WO2014142591A1 - 소수성 상호작용 부위내에 전기적 상호작용이 도입된 단백질 및 이의 제조방법 - Google Patents
소수성 상호작용 부위내에 전기적 상호작용이 도입된 단백질 및 이의 제조방법 Download PDFInfo
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"
Definitions
- BsAbs High purity heterologous bispecific antibodies
- BsFp bispecific fusion proteins
- Bispecific antibodies do not appear naturally in nature, and their simultaneous binding to two different biological targets is rather artificially made. This dual targeting capability offers BsAb a new field of application that cannot be applied with previous monospecific antibodies (MsAbs).
- MsAbs monospecific antibodies
- Of particular interest for therapeutic purposes is to (1) reliably introduce immune cells into the vicinity of the target cell, (2) prevent or activate synergistically two distant signaling pathways of the target cell, (3 ) Triggered likelihood of specific and controllable delivery of therapeutic, radioactive, medicament, toxin or a progressive to the target cell.
- Both specific antibodies were commonly used to send T cells to tumor cells in a non-MHC restricted manner by linking the cell surface antigens of tumor cells with the CD3-TCR complex of cytotoxic T cells (see FIG. 1 ).
- 1 shows Catumaxomab (Removab ® ), a hybrid monoclonal antibody of rats and mice used to treat malignant ascites. These are also called trifunctional antibodies.
- a myriad (45 different formats) of BsAb-related technologies have been developed. These techniques can be classified into four categories based on the structure.
- First the structural complementary state known as Knob-into-Hole, or simply KiH, charge polarity compensation (electrostatic steering effect), or CH3 domain suppuration (called SEEDbody TM ) Techniques for heavy chain heterologation through various methods, including;
- Second various antibody segment formats such as Diabody TM , BiTE TM, and DART TM, and thirdly, techniques using one or more functional domains such as Modular Antibody TM , Zybody TM , dAbs TM, and DVD-IG TM. Techniques for conjugation to antibodies;
- Fourth techniques employing full length length IgG-like designs such as Duobody TM (Fab-Arm Exchange), CrossMab TM , Azymetric TM , and kI body TM have been developed.
- Duobody TM Fab-Arm Exchange
- CrossMab TM
- the first form of the invention is a pair of hydrophobic amino acids selected within the site of hydrophobic interaction of a protein, wherein one hydrophobic amino acid has a positive charge, and the other hydrophobic amino acid has a negative charge. It is transformed into an excitation material to provide a protein in which electrical interaction is introduced into the hydrophobic interaction site of the protein by the positive charge and the negative charge.
- the positively charged material may be a basic amino acid, although not limited thereto, and the negatively charged material may be an acidic amino acid, but is not limited thereto.
- the hydrophobic amino acid is any one amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan
- the acidic amino acid is any one amino acid selected from aspartic acid or glutamic acid to be.
- At least one hydrophobic interaction of the Fc domain of the antibody is converted to an electrical counterpart (for example, 407 th tyrosine tyrosine hydrophobic interaction (Y407: Y407) to 407 th aspartic acid lysine (D407: K407)).
- an electrical counterpart for example, 407 th tyrosine tyrosine hydrophobic interaction (Y407: Y407) to 407 th aspartic acid lysine (D407: K407).
- SHOCAP SHOCAP technology
- two major hydrophobic residues of the Fab domain eg, leucine 128 and 118 phenylalanine (L128: F118) are replaced with 128 aspartic acid and 118 lysine (K128: D118).
- the heavy chain and the two light chains can be easily distinguished, so in principle SHOCAP technology can be applied to both Fc and Fab domains of antibodies to produce IgG-like bispecific antibodies. .
- the second aspect of the present invention is a hydrophobic amino acid selected from the site of the hydrophobic interaction of the antibody, one hydrophobic amino acid is a positive charge material, the other hydrophobic amino acid is modified to a negative charge material
- An antibody is provided wherein an electrical interaction is introduced into a hydrophobic interaction site of a protein by a positive charge and said negative charge.
