US20150093783A1 - Humanized antibodies to ca215 - Google Patents
Humanized antibodies to ca215 Download PDFInfo
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- US20150093783A1 US20150093783A1 US14/569,444 US201414569444A US2015093783A1 US 20150093783 A1 US20150093783 A1 US 20150093783A1 US 201414569444 A US201414569444 A US 201414569444A US 2015093783 A1 US2015093783 A1 US 2015093783A1
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- C—CHEMISTRY; METALLURGY
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- A—HUMAN NECESSITIES
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61P35/00—Antineoplastic agents
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
Definitions
- the invention relates to the field of humanization of RP215 monoclonal antibody which is of murine origin.
- RP215 is known to recognize specifically a carbohydrate-associated epitope of cancer cell-expressed glycoproteins, known as CA215.
- CA215 carbohydrate-associated epitope of cancer cell-expressed glycoproteins
- the primary structure of the humanized forms of RP215 can then be utilized for the therapeutic treatment of human cancers as antibody-based anticancer drugs.
- RP215 monoclonal antibody described in U.S. Pat. No. 5,650,291 and PCT publication WO2008/138,139 is one of three thousand monoclonal antibodies which were generated in mice immunized against the extract of OC-3-VGH ovarian cancer cell.
- RP215 reacts specifically with cancer cell-expressed pan cancer biomarker or glycoproteins, designated as CA215.
- the amino acid sequence of the variable regions of RP215 is disclosed in the PCT publication. The contents of these documents as related to uses for antibodies that bind to CA215 are incorporated herein by reference.
- CA215 is a mixture of glycoproteins expressed by cancer cells, each of which contains an RP215-specific carbohydrate-associated epitope.
- glycoproteins mainly immunoglobulin superfamily (IgSF) proteins including immunoglobulin heavy chains, T cell receptors and cell adhesion molecules as well as mucins and others.
- IgSF immunoglobulin superfamily
- the invention is directed to the humanized forms of RP215 monoclonal antibody.
- the humanized versions of RP215 of the invention were shown to have affinity and specificity to CA215 comparable to, or equivalent to, those of original murine RP215.
- the invention is directed to humanized antibodies or fragments that bind CA215 with specificities and affinities substantially equivalent to that of RP215.
- the antibodies or fragments with variable regions shown in FIG. 8 are part of the invention.
- the constant region of the heavy chain be IgG and the constant region of the light chain be kappa.
- Ig forms including IgM, for example, are included as well as those embodiments that have lambda constant regions in their light chains.
- the invention is directed to methods to use the antibodies of the invention in the treatment of cancer in human subjects.
- FIG. 1 shows antigen binding curves of various humanized and chimeric forms of RP215 monoclonal antibodies.
- FIG. 2 shows the results of an ELISA to determine the low cross-reactivity of various humanized RP215 monoclonal antibodies to human IgG.
- FIG. 3 shows sequence analysis of VL: 3CDR of murine RP215 loops which are highlighted in primary amino acid sequence with key residues (C-W-C-F) identified and with no free Cys and N-linked glycosylation sites.
- FIG. 4 shows human framework donors considered.
- FIG. 5 is a template antibody structure model of murine RP215 (VL shown on left-hand side, VH on right-hand side, and CDR loops shown as spheres with van der Waals radii).
- FIG. 6 is a template antibody structure model of murine RP215. Residues in close proximity to CDR loops are shown as sticks. These residue positions are candidates for back-mutation.
- FIG. 7 shows humanized sequences that exhibit high homology to human antibody sequences.
- hRP215_VH1 has ⁇ 97% sequence identity to its closest human FR donor (germline) outside of CDR regions
- hRP215_VH2 has donor outside of CDRs.
- Different residues are mostly located within or adjacent to CDRs, with the exception of Loop 3 in VH.
- FIG. 8 shows comparison of amino acid sequences of heavy chain and light chain of humanized forms of RP215 with those of murine RP215.
- FIG. 9A and 9B shows the nucleotide sequences that encode the amino acid sequences of FIG. 8 .
