,582, which discloses quinazoline derivatives having receptor tyrosine kinase inhibitory activity; in Fry et al., Science 265 1093-1095 (1994), which describes a compound having a structure that inhibits EG-FR (see Figure 1 of Fry et al.) in United States Patent 5,196,446, which describes compounds. heteroarylethenediyl or heteroaryethenediylaryl inhibiting EGFR; in Panek, et al., Journal of Pharmacology and Experimental Therapeutics 283: 1433-1444 (1997), which describe a compound identified as PD166285 which inhibits the EGFR, PDGFR, and FGFR families of PD166285 receptors is identified as 6- (2,6-dichlorophenyl) -2- (4- (2-diethylaminoethoxy) phenylarynino) -8-methyl-8H-pyrido (2,3-d) pyrimidin-7-one. In one embodiment of the invention, an antibody or antigen binding fragment thereof of the invention is provided in association with one or more of either: pegylated or non-pegylated interferon alfa-2a, pegylated or non-pegylated interferon alfa-2c pegylated 5 or non-pegylated interferon alfa-1, pegylated or non-pegylated interferon alfa-3, and pegylated, non-pegylated or alpha-interferon albumin consensus interferon.

The term "interferon alfa" as used herein means the highly homologous species-specific protein family that inhibits cell proliferation and modulates immune response. Suitable typical interferon-alpha include, but are not limited to, recombinant interferon alfa-2b, recombinant interferon alfa-2a, recombinant interferon alfa-2c, alpha 2 interferon, interferon alfa-n1 (INS), a mixture alpha interferon, a consensus alpha interferon, such as those described in U.S. Patent Nos. 4,897,471 and 4,695,623 (especially Examples 7, 8 15 or 9 thereof), or interferon alfa-n3, a mixture of Natural alpha interferons.

Interferon afa-2a is sold as ROFERON-A® by Hoffmann-La Roche (Nutley, N.J).

Interferon alfa-2b is sold as INTRON-A® by Schering Corporation (Kenilworth, NJ). The manufacture of interferon alfa 2b is described, for example, in United States Patent No. 4,530,901.

Interferon alfa-n3 is a mixture of natural interferons sold as ALFERON N INJECTION® by Hemispherx Biopharma, Inc. (Philadelphia, PA).

Interferon alfa-n1 (INS) is a mixture of natural interferons sold as WELLFERON® by Glaxo-Smith-Kline (Research Triangle Park, NC).

Consensus Interferon is sold as INFERGEN® by Intermune, Inc. (Brisbane, CA).

Interferon alfa-2c is sold as BEROFOR® by Boehringer Ingelheim Pharmaceutical, Inc. (Ridgefield, CT).

A purified blend of natural interferons is sold as SUMIFERON® by Sumitomo; Tokyo, Japan. The term "pegylated interferon alfa" as used herein means modified conjugates of interferon alfa polyethylene glycol, preferably interferon alfa-2a and alpha-2b. The preferred polyethylene glycol-interferon alfa-2b conjugate is PEG 12000-interferon alfa-2b. The phrases "12,000 molecular weight polyethylene glycol conjugated interferon alpha 5" and "PEG 12000-IFN alpha" as used herein include conjugates as prepared according to the methods of International Application No. WO 95 / 13090 and EP1039922, and containing urethane bonds between the interferon alfa-2a or -2b amino groups and polyethylene glycol having an average molecular weight of 10 12000. The pegylated interferon alfa, PEG 12000-1 FN-alpha-2b , is available from Schering-Plow Research Institute, Kenilworth, NJ

Preferred PEG 12000-interferon alfa-2b can be prepared by attaching a PEG polymer to the histidine residue on the interferon alfa-2b molecule. A single PEG 12000 molecule can be conjugated to free amino groups in an IFN alpha-2b molecule via a urethane bond. This conjugate is characterized by the fixed molecular weight of PEG 12000. PEG 12000-IFN alfa-2b conjugate can be formulated as a lyophilized powder for injection.

Pegylated interferon alfa-2b is sold as PEG-INTRON® by Schering Corporation (Kenilworth, NJ).

Pegylated Interferon-alpha-2a is sold as PEGASYS® by Hoffmann-La Roche (Nutley, N.J).

Other interferon alpha conjugates may be prepared by coupling an interferon alpha to a water soluble polymer. A non-limiting list of such polymers includes other polyalkylene oxide homopolymers such as polypropylene glycols, polyoxyethylenated polyols, their copolymers and block copolymers thereof. As an alternative to polyalkylene oxide based polymers, effectively non-antigenic materials such as dextran, polyvinylpyrrolidones, polyacrylamides, polyvinyl 30 alcohols, carbohydrate based polymers, and the like may be used. Such interferon alpha-polymer conjugates are described, for example, in United States Patent No. 4,766,106, United States Patent No. 4,917. 888, European Patent Application No. 0 236 987, or 0 593 868, or International Publication No. WO 95/13090. Preferred PEG12000-IFN alpha 2b can be prepared by fixation on a PEG polymer to a histidine residue in the interferon alfa-2b molecule.

Pegylated interferon alfa pharmaceutical compositions

Suitable for parenteral administration may be formulated with a suitable buffer, for example Tris-HCI, acetate or phosphate, such as dibasic sodium phosphate / monobasic sodium phosphate buffer, and pharmaceutically acceptable excipients (e.g. sucrose), carriers (e.g. human plasma albumin), toxicity agents (e.g. NaCl), preservatives (e.g. thimerosol, cresol or benzyl alcohol), and surfactants (e.g. tween or polysorbates) in sterile water for injection. Pegylated interferon alfa can be stored as a lyophilized powder under refrigeration at 2 ° -8 ° C. Reconstituted aqueous solutions are stable when stored at 2-8 ° C and used within 24 hours of reconstitution. See, for example, U.S. Patent Nos. 4,492,537; 5,762,923 and 5,766,582. Reconstituted aqueous solutions may also be stored in pre-filled multidose syringes as those useful for delivery of drugs such as insulin. Typical suitable syringes include systems comprising a pre-filled vial attached to a pen ring, such as NOVOLET® Novo Pen, available from Novo Nordisk, or REDIPEN®, available from Schering Corporation, Kenilworth, NJ. Other syringe systems include a pen-type syringe comprising a glass cartridge containing a diluent and freeze-dried pegylated interferon alpha powder in a separate compartment.

The scope of the present invention also includes methods of treating or preventing a medical condition or disease as set forth herein by administering a composition comprising an anti-IGF1R antibody or antigen binding fragment thereof of the invention. in combination with one or more other anticancer chemotherapeutic agents (for example as described herein), and / or in combination with one or more antiemetics, including, but not limited to, casopitant (GIaxoSmithKIine), Netupitant (MGI-HeIsinn) and others NK-1 receptor antagonists, palono-setron (sold as Aloxi by MGI Pharma), aprepitant (sold as Emend by Merck and Co.; Rahway, NJ), diphenhydramine (sold as Bene-dryl® by Pfizer; New York, NY) hydroxyzine (sold as Atarax® by Pfizer;

5 New York, NY), metoclopramide (sold as Reglan® by AH Robins Co ;; Richmond, VA), Iorazepam (sold as Ativan® by Wyeth; Madison, NJ), alprazolam (sold as Xanax® by Pfizer; New York, NY), haloperidol (sold as Haldol® by Ortho-McNeiI; Raritan, NJ), droperidol (Inapsin®), dronabinol (sold as Marinol® by Solvay Pharmaceuticals, Inc.; 10 Marietta, GA), dexamethasone (sold as Decadron® by Merck and Co.; Rahway, NJ), methylprednisolone (sold as Medrol® by Pfizer; New York, NY), prochlorperazine (sold as Compazine® by Glaxosmithkline; Research Triangle Park, NC), granisetron (sold as Kytril® by Hoffmann-La Roche Inc.; Nutley, NJ), ondansetron (sold as Zofran® by 15 Glaxosmithkline; Research Triangle Park, NC), dolasetron (sold as Anzemet® by Sanofi-Aventis; New York, NY), tropisetron (sold as Navoban® by Novartis; East Hanover, NJ).

Compositions comprising an antiemetic are useful for preventing or treating nausea; a common side effect of anticancer chemotherapy. Accordingly, the present invention includes methods for treating or preventing cancer in an individual by administering an antibody or antigen binding fragment thereof of the invention optionally in combination with one or more other chemotherapeutic agents (e.g., as herein described), and / or optionally in combination with one or more antiemetics.

Other side effects of cancer treatment include red and white cell deficiency. Accordingly, the present invention includes compositions comprising an anti-IGF1R antibody or antigen binding fragment thereof optionally in combination with an agent that treats or prevents such deficiency, such as, for example, pegfilgrastim, erythropoietin, epoetin alfa, or darbepoetin alfa. .

Another side effect of anticancer therapy is mucositis. Accordingly, the present invention provides methods and compositions for treating or preventing a medical condition or disease as disclosed herein by administering an anti-IGF1R antibody or antigen binding fragment thereof in combination with an anti-mucositis treatment. . For example, mucositis treatments include Xylocaine® 2% viscous anesthetic gel gargle (lidocaine); or mouthwashes including allopurinol, benzidamine hydrochloride, corticosteroids and / or chamomile.

The present invention further comprises a method for treating or preventing any stage or type of any medical condition set forth herein by administering an antibody or antigen-binding fragment thereof of the invention in combination with such a therapeutic procedure. such as surgical tumorectomy or anticancer radiation treatment; optionally in combination with an additional and / or antiemetic chemotherapeutic agent, for example as set forth above.

The term "in association with" indicates that the components of

A composition of the invention (eg anti-IGF1R antibody or antigen binding fragment thereof, together with docetaxel) may be formulated into a single composition for simultaneous delivery, or separately formulated into two or more compositions. (e.g., a kit). In addition, each component may be administered to an individual at a different time than when the other component is administered; For example, each administration may be given non-simultaneously (for example, separately or sequentially) at various intervals over a given period of time. In addition, the separate components may be administered to an individual by the same or different route (for example, in which an anti-IGF1R antibody is administered parenterally, and gefinib is administered orally).

Therapeutic Methods and Administration

The present invention includes methods for use of an IGF1R inhibitor, which is optionally in combination with an additional chemotherapeutic agent, or a pharmaceutical formulation thereof, for treating or preventing any head and neck cancer, squamous cell carcinoma, multiple myeloma, solitary plasmacytoma, renal cell cancer, retinoblastoma, germ cell tumors, hepatoblastoma, hepatocellular carcinoma, melanoma, rhabidoid kidney tumor, Ewing's sarcoma, chondrosarcoma, any haemotological malignancy (eg, chronic lymphoblastic leukemia 5 , chronic myelomonocytic leukemia, acute lymphoblastic leukemia (eg, T-cell lineage, B-cell precursor lineage), acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, chronic disease Hodgekin's disease, non-Hodgekin's disease, lymphocytic leukemia chronic, 10 chronic myelogenous leukemia, myelodysplastic syndrome, hair cell leukemia, mast cell leukemia, mast cell neoplasm, follicular lymphoma, diffuse large cell lymphoma, lining cell lymphoma, Burkitt's lymphoma, fungoides mycosis, seary syndrome, cutaneous T-cell lymphoma, chronic myeloproliferative disorders), and central nervous system tumors 15 (eg, brain cancer, glioblastoma, non-glioblastoma, brain cancer, meningioma, pituitary adenoma, vestibular schwannoma, a primitive neuroctodermal tumor, medulloblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma and choroid plexus papilloma), myeloproliferative disorder (eg, polycythemia vera, thrombocythemias, idiopathic cancer) thyroid, endometrial cancer, carcinoid cancer, cell tumors germ disease, liver cancer, gastric cancer, gigantism, pituitary adenoma, psoriasis and rhabdoid tumor of the kidney.

Pharmaceutical compositions comprising an IGF1R inhibitor in combination with an additional chemotherapeutic agent (e.g., as set forth above), and a pharmaceutically acceptable carrier are also within the scope of the present invention (e.g., in a single or separately in a kit). Pharmaceutical compositions may be prepared by any methods well known in the art of pharmacy; see, for example, Gilman, et al., (eds.) (1990), The Pharmacological Bases of Therapeutics. 8th Ed., Pergamon Press; A. Gennaro (ed.), Reminaton's Pharmaceutical Sciences. 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania .; Avis, et al., (Eds.) (1993) Pharmaceutical Pharmaceutical Forms: Parenteral Measurements Dekker. New York; Lieberman, et al. (Eds.) (1990) Pharmaeeutieal Dosaae Forms: Tablets Dekker, New York; and Lieberman, et al. (eds.) (1990), Pharmaeeutieal Dosa-5 Forms: Disperse Systems Dekker, New York. In one embodiment of the invention, the antibody is administered to an individual as part of a pharmaceutical composition comprising an antibody, such as LCF / HCA (e.g., 1, 5, 10, 15, 20 or 25 mg / ml), acetate. sodium trihydrate (e.g. 1.8, 2.3 or 3.1 mg / ml), glacial acetic acid (e.g. 0.5, 0.18 10 or 2.2 mg / ml); sucrose (e.g. 50 or 70 mg / ml); and water at a pH of about 5.5.

The term "head and neck cancer" and the like includes any cancer that occurs in the head and neck area of the body, including the oral cavity, pharynx, paranasal cavities; nasal cavity, larynx, and 15 salivary glands (eg, parotid, submandibular, sublingual glands). A common type of head and neck cancer is squamous cell carcinoma that occurs in the head and neck area. Other types of head and neck cancers include salivary gland tumors, melanomas, lymphomas, and sarcomas.

The term "squamous cell carcinoma" (SCC) and the like

It includes any cancer involving the squamous cells of the skin. The term includes any subtype of squamous cell carcinoma including, for example, keratoacanthoma, carcinoma cuniculatum, invasive SCC, in situ SCC, or metastatic SCC.

The term "multiple myeloma" and "solitary plasmacitoma" and the like

includes plasma cell cancer. Solitary plasmacitoma is myeloma in a unique place in the body. The term "multiple myeloma" includes embodiments in which, for example, myeloma cells occur at multiple sites in the body (e.g., bone marrow sites). The term includes any subtype of multiple myeloma including, for example, light chain myeloma, myeloma without secretion.

The term "renal cell carcinoma" and the like is also referred to as kidney cancer, or renal adenocarcinoma, and includes embodiments in which cancer cells are found in any kidney tissues. The term includes, for example, any subtype of renal cell carcinoma including, for example, clean cell carcinomas (mixed with or not granular cells), chromophilic cancers, rhabidoid kidney tumors, chromophobic cancers, oncocytic cancers , collection duct cancers, transitional cell carcinomas and sarcomatoid tumors.

The term "individual" or "patient" includes any organism, preferably a mammal (e.g., primate, dog, horse, rat, mouse, cat, rabbit) and, more preferably, a human being. In one embodiment of the invention, an "individual" or "patient" is an adult human being (e.g., 18 years or older), or a child human being (e.g., under 18 years of age, for example, less than 0, 1, 2, 3, 4, 5, 6, 7,8, 9, or 10 years old).

A pharmaceutical composition containing an IGF1R inhibitor,

which is optionally in association with an additional chemotherapeutic agent may be prepared using pharmaceutically acceptable excipients and additives and conventional techniques. Such pharmaceutically acceptable excipients and additives include compatible non-toxic fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavorants, thickeners, coloring agents, emulsifiers and the like. All routes of administration are contemplated including, but not limited to, parenteral (e.g. subcutaneous, intravenous, intraperitoneal, intramuscular, topical, intraperitoneal, inhalation, intracranial) administration and non-parenteral (e.g. oral) administration. transdermal, intranasal, intraocular, sublingual, rectal and topical).

Injectables may be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in the liquid prior to injection, or as emulsions. Injectables, solutions and emulsions may also contain one or more excipients. Excipients include, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers. and such other agents as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.

In one embodiment of the invention, pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering and chelating agents, and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose Injection and Lactated Ringers. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents at bacteriostatic or fungistatic concentrations should be added to parenteral preparations in multi-dose containers including phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifiers include Polysorbate 80 (TWEEN-80). A sequestering or chelating agent of metal ions includes EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid to adjust pH.

In one embodiment of the invention, preparations for parenteral administration may include sterile injection-ready solutions, sterile dry soluble products, such as post-lyophilisates, ready to be combined with a solvent immediately prior to use, including hypodermic tablets. sterile injection-ready suspensions, sterile dry insoluble products ready to be combined with a vehicle immediately prior to use, and sterile emulsions. The solutions may be either aqueous or non-aqueous.

Implementation of a slow release and sustained release system such that a constant dosage level is maintained is also contemplated here. Briefly, an active agent (e.g. IGF1R inhibitor, which is optionally in association with an additional chemotherapeutic agent) is dispersed in a solid internal matrix, for example, polymethyl methacrylate, polybutyl methacrylate, plasticized or non-plasticized polyvinylchloride. , plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, such as hydrophilic polymers, esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and hydrolyzed partially cross-linked polyvinyl acetate, which is surrounded by an outer polymeric membrane, for example polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, copolymer - ethylene / vinylacetate mers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl acetate vinyl chloride copolymers, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber epichloro rubber ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, which is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate control step. The percentage of active compound contained in such parenteral compositions is highly dependent upon the specific nature thereof, as well as the activity of the IGF1R inhibitor, which is optionally in association with an additional chemotherapeutic agent, and the needs of the individual. The concentration of the IGF1R inhibitor, which is optionally in association with an additional chemotherapeutic agent, may be adjusted such that an injection provides an effective amount to produce the desired pharmacological effect. As discussed below, the exact dose 5 depends on the age, weight and condition of the patient or animal as is known in the art.

In one embodiment of the invention, unit dose parenteral preparations are packaged in an ampoule, vial or needle syringe. All preparations for parenteral administration should be sterile as known and practiced in the art.

In one embodiment of the invention, an IGF1R inhibitor, which is optionally in association with an additional chemotherapeutic agent, is formulated into a lyophilized powder which may be reconstituted for administration as solutions, emulsions and other mixtures. The powder may also be reconstituted and formulated as a solid or gel.

In one embodiment of the invention, the sterile lyophilized powder is prepared by dissolving an IGF1R inhibitor (e.g., an anti-IGF1R antibody), which is optionally in association with an additional chemotherapeutic agent, or a pharmaceutically acceptable derivative. of this in a suitable solvent. The solvent may contain a stability enhancing excipient or other pharmacological components of the powder or reconstituted solution prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbitan, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate, or other such buffer known to those skilled in the art, in one embodiment, at neutral pH. Subsequent sterile filtration of the solution, followed by lyophilization under standard conditions known to those skilled in the art, provides a desired formulation. In one embodiment, the resulting solution will be divided into proportional parts into freeze-dried fractions. Each vial may contain a single dosage or multiple dosages of the IGF1R inhibitor optionally in association with the additional chemotherapeutic agent. Filling vials with a small amount above that you need for one dose or set of doses (for example, about 10%) is acceptable in order to facilitate accurate sampling and accurate dosing. The lyophilized powder may be stored under appropriate conditions, such as at about 4 ° C at room temperature.