- the positively charged material may be a basic amino acid, but is not limited thereto, and the negatively charged material may be an acidic amino acid, but is not limited thereto. More specifically
- the antibody is characterized by being mutated to any one set selected from the group consisting of a combination of Z0 to Z14 in Table 4 below.
- the antibody may have a pair of ectodomains with a pair of functions.
- the ectodomain may play an anticancer role, may be involved in signaling, and is a toxin so that other specific antibodies may be used as an anticancer agent by killing cells in the binding region.
- the ectodomain is TNR2, Her3, Tie2, TGFbR1, BMPbR1, Il-12R-b1, IL-4Ra, ITGA4, ITGA2B, INFAR1, IL-12A, IL-4, InFa, BMP2, IL-1R1L , IL-17RA, IL-17A, Fas, FltD2, Her1, Tie1, TGFbR2, IL-12R-b2, IL-13Ra1, ITGB1, ITGB3, INFAR2, IL-12B, IL-13, INFb, BMP7, IL-1RAP
- any one pair of ectodomains may be selected.
- the antibody may be an antibody in which any one ectodomain combination selected from the Her2 / FltD2 combination, the Her1 / Her3 combination, or the Tie / Tie2 combination is fused. More specifically, both specificities having a heavy chain mutated with the combination of Z14 and a common light chain comprising 4D9 ectodomain specific for A-type influenza virus and 2B9 ectodomain specific for B-type influenza virus It may be an antibody.
- the antibody comprises the heavy chains (HP) and another heavy chain (HN), light chain (LP) and another light chain (LN) of V1 to V5, W1 to W8, V2p
- the antibody may have an improved degree of pairing of heavy and light chains, which is composed of any one combination selected from the group consisting of V3p, W4p, V3W4, W4v3, and V3v1.
- the antibody mutated 103 tryptophan to lysine in one of the heavy chains, 128 lysines in another heavy chain to aspartic acid, and 118 phenylalanine in light chain to lysine.
- Another light chain, 44 is a antibody that has improved the degree of pairing of heavy and light chains by mutating to aspartic acid.
- a third form of the invention comprises the steps of selecting a pair of hydrophobic amino acids in the site of the hydrophobic interaction between the polypeptide chain and the polypeptide chain; Transforming, in the selected pair of amino acids, one hydrophobic amino acid into a positively charged material and the other hydrophobic amino acid into a negatively charged material; And it provides a method for producing a protein with increased chain selectivity, comprising the step of contacting the positive charge and the negative charge by electrical interaction.
- the positively charged material may be a basic amino acid, but is not limited thereto, and the negatively charged material may be an acidic amino acid, but is not limited thereto.
- the fourth aspect of the present invention provides a common light chain comprising a heavy chain mutated with the combination of Z14 and a 4D9 ectodomain specific for A-type influenza virus and a 2B9 ectodomain specific for B-type influenza virus.
- the present invention provides a method for measuring the degree of pairing of heavy and light chains of both specific antibodies using the bispecific antibodies.
- the SHOCAP modification of the Fc domain of two heavy chains creates positive and negatively charged heavy chains (called Ha and Hb, respectively). Their electrical interaction favors heterodimerization over heavy chain homodimerization.
- the SHOCAP modification of the two Fab domains results in positive and negatively charged light chains (called La and Lb, respectively), and the electrical interaction of the oppositely charged Fab domains of the heavy chain is accurate HC. / LC Increases the chance of pairing. Accordingly, the antibody according to the present invention can obtain a heterologous neutralized antibody or protein which is less contaminated with isoforms or monomers.
- Another advantage of the present invention is the minimal number of modifications to the natural antibody, so that no significant structural changes are made to the structure of the natural antibody, and moreover, the targeted residues are hydrophobic interactions of heavy and light chains. Deeply buried in the bond surface induces less immune rejection.