- the humanized antibodies of the present invention may be in a variety of forms—including whole antibodies, fragments that are immunoreactive with CA215, including Fab, Fab', and F(ab') 2 fragments as well as recombinantly produced single-chain antibodies.
- the resulting humanized forms as noted below are of equivalent affinity and specificity to the murine RP215 and contain substantially similar or identical CDR regions.
- the CDR regions of the variable region of both heavy and light chains can be determined by a number of art-known methods, including the numbering system of Kabat which defines, in the light chain CDR1 as residues 24-34, CDR2 as residues 50-56, CDR3 as residues 89-97 and in the heavy chain CDR1 as residues 31-35, CDR2 as residues 50-65 and CDR3 as residues 95-102 (Wu, T. T., and Kabat, E. A., Exp. Med. (1970) 132:211-250).
- CDRs can also be determined according to the system of Clothia which gives slightly different results (Clothia, C., et al., Nature (1989) 342:877-883; Al-Laziken, et al., J. Mol. Biol. (1997) 273:927-948). Various subsequent authors have suggested some minor modifications.
- the CDRs as assigned by both Kabat and Clothia systems are included within the scope of the present invention.
- Sandwich and/or binding immunoassays were used to demonstrate the substantial equivalence between the humanized forms and murine RP215. Their respective affinity and specificity to the cognate antigen, the cancer cell-expressed CA215, are two important parameters to establish their substantial equivalence.
- Human framework donor selection was made through a search of germline followed by rearrangement of human IgG data base using VL and VH sequences with or without CDRs. To obtain human IgG results, normally, we go through each hit to eliminate inappropriate donors (such as mouse sequence or humanized sequence, etc.). For VL and VH sequences, the best hits in each group were aligned. Finally, one germline FR donor and one rearranged (mature) FR donor based on sequence similarity and other factors are selected. These factors included CDR length (except for CDR-H3), CDR canonical structure, proline residues at key positions or factors which may affect proper folding of humanized antibody.
- the antigen binding region of the antibody structure model can then be optimized through the CDR loop data base and canonical structure class as well as comparison to the template structure.
- ChRP215 is a murine chimera with human IgG.
- Binding immunoassays were performed using affinity-purified CA215 coated on microwells, to determine the binding affinities of these humanized RP215 to CA215 and to compare with that of the original murine RP215. The results of such comparative binding assays are presented in FIG. 1 . As shown, all of FY1-FY6 have comparable affinities to RP215.
- RP215 was established to have no cross-reactivity to normal human IgG. It reacts only with CA215 expressed by cancer cells that contain RP215-specific carbohydrate-associated epitope. Therefore, the humanized RP215 monoclonal antibodies should also show no cross-reactivity to normal human IgG. This lack-of-cross reactivity result was demonstrated, as humanized RP215 FY1, FY4 and FY5 (similar to the murine chimera) revealed no binding to human IgG as shown in FIG. 2 .
- FIG. 8 shows the complete amino acid sequences of both heavy and light chains of the humanized antibodies. The complete nucleotide sequences for these chains is shown in FIG. 9A and Figure B.
- FIGS. 3-7 show various additional structural features of these antibodies.
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Abstract
Provided herein are humanized forms of murine RP215 monoclonal antibodies and methods of using the same. These humanized RP215 monoclonal antibodies were characterized in terms of their respective affinity and specificity to the corresponding tumor-associated antigen, CA215, and shown to be comparable to those of murine RP215.
Description
- This application is a divisional of U.S. application Ser. No. 13/797,204 filed 12 Mar. 2013, now allowed, which claims priority of U.S. Ser. No. 61/659,354 filed 13 Jun. 2012. The contents of these documents are incorporated by reference herein in their entirety.
- The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 616342000510SeqList.txt, date recorded: 11 Dec. 2014, size: 35,938 KB).
- The invention relates to the field of humanization of RP215 monoclonal antibody which is of murine origin. RP215 is known to recognize specifically a carbohydrate-associated epitope of cancer cell-expressed glycoproteins, known as CA215. The primary structure of the humanized forms of RP215 can then be utilized for the therapeutic treatment of human cancers as antibody-based anticancer drugs.