Reconstitution of a lyophilized powder with water for injection provides a formulation for use in parenteral administration. In one embodiment of the invention, for reconstitution, the lyophilized powder is added to sterile water, or another suitable carrier. The precise amount depends on the desired therapy being given. Such an amount can be empirically determined.

Administration by inhalation may be provided by the use, for example, of an aerosol containing sorbitan trioleate or oleic acid, for example, together with trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane, or any other biologically compatible propellant gas; It is also possible to use a system containing an IGF1R inhibitor, which is optionally in association with an additional chemotherapeutic agent by itself or associated with a powdered excipient.

In one embodiment of the invention, IGF1R inhibitor, which is

optionally in combination with an additional chemotherapeutic agent, it is formulated in a solid dosage form for oral administration, in one embodiment, in a capsule or tablet. Tablets, pills, capsules and tablets, and the like, may contain one or more of the following 25 ingredients, or compounds of a similar nature: a binder; a lubricant; a diluent; a slider; a disintegrating agent; a coloring agent; a sweetening agent; a flavoring agent; a dampening people; an emetic coating; and a film coating. Examples of Binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polyinylpyrrolidine, povidone, crospovidones, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Slippers include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended in alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents 10 such as saccharin, and any number of sine spray flavorings. Flavoring agents include natural flavorings extracted from plants such as fruits and synthetic mixtures of compounds that produce a pleasant sensation such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

Any of the agents placed herein may be formulated into

a sustained release formulation including liposomal formulations such as vesicular unilamellar liposomes (ULV) and vesicular multilamellar liposomes (MLV), and DepoFoam® particles (Kim et al., Biochim. Biophys. Acta (1983) 728 (3): 339-348; Kim, Methods Neurosci. (1994) 21: 118-131; 25 Kim et al., Anesthesiology (1996) 85 (2): 331-338; Katre et al., J. Pharm. Sci. (1998 ) 87 (11): 1341-1346). A feature of the DepoFoam system is that within each DepoFoam particle, discontinuous internal aqueous chambers connected by a continuous non-concentric network of lipid membranes make a higher volume to aqueous lipid ratio 30 and larger particle diameters. compared to MLV.

Dosage and Administration

The methods of the present invention include administering an IGF1R inhibitor, which is optionally in combination with an additional chemotherapeutic agent, or a pharmaceutical composition thereof. Typically, administration and dosing of such agents is, where possible, according to the table listed in the approved agents 'product information sheet in the Doctors' Desk Reference 2003 (Doctors1 Desk Reference, 57th Ed); Medical Economics Company; ISBN: 1563634457; 57th edition (November 2002), as well as therapeutic protocols well known in the art.

The term "therapeutically effective amount" or "therapeutically effective dosage" means that the amount or dosage of a composition of the invention (e.g., IGF1R inhibitor, such as anti-IGF1R antibody) that will induce a biological or medical response of a tissue, system, individual or host that is being sought by the administrator (such as a researcher, physician or veterinarian) that includes any measurable relief from signs, symptoms and / or clinical signs of cancer (including, for example, inhibition IGF1R activity, such as IGF-I or IGF-II binding or kinase activity), such as head and neck cancer, squamous cell carcinoma, multiple myeloma, solitary plasmacitoma, renal cell cancer, retinoblastoma, tumors germ cell disease, hepatoblastoma, hepatocellular carcinoma, melanoma, rhabidoid kidney tumor, Ewing's sarcoma, chondrosarcoma, any haemotological malignancy (eg leukemi chronic lymphoblastic leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia (eg, T-cell line, B-cell precursor lineage), acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, hodgekin's disease, non-hodgekin's lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, hair cell leukemia, mast cell leukemia, follicular lymphoma, diffuse large cell lymphoma, lymphoma lymphoma, Burkitt's lymphoma, mycosis fungoides, seary syndrome, cutaneous T-cell lymphoma, chronic myeloproliferative disorders), and central nervous system tumors (eg, brain cancer, glioblastoma, non- brain cancer glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, a primitive neuroctodermal tumor, medulloblastoma, astro- cytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma and choroid plexus papilloma), myeloproliferative disorders (eg, polycythemia 5 vera, thrombocythemia, idiopathic myelphibrosis), soft tissue sarcoma, thyroid cancer, carcinoma cancer, endometrial cancer, carcinoma germ cell and liver cancer (eg, tumor growth or proliferation of cancer cells) and / or the prevention, reduction or arrest of cancer progression or metastasis to any degree. For example, in one embodiment, a "therapeutically effective dosage" of any anti-IGF1R antibody; for example, an antibody or antigen binding fragment thereof comprising (a) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 2, and a heavy chain variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 15 12; (b) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 4 and a heavy chain variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 12; (c) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 6 and a heavy chain variable region comprising amino acids 20-137 of 20 SEQ ID NO: 10 or 12; or (d) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 8 and a heavy chain variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 12; or any other anti-IGF1R antibody mentioned herein is from about 0.3 to about 20 mg / kg body weight (e.g., about 0.5 mg / kg body weight, about 1 mg / kg body weight). body weight, about 2 mg / kg body weight, about 3 mg / kg body weight, about 4 mg / kg body weight, about 5 mg / kg body weight, about 6 mg / kg body weight body weight, about 7 mg / kg body weight, about 8 mg / kg body weight, about 9 mg / kg body weight, about 10 mg / kg body weight 30, about 11 mg / kg body weight, about 12 mg / kg body weight, about 13 mg / kg body weight, about 14 mg / kg body weight, about 15 mg / kg body weight, about 16 mg / kg about 17 mg / kg body weight, about 18 mg / kg body weight, about 19 mg / kg body weight, about 20 mg / kg body weight) twice a week, a V ez per week, once every two weeks, once every 3 weeks, or once a month.

Dosage regimens may be adjusted to provide

the optimal desired response (for example, a therapeutic response). For example, a single dose may be administered, or several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the requirements of the therapeutic situation. For example, the dosage may be determined or adjusted by the person skilled in the art (for example, a physician or veterinarian) according to the patient's age, weight, height, past medical history, current medications and potential for cross reaction, allergies. , sensitivities and adverse side effects. It is especially advantageous to formulate parenteral compositions in unit dosage form for ease of administration and uniformity of dosage.

A physician (eg, physician or veterinarian) having expertise in the art can readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, the physician or veterinarian may start with doses of the antibody or antigen binding fragment of the invention employed in the pharmaceutical composition at lower than required levels in order to achieve the desired therapeutic effect and gradually increase the dosage. until the desired effect is achieved. The efficiency of a given dose or treatment regimen of an antibody or combination of the invention may be determined, for example, by determining whether a tumor being treated in the individual shrinks or stops growing. Tumor size can easily be determined, for example, by X-ray, magnetic resonance imaging (MRI), visually in a surgical procedure or manually by palpation. Tumor size and proliferation can also be measured by use of a thymidine PET scan (see, for example, Wells et al., Clin. Oncol. 8: 7-14 (1996)). Generally, PET thymidine scanning includes injection of a radioactive tracer, such as [2-11C] -thymidine, followed by a PET scan of the patient's body (Vander Borght et al, Gastroenterology 101: 794-799, 1991; Vander Borght et al, J. Radiat. Appl. Instrum. Part A, 42: 103-104 (1991)). Other tracers that may be used include [18F] -FDG (18-5 fluorodeoxyglucose), [124IJIUdR (5- [124l] iodo-2'-deoxyuridine), [76BrJBrdUrd (Bromodeoxyuridine), [18F] FLT (3'-deoxy -3'fluorothymidine) or [11C] FMAU (2'-fluoro-5-methyl-1-BD-arabinofuranosyluracil).

For example, the progress of head and neck cancer may be monitored by the doctor or veterinarian by a variety of methods, and the dosage regimen may be changed accordingly. Methods by which to monitor head and neck cancer include, for example, physical examination (eg visual or tactile examination), endoscopy for area observation (eg nasopharyngoscopy, pharyngoscopy, or laryngoscopy), CT scan (CT), magnetic resonance imaging (MRI) scanning, ultrasound examination, positron emission tomography (PET) scans, panorex (jaw x-ray), barium swallow, dental X-ray, sinus X-ray, and radionuclide bone scan.

For example, the progress of squamous cell carcinoma may be monitored by the physician or veterinarian by a variety of methods, and the dosage regimen may be changed accordingly. Methods by which to monitor squamous cell carcinoma include, for example, by interviewing the patient or by physical examination (eg, visual inspection and documentation of any lesion size, shape or other visual qualities).

For example, the progress of multiple myeloma may be monitored by the physician or veterinarian by a variety of methods, and the dosage regimen may be altered accordingly. Methods by which multiple myeloma is monitored include, for example, with a full blood count (CBC), for example, to detect low hematocrit (amaemia), low red blood cell count, low platelet count. , and / or low white blood cell count, bone tuta biopsy, whey protein electrophoresis, bone X-rays to identify fractures and bone lesions, or a chemical profile to detect increased serum calcium, total protein, or abnormal kidney function.

For example, the progress of renal cell carcinoma may be monitored by the physician or veterinarian by a variety of methods, and the dosage regimen may be changed accordingly. Methods by which renal cell carcinoma is monitored include, for example, palpation of the abdomen to detect a mass, complete blood count (CBC), urine test to detect red blood cells, 10-level serum calcium assay to detect elevation, Serum glutamate pyruvate transaminase (SGPT) and alkaline phosphatase assay to detect elevation, urine cytology assay, liver function tests, an abdomen and kidney ultrasound examination, kidney X-ray, intravenous pyelogram ( PVI) or renal arteriography.

The compositions and methods of the invention include an inhibitor of

IGF1R optionally "in combination" with one or more chemotherapeutic agents. The term "in combination" indicates that the components of the combinations of the invention may be formulated into a single composition for simultaneous delivery, or separately formulated into two or more compositions (e.g., a kit). Further, each component of a combination of the invention may be administered to an individual at a different time than when the other component is administered; For example, each administration may be given non-simultaneously (for example, separately or sequentially) at various intervals over a given time period. In addition, separate components may be administered to an individual by the same or a different route (for example, orally, intravenously, subcutaneously).

Examples

The present invention is intended to exemplify the present invention and not to be a limitation thereof. Any method or composition described below falls within the scope of the present invention. Example 1: IGF1R and IGF-II are expressed in head and neck cancer cells.

In this example, head and neck cancer cells were assayed to determine the level of IGF1R or IGF-2 expression. Samples of 5 primary tumor tissue (stage 2, 3 or 4 cancers), normal adjacent tissue samples and normal tissue samples were analyzed for IGF1R RNA expression level. In addition, IGF1R, IGF-1 and IGF-2 levels in various cell lines were analyzed.

RNA was produced from tumor samples and cDNAs were synthesized from them. IGF1R expression was analyzed using a 20 ng cDNA sample in a Fluorogenic 5'-nuclease PCR assay with specific probes and primers using the ABI Prism 7700 Sequence Detection System (Applied Biosystems; Foster City) , CA). CT numbers were normalized against ubiqitin or actin mRNA 15 expression in all samples.

The primers and probes used were as follows:

IGF1R / Lead Initiator: GAAAGTGACGTCCTGCATTTCA (SEQ ID NO: 106)

IGF1R / reverse initiator: CCGGTGCCAGGTTATGATG (SEQ ID

No: 107)

Probe Sequence: CACCACCACGTCGAAGAATCGCA (SEQ

ID NO: 108)

H322 is a non-small lung cancer cell line; CAL27, SCC25, SCC15, SCC9 and HS802 are squamous cell carcinoma cell lines.

Data generated in these methods are shown in Figures 1 and 2. Figure 1 shows that IGF1R was expressed in higher head and neck tumor samples at a higher level than that of normal tissue. In addition, normal adjacent tissue (NAT) exhibited a higher level of IGF1R expression than that of normal tissue. IGF1R expression level increased slightly as the head and neck tumor stage increased (from I to IV). Each point represents the normalized level of IGF1R in a single tissue sample.

Figure 2 also demonstrates that IGF1R, IGF-I and IGF-II were expressed in various squamous cell carcinoma cell lines. The upper panel is a western blot analysis of multiple cell lines 5 demonstrating expression of total IGF1R (tlGF-1R) levels in the cell. Actin expression is also shown as an internal control. The lower panel indicates the level of IGF1 and IGF2 secreted from assayed cells (ng protein secreted per 106 cells).

Example 2: Anti-IGFIR (LCF (/ c) / HCA (y1)) inhibits in vitro proliferation of squamous cell carcinoma cell lines

This example demonstrates that the anti-IGF1R LCF / HCA antibody inhibits proliferation of various squamous cell carcinoma (SCC) cell lines.

Cell proliferation was assayed using a Glo Cell-Titration assay (Promega Corp .; Madison1 W1). A glo cell titration assay generates a glow-in-the-spot signal in the presence of viable cell ATP, which can be detected with a plate reader luminometer or CCD imaging device.

In this assay, squamous cell carcinoma cells, SCC9, SCC25 and SCC15, were trypsinized, counted and resuspended in 25,000 cells / ml in 10% HI-FBS RPMI containing NEAA1 L-Glu, Vitamins MEM and PS. 100 ml of cell suspension (2500 cells) was added to each well of BD Falcon 96-well black background TC-treated light-bottom plate. Cells were allowed to fix and diffuse overnight at 37 ° C. Then 10% RPMI medium was replaced with 100 ml 2% RPMI containing the LCF / HCA antibody at the appropriate concentration the following day. The anti-IGF1R antibody concentrations used in each experiment were 100 nM, 20 nM, 5 nM, 0.8 nM, 0.16 nM, 0.032 nM, 0.0064 nM, 0.00128 nM, and 0.000256 nM. All treatments were prepared in 2% RPMI at 20X concentration and serially diluted. Every test point was prepared in triplicate on separate assay plates. As mentioned above, cell proliferation was measured using the CeIITiter-GIo Luminescent Cell Viability Assay (Promega) at 96 hours post-treatment. Luminescence was detected on a Wallac 420 plate reader with forklift.

The results of this work are shown in Figures 3a-3c 5 demonstrating that proliferation of squamous cell carcinoma cell lines was inhibited by exposure to various concentrations of LCF / HCA (indicated in the Figures as 19D12). The data in Figures (a), (b), and (c) correspond to the cell lines discussed above as follows: (a): SCC cell line 15; (b): SCC cell line 25; (c): cell line 10 SCC 9.

Example 3: IGF2 and IGF1R are highly expressed in gastric and ovarian cancer cell lines.

In this example, IGF2 mRNA was shown to be expressed at a high level in primary gastric tumor samples and stomach adenocarcinoma cell lines as compared to normal samples and cell lines. High IGF2 expression in a tumor sample is a marker for autocrine stimulation through the IGF1R growth trajectory, and indicates that tumor growth will be inhibited by anti-IGF1R (LCF (/ c) / HCA (y1) antibody treatment. )).

The cell lines at which expression levels were to be

determined were grown, prepared and assayed essentially as set forth above. Protein levels were analyzed by western blot and mRNA levels were analyzed by Taqman analysis. Quantitative flow cytometry was conducted using cells labeled with anti-IGF1R, IR (insulin receptor), EGFR (epidermal growth factor receptor) or HER2 antibodies using the Bangs Quantitative Simply Cellular System. Laboratories, Inc. (Fishers, IN).

A2780 is a human ovarian cancer cell line and NCI-N87, SNU-16, SNU-1 and Hs746T are human gastric cancer cell lines.

The results of this work are shown in Figures 4 and 5. Figure 4 demonstrates that IGF2 was expressed at high levels in primary gastric tumor cells as compared to those of normal cells and normal adjacent cells. Each point is the normalized level of IGF2 mR-NA expressed in a single tumor tissue sample (normalized against ubiquitin expression levels).

The upper panel of Figure 5 is given by flow cytometry when

titre, related to several cell lines, indicating the number of receptors / cell for IGF1R, IR, EGFR and HER2. The lower panel of Figure 5 is western blotted for various cell lines demonstrating the level of expression of pRS-1 (phosphorylated insulin substrate-1 receptor (IRS-1)), pAKT (phosphorylated AKT ( also known as protein kinase-B) (non-isoform specific)), tlRS-1 (total IRS-1), pERK1, 2 (phosphorylated ERK1 (extracellular signal-regulated kinase-1), and ERK2 (signal-regulated kinase-2) extracellular)), tIGRIR (total IGFR1) and actin. The NCI N87 lane 3 lane strip in t-row IRS-1 migrates slightly slower than expected, suggesting that it is HER2 that crosses reacts with the anti-IRS-1 antibodies used in this experiment.

Example 4: Anti-IGF1R (LCF (/ c) / HCA (y1)) antibody inhibits in vitro proliferation of gastric carcinoma and myeloma cell lines.

This example demonstrates that proliferation of gastric cancer cell line SNU-1620 cells and myeloma cell line RP-MI8226 was inhibited by the anti-IGF1R LCF / HCA antibody. Cells were grown, prepared and assayed using Glo Cell-Titration assay essentially as placed above. The anti-IGF1R antibody concentrations used in each experiment were 100 nm, 20 nm, 5 nm, 0.8 25 nm, 0.16 nm, 0.032 nm, 0.0064 nm, 0.00128 nm, and 0.000256 nM. .

The results of this work are shown in Figure 6. Figure 6 demonstrates in vitro growth inhibition of the SNU-16 cell line at various antibody concentrations. A 40% -45% level of growth inhibition of the myeloma cell line was also observed in vitro.

Example 5: Anti-IGF1R (LCF (/ c) / HCA (y1)) antibody inhibits renal cell carcinoma in vivo and melanoma tumor cell growth in vitro.

This example demonstrates the effectiveness of anti-IGF1R therapy for treating or preventing renal cell cancer or melanoma.

Athymic scraped mice were inoculated with human A498 kidney carcinoma tumor cells on the right flank, subcutaneously, along with Matrigel (1: 1: cells: gel). In these experiments, 5 x 10 5 cells / mouse in a 1: 1 mixture with regular matrigel. The anti-IGF1R LCF / HCA antibody was inoculated intraperitoneally (ip) (0.1 mg / injection). Mice were dosed with antibody twice a week by intraperitoneal injection, seven times starting on day 12. Tumor size was measured with calipers and data were entered into the LABCAT program of analysis and experimental data collection. (Innovative Programming Associates, Inc.; Princeton, NJ). The mice were grouped with an average size of 100 mm3. Tumor size and body weight were measured twice weekly.

