TNF-alpha immunoconjugate therapy for the treatment of brain tumors

Abstract

The present invention relates to immunoconjugates, compositions, methods and uses for treating brain tumors, especially glioma, by administration of a tumour necrosis factor alpha (TNF) immunoconjugate.

Claims

1. A method of treating a brain tumor in a patient, comprising administering a TNF immunoconjugate in combination with chemotherapy to the patient, wherein the TNF immunoconjugate comprises TNF linked to an antibody molecule comprising L19 complementarity determining regions (CDRs), wherein the L19 CDRs are: TABLE-US-00004 SEQIDNO:1 VHCDR1 SFSMS SEQIDNO:2 VHCDR2 SISGSSGTTYYADSVKG SEQIDNO:3 VHCDR3 PFPYFDY SEQIDNO:4 VLCDR1 RASQSVSSSFLA SEQIDNO:5 VLCDR2 YASSRAT,and SEQIDNO:6 VLCDR3 QQTGRIPPT; and the chemotherapy is lomustine, wherein said combination increases brain tumor necrosis and Progression Free Survival (PFS) in said patient and said brain tumor is a glioma.

2. The method of claim 1, wherein the antibody molecule comprises the L19 VH domain SEQ ID NO: 7 and the L19 VL domain SEQ ID NO: 9.

3. The method of 1, wherein the TNF immunoconjugate comprises TNF linked to L19 (scFv) as set forth in SEQ ID NO: 10.

4. The method of any one of claim 1, 2, or 3, wherein the TNF immunoconjugate has an amino acid sequence of SEQ ID NO: 13.

5. The method of claim 1, wherein the immunoconjugate is administered by a route selected from intravenous injection, intratumoural injection, and intrathecal injection.

6. The method of claim 1, wherein the glioma is selected from a Grade III/IV glioma, a Grade III/IV glioma is at first relapse, an isocitrate dehydrogenase (IDH) wildtype glioma, a newly diagnosed Grade IV glioblastoma, and a Grade IV glioblastoma at first relapse.

7. The method of claim 1, wherein the immunoconjugate is administered in combination with radiotherapy.

8. The method of claim 1, wherein lomustine is administered at a dose in a range of 50-200 mg/m.sup.2, or 75-150 mg/m.sup.2.

9. The method of claim 1, wherein the lomustine is administered at a dose of about 80, about 90, or about 100, or about 110 mg/m.sup.2.

10. The method of claim 1, further comprising subsequent administrations of the TNF immunoconjugate.

11. A method of treating a glioma in a patient, comprising administering a TNF immunoconjugate in combination with chemotherapy to the patient, wherein the TNF immunoconjugate comprises TNF linked to an antibody molecule comprising L19 complementarity determining regions (CDRs), wherein the L19 CDRs are: TABLE-US-00005 SEQIDNO:1 VHCDR1 SFSMS SEQIDNO:2 VHCDR2 SISGSSGTTYYADSVKG SEQIDNO:3 VHCDR3 PFPYFDY SEQIDNO:4 VLCDR1 RASQSVSSSFLA SEQIDNO:5 VLCDR2 YASSRAT,and SEQIDNO:6 VLCDR3 QQTGRIPPT; wherein the chemotherapy is lomustine; wherein the antibody molecule comprises the L19 VH domain SEQ ID NO: 7 and the L19 VL domain SEQ ID NO: 9; wherein the TNF immunoconjugate comprises TNF linked to L19 (scFv) as set forth in SEQ ID NO: 10 and the TNF immunoconjugate has an amino acid sequence of SEQ ID NO: 13.

12. The method of claim 11, wherein the immunoconjugate is administered by a route selected from intravenous injection, intratumoural injection, and intrathecal injection.

13. The method of claim 11, wherein said glioma is selected from a Grade III/IV glioma, a Grade III/IV glioma is at first relapse, an isocitrate dehydrogenase (IDH) wildtype glioma, a newly diagnosed Grade IV glioblastoma, and a Grade IV glioblastoma at first relapse.

