NZ728534B2 - Bispecific antibodies against cd3epsilon and bcma - Google Patents
Bispecific antibodies against cd3epsilon and bcmaInfo
- Publication number
- NZ728534B2 NZ728534B2 NZ728534A NZ72853415A NZ728534B2 NZ 728534 B2 NZ728534 B2 NZ 728534B2 NZ 728534 A NZ728534 A NZ 728534A NZ 72853415 A NZ72853415 A NZ 72853415A NZ 728534 B2 NZ728534 B2 NZ 728534B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- domain
- bispecific antibody
- amino acid
- heavy chain
- fab
- Prior art date
Links
- 101100425747 Mus musculus Tnfrsf17 gene Proteins 0.000 title 1
- 235000001014 amino acid Nutrition 0.000 claims abstract 14
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims abstract 7
- 239000004475 Arginine Substances 0.000 claims abstract 4
- 101000801255 Homo sapiens Tumor necrosis factor receptor superfamily member 17 Proteins 0.000 claims abstract 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract 4
- 239000004472 Lysine Substances 0.000 claims abstract 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract 4
- 102000046935 human TNFRSF17 Human genes 0.000 claims abstract 4
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 claims abstract 3
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 claims abstract 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract 3
- 208000021161 Plasma cell disease Diseases 0.000 claims abstract 3
- 235000003704 aspartic acid Nutrition 0.000 claims abstract 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims abstract 3
- 235000013922 glutamic acid Nutrition 0.000 claims abstract 3
- 239000004220 glutamic acid Substances 0.000 claims abstract 3
- 208000034578 Multiple myelomas Diseases 0.000 claims abstract 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract 2
- 239000003814 drug Substances 0.000 claims abstract 2
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 14
- 125000000539 amino acid group Chemical group 0.000 claims 4
- 210000004027 cell Anatomy 0.000 claims 3
- BGFTWECWAICPDG-UHFFFAOYSA-N 2-[bis(4-chlorophenyl)methyl]-4-n-[3-[bis(4-chlorophenyl)methyl]-4-(dimethylamino)phenyl]-1-n,1-n-dimethylbenzene-1,4-diamine Chemical compound C1=C(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(N(C)C)=CC=C1NC(C=1)=CC=C(N(C)C)C=1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 BGFTWECWAICPDG-UHFFFAOYSA-N 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 102000039446 nucleic acids Human genes 0.000 claims 2
- 108020004707 nucleic acids Proteins 0.000 claims 2
- 150000007523 nucleic acids Chemical class 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000013598 vector Substances 0.000 claims 2
- 230000004075 alteration Effects 0.000 claims 1
- 238000012258 culturing Methods 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229920001184 polypeptide Polymers 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 102000004196 processed proteins & peptides Human genes 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 230000001131 transforming effect Effects 0.000 claims 1
- 150000001413 amino acids Chemical group 0.000 abstract 3
Classifications
-
- 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
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
-
- 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
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- 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
- C07K16/30—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
- C07K16/3061—Blood cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
- C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/35—Valency
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/522—CH1 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/526—CH3 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- 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
-
- 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
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/66—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- 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
Abstract
bispecific bi- or trivalent antibody specifically binding to the two targets which are extracellular domain of human B cell maturation antigen (BCMA) and human CD3 epsilon (CD3E), wherein the variable domains VL and VH in a light chain and the respective heavy chain are replaced by each other, characterized in comprising a constant domain CL wherein the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the respective constant domain CH1 the amino acid at position 147 and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat). A further embodiment of the invention includes the use of the bispecific bi- or trivalent antibody in the manufacture of a medicament for the treatment of plasma cell disorders including multiple myeloma.
Claims (15)
1. A bispecific antibody specifically binding to the extracellular domain of human BCMA and to human CD3, comprising: a) a first Fab which specifically binds to BCMA, wherein the first Fab comprises a first light chain and a first heavy chain, wherein the first light chain comprises a variable domain VL and a constant domain CL, and wherein the first heavy chain comprises a variable domain VH and a constant domain CH1; and b) a second Fab which specifically binds to CD3, wherein the second Fab comprises a second light chain and a second heavy chain, wherein the second light chain is a crossover light chain that comprises a variable domain VH and a constant domain CL, and wherein the second heavy chain is a crossover heavy chain that comprises a variable domain VL and a constant domain CH1; and wherein in the constant domain CL of the first light chain the amino acid at position 124 (numbering according to Kabat) is substituted independently by lysine (K), arginine (R) or histidine (H), and wherein in the constant domain CH1 of the first heavy chain the amino acid at position 147 and the amino acid at position 213 (numbering according to EU index of Kabat) is substituted independently by glutamic acid (E), or aspartic acid (D).