- RP215 monoclonal antibody described in U.S. Pat. No. 5,650,291 and PCT publication WO2008/138,139 is one of three thousand monoclonal antibodies which were generated in mice immunized against the extract of OC-3-VGH ovarian cancer cell. Through years of effort, it was documented that RP215 reacts specifically with cancer cell-expressed pan cancer biomarker or glycoproteins, designated as CA215. The amino acid sequence of the variable regions of RP215 is disclosed in the PCT publication. The contents of these documents as related to uses for antibodies that bind to CA215 are incorporated herein by reference.
- Following comprehensive analysis of more than 100 CA215-derived tryptic peptides by MALDI-TOF MS, it was further demonstrated that CA215 is a mixture of glycoproteins expressed by cancer cells, each of which contains an RP215-specific carbohydrate-associated epitope. Among these glycoproteins are mainly immunoglobulin superfamily (IgSF) proteins including immunoglobulin heavy chains, T cell receptors and cell adhesion molecules as well as mucins and others.
- Both in vitro and in vivo biochemical and immunological assays were performed to document that RP215 reacts with the surface of almost all of cancer cells or cancerous tissues in humans. Besides immunohistochemical studies, apoptosis as well as complement-dependent cytotoxicity can be induced to cancer cells in the presence of RP215 at concentrations on the order of μg/ml. Growth inhibition of implanted tumor cells in model systems by RP215 was also demonstrated in nude mouse experiments. In addition, rat anti-idiotypic (Aid) monoclonal antibodies against RP215 were generated. The Ab3 response upon immunizations of these Aid monoclonal antibodies in mice was successfully induced. The anti-aid (Ab3) anti-sera were shown to be functionally equivalent to RP215. Aid monoclonal antibodies may also be used for the development of anti-cancer vaccines for human applications.
- To develop RP215-based anti-cancer drugs for human application, it is essential to modify the original murine RP215 monoclonal antibody into humanized form.
- The invention is directed to the humanized forms of RP215 monoclonal antibody. The humanized versions of RP215 of the invention were shown to have affinity and specificity to CA215 comparable to, or equivalent to, those of original murine RP215. Thus, in one aspect, the invention is directed to humanized antibodies or fragments that bind CA215 with specificities and affinities substantially equivalent to that of RP215. In particular, the antibodies or fragments with variable regions shown in
FIG. 8 are part of the invention. - For complete antibodies of the invention, it is preferred that the constant region of the heavy chain be IgG and the constant region of the light chain be kappa. However, other Ig forms, including IgM, for example, are included as well as those embodiments that have lambda constant regions in their light chains.
- In still other aspects, the invention is directed to methods to use the antibodies of the invention in the treatment of cancer in human subjects.
-
FIG. 1 shows antigen binding curves of various humanized and chimeric forms of RP215 monoclonal antibodies. -
FIG. 2 shows the results of an ELISA to determine the low cross-reactivity of various humanized RP215 monoclonal antibodies to human IgG. -
FIG. 3 shows sequence analysis of VL: 3CDR of murine RP215 loops which are highlighted in primary amino acid sequence with key residues (C-W-C-F) identified and with no free Cys and N-linked glycosylation sites. -
FIG. 4 shows human framework donors considered. -
FIG. 5 is a template antibody structure model of murine RP215 (VL shown on left-hand side, VH on right-hand side, and CDR loops shown as spheres with van der Waals radii). -
FIG. 6 is a template antibody structure model of murine RP215. Residues in close proximity to CDR loops are shown as sticks. These residue positions are candidates for back-mutation. -
FIG. 7 shows humanized sequences that exhibit high homology to human antibody sequences. hRP215_VH1 has ˜97% sequence identity to its closest human FR donor (germline) outside of CDR regions hRP215 ˜99% identity to germline FR Alignment of Humanized VH with Human VH Framework Donors regions, while hRP215_VH2 has donor outside of CDRs. Different residues are mostly located within or adjacent to CDRs, with the exception ofLoop 3 in VH. -
FIG. 8 shows comparison of amino acid sequences of heavy chain and light chain of humanized forms of RP215 with those of murine RP215. -
FIG. 9A and 9B shows the nucleotide sequences that encode the amino acid sequences ofFIG. 8 . - The humanized antibodies of the present invention may be in a variety of forms—including whole antibodies, fragments that are immunoreactive with CA215, including Fab, Fab', and F(ab')2 fragments as well as recombinantly produced single-chain antibodies. The resulting humanized forms as noted below are of equivalent affinity and specificity to the murine RP215 and contain substantially similar or identical CDR regions.