Human melanoma cells (A375-SM) were also assayed in vitro for anti-IGF1R antibody receptivity at concentrations of 100 nM, 20 nM, 5 nM, 0.8 nM, 0.16 nM, 0.032 nM, 0 , 0064 nM, 0.00128 nM, and 0.000256 nM. Assays were conducted as above by Glo Cell-Titration assay.

The results of this work are shown in Figures 7 and 8. Figure 7 demonstrates in vivo growth inhibition of renal cell carcinoma cell line over time when the LCF / HCA antibody was administered. Figure 8 demonstrates in vitro growth inhibition of melanoma cell line at various concentrations of LCF / HCA antibody. Example 6: Anti-IGF1R (LCF (/ c) / HCA (y1)) antibody inhibits squamous cell carcinoma cell growth in vivo.

This example demonstrates the effectiveness of anti-IGF1R therapy for treating or preventing head & neck cancers such as squamous cell carcinoma.

Immunodeficient SCID mice (SCID strain) were inoculated with SCC15 human squamous cell carcinoma tumor cells on the right flank, subcutaneously, along with Matrigel (1: 1 cells: gel). In these experiments, 5 x 10 6 cells / mouse in a 1: 1 mixture with regular matrigel were inoculated. The anti-IGF1R LCF / HCA antibody was inoculated intraperitoneally (ip) (0.1 mg / injection). Mice were dosed with the antibody twice weekly by intraperitoneal injection, seven times starting on day 10 with the last dose on day 31. Tumor size was measured with calipers and data were admitted. in the labcat program. The mice were grouped with an average size of 100 mm3. Tumor size and body weight were measured twice weekly.

The data generated from these experiments are shown in Figure 9. Tumor growth in mice inoculated with the LCF / HCA antibody (indicated as "19D12" in the graph) was lower than that observed in mice only receiving a control injection without the antibody.

Example 7: Anti-IGF1R LCF (/ c) / HCA (y1) antibody PPTP panel test.

LCF / HCA is a fully human antibody directed against insulin-like growth factor 1 receptor (IGF1R), which is implicated in the growth and metastatic phenotype of a wide range of malignancies. IGF1R signaling is of particular importance in the adjustment of child cancer, for example, in conjunction with pediatric cancers such as neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma, Wilms's tumor, and osteosarcoma. Antibody activity was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical Test Program (PPTP). PPTP includes an in vitro cell line panel and 25 in vivo mouse xenograft panels, established and organized by the National Cancer Institute (NCI), which allows testing of therapies in the most common pediatric cancers (see, for example, Houghton et al., Pediatric Blood & Cancer (2007) 49 (7): 928-40).

PPTP includes a panel of molecularly characterized cell lines in vitro (n = 27) and in vivo xenograft panel (n = 61) representing many of the common types of child solid and ALL child tumors (acute lymphoblastic leukemia). . Anti-IGF1R LCF / HCA antibody was tested against the in vitro PPTP panel at concentrations ranging from 0.01 nM to 100 nM; and was tested against the in vivo PPTP panel at a dose of 0.5 mg per mouse administered twice weekly for four weeks via intraperitoneal injection. Three measures of antitumor activity 5 were used: 1) response criteria modeled after clinical adjustment; 2) control-treated tumor volume (T / C) on day 21; and 3) a time to event measurement (4-fold increase in tumor volume) based on mean EFS of treated and control lines (intermediate activity required EFS (event free survival) T / C> 2, and high activity additionally 10 requires a net reduction in mean tumor volume at the end of the experiment).

Methods

In vitro test. The in vitro test was performed using DIMSCAN, a semiautomatic fluorescence-based digital imaging microscope system that quantifies viable cell numbers (using fluorescein diacate [FDA]) in tissue culture multi-well plates (Keshelava et al., Methods Mol.Med. (2005) 110: 139-153). The test was for 96 hours at concentrations of 0.01 nM to 0.1 mM with replicates of 6 per data point. Data were analyzed using Kaleidagraph software (Syndergy Software; Reading, PA), adjusting a nonlinear regression, sigmoidal dose response model for the response; relative fluorescence values vs. the concentration. The in vitro PPTP panel contains cell lines for neuroblastoma (4), Ewing's sarcoma (4), rhabdomyosarcoma (4), acute lymphoblastic leukemia (5), NHL (2), and others.

Stage 1 testing involved testing of an agent through the

total PPTP panel of child cancer xenograft lines at their maximum tolerated dose (MTD), or at a selected dose based on PK / PD (pharmacokinetic / pharmacodynamic) studies using adult preclinical models.

In vivo solid tumor test: For each xenograft line,

10 mice supporting initiated treatment of subcutaneous tumors (SC) when tumors were between 0.2-0.5 cm3 in volume. Two perpendicular tumor diameters were measured at once-weekly intervals with digital vernier calipers. Assuming the tumors are spherical, volumes were calculated from the formula (7t / 6) xd3, where d represented the mean diameter.

Acute lymphoblastic leukemia test in vivo: For each line of

xenograft, 8 mice were inoculated with 3-5 x 10 6 mononuclear cells purified from spleens of secondary recipient mice. The graft was monitored weekly by flow cytometry, and treatment was initiated when the proportion of human CD45 + cells in the peripheral blood reached 1%. The proportion of human CD45 + cells in peripheral blood was monitored weekly throughout the entire course of treatment.

Drug: LCF / HCA was dissolved in 20 mM pH 5 sodium acetate buffer containing 150 mM sodium chloride, and administered intraperitoneally twice weekly for 4 consecutive weeks at a dose of 0.5 mg per animal. Antibody was provided for each test site in blinded coded vials according to standard PPTP operating procedures.

Solid Tumor Response Criteria:

Answer Definition Classification PD1 (Progressive Disease> 25% t in tumor volume, TGD value 0 va 1) <1.5 PD2 (Progressive Disease> 25% T in tumor volume, TGD value 2 va 2)> 1.5 SD (Disease Stable) <25% t tumor volume, <50% 4 regression PR (Partial Response) £ 50% regression, but no CR 6 CR (Full Response) <0.1 cm3 tumor volume 8 MCR (CR <0.1 cm3 tumor volume at end of study 10 Leukemia Response Criteria:

Answer Definition Rating PD1 (Progressive Disease No PR & TGD value of <1.5 & events 0 va 1) in EOS PD2 (Progressive Disease No PR & TGD value> 1.5 & Events in 2 va 2) EOS SD (Stable Disease) No PR and no event in EOS 4 PR (Partial Response) CD45% <1% for 1 week only 6 CR (Full Response) CD45% <1% for 2 consecutive weeks 8 MCR (CR maintained) CD45% <1% for last 3 weeks of study 10 Mean Group Response: Each individual mouse in

each treatment group was assigned a response rating (see Tables above) and an average rating for the treatment group was calculated, and then each treatment group was assigned a total response according to the table below._

Se Average Rating (MS) of (1): Total Group Response 0 <MS <1 PD1 1 <MS <3 PD2 3 <MS <5 SD <MS <7 PR 7 <MS <9 CR 9 <MS MCR Statistical Methods : The free survival distributions of

The event events (EFS) of each treatment group were compared to the EFS distribution of the respective control group using the exact Yog class test. P values were 2 sided & were not adjusted for multiple comparisons given the exploratory nature of this study. P values <0.05 were considered to be significant. Results Table 1. In vivo LCF / HCA activity summary

Histology strain P value EFS final RTV T / C P value Response x-graft median T / C total tumor group volume BT-29 Rabidoid 0.066 1.4> 4 0.77 0.247 PD1 KT-16 Rabidoid 0.24 1.2 > 4 0.5 0.130 PD1 KT-14 Rhabidoid <0.001 *> 3.3 # 1.6 # 0.6 # 0.6 0.009 * PD2 KT-10 Wilms 0.001 * 1.3> 4 0.43 <0.001 * PD1 KT-11 Wilms 0.547 1> 4 0.99 1,000 PD1 KT-13 Wilms 0.374 1.1> 4 0.84 0.236 PD1 SK-NEP-1 Ewings 0.428 0.9> 4 1.08 0.829 PD1 EW5 Ewings <0.001 *> 2.3! 0.4! 0.12 <0.001 * CR * EW8 Ewings 0.579 1.5> 4 0.86 0.243 PD1 TC-71 Ewings 0.246 1.2> 4 0.88 0.579 PD1 CHLA258 Ewings <0.001 * 4.2 #> 4 # 0.29 < 0.001 * PD2 Rh28 ALV Rabidomyosarcoma <0.001 *> 2.6 # 2.9 # 0.36 0.001 * PD2 Rh30R ALV Rabidomyosarcoma <0.001 * 1.8> 4 0.49 0.004 * PD2 Rh41 ALV Rabidomyosarcoma <0.001 * 1.1> 4 0, 65 0.065 PD1 Rh18 BEM Rabidomyosarcoma 0.44 1> 4 0.74 0.353 PD1 BT-28 Medulloblastoma 0.121 1.2> 4 1.18 0.529 PD1 BT-46 Medulloblastoma 0.009 * 1.2> 4 0.69 0.011 * PD1 BT -50 Medulloblastoma 0.474 1.4 0.94 0.436 PD2 BT-44 Ependioma <0.001 * 2.6 #> 4 # 0.66 0.003 * PD2 GBM2 Glioblastoma 0.005 * 1.4> 4 0.73 0.007 * PD1 BT-39 Glioblastoma 0.377 1.1> 4 0.87 0.631 PD1 D645 Glioblastoma 0.007 * 2.2 #> 4 # 0.58 <0.001 * PD2 D456 Glioblastoma 0.008 * 1, 1> 4 0.77 0.008 * PD1 NB-SD Neuroblastoma <0.001 *> 1.8Λ 3.7Λ 0.41 0.006 * PD2 NB-1771 Neuroblastoma 0.595 1.1> 4 0.64 0.063 PD1 NB-1691 Neuroblastoma 0.025 * 0, 9> 4 1.34 0.075 PD1 NB-EBcI Neuroblastoma 0.003 *> 2.0 # 1.4 # 0.8 0.043 * PD2 CHLA-79 Neuroblastoma 0.003 * 2.1 # 3.9 # 0.69 0.23 PD2 NB-1643 Neuroblastoma 0.005 * 1.8> 4 0.53 0.005 * PD2 OS-1 Osteosarcoma <0.001 *> 1.3Λ 0.1a 0.16 <0.001 * MCR * OS-2 Osteosarcoma <0.001 * 2.3 #> 4 # 0.5 <0.001 * PD2 OS-17 Osteosarcoma <0.001 * 2> 4 0.55 0.089 PD2 OS-9 Osteosarcoma 0.003 *> 1.2Λ 0.4a 0.31 <0.001 * MCR * OS-33 Osteosarcoma 0.587 0.9> 4 0.79 0.529 PD1 OS-31 Osteosarcoma 0.461 1.3> 4 0.88 0.274 PD1 ALL-2 ALL Precursor B 0.095 * 0.7> 25 PD1 ALL-3 ALL Precursor B 0.743 0.4> 25 PD1 ALL-4 Precursor B ALL 0.194 0.8> 25 PD1 ALL-7 ALL precursor B 0.544 1> 25 PD1 ALL-8 ALL T cell 0.408 1.5> 25 PD1 ALL-16 ALL T cell 0.588 1> 25 PD1 ALL-17 Precursor ALL B <0.001 * 3.1 #> 25 # PD2 ALL-19 ALL B Precursor 0.009 * 1 .5> 25 PD1 An * in the p-value columns indicates a statistically significant difference between treated and control groups. The notations in the EFS columns indicate xenographs that have activity either high (!), Intermediate (#), or undetermined (A). RTV is a relative tumor volume.

See also Figure 10 which puts a graphical analysis of the volume.

of in vivo tumor of various cell types over time.

IGF-1R expression was also evaluated using Affymetrix U133 Plus2 Series.

Five xenographs with very low IGF1R expression did not respond (ie PD1) to the antibody. For example, OS-33 was very low in expression and was one of the osteosarcoma xenographs that showed no antibody response. The 3 xenographs with CR or MCR responses had high IGF1R expression. Some xenographs with moderate to high IGF1R expression did not respond to the antibody (eg 15 Rh41).

The maximum growth inhibition achieved in in vitro assays was 30%, and was observed for the ALL, MOLT-4 T-cell line. The average growth inhibition for the in vitro panel at the highest concentration tested was 5%.

The present invention is not to be limited in scope by

specific embodiments described herein. Indeed, the scope of the present invention includes embodiments specifically set forth herein and other embodiments not specifically set forth herein; The embodiments specifically set forth herein are not necessarily intended to be exhaustive. Various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the claims.

Patents, patent applications, publications, product descriptions, and protocols are cited throughout this application, the disclosures of which are incorporated herein by reference in their entirety for all proposals. Listing String

<110> Schering Corporation

<120> Treatment Methods

<130> JB06578

<150> 60 / 874,589

<151> 2006-12-13

<150> 60 / 870,937

<151> 2006-12-20

<150> 60 / 946,011

<151> 2007-06-25

<150> 60 / 979,274

<151> 2007-10-11

<160> 108

<170> Patent version 3.3

<210> 1

<211> 384 <212> DNA

<213> Artificial Sequence <220>

<223> Modified Light Chain-19D12 / 15H12 <220>

<221> CDS <222> (1) .. (384)

<400> 1

atg tcg cca tca caa ctc att ggg ttt ctg ctg

Met Ser Pro Ser Gln Leu He Gly Phe Leu Leu Leu Trp Val Pro Wing 15 10 15

tcc agg ggt gaa att gtg ctg act cag age cca gac tet ctg tet gtg 96

Ser Arg Gly Glu He Val Leu Thr Gln Ser Pro Asp Ser Leu Ser Val

20 25 30

act cca ggc gag aga gtc acc till acc tgc egg gcc agt cag age att 14 4 Thr Pro Gly Glu Arg Val Thr He Thr Cys Arg Wing Ser Gln Ser Ile 35 40 45

ggt agt age tta cac tgg tac cag cag aaa cca ggt cag tet cca aag Gly Ser Ser Read His Trp Tyr Gln Lys Pro Gly Gln Ser Pro Lys 50 55 60

ctt ctc till aag tat gea tcc cag tcc ctc tca ggg gtc ccc tcg agg Leu Leu Ile Lys Tyr Ala Ser Gln Ser Leu Ser Gly Val Pro Ser Arg 65 70 75 80

ttc agt ggc agt gga tet ggg aca gat ttc acc ctc acc until agt age Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser

85 90 95

ctc gag gct gaa gat gct gea gcg tat tac tgt cat cag agt agt cgt Leu Glu Wing Glu Asp Wing Wing Wing Tyr Tyr Cys His Gln Ser Ser Arg 100 105 110

tta cct cac act ttc ggc caa ggg acc aag gtg gag until aaa cgt acg Leu Pro His Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr 115 120 125

<210> 2 <211> 128 <212> PRT

<213> Artificial Sequence <220>

<223> Synthetic construct <400> 2

Met Ser Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Wing 15 10 15

Ser Arg Gly Glu Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ser Val 20 25 30

Thr Pro Gly Glu Arg Val Thr Ile Thr Cys Arg Wing Be Gln Ser Ile 35 40 45

Gly Ser Being Read His Trp Tyr Gln Lys Pro Gly Gln Being Pro Lys 50 55 60

192

240

288

336

384 Leu Leu Ile Lys Tyr Wing Be Gln Be Read Be Gly Val Pro Be Arg 65 70 75 80

Phe Ser Gly Ser Gly Ser As Gly Thr Asp Phe Ser Serly Gly Thr 85 90 95

Read Glu Wing Glu Wing Asp Wing Wing Wing Tyr Tyr Cys His Gln Ser Ser Arg 100 105 110

Leu Pro His Thr Phe Gly Gn Gly Thr Lys Val Glu Ile Lys Arg Thr 115 120 125

<210> 3 <211> 384 <212> DNA

<213> Artificial Sequence <220>

<223> Modified Light Chain-D 19D12 / 15H12

<220>

<221> CDS <222> (1) .. (384)

<400> 3

atg tcg cca tca caa ctc att ggg ttt ctg ctg

Met Ser Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Wing 15 10 15

tcc agg ggt gaa att gtg ctg act cag age cca gac tet ctg tet gtg 96

Ser Arg Gly Glu Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ser Val 20 25 30

act cca ggc gag aga gtc acc till acc tgc cgg gcc agt cag age att 144

Thr Pro Gly Glu Arg Val Thr Ile Thr Cys Arg Wing Be Gln Ser Ile 35 40 45

ggt agt age tta cac tgg tac cag cag aaa cca ggt cag tet cca aag 192

Gly Ser Being Read His Trp Tyr Gln Lys Pro Gly Gln Being Pro Lys 50 55 60

ctt ctc up to aag tat gea tcc cag tcc ctc tca ggg gtc ccc tcg agg 240 Leu Leu Ile Lys Tyr Ala Ser Gln Ser Leu Ser Gly Val Pro Ser Arg 65 70 75 80

ttc agt ggc agt gga tet ggg aca gat ttc acc ctc acc till agt age Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser 85 90 95

ctc gag gct gaa gat ttc gea gtg tat tac tgt cat cag agt agt cgt Leu Glu Ala Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Ser Ser Arg 100 105 110

tta cct cac act ttc ggc caa ggg acc aag gtg gag until aaa cgt acg Leu Pro His Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr 115 120 125

<210> 4 <211> 128 <212> PRT <213> Artificial Sequence <220>

<223> Synthetic construct <4 00> 4

Met Ser Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Wing

1 5 10 15

Be Arg Gly Glu Ile Val Leu Thr Gln Be Pro Asp Be Read Ser Val 20 25 30

Thr Pro Gly Glu Arg Val Thr Ile Thr Cys Arg Wing Be Gln Ser Ile 35 40 45

Gly Ser Being Read His Trp Tyr Gln Lys Pro Gly Gln Being Pro Lys 50 55 60

Leu Leu Ile Lys Tyr Wing Be Gln Be Read Gly Val Pro Be Arg 65 70 75 80

Phe Be Gly Be Gly Be Gly Thr Asp

85 90 95

Read Glu Wing Glu Asp Phe Wing Val Tyr Tyr Cys His Gln Ser Ser Arg 100 105 110

288

336

384 Leu Pro His Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr 115 120 125

<210> 5 <211> 384 <212> DNA

<213> Artificial Sequence <220>

<223> Modified E-Light Chain 19D12 / 15H12 <220>

<221> CDS

<222> (1) .. (384)

<400> 5

atg tcg cca tca caa ctc att ggg ttt ctg ctg ctc tgg gtt cca gcc Met Ser Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Ala