- Bispecific Antibody 1 is a general form of Bispecific Antibody.
- An example is Catumaxomab (Removab ® ), a hybrid monoclonal antibody in rats and mice used to treat malignant ascites.
- FIG. 5 shows a set of 14 mutated mutations for the introduction of electrical interactions in the Fc moiety to which the TNFR2 ectodomain and the FAS ectodomain are respectively bound to show the efficiency of Fc heterologous duplication of the antibody.
- the A chain inserts a positively charged amino acid in the hydrophobic interaction and the B chain inserts a negatively charged amino acid in the hydrophobic interaction.
- FIG. 6 shows the set Z0 to Z4 sets in Table 4 on SDS-PAGE to see how well Fc heterologous biplication occurs.
- FIG. 7 shows the set Z5-Z9 sets in Table 4 on SDS-PAGE to see how well heterologous biplication occurs.
- FIG. 8 shows the set Z10 to Z14 set in Table 4 on SDS-PAGE to see how well heterologous biplication occurs.
- FIG. 10 is a comparison of the heterologous neutralization efficiency between the Her1 / Her3 heterologous neutralizing antibody prepared on the basis of Z14 and the control.
- A Her1 / Her3 heterologous neutralizing antibody schematic
- B SDS-PAGE result
- C HIC-HPLC analysis result
- FIG. 11 is a comparison of heterologous neutralization efficiencies between Tie1 / Tie2 heterologous neutralizing antibodies prepared on the basis of Z14 and a control group.
- A Schematic of Tie1 / Tie2 heterologous neutralizing antibody
- B SDS-PAGE
- C HIC-HPLC analysis
- Fig. 13 is a schematic diagram showing that three antibodies instead of ten are made in the case of antibodies sharing a common light chain.
- Figure 14 shows the results of the SDS-PAGE, purely produced bispecific antibodies in the case of antibodies sharing a common light chain prepared on the basis of Z14 in Table 4.
- FIG. 15 shows pure bispecific antibodies produced in the case of antibodies sharing a common light chain prepared based on Z14 in Table 4 as a result of HIS-HPLC chromatography.
- 19 is a schematic diagram showing that when the antibody is prepared according to the present invention, the binding of the heavy chain and the light chain can be distinguished symmetrically or asymmetrically based on the position of the charged charge.
- V3W1 combination in Table 7 is the best match for the heavy and light chains.
- Fc fusion proteins produced from single (A and B) and co-expression (A + B) sets were purified by protein A chromatography. The protein was finally eluted with 1 ml Protein A elution buffer and 10 microliters of elution sample was hung on 10% SDS-PAGE.
- the likelihood of heterologous duplication is that the band density of TNFR2-Fc / FAS-Fc heterologous duplexing is compared with the density of the band of (TNFR2-Fc) 2 and (FAS-Fc) 2 homologous neutralization in the co-expression setting (A + B) It was measured by comparison.
- TNFR2-Fc and FAS-Fc products were also compared in homogeneous (TNFR2-Fc) 2 and (FAS-Fc) 2 products in a single expression setting (A and B).
- 6 shows data from the Z0 to Z4 variant sets.
- 7 shows data of the Z5-Z9 variant set.
- 8 shows variant data of Z10-Z14.
- Variant set Z14 was finally selected as the best of these.
- Variant set Z14 was more likely to be heterologous than others.
- the heterologous heterologs of the TNFR2-Fc / FAS-Fc form were most prevalent over the (TNFR2-Fc) 2 and (FAS-Fc) 2 homodimers in the co-expression set and their single TNFR2-Fc and FAS- Fc morphology was most unstable in a single expression set. This shows that the antibody according to the present invention is less contaminated by a single type or by homodimer.
- Her3 ectodomain was positively charged Fc domain (A chain; 97 kD) and FltD2 domain was fused to negatively charged (B chain, 40 kD). Both extracellular domains are known to maintain very intrinsic allogeneic potential.