- The CDR regions of the variable region of both heavy and light chains can be determined by a number of art-known methods, including the numbering system of Kabat which defines, in the light chain CDR1 as residues 24-34, CDR2 as residues 50-56, CDR3 as residues 89-97 and in the heavy chain CDR1 as residues 31-35, CDR2 as residues 50-65 and CDR3 as residues 95-102 (Wu, T. T., and Kabat, E. A., Exp. Med. (1970) 132:211-250). CDRs can also be determined according to the system of Clothia which gives slightly different results (Clothia, C., et al., Nature (1989) 342:877-883; Al-Laziken, et al., J. Mol. Biol. (1997) 273:927-948). Various subsequent authors have suggested some minor modifications. The CDRs as assigned by both Kabat and Clothia systems are included within the scope of the present invention.
- Sandwich and/or binding immunoassays were used to demonstrate the substantial equivalence between the humanized forms and murine RP215. Their respective affinity and specificity to the cognate antigen, the cancer cell-expressed CA215, are two important parameters to establish their substantial equivalence.
- General Approach For Humanization
- Based on the published sequence of the RP215 variable chain, it was determined that five of the CDRs (excluding H3) fall into one of the canonical structure classes indicated as follows:
-
CDR L1 L2 L3 H1 H2 Canonical Structure class 3/ 17A 1/ 7A 1/ 9A 1/ 10A 2/10A - Human framework donor selection was made through a search of germline followed by rearrangement of human IgG data base using VL and VH sequences with or without CDRs. To obtain human IgG results, normally, we go through each hit to eliminate inappropriate donors (such as mouse sequence or humanized sequence, etc.). For VL and VH sequences, the best hits in each group were aligned. Finally, one germline FR donor and one rearranged (mature) FR donor based on sequence similarity and other factors are selected. These factors included CDR length (except for CDR-H3), CDR canonical structure, proline residues at key positions or factors which may affect proper folding of humanized antibody.
- Homology modeling was used to obtain template antibody structure by searching the PDB data base for the template antibody VL and VH sequences with or without CDR. The following conditions are taken into consideration:
-
- (1) Sequence homology
- (2) CDR length
- (3) CDR canonical structure, and
- (4) Model with correct disulfide linkage
- The antigen binding region of the antibody structure model can then be optimized through the CDR loop data base and canonical structure class as well as comparison to the template structure.
- Structural modeling was used to identify residues outside of the CDR loops that might affect CDR configurations. The following binding or interaction factors should be taken into consideration: hydrogen bonding, steric hindrance and other interactions to main chain and side chains of CDR residues.
- Back mutation was performed to those residues that are predicted to significantly affect CDR loop structure. Other critical residues were also verified including those in (1) the heterodimer interface in FR donors for proper VL and VH interactions, (2) the intra-chain domain interface and (3) direct interactions to antigen/epitopes in the known structure.
- Therefore, based on the above considerations, combinations of different back mutations were designed to balance the minimal need of such process. As a result, low immunogenicity to humans can be obtained and the maximal preservations of antigen-binding affinity can be preserved.
- The following examples are offered to illustrate but not to limit the invention.
- Humanized RP215 monoclonal antibodies with heavy and light chains designated 0021-0023 (VH1-VH3 and VL1-VL2) and the parent murine chains 0024 were generated, expressed and affinity-purified. Various heavy chain/light chain combinations were used to construct antibodies FY1-FY6 as shown in Table 1. ChRP215 is a murine chimera with human IgG.