1 5 10 15

tcc agg ggt gaa att gtg ctg act cag age cca ggt acc ctg tet gtg

Ser Arg Gly Glu Ile Val Leu Thr

tet cca ggg gag aga gcc acc ctc tcc cgg gcc agt cag age att

Ser Pro Gly Glu Arg Wing Thr Read Ser Cys Arg Wing Ser Gln Ser Ile 35 40 45

ggt agt age tta cac tgg tac cag cag aaa cca ggt cag gct cca agg

Gly Ser Be Read His Trp Tyr Gln Gln Lys Pro

50 55 60

ctt ctc till aag tat gea tcc cag tcc ctc tca ggg till ccc gat agg

Leu Leu Ile Lys Tyr Wing Be Gln Be Read Be Gly Ile Pro Asp Arg 65 70 75 80

ttc agt ggc agt gga tet ggg aca gat ttc acc ctc acc until agt aga

Phe Be Gly Be Gly Be Gly Thr Asp

85 90 95

ctg gag cct gaa gat gct gea gcg tat tac tgt cat cag agt agt cgt

96

144

192

240

288

336 Leu Glu Pro Glu Asp Wing Wing Wing Tyr Tyr Cys His Gln Ser Ser Arg 100 105 110

tta cct cac act ttc ggc caa ggg acc aag gtg gag atc aaa cgt aca Read His Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr 115 120 125

<210> 6 <211> 128 <212> PRT

<213> Artificial Sequence <220>

<223> Synthetic construct <4 00> 6

Met Ser Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Wing 15 10 15

Ser Gly Gle Glu Ile Val Leu Thr Gln Ser Gly Gle Thr Leu Ser Val 20 25 30

Ser Pro Gly Glu Arg Wing Thr Read Ser Cys Arg Wing Ser Gln Ser Ile 35 40 45

Gly Ser Be Read His Trp Tyr Gln Lys Pro Gly Gln Wing Pro Arg 50 55 60

Leu Leu Ile Lys Tyr Wing Be Gln Be Read Be Gly Ile Pro Asp Arg 65 70 75 80

Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Gly Thr Read Ile Be Arg 85 90 95

Read Glu Pro Glu Asp Wing Wing Wing Wing Tyr Tyr Cys His Gln Ser Ser Arg 100 105 110

Leu Pro His Thr Phe Gly Gn Gly Thr Lys Val Glu Ile Lys Arg Thr 115 120 125

<210> 7 <211> 384 <212> DNA

<213> Artificial Sequence

384 <220>

<223> Light Chain-F 19D12 / 15H12 <220>

<221> CDS <222> (1) .. (384)

<4 00> 7

atg tcg cca tca caa ctc att ggg ttt ctg ctg

Met Ser Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Wing 15 10 15

tcc agg ggt gaa att gtg ctg act cag age cca ggt acc ctg tet gtg 96

Ser Gly Gle Glu Ile Val Leu Thr Gln Ser Gly Gle Thr Leu Ser Val 20 25 30

tet cca ggc gag aga gcc acc ctc tcc tgc cgg gcc agt cag age att 144

Ser Pro Gly Glu Arg Wing Thr Read Ser Cys Arg Wing Ser Gln Ser Ile 35 40 45

ggt agt age tta cac tgg tac cag cag aaa cca ggt cag gct cca agg 192

Gly Ser Be Read His Trp Tyr Gln Lys Pro Gly Gln Wing Pro Arg 50 55 60

ctt ctc by aag tat gea tcc cag tcc ctc tca ggg by ccc gat agg 240

Leu Leu Ile Lys Tyr Wing Be Gln Be Read Be Gly Ile Pro Asp Arg 65 70 75 80

ttc agt ggc agt gga tet ggg aca gat ttc acc ctc acc until agt aga 288

Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Gly Thr Read Ile Be Arg 85 90 95

ctg gag cct gaa gat ttc gea gtg tat tac tgt cat cag agt agt cgt 336

Read Glu Pro Glu Asp Phe Wing Val Tyr Tyr Cys His Gln Ser Ser Arg 100 105 110

tta cct cac act ttc ggc caa ggg acc aag gtg gag until aaa cgt aca 384

Read His Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr

115 120 125

<210> 8 <211> 128 <212> PRT

<213> Artificial Sequence <220>

<223> Synthetic construct

<400> 8

Met Ser Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Wing 15 10 15

Ser Gly Gle Glu Ile Val Leu Thr Gln Ser Gly Gle Thr Leu Ser Val 20 25 30

Ser Pro Gly Glu Arg Wing Thr Read Ser Cys Arg Wing Ser Gln Ser Ile 35 40 45

Gly Ser Be Read His Trp Tyr Gln Lys Pro Gly Gln Wing Pro Arg 50 55 60

Leu Leu Ile Lys Tyr Wing Be Gln Be Read Be Gly Ile Pro Asp Arg 65 70 75 80

Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Gly Thr Read Ile Be Arg 85 90 95

Read Glu Pro Glu Asp Phe Wing Val Tyr Tyr Cys His Gln Ser Ser Arg 100 105 110

Leu Pro His Thr Phe Gly Gn Gly Thr Lys Val Glu Ile Lys Arg Thr 115 120 125

<210> 9 <211> 411 <212> DNA <213> Artificial Sequence <220>

<223> Heavy Chain-A 19D12 / 15H12 <220>

<221> CDS

<222> (1) .. (411)

<400> 9

atg gag ttt ggg ctg age tgg gtt ttc ctt gtt gct ata tta aaa ggt 48 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys Gly 15 10 15

gtc cag tgt gag gtt cag ctg gtg cag tet ggg

Val Gln Cys Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys 20 25 30

cct ggg ggg tcc ctg aga ctc tcc tgt gea gcc tet gga ttc acc ttc 144

Pro Gly Gly Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe 35 40 45

agt age ttt gct atg cac tgg gtt cgc cag gct cca

Be Ser Phe Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60

gag tgg ata tca gtt att gat act cgt ggt gcc aca tac tat gea gac 240

Glu Trp Ile Ser Val Ile Asp Thr Arg Gly Wing Thr Tyr Tyr Wing Asp 65 70 75 80

tcc gtg aag ggc cga ttc acc up to tcc aga gac aat gcc aag aac tcc 288

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 85 90 95

ttg tat ctt caa atg aac age ctg aga gcc gag gac act gct gtg tat 336

Leu Tyr Leu Gln Met Asn Ser Leu Arg Wing Glu Asp Thr Wing Val Tyr 100 105 110

tac tgt gea aga ctg ggg aac ttc tac tac ggt atg gac gtc

Tyr Cys Arg Wing Read Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly 115 120 125

caa ggg acc acg gtc acc gtc tcc tca 411

Gln Gly Thr Thr Val Thr Val Ser Ser 130 135

<210> 10 <211> 137 <212> PRT <213> Artificial Sequence <220>

<223> Synthetic construct <4 00> 10

Met Glu Phe Gly Leu Ser Trp Val I

Val Gln Cys

‘5

Pro gly

Ser Ser 50

Glu Trp 65

Ser Val Leu Tyr

15

Tyr cys

Gln Gly 130

20

25

30

Phe Leu Val Wing Ile Leu Lys Gly 10 15

Gln Ser Gly Gly Gly Read Val Lys 30

Cys Wing Wing Be Gly Phe Thr Phe 45

Arg Gln Pro Wing Gly Lys Gly Leu 60

Arg Gly Wing Thr Tyr Tyr Wing Asp 75 80

Ser Arg Asp Asn Ala Lys Asn Ser 90 95

Arg Wing Glu Asp Thr Wing Val Tyr 105 110

Tyr Tyr Gly Met Asp Val Trp Gly 125

To be

modified

atg gag ttt ggg ctg age tgg gtt ttc ctt gtt gct ata tta aaa ggt 48

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Wing Ile Leu Lys Gly 10 15

5th

Glu Val Gln Leu Val 20

Gly Ser Leu Arg Leu Ser 35 35

Phe Ala Met His Trp Val 55

Ile Ser Val Ile Asp Thr 70

Lys Gly Arg Phe Thr Ile 85

Read Gln Met Asn Ser Read 100

Arg Wing Read Gly Asn Phe 115 120

Thr Thr Val Thr Thr Ser 135

<210> 11 <211> 411 <212> DNA

<213> Artificial Sequence <220>

<223> Heavy Chain-B 19D12 / 15H12 <220>

<221> CDS <222> (1) .. (411)

<400> 11 gtc cag tgt gag gtt cag ctg gtg cag tet ggg

Val Gln Cys Glu Val Gln Read Val Gln Ser Gly Gly Gly Leu Val Gln 20 25 30

ccc ggg ggg tcc ctg aga ctc tcc tgt gea gcc tet gga ttc acc ttc 144

Pro Gly Gly Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe 35 40 45

agt age ttt gct atg cac tgg gtt cgc cag gct cca

Be Ser Phe Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60

gag tgg ata tca gtt att gat act cgt ggt gcc aca tac tat gea gac 240

Glu Trp Ile Ser Val Ile Asp Thr Arg Gly Wing Thr Tyr Tyr Wing Asp 65 70 75 80

tcc gtg aag ggc cga ttc acc up to tcc aga gac aat gcc aag aac tcc 288

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 85 90 95

ttg tat ctt caa atg aac age ctg aga gcc gag gac act gct gtg tat 336

Leu Tyr Leu Gln Met Asn Ser Leu Arg Wing Glu Asp Thr Wing Val Tyr 100 105 110

tac tgt gea aga ctg ggg aac ttc tac tac ggt atg gac gtc

Tyr Cys Arg Wing Read Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly 115 120 125

caa ggg acc acg gtc acc gtc tcc tca 411

Gln Gly Thr Thr Val Thr Val Ser Ser 130 135

<210> 12 <211> 137 <212> PRT

<213> Artificial Sequence <220>

<223> Synthetic Construct <400> 12 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Wing Ile Leu Lys Gly I 5 10 ■ 15

Val Gln Cys Glu Val Gln Read Val Gln Ser Gly Gly Gly Leu Val Gln 20 25 30

Pro Gly Gly Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe 35 40 45

Be Ser Phe Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60

Glu Trp Ile Ser Val Ile Asp Thr Arg Gly Wing Thr Tyr Tyr Wing Asp 65 70 75 80

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 85 90 95

Leu Tyr Leu Gln Met Asn Ser Leu Arg Wing Glu Asp Thr Wing Val Tyr 100 105 110

Tyr Cys Arg Wing Read Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly 115 120 125

Gln Gly Thr Thr Val Thr Val Ser Ser 130 135

<210> 13 <211> 174 <212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin heavy chain variable region <400> 13

Gly Arg Read Gly Gln Wing Trp Arg Be Read Arg Read Le Read Be Cys Wing 15 10 15

Be Gly Phe Thr Phe Be Asp Tyr Tyr Met Be Trp Ile Arg Gln Wing 20 25 30

Pro Gly Lys Gly Leu Glu Trp Val Be Tyr Ile Be Ser Be Gly Be 35 40 45 Thr Arg Asp Tyr Wing Asp Be Val Lys Gly Arg Phe Thr Ile Be Arg 50 55 60 Asp Asn Wing Lys Asn Be Leu Tyr Leu Gln Met Asn Ser Leu Arg Wing 65 70 75 80

Glu Asp Thr Wing Val Tyr Cyr Val Arg Asp Gly Val Glu Thr Thr

85 90 95

Phe Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp

100 105 110

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

115 120 125

Wing Pro Cys Be Arg Be Thr Be Glu Be Thr Wing Wing Read Gly Cys 130 135 140

Read Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160

Gly Wing Read Thr Be Gly Val His Thr Phe Pro Be Cys Wing

165 170

<210> 14 <211> 124 <212> PRT <213> Artificial Sequence <220>

<223> Immunoglobulin heavy chain variable region <400> 14

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

1 5 10 15

Leu Arg Leu Be Cys Thr Wing Be Gly Phe Thr Phe Be Ser Tyr Wing 20 25 30

Met Asn Trp Val Arg Gln Pro Wing Gly Lys Gly Leu Glu Trp Val Ser 35 40 45

Wing Ile Be Gly Be Gly Gly Thr Thr Phe Tyr Wing Asp Be Val Lys 50 55 60 Gly Arg Phe Thr Ile Be Arg Asp Asn Be Arg Thr Thr Read Tyr Leu 65 70 75 80

Gln Met Asn Be Read Arg Wing Glu Asp Thr Wing Val Tyr Tyr Cys Wing 85 90 95

Lys Asp Read Gly Trp Be Asp Be Tyr Tyr Tyr Tyr Tyr Gly Met Asp

*

100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120

<210> 15 <211> 112 <212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin heavy chain variable region

<400> 15

Gly Pro Gly Read Val Lys Pro Be Glu Thr Read Le Be Read Thr Cys Thr 15 10 15

Val Be Gly Gly Be Ile Be Asn Tyr Tyr Trp Be Trp Ile Arg Gln 20 25 30

Pro Wing Gly Lys Gly Leu Glu Trp Ile Gly Arg Ile Tyr Thr Ser Gly 35 40 45

Be Pro Asn Tyr Asn Pro Be Read Lys Be Arg Val Thr Met Be Val 50 55 60

Asp Thr Be Lys Asn Gln Phe Be Read Lys Read Asn Be Val Thr Wing 65 70 75 80

Wing Asp Thr Wing Val Tyr Tyr Cys Wing Val Thr Ile Phe Gly Val Val 85 90 95

Ile Ile Phe Asp Tyr Trp Gly Gln Gly Thr Read Val Val Val Ser Ser 100 105 110

<210> 16

<211> 125 <212> PRT <213> Artificial Sequence <220>

<223> Immunoglobulin heavy chain variable region <4 00> 16

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 15 10 15

Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe Be Ser Tyr 20 25 30

Wing Met Ser Trp Val Arg Gln Pro Wing Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Ile Be Arg Asp Asn Be Lys Asn Thr Read Tyr 65 70 75 80

Read Gln Met Asn Be Read Arg Wing Glu Asp Thr Wing Val Tyr Tyr Cys

85 90 95

Wing Lys Asp Read Gly Tyr Gly Asp Phe Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 110

Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125

<210> 17 <211> 113 <212> PRT

<213> Artificial Sequence

<220>

<223> Immunoglobulin heavy chain variable region <400> 17

Pro Gly Leu Val Lys Pro Be Glu Thr Leu Be Leu Thr Cys Thr Val 15 10 15

Be Gly Gly Be Ile Be Be Tyr Tyr Trp Be Trp Ile Arg Gln Pro 20 25 30 Pro Gly Lys Gly Read Glu Trp Ile Gly Tyr Ile Tyr Tyr Be Gly Ser

40 45

Thr Asn Tyr Asn Pro To Be Read Lys To Be Arg Val Thr Ile To Be Val Asp

50 55 60

Thr Be Lys Asn Gln Phe Be Read Lys Read Le Be Ser Val Thr Wing Wing 65 70 75 80

Asp Thr Wing Val Tyr Tyr Cys Wing Arg Thr Tyr Ser Ser Ser Phe Tyr 85 90 95

Tyr Tyr Gly Met Asp Val Trp

100 105 110

Ser <210> 18

<211> 122

<212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin heavy chain variable region

<400> 18

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

1 5 10 15

Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe Be Ser Tyr 20 25 30

Wing Met Ser Trp Val Arg Gln Pro Wing Gly Lys Gly Leu Glu Trp Val 35 40 45

Be Gly Ile Thr Gly Be Gly Gly Be Thr Tyr Tyr Wing Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Ile Be Arg Asp Asn Be Lys Asn Thr Read Tyr 65 70 75 80

Read Gln Met Asn Be Read Arg Wing Glu Asp Thr Wing Val Tyr Tyr Cys 85 90 95

Alys Lys Asp Pro Gly Thr Thr Val Ile Met Ser Trp Phe Asp Pro Trp 100 105 110 Gly Gln Gly Thr Read Val Thr Val Ser Ser 115 120

<210> 19 <211> 136 <212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin light chain variable region <400> 19

Wing Be Val Gly Asp Arg Val Thr Phe Thr Cys Arg Wing Be Gln Asp 15 10 15

Ile Arg Arg Asp Read Gly Trp Tyr Gln Gln Lys Pro Gly Lys Wing Pro 20 25 30

Lys Arg Leu Ile Tyr Wing Ala Ser Arg Leu Gln Ser Gly Val Pro Ser 35 40 45

Arg Phe Be Gly Be Gly Be Gly Thr Glu Phe Thr Read Le Thr Ile Ser 50 55 60

Get Read Gln Pro Glu Asp Phe Wing Thr Tyr Tyr Cys Read Gln His Asn 65 70 75 80

Asn Tyr Pro Arg Thr Phe Gly Gln Gly Thr Glu Val Glu Ile Ile Arg

85 90 95

Thr Val Wing Ward Pro Be Val Phe Ile Phe Pro Pro Asp Glu Gln 100 105 110

Leu Lys Be Gly Thr Wing Be Val Val Cys Leu Leu Asn Asn Phe Tyr 115 120 125

Pro Arg Glu Wing Lys Val Gln Trp 130 135

<210> 20 <211> 107

<212> PRT

<213> Artificial Sequence <220> <223> Immunoglobulin Light Chain Variable Region <4 00> 20

Asp Ile Gln Met Thr Gln Phe Pro To Be To Be Read To Be To Be Val Gly 15 10 15

Asp Arg Val Thr Ile Thr Cys Arg Wing Be Gln Gly Ile Arg Asn Asp 20 25 30

Read Gly Trp Tyr Gln Gln Lys Pro Gly Lys Pro Wing Lys Arg Leu Ile 35 40 45

Tyr Wing Wing Be Arg Read His Arg Gly Val Pro Be Arg Phe Be Gly 50 55 60

Be Gly Be Gly Thr Glu Phe Thr Read It Thr Ile Be Be Read Gln Pro 65 70 75 80

Glu Asp Phe Wing Thr Tyr Tyr Cys Read Gln His Asn Ser Tyr Pro Cys 85 90 95

Ser Phe Gly Gln Gly Thr Lys Read Glu Ile Lys 100 105

<210> 21 <211> 100 <212> PRT <213> Artificial Sequence <220>

<223> Immunoglobulin light chain variable region <400> 21

Be Be Read Be Be Wing Val Gly Asp Arg Val Thr Phe Thr Cys Arg

1 5 10 15

Ala Ser Gln Asp Ile Arg Arg Asp Read Gly Trp Tyr Gln Gln Lys Pro 20 25 30

Gly Lys Wing Pro Lys Arg Leu Ile Tyr Wing Ala Ser Arg Leu Gln Ser 35 40 45

Gly Val Pro To Be Arg Phe To Be Gly To Be Gly To Be Gly To Thr Glu Phe Thr 50 55 60 Leu Thr Ile To Be Read Le Gln Pro Glu Asp Phe Wing Thr