- Her3 ectodomain was fused with a positively charged Fc domain (A chain; 97 kD) and Her1 ectodomain was fused with a negatively charged Fc domain (B chain, 95 KD). Both extracellular domains are known to maintain very intrinsic allogeneic potential.
- Tie1 ectodomains were fused with a positively charged Fc domain (A chain) and Tie2 ectodomains were fused with a negatively charged Fc domain (B chain).
- HIC-HPLC analysis was performed as previously described. Similar to SDS-PAGE, it is shown that Z14 is highly likely to be heterologous (see FIG. 11 (C) ).
- CLC-BsAb common light chain bispecific antibody
- Table 6 set H A H B L C Z0 HA0 - HB0 - - Z14 HA14 L351K / T394K / P395K / V397K HB14 L351D / T394D / P395D / V397D - CPC HPC D399K / E356K HNC K409D / K392D KiH HKC T366S / L368A / Y407V HHC T366W AzS HAC T350V / T366L / K392L / T394W HBC T350V / L351Y / F405A / Y407V
- the purity of Z14 was evaluated by HIC-HPLC chromatography.
- the Z0 set has three peaks each corresponding to (HA / LC) 2 , (HA / LC) // (HB / LC) and (HB / LC) 2 .
- the Z14 set has one peak corresponding to both specific (HA / LC) // (HB / LC) antibodies. This shows that the samples co-expressed by the Z14 set, as in the SDS-PAGE results, are not contaminated by a very single antibody but have high purity only with both specific antibody forms (see FIG. 15 ).
- A-HA5 and B-HA Two antigens, A-HA5 and B-HA, were coated in three different amounts (100, 50 and 25 ng / well) and separately coated on ELISA plates. After blocking with blocking solution, 100 ng of antibody was added and incubated overnight. After complete washing of the plate, HRP-conjugated anti-human Fc mouse antibody was added to each well.
- Z14 has both binding activity against A-HA5 and B-HA antigens.
- the two control antibodies 4D9 HA0 + LC
- 2B ((HB0 + LC) had single binding activity (see FIG. 16 ).
- FcRn-Fc fusion protein 100 ng was coated in each well of the ELIZA plate. After blocking with blocking solution, 100ng of 4D9 (HA0 + LC), 2B9 (HB0 + LC), Z14 antibody was added overnight and incubated. Plates were washed thoroughly and HRP-conjugated anti-human Fc mouse antibody was added to each well.
- B6CBA rats were injected at a dose of Remicade 10 mg / ml and CLC-BsAb 4 mg / kg, with different sample concentrations measured up to 14 days post dose. There was no significant difference in the profile of antibody concentration between the two antibodies.
- the ANOVA test was calculated by NCA and two-compartment model analysis to determine various pharmacokinetic factors (CL, V1, AUC, MRT, t1 / 2). ) (See FIG. 18 ).
- light chain LP positive charged light chain
- HP positive charged heavy chain
- 50kD HN and 25kD CP positively charged common light chain
- the modification of the protein does not give chain distinction, the light chain LP will bind to the HP and HN heavy chains, resulting in three different Abs. This makes 60 kD HP as well as 50 kD HN, 25 kD LP in the reduced SDS-PAGE gel.
- the variant is made of two different designs. It may be symmetrical or asymmetrical in terms of the charge distribution pattern in the two Fab domains (see FIG. 19).
- a total of 21 hydrophobic residues were modified, either separately or in combination, electrically paired with interaction residues and combined into a set of 21 variants (see Table 7 ).
- V3W1 variant set was chosen as the best variant resulting in correct HC / LC pairing in 21 sets (see FIG. 20 ).
