NZ765527B2 - Antibodies with increased affinity for the epidermal growth factor receptor and fragments derived therefrom - Google Patents
Antibodies with increased affinity for the epidermal growth factor receptor and fragments derived therefrom Download PDFInfo
- Publication number
- NZ765527B2 NZ765527B2 NZ765527A NZ76552718A NZ765527B2 NZ 765527 B2 NZ765527 B2 NZ 765527B2 NZ 765527 A NZ765527 A NZ 765527A NZ 76552718 A NZ76552718 A NZ 76552718A NZ 765527 B2 NZ765527 B2 NZ 765527B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- seq
- cdr
- mab
- sequence
- variable region
- Prior art date
Links
- 239000012634 fragment Substances 0.000 title claims abstract 17
- 102000001301 EGF receptor Human genes 0.000 title 1
- 108060006698 EGF receptor Proteins 0.000 title 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract 7
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract 7
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims abstract 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract 6
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 claims abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 3
- 230000001900 immune effect Effects 0.000 claims abstract 2
- 230000028993 immune response Effects 0.000 claims abstract 2
- 229950010203 nimotuzumab Drugs 0.000 claims abstract 2
- 108020001580 protein domains Proteins 0.000 claims abstract 2
- 102000004169 proteins and genes Human genes 0.000 claims abstract 2
- 108090000623 proteins and genes Proteins 0.000 claims abstract 2
- 238000002560 therapeutic procedure Methods 0.000 claims abstract 2
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims 25
- 239000000427 antigen Substances 0.000 claims 9
- 102000036639 antigens Human genes 0.000 claims 9
- 108091007433 antigens Proteins 0.000 claims 9
- 101100123850 Caenorhabditis elegans her-1 gene Proteins 0.000 claims 5
- 102100035361 Cerebellar degeneration-related protein 2 Human genes 0.000 claims 5
- 101000737793 Homo sapiens Cerebellar degeneration-related antigen 1 Proteins 0.000 claims 5
- 101000737796 Homo sapiens Cerebellar degeneration-related protein 2 Proteins 0.000 claims 5
- 239000003814 drug Substances 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000004480 active ingredient Substances 0.000 claims 2
- 238000003745 diagnosis Methods 0.000 claims 2
- 239000003550 marker Substances 0.000 claims 1
- 238000011275 oncology therapy Methods 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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
- 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
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/54—F(ab')2
-
- 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]
-
- 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
- C07K2317/567—Framework region [FR]
-
- 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
- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/70—Mechanisms involved in disease identification
- G01N2800/7023—(Hyper)proliferation
- G01N2800/7028—Cancer
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
Abstract
The invention relates to new antibodies (Ab) and fragments that recognize the extracellular region of the human epidermal growth factor receptor (hEGFR) with a higher affinity than the Ab nimotuzumab, thus being able to recognize more efficiently lines with medium expression of EGFR. The present invention also relates to pharmaceutical compositions comprising the aforementioned Abs and fragments as active principle, and to the use thereof in therapy for EGFR-expressing tumors. In addition, the Abs and fragments can be used to locate EGFR positive tumors when linked to a radioisotope or fluorophore. Additionally, said Abs and fragments can be used in directing the immune response to EGFR positive tumor cells when they are fused to proteins or protein domains of immunological interest.
Claims (18)
1.CLAIMS 5 1. A recombinant monoclonal antibody (mAb) that recognizes the extracellular region of the human epidermal growth factor receptor (Her1) characterized in that it shares more than 95% identity with respect to the nimotuzumab antibody and that the CDR2 sequence of the variable region of the heavy chains are selected from the group comprising: 10 - SEQ ID NO. 17 and - SEQ ID NO. 18, the sequence of CDR1 is SEQ ID NO. 9 and the sequence of CDR3 is SEQ ID NO.3 in these heavy chains and the CDR sequences of the variable region of the light chains are: 15 - CDR 1 SEQ ID NO. 22 - CDR 2 SEQ ID NO. 23 - CDR 3 SEQ ID NO. 24.
2. A mAb that recognizes the Her1 characterized in that the CDR2 sequence of the variable region of the heavy chains is selected from the group comprising: 20 - SEQ ID NO. 10, - SEQ ID NO. 11, - SEQ ID NO. 12, - and - SEQ ID NO. 29, 25 the sequence of CDR1 is SEQ ID NO. 9 and the sequence of CDR3 is SEQ ID NO.3, these heavy chains and the CDR sequences of the variable region of the light chains are: - CDR 1 SEQ ID NO. 22 - CDR 2 SEQ ID NO. 23 30 - CDR 3 SEQ ID NO. 24.