Read Gln His Asn Asn Tyr Pro Arg Thr Phe Gly Gln Gly Thr Glu Val 85 90 95

Glu Ile Ile Arg 100

<210> 22 <211> 107 <212> PRT <213> Artificial Sequence <220>

<223> Immunoglobulin light chain variable region <400> 22

Asp Ile Gln Met Thr Gln Be Pro Be Be Read Be Wing Be Val Gly

1 5 10 15

Asp Arg Val Ile Thr Thr Cys Arg Wing Be Gln Gly Ile Arg Be Asp 20 25 30

Read Gly Trp Phe Gln Gln Lys Pro Gly Lys Wing Pro Lys Arg Leu Ile 35 40 45

Tyr Wing Wing Be Lys Read His Arg Gly Val Pro Be Arg Phe Be Gly 50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Read Ile Thr Ile Be Arg Read Le Gln Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105

<210> 23 <211> 92

<212> PRT

<213> Artificial Sequence <220> <223> Immunoglobulin Light Chain Variable Region <400> 23

Gly Asp Arg Val Ile Thr Thr Cys Arg Wing Be Gln Be Ile Be Thr 15 10 15

Phe Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 20 25 30

Ile His Val Wing Be Ser Leu Gln Gly Gly Val Pro Ser Arg Phe Ser 35 40 45

Gly Ser Gly Ser Gly Thr Asp Phe Thr Read Le Thr Ile Be Le Read Gln 50 55 60

Pro Glu Asp Phe Wing Thr Tyr Cyr Gln Gln Ser Tyr Asn Wing Pro 65 70 75 80

Read Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 85 90

<210> 24 <211> 91 <212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin light chain variable region <400> 24

Arg Wing Thr Read Cys Arg Wing Arg Be Gln Be Val Arg Gly Arg Tyr 15 10 15

Leu Wing Trp Tyr Gln Gln Lys Pro Gly Gln Wing Pro Arg Leu Leu Ile

20 25 30

Tyr Gly Wing To Be Arg Wing Thr Gly Ile Pro Asp Arg To Be Gly

40 45

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 50 55 60

Glu Asp Phe Wing Val Phe Tyr Cys Gln Gln Tyr Gly Being Ser Pro Arg 65 70 75 80 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90

<210> 25 <211> 236 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin <400> 25

Met Asp Met Arg Val Pro Wing Gln Leu Leu Gly Leu Leu Leu Leu Trp 1-5 10 15

Phe Pro Gly Wing Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser 20 20 30

Read Sera Wing Be Val Gly Asp Arg Val Thr Ile Thr Cys Arg Wing Be 35 40 45

Gln Gly Ile Arg Asn Asp Read Gly Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60

Pro Wing Lys Arg Leu Ile Tyr Wing Wing Ser Be Read Gln Ser Gly Val 65 70 75 80

Pro Be Arg Phe Be Gly Be Gly Be Gly Thr

85 90 95

Ile Ser Ser Leu Gln Pro Glu Asp Phe Wing Thr Tyr Tyr Cys Leu Gln 100 105 110

His Asn Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 115 120 125

Lys Arg Thr Val Wing Pro Wing Ser Val Phe Ile Phe Pro Val Ser Asp 130 135 140

Glu Gln Leu Lys Be Gly Thr Wing Be Val Val Cys Leu Leu Asn Asn 145 150 155 160

Phe Tyr Pro Arg Glu Wing Lys Val Gln Trp Lys Val Asp Asn Wing Leu

165 170 175 Gln Be Gly Asn Be Gln Glu Be Val Thr Glu Gln Asp Be Lys Asp 180 185 190

Be Thr Tyr Be Read Be Be Thr Read Read Thr Be Read Lys Wing Asp Tyr 195 200 205

Glu Lys His Lys Val Tyr Wing Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235

<210> 26 <211> 236

<212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin

<400> 26

Met Asp Met Arg Val Pro Wing Gln Leu Leu Gly Leu Leu Leu Leu Trp 15 10 15

Phe Pro Gly Wing Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser 20 20 30

Leu Be Ala Ser Val Gly Asp Arg Val Thr Phe Thr Cys Arg Ala Ser 35 40 45

Gln Asp Ile Arg Arg Asp Read Gly Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60

Pro Wing Lys Arg Leu Ile Tyr Wing Wing Be Arg Leu Gln Ser Gly Val 65 70 75 80

Pro Be Arg Phe Be Gly Be Gly Be Gly Thr Gly Thr Glu Phe Thr Read 85 85 95

Ile Ser Ser Leu Gln Pro Glu Asp Phe Wing Thr Tyr Tyr Cys Leu Gln 100 105 110

His Asn Asn Tyr Pro Arg Thr Phe Gly Gln Gly Thr Glu Val Glu Ile 115 120 125 Ile Arg Thr Val Wing Ward Pro Be Val Phe Ile Phe Pro Pro As Asp 130 135 140

Glu Gln Leu Lys Be Gly Thr Wing Be Val Val Cys Leu Leu Asn Asn 145 150 155 160

Phe Tyr Pro Arg Glu Wing Lys Val Gln Trp Lys Val Asp Asn Wing Leu

165 170 175

Gln Be Gly Asn Be Gln Glu Be Val Thr Glu Gln Asp Be Lys Asp 180 185 190

Be Thr Tyr Be Read Be Be Thr Read Read Thr Be Read Lys Wing Asp Tyr 195 200 205

Glu Lys His Lys Val Tyr Wing Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235

<210> 27 <211> 236 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin <400> 27

Met Asp Met Arg Val Pro Wing Gln Leu Leu Gly Leu Leu Leu Leu Trp 15 10 15

Phe Pro Gly Wing Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser 20 20 30

Read Sera Wing Be Val Gly Asp Arg Val Thr Ile Thr Cys Arg Wing Be 35 40 45

Gln Gly Ile Arg Asn Asp Read Gly Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60

Ala Pro Lys Arg Leu Ile Tyr Ala Wing To Be Leu Gln To Be Gly Val 65 70 75 80 Pro To Be Arg Phe To Be Gly To Be Gly To Be Gly Thr To Leu Thr 85 90 95

Ile Ser Ser Leu Gln Pro Glu Asp Phe Wing Thr Tyr Tyr Cys Leu Gln 100 105 110

His Asn Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 115 120 125

Lys Arg Thr Val Wing Pro Wing Ser Val Phe Ile Phe Pro Val Ser Asp 130 135 140

Glu Gln Leu Lys Be Gly Thr Wing Be Val Val Cys Leu Leu Asn Asn 145 150 155 160

Phe Tyr Pro Arg Glu Wing Lys Val Gln Trp Lys Val Asp Asn Wing Leu 165 170 175

Gln Be Gly Asn Be Gln Glu Be Val Thr Glu Gln Asp Be Lys Asp 180 185 190

Be Thr Tyr Be Read Be Be Thr Read Read Thr Be Read Lys Wing Asp Tyr 195 200 205

Glu Lys His Lys Val Tyr Wing Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 28 <211> 236 <212> PRT <213> Artificial Sequence <220> <223> Light Chain Immunoglobulin <400> 28 Met Asp 'Met Arg Val Pro Wing Gln Leu Leu Gly Leu Leu Leu Leu 1 5 10 15 Phe Pro Gly Wing Arg Cys Asp Ile Gln Met Thr Gln Phe Pro Ser 20 25 30 Leu Ser Wing Val Val Gly Asp Arg Val Thr Ile Thr Cys Arg Wing Ser 35 40 45

Gln Gly Ile Arg Asn Asp Read Gly Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60

Pro Wing Lys Arg Leu Ile Tyr Wing Ala Ser Arg Read His Arg Gly Val 65 70 75 80

Pro Be Arg Phe Be Gly Be Gly Be Gly Thr Gly Thr Glu Phe Thr Read 85 85 95

Ile Ser Ser Leu Gln Pro Glu Asp Phe Wing Thr Tyr Tyr Cys Leu Gln 100 105 110

His Asn Being Tyr Pro Cys Being Phe Gly Gln Gly Thr Lys Leu Glu Ile 115 120 125

Lys Arg Thr Val Wing Pro Wing Ser Val Phe Ile Phe Pro Val Ser Asp 130 135 140

Glu Gln Leu Lys Be Gly Thr Wing Be Val Val Cys Leu Leu Asn Asn 145 150 155 160

Phe Tyr Pro Arg Glu Wing Lys Val Gln Trp Lys Val Asp Asn Wing Leu 165 170 175

Gln Be Gly Asn Be Gln Glu Be Val Thr Glu Gln Asp Be Lys Asp 180 185 190

Be Thr Tyr Be Read Be Be Thr Read Read Thr Be Read Lys Wing Asp Tyr 195 200 205

Glu Lys His Lys Val Tyr Wing Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220

Ser Pro Val Thr Lys Ser Phe "Asn Arg Gly Glu Cys 225 230 235

<210> 29 <211> 473 <212> PRT <213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin <400> 29

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Wing Ile Ile Lys Gly 15 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30

Pro Gly Gly Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe 35 40 45

Be Asp Tyr Tyr Met Be Trp Ile Arg Gln Wing Pro Gly Lys Gly Leu 50 55 60

Glu Trp Val Ser Tyr Ile Ser Ser Gly Ser Thr Ile Tyr Tyr Wing 65 70 75 80

Asp Be Val Lys Gly Arg Phe Thr Ile Be Arg Asp Asn Wing Alys Lys Asn 85 90 95

Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Wing Glu Asp Thr Wing Wing

100 105 110

Tyr Tyr Cys Wing Arg Val Leu Arg Phe Leu Glu Trp Leu Leu Tyr Tyr

115 120 125

Tyr Tyr Tyr Tyr Gly Met Asp Val Trp

130 135 140

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

145 150 155 160

Cys Be Arg Be Thr Be Glu Be Thr Ward Wing Leu Gly Cys Be Val

165 170 175 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Wing

180 185 190

Read Thr Be Gly Val His Thr Phe Pro Wing Val Read Gln Be Ser Gly 195 200 205

Read Tyr Be Read Be Ser Val Val Thr Val Pro Ser As Asn Phe Gly

210 215 220

Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Being Asn Thr Lys

225 230 235 240 Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Cys 245 250 255

Pro Wing Pro Pro Val Gly Wing Pro Ser Val Phe Leu Phe Pro Pro Lys 260 265 270

Pro Lys Asp Thr Read Met Ile Be Arg Thr Pro Glu Val Thr Cys Val 275 280 285

Val Val Asp Val Be His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 290 295 300

Val Asp Gly Val Glu Val His Asn Wing Lys Thr Lys Pro Arg Glu Glu 305 310 315 320

Gln Phe Asn Be Thr Phe Arg Val Val Be Val Leu Thr Val Val His 325 330 335

Gln Asp Trp Read Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 340 345 350

Gly Leu Pro Wing Pro Ile Glu Lys Thr Ile Be Lys Thr Lys Gly Gln 355 360 365

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Being Arg Glu Glu Met 370 375 380

Thr Lys Asn Gln Val Ser Read Thr Cys Read Val Lys Gly Phe Tyr Pro 385 390 395 400

Ser Asp Ile Wing Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 405 410 415

Tyr Lys Thr Thr Pro Pro Met Asu Asp Be Asp Gly Be Phe Phe Leu 420 425 430

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 435 440 445

Phe Ser Cys Ser Val Met His Glu Wing Read His Asn His Tyr Thr Gln 450 455 460

Lys Be Read Be Read Be Pro Gly Lys 465 470

<210> 30 <211> 470 <212> PRT

<213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin <400> 30

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Wing Ile Ile Lys Gly 15 10 15

Val Gln Cys Gln Wing Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30

Pro Gly Gly Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe 35 40 45

Be Asp Tyr Tyr Met Be Trp Ile Arg Gln Wing Pro Gly Lys Gly Leu 50 55 60

Glu Trp Val Be Tyr Ile Be Be Gly Be Thr Arg Asp Tyr Wing 65 70 75 80

Asp Be Val Lys Gly Arg Phe Thr Ile Be Arg Asp Asn Wing Alys Lys Asn 85 90 95

Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Wing Glu Asp Thr Wing Val 100 105 110

Tyr Tyr Cys Val Arg Asp Gly Val Glu Thr Thr Phe Tyr Tyr Tyr Tyr 115 120 125

Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 130 135 140

Wing Be Thr Lys Gly Pro Be Val Phe Pro Read Wing Pro Cys Be Arg 145 150 155 160

Be Thr Be Glu Be Thr Ward Wing Read Gly Cys Read Val Val Lys Asp Tyr 165 170 175

Phe Pro Glu Pro Val Thr Val Ser Tr Asn Ser Gly Wing Leu Thr Ser 180 185 190

Gly Val His Thr Phe Pro Wing Val Leu Gln Be Ser Gly Leu Tyr Ser 195 200 205 Leu Be Ser Val Val Thr Val Pro Be Asn Phe Gly Thr Gln Thr 210 215 220

Tyr Thr Cys Asn Val Asp His Lys Pro Being Asn Thr Lys Val Asp Lys 225 230 235 240

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Cys Pro Wing Pro

245 250 255

Pro Val Gly Wing Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285

Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 290 295 300

Val Glu Val His Asn Wing Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 305 310 315 320

Be Thr Phe Arg Val Val Be Val Leu Thr Val Val His Gln Asp Trp

325 330 335

Read Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 340 345 350

Pro Ile Glu Wing Lys Thr Ile Be Lys Thr Lys Gly Gln Pro Arg Glu 355 360 365

Pro Gln Val Tyr Thr Leu Pro Pro Be Arg Glu Glu Met Thr Lys Asn 370 375 380

Gln Val Ser Read Thr Cys Read Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400

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

405 410 415

Thr Pro Pro Met Read Asp Be Asp Gly Be Phe Phe Read Tyr Be Lys 420 425 430

Leu Thr Val Asp Lys Be Arg Trp Gln Gln Gly Asn Val Phe Be Cys 435 440 445

Ser Val Met His Glu Ala Read His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460 Ser Leu Ser Pro Gly Lys 465 470

<210> 31 <211> 470 <212> PRT

<213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin <400> 31

Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Wing Ile Leu Lys Gly 15 10 15

Val Gln Cys Glu Val Gln Read Leu Read Glu Ser Gly Gly Gly Leu Read Val Gln 20 25 30

Pro Gly Gly Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe 35 40 45

Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60

Glu Trp Val Be Wing Ile Be Gly Be Gly Gly Be Thr Tyr Tyr Wing 65 70 75 80

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

85 90 95

Thr Leu Tyr Leu Gln Met Asn Be Read Arg Wing Glu Asp Thr Wing Val 100 105 110

Tyr Tyr Cys Wing Lys Gly Tyr Ser Ser Gly Trp Tyr Tyr Tyr Tyr Tyr 115 120 125

Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 130 135 140

Wing Be Thr Lys Gly Pro Be Val Phe Pro Read Wing Pro Cys Be Arg 145 150 155 160

Be Thr Be Glu Be Thr Wing Ward Leu Gly Cys Leu Val Lys Asp Tyr

165 170 175 Phe Pro Glu Pro Val Thr Val Ser Tr Asn Ser Gly Wing Leu Thr Ser 180 185 190

Gly Val His Thr Phe Pro Wing Val Leu Gln Ser Ser Gly Leu Tyr Ser 195 200 205

Read Be Ser Val Val Thr Val Pro Ser As As Phe Gly Thr Gln Thr 210 215 220

Tyr Thr Cys Asn Val Asp His Lys Pro Being Asn Thr Lys Val Asp Lys 225 230 235 240

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Cys Pro Wing Pro 245 250 255

Pro Val Gly Wing Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285

Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 290 295 300

Val Glu Val His Asn Wing Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 305 310 315 320

Be Thr Phe Arg Val Val Be Val Leu Thr Val Val His Gln Asp Trp 325 330 335

Read Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 340 345 350

Pro Ile Glu Wing Lys Thr Ile Be Lys Thr Lys Gly Gln Pro Arg Glu 355 360 365

Pro Gln Val Tyr Thr Leu Pro Pro Be Arg Glu Glu Met Thr Lys Asn 370 375 380

Gln Val Ser Read Thr Cys Read Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400

Val Glu Wing Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415

Thr Pro Pro Met Read Asp Be Asp Gly Be Phe Phe Read Tyr Be Lys 420 425 430 Read Thr Val Asp Lys Be Arg Trp Gln Gly Asn Val Phe Be Cys 435 440 445

Ser Val Met His Glu Wing Read His Asn HisTyr Thr Gln Lys Ser Leu 450 455 460

Ser Leu Ser Pro Gly Lys 465 470

<210> 32 <211> 470 <212> PRT <213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin <400> 32

Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Wing Ile Leu Lys Gly

1 5 10 15

Val Gln Cys Glu Val Gln Read Leu Read Glu Ser Gly Gly Gly Leu Read Val Gln 20 25 30

Pro Gly Gly Be Read Arg Read Be Cys Thr Wing Be Gly Phe Thr Phe 35 40 45

Ser Ser Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60

Glu Trp Val Be Wing Ile Be Gly Be Gly Gly Thr Thr Phe Tyr Wing 65 70 75 80

Asp Be Val Lys Gly Arg Phe Thr Ile Be Arg Asp Asn Be Arg Thr 85 90 95

Thr Leu Tyr Leu Gln Met Asn Be Read Arg Wing Glu Asp Thr Wing Val 100 105 110

Tyr Tyr Cys Wing Lys Asp Read Gly Trp Be Asp Be Tyr Tyr Tyr Tyr 115 120 125

Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 130 135 140 Wing Ser Thr Lys Gly Pro Ser Val Phe Pro Read Wing Pro Cys Ser Arg

145 150 155 160

Be Thr Be Glu Be Thr Wing Ward Leu Gly Cys Leu Val Lys Asp Tyr

165 170 175

Phe Pro Glu Pro Val Thr Val Ser Tr Asn Ser Gly Wing Leu Thr Ser

180 185 190

Gly Val His Thr Phe Pro Wing Val Leu Gln Ser Ser Gly Leu Tyr Ser

195 200 205

Read Be Ser Val Val Thr Val Pro Be Asn Phe Gly Thr Gln Thr

210 215 220

Tyr Thr Cys Asn Val Asp His Lys Pro Being Asn Thr Lys Val Asp Lys 225 230 235 240

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Cys Pro Wing Pro 245 250 255

Pro Val Gly Wing Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285

Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 290 295 300

Val Glu Val His Asn Wing Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 305 310 315 320

Be Thr Phe Arg Val Val Be Val Leu Thr Val Val His Gln Asp Trp 325 330 335

Read Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 340 345 350

Pro Ile Glu Wing Lys Thr Ile Be Lys Thr Lys Gly Gln Pro Arg Glu 355 360 365

Pro Gln Val Tyr Thr Leu Pro Pro Be Arg Glu Glu Met Thr Lys Asn 370 375 380

Gln Val Ser Read Thr Cys Read Val Lys Gly Phe Tyr Pro Be Asp Ile 385 390 395 400 Wing Val Glu Trp Glu Be Asn Gly Gln Pro Asn Tyr Lys Thr 405 410 415