14. The method of claim 11, further comprising administration of radiotherapy.

15. The method of claim 11, wherein the lomustine is administered at a dose in a range of 50-200 mg/m.sup.2, or 75-150 mg/m.sup.2.

16. The method of claim 11 further comprising subsequent administrations of the TNF immunoconjugate.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1A shows glioma lesions in two different patients before and after treatment with L19-TNF. The lesions gradually shrink after two and six cycles. The dark inner part of the lesions indicates the expanding necrotic core, confirming the therapeutic action of targeted TNF.

(2) FIG. 1B Immunohistochemistry analysis before and after treatment with L19-TNF. The increase in tumor-infiltrating CD4 and CD8 T-cells after treatment confirmed the therapeutic action of targeted TNF. Similarly, the increase of caspase-3 indicates a higher number of dead tumor cells.

(3) FIG. 2 shows the amino acid sequence of L19(scFv) (SEQ ID NO: 10). The VH and VL domains are shown separately (SEQ ID NO: 7 and SEQ ID NO: 9, respectively). The CDR 1, 2 and 3 sequences in both the VH and VL domains are shown underlined. The VH and VL domains are linked by a 12-residue peptide linker sequence (SEQ ID NO: 8).

(4) FIG. 3 shows MRI images of a glioblastoma patient who was administered L19-TNF in accordance with the invention. The upper panel (A) is the initial (baseline) MRI image, which shows the glioblastoma indicated in the white circle. The lower panel (B) shows an MRI image taken following treatment, 40 days after the baseline image was taken. The glioblastoma shown in panel B is indicated with an arrow and white circle. It is substantially reduced.

DETAILED DESCRIPTION OF THE INVENTION

(5) Certain aspects of the invention are as set out in the appended claims, which may be combined with any other part of the present disclosure.

(6) An antibody molecule is an immunoglobulin whether natural or partly or wholly synthetically produced. The term also covers any polypeptide or protein comprising an antibody antigen-binding site. Thus, this term covers antibody fragments and derivatives, including any polypeptide comprising an antibody antigen-binding site, whether natural or wholly or partially synthetic. Fusion proteins comprising an antibody antigen-binding site, or equivalent, fused to another polypeptide are therefore included. Cloning and expression of chimeric antibodies is well known (EP0120694, EP0125023).

(7) Further techniques available in the art of antibody engineering have made it possible to isolate human and humanised antibodies. For example, human hybridomas can be made as previously described. Phage display is another established technique (WO92/01047). Transgenic mice in which the mouse antibody genes are inactivated and functionally replaced with human antibody genes while leaving intact other components of the mouse immune system can be used for isolating human antibodies.

(8) Synthetic antibody molecules may be created by expression from genes generated by means of oligonucleotides synthesised and assembled within suitable expression vectors.

(9) It has been shown that fragments of a whole antibody can perform the function of binding antigens. Antibody fragments are preferred in conjugates of the invention owing to their small size and minimised interaction with other molecules and receptors (e.g. Fc receptor). Particularly preferred are single chain Fv molecules (scFv), wherein a VH domain and a VL domain are linked by a peptide linker which allows the two domains to associate to form an antigen binding site. scFv may be stabilised by the incorporation of disulphide bridges linking the VH and VL domains.

(10) Another small antigen-binding antibody fragment is a dAb (domain antibody), namely the variable region of an antibody heavy or light chain. VH dAbs occur naturally in camelids (e.g. camel, llama) and may be produced by immunising a camelid with a target antigen, isolating antigen-specific B cells and directly cloning dAb genes from individual B cells. dAbs are also producible in cell culture. Their small size, good solubility and temperature stability makes them particularly physiologically useful and suitable for selection and affinity maturation.

(11) An antigen-binding site is the part of a molecule that specifically binds to and is complementary to all or part of the target antigen. In an antibody molecule it is referred to as the antibody antigen-binding site, and comprises the part of the antibody that specifically binds to and is complementary to all or part of the target antigen. Where an antigen is large, an antibody may only bind to a particular part of the antigen, which part is termed an epitope. An antibody antigen-binding site may be provided by one or more antibody variable domains. Preferably, an antibody antigen-binding site comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH).