Abstract
Description
HIP 번호 | CH3 도메인 (사슬 A) | CH3 도메인 (사슬 B) |
1 | L351 | L351 |
2 | P395 | V397 |
3 | P395 | P395 |
4 | V397 | P395 |
5 | Y407 | Y407 |
HIP 번호 | CH1 도메인 | CL 도메인 |
6 | L128 | F118 |
7 | L128 | V133 |
8 | A141 | F116 |
9 | A141 | F118 |
10 | A141 | L135 |
11 | L145 | V133 |
12 | F170 | L135 |
13 | V185 | F118 |
14 | V185 | L135 |
HIP 번호 | VH 도메인 | VL 도메인 |
15 | V37 | F98 |
16 | F45 | P44 |
17 | F45 | Y87 |
18 | F45 | F98 |
19 | W47 | Y96 |
20 | W47 | F98 |
21 | W50 | Y96 |
22 | Y91 | P44 |
23 | W103 | Y36 |
24 | W103 | Y36 |
25 | W103 | A43 |
26 | W103 | P44 |
27 | W103 | F98 |
세트번호 | 사슬 A (TNFR2) | 사슬 B (FAS) | ||
Z0 | A0 | - | B0 | - |
Z1 | A1 | L351K | B1 | L351D |
Z2 | A2 | P395K | B2 | P395D |
Z3 | A3 | Y407K | B3 | Y407D |
Z4 | A4 | L351K/P395K | B4 | L351D/P395D |
Z5 | A5 | L351K/Y407K | B5 | L351D/Y407D |
Z6 | A6 | T394K/P395K | B6 | T394D/P395D |
Z7 | A7 | T394K/V397K | B7 | T394D/V397D |
Z8 | A8 | P395K/V397K | B8 | P395D/V397D |
Z9 | A9 | P395K/Y407K | B9 | P395D/Y407D |
Z10 | A10 | L351K/T394K/P395K | B10 | L351D/T394D/P395D |
Z11 | A11 | L351K/T394K/V397K | B11 | L351D/T394D/V397D |
Z12 | A12 | L351K/P395K/V397K | B12 | L351D/P395D/V397D |
Z13 | A13 | L351K/P395K/Y407K | B13 | L351D/P395D/Y407D |
Z14 | A14 | L351K/T394K/P395K/V397K | B14 | L351D/T394D/P395D/V397D |
Fc 기원 | A 사슬 | B 사슬 | 타겟 질병 | |
I | Human (G1) | TNFR2 | Fas | 자가 면역 질환 |
II | Human (G1) | Her3 | Flt1D2 | 암 |
III | Human (G1) | Her3 | Her1 | 암 |
IV | Human (G1) | Tie2 | Tie1 | 암 |
V | Human (G1) | TGFbR1 | TGFbR2 | 섬유증, 상처치유 및 암 |
VI | Human (G1) | BMPbR1 | BMPbR2 | 골석화증 |
VII | Human (G1) | IL-12R-b1 | IL-12R-b2 | 자가면역질환 (건선, MS 및 Crohn) |
VIII | Human (G1) | IL-4Ra | IL-13Ra1 | 천식 및 아토피 |
IX | Human (G1) | ITGA4 | ITGB1 | MS |
X | Human (G1) | ITGA2B | ITGB3 | 혈전증 |
XI | Human (G1) | INFAR1 | INFAR2 | 자가면역질환 |
XII | Human (G2) | IL-12A | IL-12B | 암 면역치료제 |
XIII | Human (G2) | IL-4 | IL-13 | 자가면역질환(건선, MS & Crohn) |
XIV | Human (G2) | INFa | INFb | 암, 간염, MS |
XV | Human (u/dG2) | BMP2 | BMP7 | 골석화증 |
XVI | Human (E) | IL-1R1L | IL-1RAP | 아토피 (항 IL-33 차단제) |
XVIII | Human (G1) | IL-17RA | IL-17RC | 자가면역질환 (건선, MS 및 Crohn) |
XIV | Human (u/dG2) | IL-17A | IL-17F | 암 면역치료제 |
세트 | HA | HB | LC | ||
Z0 | HA0 | - | HB0 | - | - |
Z14 | HA14 | L351K/T394K/P395K/V397K | HB14 | L351D/T394D/P395D/V397D | - |