Thr Pro Pro Met Read Asp Be Asp Gly Be Phe Phe Read Tyr Be Lys 420 425 430

Leu Thr Val Asp Lys Be Arg Trp Gln Gln Gly Asn Val Phe Be Cys 435 440 445

Ser Val Met His Glu Wing Read His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460

Ser Leu Ser Pro Gly Lys 4 65 470 <210> 33 <211> 470 <212> PRT <213> Artificial Sequence <220> <223> Immunoglobulin heavy chain of 2.12.1. fx <400> 33 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile 1 5 10 Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly 20 25 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ser Gly 35 40 45 Be Asp Tyr Tyr Met Be Trp Ile Arg Gln Wing Pro Gly 50 55 60 Glu Trp Val Be Tyr Ile Be Be Gly Be Thr Arg 15

30

65 70 75 80

Asp Be Val Lys Gly Arg Phe Thr Ile Be Arg Asp Asn Wing Alys Lys Asn 85 90 95

Be Leu Tyr Leu Gln Met Asn Be Leu Arg Wing Glu Asp Thr Wing Val 100 105 110 Tyr Tyr Cys Wing Arg Asp Gly Val Glu Thr Thr Phe Tyr Tyr Tyr 115 120 125

Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 130 135 140

Wing Be Thr Lys Gly Pro Be Val Phe Pro Read Wing Pro Cys Be Arg 145 150 155 160

Be Thr Be Glu Be Thr Ward Wing Read Gly Cys Read Val Val Lys Asp Tyr 165 170 175

Phe Pro Glu Pro Val Thr Val Ser Tr Asn Ser Gly Wing Leu Thr Ser 180 185 190

Gly Val His Thr Phe Pro Wing Val Leu Gln Ser Ser Gly Leu Tyr Ser 195 200 205

Read Be Ser Val Val Thr Val Pro Ser As As Phe Gly Thr Gln Thr 210 215 220

Tyr Thr Cys Asn Val Asp His Lys Pro Being Asn Thr Lys Val Asp Lys 225 230 235 240

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Cys Pro Wing Pro 245 250 255

Pro Val Gly Wing Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 260 265 270

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 275 280 285

Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 290 295 300

Val Glu Val His Asn Wing Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 305 310 315 320

Be Thr Phe Arg Val Val Be Val Leu Thr Val Val His Gln Asp Trp 325 330 335

Read Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 340 345 350

Wing Pro Ile Glu Lys Thr Ile Be Lys Thr Lys Gly Gln Pro Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Be Glu Glu Met Thr Lys Asn 370 375 380

Gln Val Ser Read Thr Cys Read Val Lys Gly Phe Tyr Pro Ser Asp Ile 385 390 395 400

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

405 410 415

Thr Pro Pro Met Read Asp Be Asp Gly Be Phe Phe Read Tyr Be Lys 420 425 430

Leu Thr Val Asp Lys Be Arg Trp Gln Gln Gly Asn Val Phe Be Cys 435 440 445

Ser Val Met His Glu Wing Read His Asn His Tyr Thr Gln Lys Ser Leu 450 455 460

Ser Leu Ser Pro Gly Lys 465 470

<210> 34

<211> 125 <212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin mature heavy chain variable region of 2.12.1 fx <400> 34

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe Be Asp Tyr

20 25 30

Tyr Met Ser Trp Ile Arg Gln Pro Wing Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Tyr Ile Ser Ser Ser Gly Ser Thr Arg Asp Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Ile Be Arg Asp Asn Wing Lys Asn Be Read Le Tyr 65 70 75 80 Leu Gln Met Asn Be Read Arg Wing Glu Asp Thr Wing Val Tyr Cyr 85 90 95

Arg Asp Wing Gly Val Glu Thr Thr Phe Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 HO

Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125

<210> 35 <211> 236 <212> PRT <213> Artificial Sequence <220>

<223> Immunoglobulin light chain of 2.12.1 fx <400> 35

Met Asp Met Arg Val Pro Wing Gln Leu Leu Gly Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Wing Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser 20 20 30

Read Sera Wing Be Val Gly Asp Arg Val Thr Ile Thr Cys Arg Wing Be 35 40 45

Gln Asp Ile Arg Arg Asp Read Gly Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60

Pro Wing Lys Arg Leu Ile Tyr Wing Wing Be Arg Leu Gln Ser Gly Val 65 70 75 80

Pro Be Arg Phe Be Gly Be Gly Be Gly Thr Gly Thr Glu Phe Thr Read Le Thr a5 90 95

Ile Ser Ser Leu Gln Pro Glu Asp Phe Wing Thr Tyr Tyr Cys Leu Gln 100 105 110

His Asn Asn Tyr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 115 120 125

Lys Arg Thr Val Wing Ward Pro Be Val Phe Ile Phe Pro Pro As Asp 130 135 140 Glu Gln Leu Lys Ser Gly Thr Wing Be Val Val Cys Leu Asn Asn 145 150 155 160

Phe Tyr Pro Arg Glu Wing Lys Val Gln Trp Lys Val Asp Asn Wing Leu 165 170 175

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

180 185 190

Be Thr Tyr Be Read Be Be Thr Read Read Thr Be Read Lys Wing Asp Tyr

195 200 205

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

210 215 220

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235

<210> 36 <211> 108 <212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin light chain variable region of maturity 2.12.1 fx <400> 36

Asp Ile Gln Met Thr Gln Be Pro Be Be Read Be Wing Be Val Gly 15 10 15

Asp Arg Val Thr Ile Thr Cys Arg Wing Be Gln Asp Ile Arg Arg Asp 20 25 30

Read Gly Trp Tyr Gln Gln Lys Pro Gly Lys Pro Wing Lys Arg Leu Ile 35 40 45

Tyr Wing Wing Be Arg Read Gln Be Gly Val Pro Be Arg Phe Be Gly 50 55 60

Be Gly Be Gly Thr Glu Phe Thr Read It Thr Ile Be Be Read Gln Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Read Gln His Asn Asn Tyr Pro Arg

85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105

<210> 37 <211> 112 <212> PRT

<213> Artificial Sequence <220>

<223> Humanized 7C10 immunoglobulin light chain variable region; version 1 <4 00> 37

Asp Val Val Met Thr Gln Be Pro Read Be Read Pro Val Thr Pro Gly 15 10 15

Glu Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Gly Asn Thr Tyr Gave Gln Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Gln Read Leu Ile Tyr Lys Val Ser Asn Arg Read Le Tyr Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110

<210> 38 <211> 112 <212> PRT

<213> Artificial Sequence <220>

<223> Humanized 7C10 immunoglobulin light chain variable region; version 2 <4 00> 38 Asp Ile Val Met Thr Gln Be Pro Read Be Read Pro Val Thr Pro Gly 15 10 15

Glu Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Gly Asn Thr Tyr Gave Gln Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Gln Read Leu Ile Tyr Lys Val Ser Asn Arg Read Le Tyr Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110

<210> 39 <211> 117 <212> PRT

<213> Artificial Sequence <220>

<223> Humanized 7C10 immunoglobulin heavy chain variable region; version 1 <4 00> 39

Gln Val Gln Leu Gln Glu Be Gly Pro Gly Leu Val Lys Pro Be Glu 15 10 15

Thr Read Be Read Thr Cys Thr Val Be Gly Tyr Be Ile Thr Gly Gly 20 25 30

Tyr Leu Trp Asn Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp 35 40 45

Met Gly Tyr Ile Being Tyr Asp Gly Thr Asn Asn Tyr Lys Pro Being Read 50 55 60

Lys Asp Arg Ile Thr Ile Be Arg Asp Thr Be Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Read Le Ser Be Val Thr Wing Asp Thr Wing Val Tyr Tyr Cys 85 90 95

Wing Arg Tyr Gly Arg Val Phe Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110

Val Thr Val Ser Ser 115 <210> 40 <211> 117 <212> PRT

<213> Artificial Sequence <220>

<223> Humanized immunoglobulin 7C10 heavy chain variable region version 2 <400> 40

Gln Val Gln Leu Gln Glu Be Gly Pro Gly Leu Val Lys Pro Be Glu 10 15

Thr Read Be Read Thr Cys Thr Val Be Gly Tyr Be Ile Thr Gly Gly 20 25 30

Tyr Leu Trp Asn Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp 35 40 45

Ile Gly Tyr Ile Be Tyr Asp Gly Thr Asn Asn Tyr Lys Pro Ser Leu 50 55 60

Lys Asp Arg Val Thr Ile Be Arg Asp Thr Be Lys Asn Gln Phe Ser 65 70 75 80

Leu Lys Leu Being Ser Val Thr Wing Asp Thr Wing Val Tyr Tyr Cys 85 90 95

Wing Arg Tyr Gly Arg Val Phe Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110

Val Thr Val Ser Ser 115 <210> 41 <211> 117 <212> PRT

<213> Artificial Sequence <220>

<223> Humanized 7C10 immunoglobulin heavy chain variable region; version 3

<400> 41

Gln Val Gln Leu Gln Glu Be Gly Pro Gly Leu Val Lys Pro Be Glu 15 10 15

Thr Read Be Read Thr Cys Thr Val Be Gly Tyr Be Ile Be Gly Gly

20 25 30

Tyr Leu Trp Asn Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp 35 40 45

Ile Gly Tyr Ile Be Tyr Asp Gly Thr Asn Asn Tyr Lys Pro Ser Leu 50 55 60

Lys Asp Arg Val Thr Ile Be Val Asp Thr Be Lys Asn Gln Phe Be

65 70 75 80

Leu Lys Leu Being Ser Val Thr Wing Asp Thr Wing Val Tyr Tyr Cys 85 90 95

Wing Arg Tyr Gly Arg Val Phe Phe Asp

100 105 110

Val Thr Val Ser Ser 115 <210> 42 <211> 130 <212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin A12 heavy chain variable region <400> 42

Glu Val Gln Leu Val Gln Ser Gly Wing Glu Val Lys Lys Pro Gly Ser 15 10 15 Ser Val Lys Val Ser Cys Lys Wing Gly Gly Thr Phe Ser Ser Tyr 20 25 30

Wing Ile Ser Trp Val Arg Gln Pro Wing Gly Gln Gly Leu Glu Trp Met 35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Wing Asn Tyr Wing Gln Lys Phe 50 55 60

Gln Gly Arg Val Thr Ile Thr Wing Asp Lys Be Thr Be Thr Wing Tyr 65 70 75 80

Met Glu Read Be Ser Read Le Be Glu Asp Thr Wing Val Tyr Tyr Cys 85 90 95

Arg Wing Pro Wing Read Arg Phe Read Glu Trp Ser Thr Gln Asp His Tyr 100 105 110

Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val 115 120 125

Ser Ser 130 <210> 43 <211> 109 <212> PRT 20 <213> Artificial Sequence <220>

<223> Immunoglobulin A12 light chain variable region <400> 43

Be Ser Glu Leu Thr Gln Asp Pro Val Wing Be Val Wing Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Gln Gly Asp Be Read Arg Be Tyr Tyr Wing 20 25 30

Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Wing Val Leu Val Ile Tyr

40 45

Gly Lys Asn Asn Arg Pro Be Gly Ile Asn Arg Pro Phe Be Gly Ser

50 55 60 Be Ser Gly Asn Thr Wing Be Read Thr Ile Thr Gly Wing Gln Wing Glu 65 70 75 80

Asp Glu Wing Asp Tyr Tyr Cys Asn Be Arg Asp Asn Be Asp Asn Arg 85 90 95

Leu Ile Phe Gly Gly Gly Gly Thr Lys Leu Thr Val Leu Ser 100 105

<210> 44 <211> 119 <212> PRT <213> Artificial Sequence <220>

<223> Immunoglobulin IA heavy chain variable region <220>

<221> region of biological interest <222> (1) .. (119)

Possible mutations: R30, S30, N31, S31, Y94, H94, D104, E104. <400> 44

Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val His Pro Gly Gly 15 10 15

Be Read Arg Read Be Cys Wing Gly Be Gly Phe Thr Phe Arg Asn Tyr 20 25 30

Met Tyr Wing Trp Val Arg Gln Pro Wing Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ala Ile Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60

Gly Arg Phe Thr Ile Be Arg Asp Asn Wing Lys Asn Be Read Tyr Leu 65 70 75 80

Gln Met Asn Be Read Arg Wing Glu Asp Met Wing Val Tyr Tyr Cys Wing 85 90 95

Arg Wing Pro Asn Trp Gly Ser Asp Wing Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <210> 45 <211> 107 <212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin IA light chain variable region <220>

<221> region of biological interest <222> (1) .. (107)

Possible mutations: P96, 196, P100, Q100, R103, K103, V104, L104, D105, E105 <400> 45

Asp Ile Gln Met Thr Gln Be Pro Be Be Read Be Wing Be Val Gly 15 10 15

Asp Arg Val Ile Thr Cys Arg Wing Be Gln Gly Ile Be Ser Trp 20. 25 30

Leu Trp Wing Tyr Gln Gln Lys Pro Glu Lys Pro Wing Lys Ser Leu Ile 35 40 45

Tyr Wing Wing Ser Be Read 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 Leu Gln Pro 65 70 75 80

Glu Asp Phe Wing Thr Tyr Cyr Gln Gln Tyr Asn Ser Tyr Pro

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105

<210> 46 <211> 251 <212> PRT

<213> Artificial Sequence <220>

<223> single chain fv 8A1 <400> 46

Glu Val Gln Leu Val Gln Ser Gly Wing Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Be Leu Thr Ile Be Cys Lys Gly Pro Gly Tyr Asn Phe Phe Asn Tyr 20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly Ile Ile Tyr Pro Thr Asp Be Asp Thr Arg Tyr Be Pro Be Phe 50 55 60

Gln Gly Gln Val Thr Ile Be Val Asp Lys Be Ile Be Thr Wing Tyr 65 70 75 80

Read Gln Trp Be Ser Read Le Lys Wing Be Asp Thr Wing Met Tyr Tyr Cys 85 90 95

Wing Arg Be Ile Arg Tyr Cys Gly Gly Arg Cys Tyr Be Gly Tyr 100 105 110

Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 130 130 140 140

Glu Leu Thr Gln Asp Pro Val Wing Ser Val Valu Wing Gly Gln Thr Val 145 150 155 160

Arg Ile Thr Cys Gln Gly Asp Be Read Arg Be Tyr Tyr Wing Be Trp 165 170 175

Tyr Gln Gln Lys Pro Gly Gln Pro Wing Val Leu Val Ile Tyr Gly Lys 180 185 190

Asn Asn Arg Pro Be Gly Ile Pro Asp Arg Phe Be Gly Be Ser 195 195 205

Gly Asn Thr Wing Be Leu Thr Ile Thr Gly Wing Gln Wing Glu Asp Glu 210 215 220 Wing Asp Tyr Tyr Cys Asn Be Arg Asp Be Gly Asn His Val 225 230 235 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 245 250 <210> 47 <211> 245 <212> PRT <213> Artificial Sequence <220> <223> single strand fv 9Α2 <400> 47 Gln Val Gln Leu Val Gln Ser Gly Wing Glu Val Arg Lys Pro Gly I 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Arg Asn 20 25 30 Asp Ile Asn Trp Val Arg Gln Pro Wing Gly Gln Gly Leu Glu Trp 35 40 45 Gly Arg Ile Be Gly His Tyr Gly Asn Thr Asp His Wing Gln Lys 50 55 60 Gln Gly Arg Phe Thr Met Thr Lys Asp Thr Be Thr Be Thr Wing 65 70 75 Met Glu Leu Arg Be Read Thr Phe Asp Asp Thr Wing Val Tyr Tyr 85 90 95 Wing Arg Be Gln Trp Asn Val Asp Tyr Trp Gly Arg Gly Thr Leu 100 105 110 Thr Val Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 115 115 125 125 Gly Gly Ala Read Asn Phe Met Leu Thr Gln Pro His Ser Val 130 135 140 Glu Ser Pro Gly Lys Thr Val Thr Ile Ser Cys Thr Arg Ser Ser 145 150 155 240

80

160 Ser Ile Wing Ser Asn Tyr Val Gln Trp Tyr Gln Arg Pro Gly Ser 165 170 175

Ser Pro Thr Thr Val Ile Phe Asu Asp Arg Arg Pro Pro Ser Gly Val 180 185 190

Pro Asp Arg Phe Ser Gly Ser Ile Asp Thr Ser Ser Ser Asn Ser Ser Ser 195 195 205

Leu Thr Ile Ser Gly Leu Lys Thr Glu Asp Glu Wing Asp Tyr Cyr 210 215 220

Gln Be Phe Asp Be Thr Asn Read Val Val Phe Gly Gly Gly Gly Thr Lys 225 230 235 240

Val Thr Val Leu Gly 245

<210> 48 <211> 245 <212> PRT

<213> Artificial Sequence <220>

<223> single string fv 11Α4 <4 00> 48

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly I 5 10 15

Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe Be Ser Tyr 20 25 30

Wing Met Ser Trp Val Arg Gln Pro Wing Gly Lys Gly Leu Glu Trp Val 35 40 45

Be Wing Ile Be Gly Be Gly Gly Be Thr Tyr Tyr Wing Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Ile Be Arg Asp Asn Be Lys Asn Thr Read Tyr 65 70 75 80

Read Gln Met Asn Be Read Arg Wing Glu Asp Thr Wing Val Tyr Tyr Cys

85 90 95 Wing Ser Be Pro Tyr Ser Be Arg Trp Tyr Ser Phe Asp Pro Trp Gly 100 105 110

Gln Gly Thr Met Val Thr Val Be Gly Gly Gly Gly Gly Gly Gly 115 120 125

Gly Gly Ser Gly Gly Gly Gly Gly Wing Read Tyr Glu Read Thr Gln 130 135 140

Pro Pro Ser Val Ser Val Gly Gln Thr Wing Thr Ile Thr Cys 145 150 155 160

Ser Gly Asp Asp Read Gly Asn Lys Tyr Val Ser Trp Tyr Gln Gln Lys 165 170 175

Pro Gly Gln Ser Pro Val Leu Val Ile Tyr Gln Asp Thr Lys Arg Pro 180 185 190

Be Gly Ile Pro Glu Arg Phe Be Gly Be Asn Be Gly Asn Ile Wing 195 200 205

Thr Leu Thr Ile Be Gly Thr Gln Wing Val Asp Glu Wing Asp Tyr Tyr 210 215 220

Cys Gln Val Trp Asp Gly Thr Val Val Phe Gly Gly Gly Thr Lys 225 230 235 240

Leu Thr Val Leu Gly

245

<210> 49

<211> 251

<212> PRT

<213> Artificial Sequence

<220>

<223> single strand fv 7Α4 <400> 49

Glu Val Gln Leu Val Gln Ser Gly Wing Glu Val Lys Lys Pro Gly Glu 15 10 15

Be Leu Thr Ile Be Cys Lys Gly Be Gly Tyr Asn Phe Phe Asn Tyr 20 25 30 Trp Xle Gly Trp Val Arg Gln Met Pro Gly Lys Asp Leu Glu Trp Met 35 40 45