2. A bispecific antibody specifically binding to the extracellular domain of human BCMA and to human CD3, comprising: a) a first Fab which specifically binds to BCMA, wherein the first Fab comprises a first light chain and a first heavy chain, wherein the first light chain comprises a variable domain VL and a constant domain CL, and wherein the first heavy chain comprises a variable domain VH and a constant domain CH1; and b) a second Fab which specifically binds to CD3, wherein the second Fab comprises a second light chain and a second heavy chain, wherein the second light chain is a crossover light chain that comprises a variable domain VH and a constant domain CL, and wherein the second heavy chain is a crossover heavy chain that comprises a variable domain VL and a constant domain CH1; and wherein in the constant domain CL of the second light chain the amino acid at position 124 (numbering according to Kabat) is substituted independently by lysine (K), arginine (R) or histidine (H), and wherein in the constant domain CH1 of the second heavy chain the amino acid at positions 147 and the amino acid at position 213 (numbering according to EU index of Kabat) is substituted independently by glutamic acid (E), or aspartic acid (D).
3. A bispecific antibody according to claim 1 or claim 2, wherein the amino acid at position 123 in the constant domain CL (numbering according to Kabat) is substituted independently by lysine (K), arginine (R) or histidine (H).
4. A bispecific antibody according to claim 3, wherein said amino acid at position 124 is K, said amino acid at position 147 is E, said amino acid at position 213 is E, and said amino acid at position 123 is R.
5. A bispecific antibody according to any one of claims 1 to 4, wherein the bispecific antibody further comprises an Fc part, wherein the first Fab and the second Fab are linked via their C-termini to the hinge region of the Fc part.
6. A bispecific antibody according to any one of claims 1 to 4, wherein the bispecific antibody further comprises a third Fab, wherein the third Fab is identical to the first Fab.
7. A bispecific antibody according to claim 6, wherein the bispecific antibody further comprises an Fc part, wherein the first Fab and the second Fab are linked via their C-termini to the hinge region of the Fc part, and the third Fab is linked with its C-terminus to the N-terminus of the second Fab.
8. A bispecific antibody specifically binding to the extracellular domain of human BCMA and to human CD3, comprising a heavy and light chain set selected from the group consisting of polypeptides having the amino acid sequences of: i) SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46 (set 1), ii) SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:48, and SEQ ID NO:49 (set 2), and iii) SEQ ID NO:45, SEQ ID NO:50, SEQ ID NO:51, and SEQ ID NO:52 (set 3).
9. A bispecific antibody according to claim 8, wherein in the antibody portion specifically binding to human CD3 the variable domain VH comprises the heavy chain CDRs having the amino acid sequences of SEQ ID NO: 1, 2 and 3, as heavy chain CDR1, CDR2 and CDR3 respectively, and the variable domain VL comprises the amino acid sequences of SEQ ID NO: 4, 5 and 6 as light chain CDR1, CDR2 and CDR3 respectively.
10. A bispecific antibody according to claim 5 or claim 7, wherein in the Fc part the CH3 domain of one heavy chain and the CH3 domain of the other heavy chain each meet at an interface which comprises an original interface between the antibody CH3 domains; wherein said interface is altered to promote the formation of the bispecific antibody, wherein in the alteration: a) the CH3 domain of one heavy chain is altered, so that within the original interface the CH3 domain of one heavy chain that meets the original interface of the CH3 domain of the other heavy chain within the bispecific antibody, an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the interface of the CH3 domain of one heavy chain, which is positionable in a cavity within the interface of the CH3 domain of the other heavy chain; and b) the CH3 domain of the other heavy chain is altered, so that within the original interface of the second CH3 domain that meets the original interface of the first CH3 domain within the bispecific antibody, an amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity within the interface of the second CH3 domain within which a protuberance within the interface of the first CH3 domain is positionable.
11. A method for the preparation of a bispecific antibody according to any one of claims 1 to 10 comprising the steps of a) transforming an ex vivo host cell with one or more vectors comprising nucleic acid molecules encoding the light chains and heavy chains of a bispecific antibody according to any one of claims 1 to 10, b) culturing the ex vivo host cell under conditions that allow expression of said light chains and said heavy chains and synthesis of said bispecific antibody; and c) recovering said bispecific antibody from said culture.
12. An ex vivo host cell comprising one or more vectors comprising nucleic acid molecules encoding the light chain and heavy chains of a bispecific antibody according to any one of claims 1 to 10.
13. A pharmaceutical composition comprising a bispecific antibody according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient.
14. Use of a bispecific antibody according to any one of claims 1 to 10 or the pharmaceutical composition of claim 13 in the manufacture of a medicament for the treatment of plasma cell disorders.
15. The use according to claim 14, wherein said plasma cell disorder is multiple myeloma.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP14179705.0A EP2982692A1 (en) | 2014-08-04 | 2014-08-04 | Bispecific antibodies against CD3epsilon and BCMA |
| PCT/EP2015/067841 WO2016020332A1 (en) | 2014-08-04 | 2015-08-03 | Bispecific antibodies against cd3epsilon and bcma |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ728534A NZ728534A (en) | 2023-12-22 |
| NZ728534B2 true NZ728534B2 (en) | 2024-03-26 |
Family
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