(12) The term specific may be used to refer to the situation in which one member of a specific binding pair will not show any significant binding to molecules other than its specific binding partner(s). The term is also applicable where e.g. an antigen-binding site is specific for a particular epitope that is carried by a number of antigens, in which case the antibody carrying the antigen-binding site will be able to bind to the various antigens carrying the epitope.

(13) In immunoconjugates of the invention, the antibody molecule preferably binds an extracellular matrix component which is a marker of tumour growth. The extracellular matrix (ECM) is remodeled during tumour growth, and alternative splice variants of ECM components may be selectively expressed at the site of the lesion.

(14) One example is fibronectin. For example, the B-FN isoform of fibronectin contains an extra domain ED-B. An antibody molecule preferably binds specifically to ED-B of fibronectin isoform B-FN. The antibody molecule may comprise the L19 CDRs. For example, the antibody molecule may be a scFv having a VH domain with an amino acid sequence comprising VH CDR1, VH CDR2 and/or VH CDR3 of L19, and a VL domain with an amino acid sequence comprising VL CDR1, VL CDR2 and/or VL CDR3 of L19. An antibody molecule may comprise a VH domain having an amino acid sequence with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% sequence identity with the amino acid sequence of the L19 VH domain as set out in SEQ ID NO: 7, and/or comprises a VL domain having an amino acid sequence with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% sequence identity with the amino acid sequence of the L19 VL domain as set out in SEQ ID NO: 9. Preferably the antibody molecule is an scFv(L19) comprising an L19 VH domain (SEQ ID NO: 7) and an L19 VL domain (SEQ ID NO: 9). In a preferred embodiment, the antibody molecule is L19(scFv) having the amino acid sequence SEQ ID NO: 10 (FIG. 2).

(15) Modified forms of the L19 VH and/or VL domain may be employed in immunoconjugates of the invention, for example an antibody molecule may comprise the L19 VH or L19 VL domain in which 1, 2, 3, 4 or 5 amino acid substitutions have been made in a CDR and/or framework region, while retaining specific binding to fibronectin ED-B. Such amino acid substitutions are preferably conservative, e.g. substitution of one hydrophobic residue for another, one polar residue for another, arginine for lysine, glutamic for aspartic acid, or glutamine for asparagine.

(16) Nucleic acid molecules encoding the immunoconjugates and parts thereof also form part of the invention. The nucleic acid molecule may be a vector, e.g. a plasmid suitable for expression of the nucleotide sequence. Normally the nucleotide sequence is operably linked to a regulatory element such as a promoter for transcription.

(17) The nucleic acid molecules may be contained in a host cell, which may be a cell cotransfected with the nucleic acid molecules or a daughter of such a cell. Cells, especially eukaryotic cells e.g. HEK and CHO cells, or bacterial cells e.g. Escherichia coli, containing the nucleic acid molecules also form part of the invention.

(18) Immunoconjugates of the invention may be produced using recombinant techniques, for example by expressing all or part of the immunoconjugate as a fusion protein. Normally the expression is performed in a host cell containing nucleic acid, as described above. Expression may therefore comprise culturing such a host cell. For TNF fusion proteins, trimerisation of the subunits may occur in the cell or during purification of the fusion proteins from the cell.

(19) Preferably the antibody molecule is conjugated with the cytokine by means of a peptide bond, e.g. within a fusion protein comprising the TNF and the antibody molecule or a polypeptide chain thereof. See WO2001/062298. An example of a suitable linker is set out in SEQ ID NO: 12.

(20) TNF used in immunoconjugates of the invention is preferably human TN Fa. The human TNF preferably comprises or consists of the amino acid sequence set out in SEQ ID NO: 11. Antibody molecules are preferably human or humanised antibody molecules. The L19-huTNF conjugate may comprise or consist of the amino acid sequence set out in SEQ ID NO: 13.