Gly Ile Ile Tyr Pro Thr Asp Be Asp Thr Arg Tyr Be Pro Be Phe 50 55 60

Gln Gly Gln Val Thr Ile Be Val Asp Lys Be Ile Be Thr Wing Tyr 65 70 75 80

Read Gln Trp Be Ser Read Le Lys Wing Be Asp Thr Wing Met Tyr Tyr Cys 85 90 95

Wing Arg Be Ile Arg Tyr Cys Gly Gly Arg Cys Tyr Be Gly Tyr 100 105 110

Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 125

Gly Gly Gly Be Ser Gly Gly Gly Gly Ser Be Gly Gly Gly Gly Be Ser 130 135 140

Glu Leu Thr Gln Asp Pro Val Wing Ser Val Valu Wing Gly Gln Thr Val 145 150 155 160

Arg Ile Thr Cys Arg Gly Asp Be Read Arg Asn Tyr Tyr Wing Be Trp 165 170 175

Tyr Gln Gln Lys Pro Gly Gln Pro Wing Val Leu Val Ile Tyr Gly Lys 180 185 190

Asn Asn Arg Pro Be Gly Ile Pro Asp Arg Phe Be Gly Be Ser 195 195 205

Gly Asn Thr Wing Be Read Thr Ile Thr Gly Wing Gln Wing Glu Asp Glu 210 215 220

Asp Wing Tyr Tyr Cys Asn Be Arg Asp Be Gly Asn His Met Val 225 230 235 240

Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 245 250

<210> 50 <211> 249 <212> PRT

<213> Artificial Sequence <220>

<223> single strand fv IlAl <4 00> 50

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15

Be Read Arg Read Be Cys Wing Wing Be Gly Phe Thr Phe Be Asp Phe 20 25 30

Ala Met His Trp Val Arg Gln Ile Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45

Ser Gly Leu Arg His Asp Gly Ser Thr Wing Tyr Tyr Wing Gly Ser Val 50 55 60

Lys Gly Arg Phe Thr Ile Be Arg Asp Asn Be Arg Asn Thr Val Tyr 65 70 75 80

Read Gln Met Asn Be Read Arg Wing Glu Asp Thr Wing Thr Tyr Tys Cys 85 90 95

Val Thr Gly Ser Gly Ser Ser Gly Pro His Wing Phe Pro Val Trp Gly 100 105 110

Lys Gly Thr Read Val Val Val Be Ser Gly Gly Gly Gly Be Gly Gly 115 120 125

Gly Gly Be Gly Gly Gly Gly Gly Wing Read Tyr Val Leu Thr Gln 130 135 140

Pro Pro Be Ala Be Gly Thr Pro Gly Gln Arg Val Thr Ile Be Cys 145 150 155 160

Ser Gly Ser Asn Ser Asn Ile Gly Thr Tyr Thr Val Asn Trp Phe Gln 165 170 175

Gln Leu Pro Gly Thr Wing Pro Lys Leu Read Ile Tyr Ser Asn Asn Gln 180 185 190

Arg Pro Being Gly Val Pro Asp Arg Phe Being Gly Being Lys Being Gly Thr 195 200 205

Ser Ala Ser Leu Wing Ile Ser Gly Leu Gln Ser Glu Asp Glu Asp Wing 210 215 220 Tyr Tyr Cys Wing Trp Asp Asp Wing Be Asu Gn Pro Val Phe 225 '230 235 Gly Gly Thr Lys Val Thr Val Leu Gly 245 <210 > 51 <211> 251 <212> PRT <213> Artificial Sequence <220> <223> single chain fv 7A6 <4 00> 51 Glu Val Gln Leu Val Gln Ser Gly Wing Glu Val Lys Lys Pro Gly 1 5 10 15 Ser Read Thr Ile Being Cys Lys Gly Being Gly Tyr As n Phe Phe Asn 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp 35 40 45 Gly Ile Ile Tyr Pro Thr Asp Be Asp Thr Arg Tyr Ser Pro 50 55 60 Gln Gly Gln Val Thr Ile Ser Val Asp Lys Be Ile Be Thr Wing 65 70 75 Read Gln Trp Be Be Leu Lys Wing Be Asp Thr Wing Met Tyr Tyr 85 90 95 Wing Arg Be Ile Arg Tyr Cys Pro Gly Gly Arg Cys Tyr Be Gly 100 105 110 Tyr Gly Met Asp Val Trp Gly Gly Gly Thr Read Val Thr Val Ser 115 120 125 Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Ser 130 130 140 140 Glu Leu Thr Gln Asp Pro Wing Val Ser Val Wing Leu Gly Gln Thr 145 150 155 Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Thr Asn Trp 165 170 175

Phe Gln Gln Lys Pro Gly Gln Pro Wing Read Leu Val Val Tyr Wing Lys 180 185 190

Asn Lys Arg Pro Be Gly Ile Pro Asp Arg Phe Be Gly Be Ser 195 195 205

Gly Asn Thr Wing Be Read Thr Ile Thr Gly Wing Gln Wing Glu Asp Glu 210 215 220

Asp Wing Tyr Tyr Cys Asn Be Arg Asp Be Gly Asn His Val Val 225 230 235 240

Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 245 250

<210> 52 <211> 5 <212> PRT

<213> Artificial Sequence <220>

<223> CDR <400> 52 Ser Tyr Trp Met His 1 5

<210> 53 <211> 17 <212> PRT <213> Artificial Sequence <220>

<223> CDR <400> 53

Glu Ile Asn Pro Being Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe Lys

1 5 10 15

Arg

<210> 54 <211> 15 <212> PRT

<213> Artificial Sequence <220>

<223> CDR <400> 54

Gly Arg Pro Asp Tyr Tyr Gly Being Ser Lys Trp Tyr Phe Asp Val 15 10 15

<210> 55 <211> 16 <212> PRT

<213> Artificial Sequence <220>

<223> CDR <4 00> 55

Arg Be Ser Gln Ser Ile Val His Ser Asn Val Asn Thr Tyr Leu Glu 15 10 15

<210> 56 <211> 7 <212> PRT

<213> Artificial Sequence <220>

<223> CDR <4 00> 56 Lys Val Ser Asn Arg Phe Ser 1 5

<210> 57 <211> 9 <212> PRT <213> Artificial Sequence <220>

<223> CDR <400> 57

Phe Gln Gly Being His Val Pro Pro Thr 5

<210> 58 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Heavy Chain Immunoglobulin Variable Region <400> 58 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly 1 5 10 15 Be Val Lys Leu Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Be 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp 35 40 45 Gly Glu Ile Asn Pro Be Asn Gly Arg Thr Asn Tyr Asn Gln Lys 50 55 60 Gln Gly Lys Wing Thr Thr Read Val Thr Asp Lys Be Ser Be Thr Thr Wing 65 70 75 Met Gln Read Le Be Ser Read Thr Glu Asp Be Wing Val Tyr Tyr 85 90 95 Wing Arg Gly Arg Pro Asp Tyr Tyr Gly Be Ser Lys Trp Tyr Phe 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 <210> 59

<211> 118

<212> PRT

<213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin variable region <400> 59

Gln Val Gln Phe Gln Gln Ser Gly Wing Glu Read Val Lys Pro Gly Wing 15 10 15

Be Val Lys Read Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Be Tyr 20 25 30

Met Le His Trp Ile Lys Gln Arg Pro Gly Arg Gly Met Leu Glu Trp Ile 35 40 45

Gly Arg Ile Asp Pro Asn Val Val Asn Val Lys Phe Asn Glu Lys Phe 50 55 60

Lys Be Lys Wing Thr Thr Read Val Asp Lys Pro Be Wing Thr Tyr 65 70 75 80

Met Glu Read Be Ser Read Thr Be Glu Asp Be Wing Val Tyr Tyr Cys 85 90 95

Wing Tyr Arg Wing Tyr Cys Arg Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110

Thr Val Thr Val Ser Ser 115 <210> 60 <211> 123 <212> PRT

<213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin variable region <400> 60

Gln Val Gln Leu Gln Gln Ser Gly Wing Glu Leu Val Lys Pro Gly Wing 15 10 15

Be Val Lys Read Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Be Tyr 20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45

Gly Glu Ile Asn Pro Be Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Arg Lys Wing Thr Thru Leu Thr Val Asp Lys Be Ser Be Thr Wing Tyr 65 70 75 80

Met Gln Read Be Ser Read Thr Be Glu Asp Be Wing Val Tyr Tyr Phe 85 90 95

Wing Arg Gly Arg Pro Asp Tyr Tyr Gly Ser Ser Lys Trp Tyr Phe Asp 100 105 110

Val Trp Gly Wing Gly Thr Thr Val Thr Val Ser 115 120

<210> 61 <211> 120 <212> PRT

<213> Artificial Sequence <220>

<223> Heavy Chain Immunoglobulin Variable Region <400> 61

Gln Val Gln Leu Gln Gln Ser Gly Wing Glu Leu Met Lys Pro Gly Wing 15 10 15

Be Val Lys Ile Be Cys Lys Wing Thr Gly Tyr Thr Phe Be Ser Phe 20 25 30

Trp Ile Glu Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile 35 40 45

Gly Glu Ile Leu Pro Gly Ser Gly Gly Thr His Tyr Asn Glu Lys Phe 50 55 60

Lys Gly Lys Wing Thr Phe Thr Wing Asp Lys Be Ser Asn Thr Wing Tyr 65 70 75 80

Met Gln Read Be Ser Read Thr Be Glu Asp Be Wing Val Tyr Tyr Cys 85 90 95

Wing Arg Gly His Ser Tyr Tyr Phe Tyr Asp Gly Asp Tyr Trp Gly Gln 100 105 110

Gly Thr Be Val Thr Val Ser Ser 115 120

<210> 62 <211> 120 <212> PRT

<213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin variable region <400> 62

Gln Val Gln Leu Gln Gln Pro Gly Ser Val Leu Val Arg Pro Gly Wing 15 10 15

Be Val Lys Read Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Be

20 25 30

Trp Ile His Trp Wing Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45

Gly Glu Ile His Pro Asn Ser Gly Asn Thr Asn Tyr Asn Glu Lys Phe 50 55 60

Lys Gly Lys Wing Thr Read Le Thr Val Asp Thr Be Ser Be Thr Wing Tyr 65 70 75 80

Val Asp Read Be Ser Read Thr Be Glu Asp Ser Wing Val Tyr Tyr Cys 85 90 95

Wing Arg Trp Arg Tyr Gly Ser Pro Tyr Tyr Phe Asp Tyr Trp Gly Gln 100 105 110

Gly Thr Thr Read Thr Val Ser Ser 115 120

<210> 63 <211> 120 <212> PRT

<213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin variable region <400> 63

Gln Val Gln Leu Gln Gln Pro Gly Wing Glu Leu Val Lys Pro Gly Wing 15 10 15 Ser Val Lys Leu Ser Cys Lys Wing Gly Tyr Thr Phe Thr Tyr 20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45

Gly Arg Ile Asp Pro Asn Being Gly Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60

Lys Be Lys Wing Thr Thr Read Val Asp Lys Pro Be Wing Thr Tyr 65 70 75 80

Met Gln Read Be Ser Read Thr Be Glu Asp Be Wing Val Tyr Tyr Cys 85 90 95

Wing Arg Tyr Asp Tyr Tyr Gly Be Ser Tyr Phe Asp Tyr Trp Gly Gln 100 105 110

Gly Thr Thr Read Thr Val Ser Ser 115 120

<210> 64

<211> 123 <212> PRT

<213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin variable region <400> 64

Gln Val Gln Leu Val Gln Ser Gly Wing Glu Val Val Lys Pro Gly Wing 15 10 15

Be Val Lys Read Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Be Tyr 20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45

Gly Glu Ile Asn Pro Being Asn Gly Arg Thr Asn Tyr Asn Gln Lys Phe 50 55 60

Gln Gly Lys Wing Thr Thr Read Val Val Asp Lys Be Ser Be Thr Wing Tyr 65 70 75 80 Met Gln Gly Lys Wing Be Thr Read Thr Be Glu Asp Wing Val Tyr Tyr Phe 85 90 95

Wing Arg Gly Arg Pro Asp Tyr Tyr Gly Ser Ser Lys Trp Tyr Phe Asp 100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120

<210> 65 <211> 124 <212> PRT <213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin variable region <400> 65

Gln Val Gln Leu Gln Gln Ser Gly Wing Glu Leu Val Lys Pro Gly Wing

1 5 10 15

Be Val Lys Read Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Be Tyr 20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45

Gly Glu Ile Asn Pro Be Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60

Lys Arg Lys Wing Thr Read Le Val Thr Asp Lys Be Being Wing Thr Tyr 65 70 75 80

Met Gln Read Be Ser Read Thr Be Glu Asp Be Wing Val Tyr Tyr Phe 85 90 95

Wing Arg Gly Arg Pro Asp Tyr Tyr Gly Ser Ser Lys Trp Tyr Phe Asp 100 105 110

Val Trp Gly Wing Gly Thr Thr Val Thr Val Ser Ser 115 120

<210> 66

<211> 124 <212> PRT <213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin variable region <400> 66

Gln Val Gln Leu Val Gln Ser Gly Wing Glu Val Val Lys Pro Gly Wing 15 10 15

Be Val Lys Read Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Be Tyr 20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45

Gly Glu Ile Asn Pro Being Asn Gly Arg Thr Asn Tyr Asn Gln Lys Phe 50 55 60

Gln Gly Lys Wing Thr Read Le Thr Val Asp Lys Being Be Wing Thr Tyr 65 70 75 80

Met Gln Read Be Ser Read Thr Be Glu Asp Be Wing Val Tyr Tyr Phe

85 90 95

Wing Arg Gly Arg Pro Asp Tyr Tyr Gly Ser Ser Lys Trp Tyr Phe Asp 100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120

<210> 67 <211> 120 <212> PRT

<213> Artificial Sequence

<220>

<223> Heavy chain immunoglobulin variable region <400> 67

Gln Val Gln Leu Gln Gln Ser Gly Wing Glu Leu Val Lys Pro Gly Wing 15 10 15

Be Val Lys Leu Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Be Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Arg Gly Leu Glu Trp Ile

40 45

Gly Arg Ile Asp Pro Asn Being Gly Gly Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Be Lys Wing Thr Thr Read Val Asp Lys Pro Be Wing Thr Tyr 65 70 75 80

Met Gln Read Be Ser Read Thr Be Glu Asp Be Wing Val Tyr Tyr Cys 85 90 95

Wing Arg Tyr Asp Tyr Tyr Gly Ser Tyr Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser 115 120

<210> 68 <211> 117 <212> PRT

<213> Artificial Sequence <220>

<223> Heavy Chain Immunoglobulin Variable Region <400> 68

Gln Ile Gln Read Gln Gln Be Gly Pro Glu Read Val Val Pro Gly Wing 15 10 15

Be Val Lys Ile Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Asp Tyr 20 25 30

Tyr Ile His Trp Val Lys Gln Arg Pro Gly Glu Gly Leu Glu Trp Ile 35 40 45

Gly Trp Ile Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60

Lys Gly Lys Wing Thr Read Le Thr Val Asp Thr Be Ser Be Thr Wing Tyr 65 70 75 80

Met Gln Read Be Ser Read Thr Be Glu Asp Be Wing Val Tyr Phe Cys

85 90 95 Wing Arg Gly Gly Lys Phe Wing Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110

Val Thr Val Ser Ser 115

<210> 69

<211> 124 <212> PRT

<213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin variable region <400> 69

Gln Val Gln Leu Gln Gln Ser Gly Wing Glu Leu Val Lys Pro Gly Wing 15 10 15

Be Val Lys Read Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Be Tyr 20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45

Gly Glu Ile Asn Pro Be Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60

Lys Arg Lys Wing Thr Read Le Val Thr Asp Lys Be Being Wing Thr Tyr 65 70 75 80

Met Gln Read Be Ser Read Thr Be Glu Asp Be Wing Val Tyr Tyr Phe 85 90 95

Wing Arg Gly Arg Pro Asp Tyr Tyr Gly Ser Ser Lys Trp Tyr Phe Asp 100 105 110

Val Trp Gly Wing Gly Thr Thr Val Thr Val Ser Ser 115 120

<210> 70 <211> 120 <212> PRT

<213> Artificial Sequence <220> <223> Heavy Chain Immunoglobulin Variable Region <400> 70

Gln Ile Gln Read Gln Gln Be Gly Pro Glu Read Val Lys Pro Gly Wing 15 10 15

Be Val Lys Ile Be Cys Lys Wing Be Gly Tyr Thr Phe Thr Asp Tyr 20 25 30

Tyr Ile Asn Trp Met Lys Gln Lys Pro Gly Gln Gly Read Glu Trp Ile 35 40 45

Gly Trp Ile Asp Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60

Lys Gly Lys Wing Thr Read Le Thr Val Asp Thr Be Ser Be Thr Wing Tyr 65 70 75 80

Met Gln Read Be Be Read Thr Be Glu Asp Thr Wing Val Tyr Phe Cys 85 90 95

Wing Arg Glu Lys Thr Thr Tyr Tyr Tyr Wing Met Asp Tyr Trp Gly Gln 100 105 110

Gly Thr Be Val Thr Val Ser Wing 115 120

<210> 71 <211> 115 <212> PRT

<213> Artificial Sequence <220>

<223> Heavy chain immunoglobulin variable region <400> 71

Val Gln Read Gln Gln Ser Gly Wing Glu Read Met Lys Pro Gly Wing Ser 15 10 15

Val Lys Ile Be Cys Lys Wing Be Gly Tyr Thr Phe Be Asp Tyr Trp 20 25 30

Ile Glu Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile Gly 35 40 45 Glu Ile Leu Pro Gly Ser Gly Be Thr Asn

Gly Lys Wing Thr Phe Thr Wing Asp Thr Be Be Be Thr Wing Tyr Met 65 70 75 80

Gln Leu Asn Be Leu Thr Be Glu Asp Be Gly Val Tyr Tyr Cys Leu

85 90 95

His Gly Asn Tyr Asp Phe Asp Gly Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110

Val Ser Ser

115

<210> 72

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy chain immunoglobulin variable region <400> 72

Gln Val Gln Leu Leu Glu Ser Gly Wing Glu Leu Met Lys Pro Gly Wing 15 10 15

Be Val Lys Ile Be Cys Lys Wing Thr Gly Tyr Thr Phe Be Ser Phe 20 25 30

Trp Ile Glu Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile 35 40 45

Gly Glu Ile Leu Pro Gly Ser Gly Gly Thr His Tyr Asn Glu Lys Phe 50 55 60

Lys Gly Lys Wing Thr Phe Thr Wing Asp Lys Be Ser Asn Thr Wing Tyr 65 70 75 80

Met Gln Read Be Ser Read Thr Be Glu Asp Be Wing Val Tyr Tyr Cys 85 90 95

Wing Arg Gly His Ser Tyr Tyr Phe Tyr Asp Gly Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Be Val Thr Val Ser Ser 115 120