CPC | HPC | D399K/E356K | HNC | K409D/K392D | |
KiH | HKC | T366S/L368A/Y407V | HHC | T366W | |
AzS | HAC | T350V/T366L/K392L/T394W | HBC | T350V/L351Y/F405A/Y407V |
설계 | 세트이름 | HP | HN | LP | LN | ||||
Name | HP(2B9) | Name | HN(4D9) | Name | LP | Name | LN | ||
대칭형 | V1 | HPa | F45K | HNa | F45D | LPa | F98K | LNa | F98D |
V2 | HPb | W47K | HNb | V47D | LPb | Y96K | LNb | Y96D | |
V3 | HPc | W103K | HNc | W103D | LPc | P44K | LNc | P44D | |
V4 | HPd | V37K | HNd | V37D | LPa | F98K | LNa | F98D | |
V5 | HPa | F45K | HNa | F45D | LPe | Y87K | LNe | Y87D | |
W1 | HP1 | L128K | HN1 | L128D | LP1 | F118K | LN1 | F118D | |
W2 | HP2 | A141K | HN2 | A141D | LP2 | F116K | LN2 | F116D | |
W3 | HP3 | L145K | HN3 | L145D | LP3 | V133K | LN3 | V133D | |
W4 | HP4 | V185K | HN4 | V185D | LP4 | L135K | LN4 | L135D | |
W5 | HP1 | L128K | HN1 | L128D | LP3 | V133K | LN3 | V133D | |
W6 | HP2 | A141K | HN2 | A141D | LP4 | L135K | LN4 | L135D | |
W7 | HP7 | L145K/ V185K | HN7 | L145D/V185D | LP7 | V133K/ L135K | LN7 | V133D/ L135D | |
W8 | HP8 | A141K/V185K | HP8 | A141D/V185D | LP8 | F116K/ L135K | LN8 | F116D/ L135D | |
비대칭형 | V2P | HPb | W47K | H0 | - | L0 | - | LNb | Y96D |
V3P | HPc | W103K | H0 | - | L0 | - | LNc | P44D | |
W2P | HP2 | A141K | H0 | - | L0 | - | LN2 | F116D | |
W4P | HP4 | V185K | H0 | - | L0 | - | LN4 | L135D | |
V3W4 | HPc | W103K | HN4 | V185D | LP4 | L135K | LNc | P44D | |
W4V3 | HP4 | V185K | HNc | W103D | LPc | P44K | LN4 | L135D | |
V3V1 | HPc | W103K | HNa | F45D | LPa | F98K | LNc | P44D | |
V3W1 | HPc | W103K | HN1 | L128D | LP1 | F118K | LNc | P44D |
Claims (26)
- 단백질의 소수성 상호작용을 하는 부위내에서 선택된 한쌍의 소수성 아미노산에서, 하나의 소수성 아미노산이 포지티브 전하를 가진 물질로, 다른 소수성 아미노산이 네가티브 전하를 가진 물질로 변형되어 상기 포지티브 전하와 상기 네가티브 전하에 의해 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 단백질.
- 제 1 항에 있어서, 상기 포지티브 전하를 가진 물질은 염기성 아미노산인 것을 특징으로 하는 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 단백질.
- 제 1 항에 있어서, 상기 네가티브 전하를 가진 물질은 산성 아미노산인 것을 특징으로 하는 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 단백질.
- 제 1 항에서, 상기 포지티브 전하를 가진 물질은 염기성 아미노산이고, 상기 네가티브 전하를 가진 물질은 산성 아미노산인 것을 특징으로 하는 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 단백질.
- 제 1 항 내지 제 4 항중 어느 한 항에 있어서, 상기 소수성 아미노산은 글리신,알라닌, 발린, 루신, 이소루신, 메티오닌, 프롤린, 페닐알라닌, 트립토판으로 이루어진 그룹에서 선택되는 어느 하나의 아미노산인 것을 특징으로 하는 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 단백질.