(21) Also described is a method comprising formulating the immunoconjugate or immunoconjugates into a pharmaceutical composition. Generally, this involves purifying the immunoconjugate or immunoconjugates and combining it with a physiologically acceptable carrier.

(22) Immunoconjugates and compositions in accordance with the present invention may comprise, in addition to the active ingredient (immunoconjugate), a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. For injection at the tumour site, the immunoconjugate may be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.

(23) The therapeutic uses and methods described herein can be applied to different types of brain tumor. The tumor may be any unwanted cell proliferation (or any disease manifesting itself by unwanted cell proliferation), neoplasm or tumor. For instance, the brain tumor could be a primary malignant neoplasm of brain, a secondary malignant neoplasm of brain, a secondary malignant neoplasm of brain and cerebral meninges, a benign neoplasm of brain and central nervous system or a neoplasm of uncertain behaviour of brain. The neoplasm may be a glioma.

(24) Some embodiments of this invention involve the use of the TNF immunoconjugate administered in combination with chemotherapy. Chemotherapy may be based on alkylating agents such as, chlorambucil, melphalan, cyclophosphamide, chlormethine, uramustine, ifosfamide, bemdamustine, carmustine, lomustine, streptozocin, busulfan, procarbazine, dacarbazine and temozolomide. Chemotherapy may be also based on alkylating-like agents such as cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxalilatin, picoplatin, satraplatin,

(25) Some embodiments of this invention involve the use of the TNF immunoconjugate formulated as a pharmaceutical composition. Pharmaceutical compositions may include a pharmaceutically acceptable excipient composed of materials that are considered safe and effective. Pharmaceutically acceptable refers to molecular entities and compositions that are generally regarded as safe, e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human. The excipients may include solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, antioxidants or antimicrobial preservatives. Certain compositions of L19-TNF are disclosed in WO2018/011404.

(26) It must be noted that, as used in the specification and the appended claims, the singular forms a, an, and the include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from about one particular value, and/or to about another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent about, it will be understood that the particular value forms another embodiment. The term about in relation to a numerical value is optional and means for example +/10%.

(27) All patents, patent applications and publications mentioned herein are hereby incorporated by reference in their entirety.

(28) Although disclosure has been provided in some detail by way of illustration and example for the purposes of clarity of understanding, it will be apparent to those skilled in the art that various changes and modifications can be practiced without departing from the spirit or scope of the disclosure. Accordingly, the description and examples should not be construed as limiting.

(29) The present invention is illustrated by the following examples.

EXAMPLES

Example 1Effect of L19-TNF on Brain Tumour

(30) Three patients with recurrent glioblastoma were treated with L19-TNF at a dose level of 10 g/kg. Already twenty-four hours after the infusion, a decrease in overall tumor perfusion and an emerging tumor necrosis was detected, as shown in FIG. 1A. One patient had progressive disease after three months and two patients still have stable disease with an increasing area of necrosis in the tumor region at six months after treatment. This is surprising considering that the Progression Free Survival (PFS) for recurrent glioblastoma is 1.5 months.

(31) The patient with progressive disease underwent re-section and the tissue from this surgery, i.e. after treatment with L19-TNF, was compared with the tissue obtained during first surgery. By immunohistochemistry, a significant increase in tumor-infiltrating CD4 and CD8 T-cells in the tumor after L19-TNF treatment was detected. Furthermore, increased levels of cleaved caspase-3 were found suggesting a higher number of dead tumor cells, as shown in FIG. 1B. These data demonstrate the in situ activation due to the targeted delivery of TNF.

Example 2Effect of L19-TNF with Chemotherapy on Brain Tumour

(32) This example describes the effect of a combination therapy on a patient with recurrent glioblastoma after chemoradiotherapy followed by temozolomide maintenance therapy.

(33) A 61-year old male patient with glioblastoma (WHO grade IV) at first recurrence, received 90 mg/m2 lomustine (CCNU) on Day 1. Additionally, this patient received 13 g/kg L19-TNF, by iv infusion, on Days 1, 3, 5, 22, 24 and 26.