<210> 73 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 73

Asp Val Leu Met Thr Gln Ile Pro Val Ser Leu Pro Val Ser Leu Gly 15 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Be Gln Ile Ile Val His Asn 20 25 30

Asn Gly Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Gln Read Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Be His Val Pro Phe Thr Phe Gly Be Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 74 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin light chain variable region <400> 74 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Leu Gly 15 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

5 Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Ala Gly Thr Asp Phe Be Read Arg Ile 10 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

15 Arg

<210> 75 <211> 113 <212> PRT

<213> Artificial Sequence 20 <220>

<223> Light chain immunoglobulin variable region <400> 75

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

. 25 Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be

20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Arg Read Le Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Be Gly Be Gly Wing Gly Thr Asp Phe Thr Read Le Arg Arg Ile 65 70 75 80 Be Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 76 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 76

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Ser Ser Gly Al I 65 65 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 77 <211> 113 <212> PRT

<213> Artificial Sequence <220> <223> Light Chain Immunoglobulin Variable Region <400> 77

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Arg Read Le Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Ser Ser Gly Al I 65 65 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 78 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <220>

<221> region of biological interest <222> (28) .. (28)

<223> Xaa can be any naturally occurring amino acid <220>

<221> region of biological interest

<222> (101) .. (101)

<223> Xaa can be any naturally occurring amino acid <4 00> 78 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Leu Gly 15 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Be Gln Xaa Ile Val His Be 20 25 30

Asn Gly Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Xaa Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 79 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 79

Asp Val Val Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Be Gly Be Gly Wing Gly Thr Asp Phe Thr Read Le Arg Ile 65 70 75 80 Be Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 80 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <4 00> 80

Asp Val Val Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Arg Read Le Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Ser Ser Gly Al I 65 65 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg <210> 81 <211> 113 <212> PRT

<213> Artificial Sequence <220> <223> Light Chain Immunoglobulin Variable Region <400> 81

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be

20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Arg Read Le Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Ser Ser Gly Al I 65 65 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg <210> 82 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 82

Asp Val Leu Met Thr Gln Ile Pro Val Ser Leu Pro Val Ser Leu Gly 15 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Be Gln Ile Ile Val His Asn 20 25 30

Asn Gly Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Gln Read Leu Ile Tyr Lys Val Ser Asn Arg Phe Be Gly Val Pro 50 55 60 Asp Arg Phe Be Gly Ser Gly Be As Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Phe Thr Phe Gly Be Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 83 <211> 113 <212> PRT

<213> Artificial Sequence

<220>

<223> Light chain immunoglobulin variable region <400> 83

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Gln Wing Be Ile Be Cys Arg Phe Be Gln Be Ile Val His Be 20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Ser Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Be His Val Pro Arg Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 84 <211> 113 <212> PRT <213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 84

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Arg Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly

85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 85 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <4 00> 85

Asp Val Val Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be

20 25 30

Asn Val Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Ser Ser Gly Al I 65 65 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly

85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 86 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <4 00> 86

Glu Leu Val Met Thr Gln Leu Pro Pro Leu Be Valu Le Val Gly 15 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Be Gln Thr Ile Val His Be 20 25 30

Asn Gly Asp Thr Tyr Read Asp Trp Phe Read Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

Arg

<210> 87 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 87

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Ser Ser Gly Al I 65 65 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg <210> 88 <211> 113 <212> PRT 25 <213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 88

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

1 5 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30 Asn Val Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 35

Pro Arg Read Le Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Ser Ser Gly Al I 65 65 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 89 <211> 113 <212> PRT <213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 89

Asp Val Leu Met Thr Gln Thr Pro Val Valu Le Val Valu Gly

1 5 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Thr Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Read Leu Ile Tyr Lys Ile Be Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Wing 85 90 95

Be His Wing Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg

<210> 90

<211> 113

<212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region

<400> 90

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

1 5 10 15

Asp Gln Wing Be Ile Be Cys Lys Be Be Gln Be Ile Val His Be 20 25 30

Ser Gly Asn Thr Tyr Phe Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Ile Pro Phe Thr Phe Gly Be Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 91 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 91

Asp Ile Glu Leu Thr Gln Thr Pro Leu Be Leu Pro Val Be Leu Gly 15 10 15 Asp Gln Ala Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be

Asn Gly Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 - 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 92 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 92

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Read Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 .55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Arg Ile 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Tyr Cyr Phe Gln Gly 85 90 95 Being His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 93 <211> 113

<212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 93

Asp Val Val Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Arg Read Le Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Ser Ser Gly Al I 65 65 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 94

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Immunoglobulin light chain variable region <4 00> 94 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Leu Gly .1 5 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Arg Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 95 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 95

Asp Val Val Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Pro Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Val Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Be Gly Be Gly Wing Gly Thr Asp Phe Thr Read Le Arg Arg Ile 65 70 75 80 Be Arg Val Glu Wing Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 96 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 96

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Asn Gln Thr Ile Read Leu Be 20 25 30

Asp Gly Asp Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95

Be His Val Pro Pro Phe Gly Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 97 <211> 113 <212> PRT

<213> Artificial Sequence <220> <223> Light Chain Immunoglobulin Variable Region <400> 97

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Be Gln Thr Ile Val His Be

Asn Gly Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Lys Val Thr Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Be Gly Be Gly Be Gly Thr Asp Phe Be Read Lys Ile 65 70 75 80

Ser Arg Val Glu Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95

Thr His Wing Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110

Arg

<210> 98 <211> 113 <212> PRT

<213> Artificial Sequence <220>

<223> Light chain immunoglobulin variable region <400> 98

Asp Val Leu Met Thr Gln Thr Pro Leu Be Leu Pro Val Leu Gly 15 10 15

Asp Gln Wing Be Ile Be Cys Arg Be Be Gln Be Ile Val His Be 20 25 30

Asn Gly Asn Thr Tyr Gave Glu Trp Tyr Gave Gln Lys Pro Gly Gln Ser 35 40 45

Pro Lys Leu Read Ile Tyr Be Ile Be Ser Arg Be Phe Be Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Be Gly Be Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80

Ser Arg Val Gln Wing Glu Asp Read Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95

Being His Val Pro Tyr Thr Phe Gly Gly Gly Thr.Lys Read Glu Ile Lys 100 105 110

Arg

<210> 99 <212> DNA <213> Artificial Sequence <220>

<223> Initiator <4 00> 99

ctccgcttcc tttc 14

<210> 100

<211> 18

<212> DNA

<213> Artificial Sequence <220>

<223> antisense

<400> 100

atctctccgc ttcctttc 18

<210> 101

<211> 18

<212> DNA

<213> Artificial Sequence <220>

<223> antisense

<400> 101

atctctccgc ttcctttc 18

<210> 102

<211> 19 <212> DNA

<213> Artificial Sequence <220>

<223> Initiator

<400> 102

aggagctcga ggcgttcag 19

<210> 103

<211> 22

<212> DNA

<213> Artificial Sequence <220>

<223> Initiator

<4 00> 103

gtcttgggtg ggtagagcaa tc 22

<210> 104 <211> 21 <212> DNA

<213> Artificial Sequence <220>

<223> Initiator <400> 104

aggccaaacg tcaccgtccc c ??? 21

<210> 105 <211> 109 <212> PRT

<213> Artificial Sequence <220>

<223> Immunoglobulin A12 light chain variable region <400> 105

Be Ser Glu Leu Thr Gln Asp Pro Wing Val Ser Val Wing Leu Gly Gln 15 10 15 Thr Val Arg He Thr Cys Gln Gly Asp Ser Read Arg Ser Tyr Tyr Wing 20 25 .30

Thr Trp Tyr Gln Lys Pro Gly Gln Wing Pro Ile Read Val Ile Tyr 35 40 45

Gly Glu Asn Lys Arg Pro Be Gly Ile Pro Asp Arg Phe Be Gly Ser 50 55 60

Be Ser Gly Asn Thr Wing Be Read Thr Ile Thr Gly Wing Gln Wing Glu 65 70 75 80

Asp Glu Wing Asp Tyr Tyr Cys Lys Be Arg

Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105

<210> 106 <211> 22 <212> DNA

<213> Artificial Sequence <220>

<223> IGFIR / Lead Initiator <400> 106

gaaagtgacg tcctgcattt ca 22

<210> 107 <211> 19 <212> DNA

<213> Artificial Sequence

<220>

<223> IGFIR / Reverse Primer <400> 107

ccggtgccag gttatgatg 19

<210> 108 <211> 23

<212> DNA

<213> Artificial Sequence <220>

<223> Probe sequence <400> 108

caccaccacg tcgaagaatc gca 23

Claims (18)

1. Method for treating or preventing the medical condition in a mammalian subject selected from the group consisting of head and neck cancer, squamous cell carcinoma, multiple myeloma, solitary plasmacitoma, renal cell cancer, retinoblastoma, cell tumors. germ disease, hepatoblastoma, hepatocellular carcinoma, melanoma, renal rabidoid tumor, Ewing's sarcoma, chondrosarcoma, hematological malignancy, chronic lymphoblastic leukemia, acute myelomonocytic leukemia, acute T-cell lymphoblastic leukemia, leukemia B cell precursor lineage acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, Hodgekin's disease, non-Hodgekin's lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome , capillary cell leukemia, mast cell leukemia, mast cell neoplasm, follicular lymphoma, diffuse large cell lymphoma, lining cell lymphoma, Burkitt lymphoma, ringworm fungi, seary syndrome, lymphoma T-cell disease, chronic myeloproliferative disorders, central nervous system tumor, brain cancer, glioblastoma, non-glioblastoma brain cancer, meningioma, pituitary adenoma, vestibular schwanoma, a primitive neuroctodermal tumor, medulloblastoma, astrocytoma, astrocytoma anaplasia , oligodendroglioma, ependymoma, choroidal plexus papilloma, a myeloproliferative disorder, polycythemia vera, thrombocythemia, idiopathic myelfibrosis, soft tissue sarcoma, endometrial cancer, carcinoid cancer, germ cell tumor and liver cancer comprising administering a therapeutically effective amount of an isolated antibody or antigen-binding fragment thereof comprising CDR-H1, CDR-H2 and CDR-H3 from a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 10; or CDR-L1, CDR-L2 and CDRL3 from a light chain immunoglobulin comprising the amino acid sequence set to SEQ ID NO: 8; or both to the individual. A method according to claim 1, wherein the medical condition is a member selected from the group consisting of: acute B-cell precursor lineage acute lymphoblastic leukemia; T cell line acute lymphoblastic leukemia; acute lymphocytic leukemia; acute myeloblastic leukemia; anaplastic astrocytoma; astrocytoma; Burkitt's lymphoma; carcinoid cancer; central nervous system tumor; Chondrosarcoma; choroid plexus papilloma; chronic lymphoblastic leukemia; chronic lymphocytic leukemia; chronic myeloblastic leukemia; chronic myelogenous leukemia; chronic myelomonocytic leukemia; chronic myeloproliferative disorders; Cutaneous T-cell lymphoma; Diffuse large cell lymphoma; endometrial cancer; ependymoma; Follicular lymphoma; germ cell tumor; germ cell tumors; glioblastoma; hair cell leukemia; head and neck cancer; hepatoblastoma; hepatocellular carcinoma; Hodgekin's disease; idiopathic myelfibrosis; Coating cell lymphoma; mast cell leukemia; mast cell neoplasm; medulloblastoma; melanoma; meningioma; ringworm fungoids; myeloproliferative disorder; non-glioblastoma brain cancer; Non-Hodgekin's lymphoma; oligodendroglioma; pituitary adenoma; polycythemia vera; primitive neuroctodermal tumor; rabidoid kidney tumor; seary syndrome; soft tissue sarcoma; solitary plasmacytoma; squamous cell carcinoma; thrombocythemia; thyroid cancer; and vestibular schwannoma. A method according to claim 1, wherein the antibody or antigen binding fragment thereof is an antibody comprising (i) CDR-L1 comprising the amino acid sequence: RASQ-SIGSSLH; and CDR-L2 comprising the amino acid sequence: YASQS-LS; and CDR-L3 comprising the amino acid sequence: HQSSRLPHT; or (ii) CDR-H1 comprising the amino acid sequence: SFAMH; and CDR-H2 comprising the amino acid sequence: VIDTRGATY-YADSVKG; and CDR-H3 comprising the amino acid sequence: LGNFYYGMDV; or both (i) and (ii). A method according to claim 1, wherein the antibody or antigen binding fragment thereof is a monoclonal antibody comprising a light chain immunoglobulin variable region comprising amino acids 20-128 of SEQ ID NO: 8 ; and a heavy chain immunoglobulin variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 12. The method of claim 1, wherein the inhibitor is an antibody wherein said antibody comprises: (a) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 2 and a variable region heavy chain comprising amino acids 20-137 of SEQ ID NO: 10 or 12; or (b) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 4 and a heavy chain variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 12; or (c) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 6 and a heavy chain variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 12; or (d) a light chain variable region comprising amino acids 20-128 of SEQ ID NO: 8 and a heavy chain variable region comprising amino acids 20-137 of SEQ ID NO: 10 or 12. A method according to claim 1, wherein the antibody or antigen binding fragment is administered in combination with one or more additional chemotherapeutic agents or a pharmaceutical composition thereof. The method of claim 6, wherein the additional chemotherapeutic agent is an anticancer agent, an antiemetic agent, an anti-anemic agent or an anti-mucositis agent. The method of claim 6, wherein the additional chemotherapeutic agent is one or more members selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enastastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R -763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, HDAC, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, a TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, PI3 kinase inhibitors, an AKT inhibitor, a JAK / STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase inhibitor (mek), a VEGF trap antibody, pemetrexed , erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimu- mab, edotecarin, tetrandrin, rubitecan, tesmilimene, tymilimene, tymolimene 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR, KRX-0402, Iucantone, LY 317615, neuradiab, vitespan, Rta 744 , Sdx 102, thalampanel, atrentan, Xr 311, romidepsin, ADS-100380, <formula> formula see original document page 197 </formula> <formula> formula see original document page 198 </formula>, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, selicyclib; PD0325901, AZD-6244, Capecitabine, L-Glutamic Acid, N - [4- [2- (2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -, disodium salt, heptahydrate, camptothecin, irino-tecan; a combination of irinotecan, 5-fluorouracil and leucovorin; irinitecan labeled with PEG1 regimen FOLFOX, tamoxifen, toremifene citrate, anastrazole, exemestane, Ietrozole1 DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, BMI-1C11, CHIR-258 original <document formula see see page 198 </formula>); 3- [5- (methylsulfonylpiperadinamethyl) indolyl] quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser (Bu t) 6, Azgly 10] (piro-Glu-His-Trp -Ser-Tyr-D-Ser (Bu t) -Leu-Arg-Pro-Azgly-NH2 acetate [C59H84N18O14 (C2H4O2) x where x = 1 to 2.4], goserelin acetate, Ieuprolide acetate, triptorelin pamoate, sunitinib, sunitinib malate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxyphene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canX antibody, canX EGF, erbi- <formula> formula see original document page 199 </formula> tux, EKB-569, PKI-166, GW-572016, canvasfarnib, <formula> formula see original document page 199 </formula> BMS-214662, amifostine, NVP-LAQ824, suberoyl analyte hydroxamic acid, valproic acid, tricostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anegelide, L-asparaginase, B vaccine acillus Calmette-Guerin (BCG) 1 bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, claudronine, clodronate, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactomycinin, daunorubicin, diethylpyrrubicin, diethylpyridine, fludrocortisone, fluoxymesterone, flutamide, hydroxyurea, idarrubicin, ifosfamide, immatinib, leucovorin, leuprolide, Levaisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mithitoxone, mothitoxone, mothitoxone, mitoxide satraplatin pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine, mustard, mustard altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformicin, calcitriol, valrubicin, mitramicin, vinblastine, vinorelbine, potecan razoxin marimastat COL-3 neovastat BMS-275291 squalamine endostatin SU5416 SU6668 EMD121974 interleukin-12 IM862 angiosta-tin vitaxin droloxifene oxyphene spironolactone finasteride trasidine denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremofor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxy tamoxifen, pipendoxifene, ERA-923, arofifenene, aofoxen oxide, TSE-424, HMR-3339, ZK186619, topotan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-0- (2-hydroxyethyl) -rapamycin, temsirolimus, AP-23573, RAD001 , ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, 5-fluorouracil, erythropoietin, colony granulocyte z-stimulation factor, , prednisone, cetuximab, stimulation factor granulocyte macrophage colony, histrelin, pegylated interferon alfa-2a, pegylated interferon alfa-2b, pegylated interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemutuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, total transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, mustard nitrogen, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotenoate, cortisone tritronate, coxumotronate, trixomalate , mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxizine, metoclopramide, lorazepam, alprazolam, halproperamide , methylprednisolone, prochlorperazine, granisetron, ondanetron, dolasetron, tropisetron, pegfilgra stim, erythropoietin, epoetin alfa and darbepoetin alfa. The method of claim 6, wherein the antibody or antigen binding fragment and additional chemotherapeutic agent are administered simultaneously. The method of claim 6, wherein the antigen binding antibody or fragment and additional chemotherapeutic agent are administered non-simultaneously. A method according to claim 4, wherein the light chain immunoglobulin is bound to an immunoglobulin kappa constant region; and the heavy chain immunoglobulin is bound to a constant region of gamma-1 immunoglobulin. A method according to claim 1, wherein the individual is a human being. A method according to claim 12, wherein the subject is a child. A method according to claim 1, wherein the antigen binding antibody or fragment is administered in combination with an anticancer therapeutic procedure. The method of claim 14, wherein the anticancer therapeutic procedure is tumorectomy surgery and / or anticancer radiation treatment. A method according to claim 1, wherein the subject is administered the antibody or fragment in a pharmaceutical composition comprising 20 mg / ml antibody or fragment, 2.3 mg / ml ammonium acetate. sodium trihydrate, 0.18 mg / ml acetic acid glacia1, 70 mg / ml sucrose, and water, pH 5.5. The method of claim 1, wherein the subject is administered antibody or fragment at a dosage of 10 mg / kg body weight every two weeks. The method of claim 4, wherein the subject is a human being who is administered the antibody or fragment which is a monoclonal antibody in a pharmaceutical composition comprising 20 mg / ml antibody, 2.3 mg / ml sodium acetate trihydrate, 0.18 mg / ml glacial acetic acid, 70 mg / ml sucrose, and water, pH 5.5; intravenously, at a dosage of 10 mg / kg body weight every two weeks; in which the medical condition is Ewing's sarcoma.