- 제 4 항에 있어서, 상기 산성 아미노산은 아스파트산 또는 글루탐산에서 선택되는 어느 하나의 아미노산이고, 상기 염기성 아미노산은 리신, 아르기닌, 히스티딘에서 선택되는 어느 하나의 아미노산인 것을 특징으로 하는 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 단백질.
- 항체의 소수성 상호작용을 하는 부위내에서 선택된 한쌍의 소수성 아미노산에서, 하나의 소수성 아미노산이 포지티브 전하를 가진 물질로, 다른 소수성 아미노산이 네가티브 전하를 가진 물질로 변형되어 상기 포지티브 전하와 상기 네가티브 전하에 의해 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 항체.
- 제 7 항에 있어서, 상기 포지티브 전하를 가진 물질은 염기성 아미노산인 것을 특징으로 하는 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 항체.
- 제 7 항에 있어서, 상기 네가티브 전하를 가진 물질은 산성 아미노산인 것을 특징으로 하는 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 항체.
- 제 7 항에서, 상기 포지티브 전하를 가진 물질은 염기성 아미노산이고, 상기 네가티브 전하를 가진 물질은 산성 아미노산인 것을 특징으로 하는 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 항체.
- 제 7 항 내지 제 10 항중 어느 한 항에 있어서, 상기 소수성 아미노산은 글리신,알라닌, 발린, 루신, 이소루신, 메티오닌, 프롤린, 페닐알라닌, 트립토판으로 이루어진 그룹에서 선택되는 어느 하나의 아미노산인 것을 특징으로 하는 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 항체.
- 제 10 항에 있어서, 상기 산성 아미노산은 아스파트산 또는 글루탐산에서 선택되는 어느 하나의 아미노산이고, 상기 염기성 아미노산은 리신, 아르기닌, 히스티딘에서 선택되는 어느 하나의 아미노산인 것을 특징으로 하는 단백질의 소수성 상호작용 부위내에 전기적 상호작용이 도입된 단백질.
- 폴리펩타이드 사슬과 폴리펩타이드 사슬 사이의 소수성 상호작용을 하는 부위내에서 한쌍의 소수성 아미노산을 선택하는 단계;상기 선택된 한쌍의 아미노산에서, 하나의 소수성 아미노산이 포지티브 전하를 가진 물질로, 다른 소수성 아미노산이 네가티브 전하를 가진 물질로 변형시키는 단계; 및상기 포지티브 전하와 상기 네가티브 전하가 접촉하여 전기적 상호작용으로 결합되는 단계를 포함하는 것을 특징으로 하는 사슬 선택성이 증가된 단백질의 제조 방법.
- 제 13 항에 있어서, 상기 포지티브 전하를 가진 물질은 염기성 아미노산인 것을 특징으로 하는 사슬 선택성이 증가된 단백질의 제조 방법.
- 제 13 항에 있어서, 상기 네가티브 전하를 가진 물질은 산성 아미노산인 것을 특징으로 하는 사슬 선택성이 증가된 단백질의 제조 방법.
- 제 13 항에서, 상기 포지티브 전하를 가진 물질은 염기성 아미노산이고, 상기 네가티브 전하를 가진 물질은 산성 아미노산인 것을 특징으로 하는 사슬 선택성이 증가된 단백질의 제조 방법.
- 제 13 항 내지 제 16 항중 어느 한 항에 있어서, 상기 소수성 아미노산은 글리신,알라닌, 발린, 루신, 이소루신, 메티오닌, 프롤린, 페닐알라닌, 트립토판으로 이루어진 그룹에서 선택되는 어느 하나의 아미노산인 것을 특징으로 하는 사슬 선택성이 증가된 단백질의 제조 방법.