(34) The patient had been pretreated for newly diagnosed glioblastoma with resection and chemoradiotherapy followed by temozolomide maintenance therapy.

(35) Contrast enhanced MRI was performed initially, before receiving the lomustine and L19-TNF (baseline image; see FIG. 3A) and 40 days after baseline image (FIG. 3B). The tumour was substantially reduced.

(36) Numbered Paragraphs 1. A TNF immunoconjugate for use in a method of treating a brain tumor in a patient, the method comprising administering the TNF immunoconjugate to the patient. 2. The TNF immunoconjugate for the use according to paragraph 1, wherein the brain tumor is a glioma. 3. The TNF immunoconjugate for the use according to any one of the preceding paragraphs, wherein the TNF immunoconjugate comprises TNF linked to an antibody molecule that binds to a splice isoform of an extracellular matrix component. 4. The TNF immunoconjugate for the use according to any one of the preceding paragraphs, wherein the antibody molecule binds a splice isoform of fibronectin which is B-FN. 5. The TNF immunoconjugate for the use according to any one of the preceding paragraphs, wherein the TN Fa immunoconjugate comprises TN Fa linked to an antibody molecule comprising L19 complementarity determining regions (CDRs), wherein the L19 CDRs are:

(37) TABLE-US-00002 SEQIDNO:1 VHCDR1 SFSMS SEQIDNO:2 VHCDR2 SISGSSGTTYYADSVKG SEQIDNO:3 VHCDR3 PFPYFDY SEQIDNO:4 VLCDR1 RASQSVSSSFLA SEQIDNO:5 VLCDR2 YASSRAT SEQIDNO:6 VLCDR3 QQTGRIPPT. 6. The TNF immunoconjugate for the use according to paragraph 5, wherein the antibody molecule comprises the L19 VH domain SEQ ID NO: 7 and the L19 VL domain SEQ ID NO: 9. 7. The TNF immunoconjugate for the use according to any one of the preceding paragraphs, wherein the TNF immunoconjugate comprises TN Fa linked to an antibody molecule which is a scFv, optionally wherein the antibody molecule is L19 (scFv) as set forth in SEQ ID NO: 10. 8. The TNF immunoconjugate for the use according to any one of the preceding paragraphs, wherein the TNF immunoconjugate has an amino acid sequence of SEQ ID NO: 13. 9. The TNF immunoconjugate for the use according to any one of the preceding paragraphs, wherein the immunoconjugate is administered by intravenous injection. 10. The TNF immunoconjugate for the use according to paragraph 9, wherein the injection is intratumoural injection or intrathecal injection. 11. The TNF immunoconjugate for the use according to any one of the preceding paragraphs, wherein the brain tumor is a Grade III/IV glioma. 12. The TNF immunoconjugate for the use according to paragraph 11, wherein the glioma is isocitrate dehydrogenase (IDH) wildtype. 13. The TNF immunoconjugate for the use according to paragraph 11 or paragraph 12, wherein the Grade III/IV glioma is at first relapse. 14. The TNF immunoconjugate for the use according to paragraph 11 or paragraph 12, wherein the glioma is a Grade IV glioblastoma, which is newly diagnosed. 15. The TNF immunoconjugate for the use according to any one of paragraphs 11 to 13, wherein the glioma is a Grade IV glioblastoma at first relapse. 16. The TNF immunoconjugate for the use according any of the preceding paragraphs, wherein the immunoconjugate is administered in combination with chemotherapy and/or radiotherapy. 17. The TNF immunoconjugate for the use according to paragraph 16, wherein the chemotherapy is the alkylating agent temozolomide (TMZ). 18. The TNF immunoconjugate for the use according to paragraph 17, wherein temozolomide (TMZ) is administered at 75-200 mg/m.sup.2. 19. The TNF immunoconjugate for the use according to paragraph 17 or paragraph 18, wherein the radiotherapy is administered at a dose of 20-100 Gy, 40-80 Gy, or 60 Gy, 20. The TNF immunoconjugate for the use according to paragraph 19, wherein the radiotherapy is administered at a dose of 60 Gy in fractions, preferably 60 Gy/30 fractions. 21. The TNF immunoconjugate for the use according to paragraph 19 or 20, wherein the glioma is a newly diagnosed glioblastoma. 22. The TNF immunoconjugate for the use according to paragraph 16, wherein the chemotherapy is the alkylating agent lomustine. 23. The TNF immunoconjugate for the use according to paragraph 21, wherein lomustine is administered at a dose that is within the range of 50-200 mg/m.sup.2, or 75-150 mg/m.sup.2. 24. The TNF immunoconjugate for the use according to paragraph 22, wherein the lomustine is administered at a dose of about 80, about 90, about 100, or about 110 mg/m.sup.2. 25. The TNF immunoconjugate for the use according to paragraph 22 or 23, wherein lomustine is administered at 90 mg/m.sup.2. 25. The TNF immunoconjugate for the use according to any one of paragraphs 22-25, wherein the glioblastoma is at first relapse. 26. The TNF immunoconjugate for the use according to any one of the preceding paragraphs, wherein the method comprises subsequent administrations of the TNF immunoconjugate. 27. The TNF immunoconjugate for the use according any of the preceding paragraphs, wherein tumor necrosis is detectable one day after the TNF immunoconjugate is administered to the patient. 28. The TNF immunoconjugate for the use according any of the preceding paragraphs, wherein a reduction of blood perfusion to the tumor is detectable one day after the TNF immunoconjugate is administered to the patient. 29. The TNF immunoconjugate for the use according any of the preceding paragraphs, wherein the method induces infiltration of T cells into the tumor.