3. A mAb that recognizes Her1 characterized in that the CDR2 sequence of the variable region of the heavy chains is selected from the group comprising: - SEQ ID NO. 2 and - SEQ ID NO. 8, the sequence of CDR1 is SEQ ID NO. 1 and the sequence of the CDR3 is SEQ ID NO.3, these heavy chains and the CDR sequences of the variable region of the light chains are shown below: - CDR 1 SEQ ID NO. 22 5 - CDR 2 SEQ ID NO. 23 - CDR 3 SEQ ID NO. 24.
4. A mAb that recognizes Her1 characterized in that the CDR1 sequence of the variable region of the heavy chains is selected from the group comprising: - SEQ ID NO. 13 and 10 - SEQ ID NO. 19, the CDR2 sequence is SEQ ID NO. 14 and the sequence of CDR3 is SEQ ID NO.3 these heavy chains and the CDR sequences of the variable region of the light chains are: - CDR 1 SEQ ID NO. 22 15 - CDR 2 SEQ ID NO. 23 - CDR 3 SEQ ID NO. 24.
5. A mAb that recognizes the Her1 characterized because the CDR of the variable region of the heavy and light chains contains the following sequences: Heavy chain 20 - CDR1 SEQ ID NO. 15 - CDR2 SEQ ID NO. 16 - CDR3 SEQ ID NO.3 Light chain - CDR 1 SEQ ID NO. 22 25 - CDR 2 SEQ ID NO. 23 - CDR 3 SEQ ID NO. 24.
6. The mAb according to claims 1-5 characterized in that the framework regions (FW) of the variable region of the heavy and light chains have the following sequences: 30 Heavy chain - FW 1 SEQ ID NO. 4 - FW 2 SEQ ID NO. 5 - FW 3 SEQ ID NO. 6 - FW 4 SEQ ID NO. 7 35 Light chain - FW 1 SEQ ID NO. 25 - FW 2 SEQ ID NO. 26 - FW 3 SEQ ID NO. 27 - FW 4 SEQ ID NO. 28
7. The mAb according to any one of claims 1 to 6, characterized in that the sequence of the heavy chain constant regions is a human IgG1. 5
8. The mAb according to any one of claims 1 to 6 characterized in that the constant regions of light chain is a human kappa.
9. An antigen binding fragment derived from the mAb of any one of claims 1-8 characterized in that it is a fragment of Fab type.
10. An antigen binding fragment according to any one of claims 1-8 characterized in 10 that it is a fragment of (Fab) 2 type.
11. An antigen binding fragment according to any one of claims 1-6, characterized in that it is a single-chain variable region fragment.
12. A pharmaceutical composition useful in cancer therapy having as active ingredient the mAb or the antigen binding fragment of any one of claims 1-11 in 15 a range from 50 to 400 mg and a pharmaceutically acceptable vehicle.
13. A pharmaceutical composition useful in the diagnosis of tumors having as active ingredient the mAb or the antigen binding fragment of any one of claims 1-11 in a range from 1 to 9 mg and a pharmaceutically acceptable vehicle.
14. The use of the mAb or the antigen binding fragment of any one of claims 1-11 for 20 the manufacture of a medicament for the therapy of tumors expressing EGFR.
15. The use of the mAb or the antigen binding fragment of any one of claims 1-11 conjugated to an appropriate marker for the manufacture of a medicament for the diagnosis of tumors bearing EGFR.
16. The use of the mAb or the antigen binding fragment of any one of claims 1-11 25 conjugated with proteins or protein domains of immunological interest for the manufacture of a medicament to direct the immune response against EGFR positive tumors.
17. A mAb of any one of claims 1 to 6 substantially as herein described and with reference to any example thereof. 30
18. An antigen binding fragment of any one of claims 9 to 11 substantially as herein described and with reference to any example thereof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
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CU2017000148A CU24558B1 (en) | 2017-11-28 | 2017-11-28 | MONOCLONAL ANTIBODIES RECOGNIZING THE EPIDERMAL GROWTH FACTOR RECEPTOR AND ITS DERIVED FRAGMENTS |
| PCT/CU2018/050004 WO2019105492A1 (en) | 2017-11-28 | 2018-11-20 | Antibodies with increased affinity for the epidermal growth factor receptor and fragments derived therefrom |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ765527A NZ765527A (en) | 2024-02-23 |
| NZ765527B2 true NZ765527B2 (en) | 2024-05-24 |
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