-
TABLE 1 VL1 VL2 L0024 VH1 FY1 FY4 VH2 FY2 FY5 VH3 FY3 FY6 H0024 ChRP215 - The titers and amounts of FY1-FY6 from CHO cells are shown in Table 2.
-
TABLE 2 Apparent titer Production yield Name of antibody (ng/ml) (N = 1) Neg. control NA 305 RP215 chimera 4.2 219 (with human IgG) FY1 5.7 287 FY2 13.1 166 FY3 8.4 152 FY4 4.4 351 FY5 9.6 158 FY6 7.1 350 - Binding immunoassays were performed using affinity-purified CA215 coated on microwells, to determine the binding affinities of these humanized RP215 to CA215 and to compare with that of the original murine RP215. The results of such comparative binding assays are presented in
FIG. 1 . As shown, all of FY1-FY6 have comparable affinities to RP215. - Previously, RP215 was established to have no cross-reactivity to normal human IgG. It reacts only with CA215 expressed by cancer cells that contain RP215-specific carbohydrate-associated epitope. Therefore, the humanized RP215 monoclonal antibodies should also show no cross-reactivity to normal human IgG. This lack-of-cross reactivity result was demonstrated, as humanized RP215 FY1, FY4 and FY5 (similar to the murine chimera) revealed no binding to human IgG as shown in
FIG. 2 . -
FIG. 8 shows the complete amino acid sequences of both heavy and light chains of the humanized antibodies. The complete nucleotide sequences for these chains is shown inFIG. 9A and Figure B. - As a matter of interest,
FIGS. 3-7 show various additional structural features of these antibodies.
Claims (14)
1. A recombinant expression system which comprises a nucleotide sequence encoding a humanized monoclonal antibody (mAb) or antigen-binding fragment thereof that reacts specifically with a CA215, and
that binds to the CA215 with an affinity substantially equivalent to that of RP215,
which mAb comprises the CDR regions inherent in one of the heavy chain variable regions set forth in SEQ ID NOS:24-26 and in one of the light chain variable regions set forth in SEQ ID NO:28 or 29 according to the numbering system of either Kabat or Clothia;
said encoding nucleotide sequence operably linked to a heterologous promoter.
2. The expression system of claim 1 , wherein in said mAb or fragment:
a) the CDR1 region of the heavy chain is DYWMH (SEQ ID NO:1); and
b) the CDR2 region of the heavy chain is AIDTSDSYTRYAQKFQG (SEQ ID NO:2) or GIDTSDSYTRYAQKFQG (SEQ ID NO:3); and
c) the CDR3 region of the heavy chain is SIYD (SEQ ID NO:4); and
d) the CDR1 region of the light chain is KSSQSLLNSSNQKSYLA (SEQ ID NO:5); and
e) the CDR2 region of the light chain is FASTRES (SEQ ID NO:6); and
f) the CDR3 region of light chain is QGHYSTPST (SEQ ID NO:7).
3. A recombinant expression system which comprises a nucleotide sequence encoding an mAb or antigen-binding fragment thereof which comprises the variable regions of
VH1 (SEQ ID NO:24)+VL1 (SEQ ID NO:28); VH1 (SEQ ID NO:24)+VL2 (SEQ ID NO:29);
VH2 (SEQ ID NO:25)+VL1 (SEQ ID NO:28); VH2 (SEQ ID NO:25)+VL2 (SEQ ID NO:29);
VH3 (SEQ ID NO:26)+VL1 (SEQ ID NO:28); or VH3 (SEQ ID NO:26)+VL2 (SEQ ID NO:29);
said encoding nucleotide sequence operably linked to a heterologous promoter.