SEQUENCE LISTING

(38) TABLE-US-00003 AminoacidsequenceofL19CDRs L19CDR1VH (SEQIDNO:1) SFSMS L19CDR2VH (SEQIDNO:2) SISGSSGTTYYADSVKG L19CDR3VH (SEQIDNO:3) PFPYFDY L19CDR1VL (SEQIDNO:4) RASQSVSSSFLA L19CDR2VL (SEQIDNO:5) YASSRAT L19CDR3VL (SEQIDNO:6) QQTGRIPPT AminoacidsequenceoftheL19VHdomain (SEQIDNO:7) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFSMSWVRQAPGKGLEWVSS ISGSSGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPF PYFDYWGQGTLVTVSS AminoacidsequenceofthelinkerbetweenVHand VL (SEQIDNO:8) GDGSSGGSGGAS AminoacidsequenceoftheL19VLdomain (SEQIDNO:9) EIVLTQSPGTLSLSPGERATLSCRASQSVSSSFLAWYQQKPGQAPRLLIY YASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQTGRIPPTFG QGTKVEIK AminoacidsequenceoftheL19scFv (SEQIDNO:10) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFSMSWVRQAPGKGLEWVSS ISGSSGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPF PYFDYWGQGTLVTVSSGDGSSGGSGGASEIVLTQSPGTLSLSPGERATLS CRASQSVSSSFLAWYQQKPGQAPRLLIYYASSRATGIPDRFSGSGSGTDF TLTISRLEPEDFAVYYCQQTGRIPPTFGQGTKVEIK Aminoacidsequenceofthesolubleformofthe extracellulardomainofhumanTNF(huTNF). (SEQIDNO:11) VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVV PSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSP CQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQV YFGIIAL AminoacidsequenceofthelinkerbetweenscFvand TNF (SEQIDNO:12) EFSSSSGSSSSGSSSSG AminoacidsequenceoftheL19-huTNFconjugate (SEQIDNO:13) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFSMSWVRQAPGKGLEWVSS ISGSSGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPF PYFDYWGQGTLVTVSSGDGSSGGSGGASEIVLTQSPGTLSLSPGERATLS CRASQSVSSSFLAWYQQKPGQAPRLLIYYASSRATGIPDRFSGSGSGTDF TLTISRLEPEDFAVYYCQQTGRIPPTFGQGTKVEIKEFSSSSGSSSSGSS SSGVRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQ LVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAI KSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAES GQVYFGIIAL