4. The expression system of claim 1 which encodes a complete antibody.
5. The expression system of claim 1 which encodes a single-chain antibody.
6. The expression system of claim 3 which encodes a complete antibody.
7. The expression system of claim 3 which encodes a single-chain antibody.
8. Recombinant host cells or immortalized cells that produce an mAb or antigen-binding fragment thereof that reacts specifically with a CA215, and
that binds to the CA215 with an affinity substantially equivalent to that of RP215,
which mAb comprises the CDR regions inherent in one of the heavy chain variable regions set forth in SEQ ID NOS:24-26 and in one of the light chain variable regions set forth in SEQ ID NO:28 or 29 according to the numbering system of either Kabat or Clothia.
9. The cells of claim 8 , wherein in said mAb or fragment:
a) the CDR1 region of the heavy chain is DYWMH (SEQ ID NO:1); and
b) the CDR2 region of the heavy chain is AIDTSDSYTRYAQKFQG (SEQ ID NO:2) or GIDTSDSYTRYAQKFQG (SEQ ID NO:3); and
c) the CDR3 region of the heavy chain is SIYD (SEQ ID NO:4); and
d) the CDR1 region of the light chain is KSSQSLLNSSNQKSYLA (SEQ ID NO:5); and
e) the CDR2 region of the light chain is FASTRES (SEQ ID NO:6); and
f) the CDR3 region of light chain is QGHYSTPST (SEQ ID NO:7).
10. The cells of claim 8 that are contained in a transgenic non-human animal or transgenic plant.
11. A method to produce a humanized mAb or fragment that reacts specifically with CA215 which method comprises culturing the cells of claim 8 and recovering said mAb or fragment.
12. Recombinant host cells or immortalized cells that produce an mAb or antigen-binding fragment which comprises the variable regions of
VH1 (SEQ ID NO:24)+VL1 (SEQ ID NO:28); VH1 (SEQ ID NO:24)+VL2 (SEQ ID NO:29);
VH2 (SEQ ID NO:25)+VL1 (SEQ ID NO:28); VH2 (SEQ ID NO:25)+VL2 (SEQ ID NO:29);
VH3 (SEQ ID NO:26)+VL1 (SEQ ID NO:28); or VH3 (SEQ ID NO:26)+VL2 (SEQ ID NO:29).
13. The cells of claim 12 that are contained in a transgenic non-human animal or transgenic plant.
14. A method to produce a humanized mAb or fragment that reacts specifically with CA215 which method comprises culturing the cells of claim 12 and recovering said mAb or fragment.
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CN108610414B (en) * | 2018-02-12 | 2022-09-13 | 北京大学 | IgG epitope and application thereof as target spot |
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AU6031090A (en) | 1989-07-31 | 1991-03-11 | University Of British Columbia, The | Monoclonal antibodies against a tumor-associated antigen |
CA2687403A1 (en) * | 2007-05-14 | 2008-11-20 | Vancouver Biotech Ltd. | Carbohydrate-containing pan cancer marker |
-
2013
- 2013-03-12 US US13/797,204 patent/US8974786B2/en active Active
- 2013-06-13 CA CA2876796A patent/CA2876796A1/en not_active Abandoned
- 2013-06-13 JP JP2015516701A patent/JP2015525075A/en active Pending
- 2013-06-13 EP EP13803890.6A patent/EP2861625A2/en not_active Withdrawn
- 2013-06-13 WO PCT/IB2013/001834 patent/WO2013186630A2/en active Application Filing
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2014
- 2014-12-12 US US14/569,444 patent/US20150093783A1/en not_active Abandoned
Cited By (1)
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---|---|---|---|---|
CN108484777A (en) * | 2017-03-31 | 2018-09-04 | 李吉祐 | The Chimeric antigen receptor construct and nucleic acid molecules of humanization RP215 monoclonal antibodies and application |
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WO2013186630A3 (en) | 2014-02-20 |
US8974786B2 (en) | 2015-03-10 |
CA2876796A1 (en) | 2013-12-19 |
WO2013186630A2 (en) | 2013-12-19 |
EP2861625A2 (en) | 2015-04-22 |
JP2015525075A (en) | 2015-09-03 |
US20130340102A1 (en) | 2013-12-19 |
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