- 제 16 항에 있어서, 상기 산성 아미노산은 아스파트산 또는 글루탐산에서 선택되는 어느 하나의 아미노산이고, 상기 염기성 아미노산은 리신, 아르기닌, 히스티딘에서 선택되는 어느 하나의 아미노산인 것을 특징으로 하는 사슬 선택성이 증가된 단백질의 제조 방법.
- 인간의 항체의 CH3 도메인의 소수성 상호작용 351 류신과 351 류신, 395 프롤린과 397 발린, 395 프롤린과 395프롤린, 407 타이로신과 407 타이로신; CH1 도메인과 CL 도메인 사이의 128 류신과 118 페닐알라닌, 128 류신과 133 발린, 141 알라닌과 116 페닐알라닌, 141 알라닌과 135 류신, 145 류신과 133 발린, 170 페닐알라닌과 135 류신, 185 발린과 118 페닐알라닌, 185 발린과 135 류신으로 이루어진 그룹에서 선택된 어느 한 쌍 이상의 하나의 아미노산 중 한 쌍의 아미노산 중 어느 하나를 아스파트산 또는 글루탐산에서 선택되는 산성아미노산으로 돌연변이화하고, 또다른 하나의 아미노산을 리신, 아르기닌, 히스티딘에서 선택되는 염기성 아미노산으로 돌연변이화하여 상기 돌연변이화된 아미노산들의 전기적 상호작용에 의해 결합력이 발생하는 항체.
- 제 19 항에 있어서, 표4의 Z0 내지 Z14의 조합으로 이루어진 그룹에서 선택된 어느 하나의 세트로 돌연변이화된 것을 특징으로 하는 항체.
- 제 19 항에 있어서, 상기 항체는 TNR2, Her3, Tie2, TGFbR1, BMPbR1, Il-12R-b1, IL-4Ra, ITGA4, ITGA2B, INFAR1, IL-12A, IL-4, InFa, BMP2, IL-1R1L, IL-17RA, IL-17A, Fas, FltD2, Her1, Tie1, TGFbR2, IL-12R-b2, IL-13Ra1, ITGB1, ITGB3, INFAR2, IL-12B, IL-13, INFb, BMP7, IL-1RAP, IL-17RC, IL-17F로 이루어진 그룹에선 선택된 어느 한 쌍의 엑토도메인이 융합된 항체.
- 제 21 항에 있어서, 상기 항체는 Her2/FltD2 조합, Her1/Her3 조합, 또는 Tie/Tie2 조합에서 선택된 어느 하나의 엑토도메인 조합이 융합된 항체.
- 제 19 항에 있어서, 상기 Z14의 조합으로 돌연변이화된 무거운 사슬과 A-타입 인플루엔자 바이러스에 특이적인 4D9 엑토도메인 및 B-타입 인플루엔자 바이러스에 특이적인 2B9 엑토도메인을 포함하는 공통의 가벼운 사슬을 가진 양쪽 특이성 항체.
- 제 23 항의 항체를 이용한 양쪽 특이성 항체의 무거운 사슬과 가벼운 사슬의 짝지음 정도 측정 방법.
- 항체에서 표7의 무거운 사슬(HP)와 또다른 무거운 사슬(HN), 가벼운사슬(LP)와 또다른 가벼운 사슬(LN)의 V1 내지 V5, W1 내지 W8, V2p, V3p, W4p, V3W4, W4v3, V3v1의 조합으로 이루어진 그룹에서 선택된 어느 하나의 조합으로 이루어진 무거운 사슬과 가벼운 사슬의 짝지음 정도가 향상된 항체.
- 제 25 항에 있어서, 상기 항체는 무거운 사슬의 하나에서 103 트립토판이 리신으로 돌연변이화되고, 또다른 무거운 사슬의 128번 리신이 아스파트산으로 돌연변이화되고, 가벼운 사슬의 118번 페닐알라닌이 리신으로 돌연변이화 되고, 또다른 가벼운 사슬의 44번 프롤린이 아스파트산으로 돌연변이화되어 이루어진 무거운 사슬과 가벼운 사슬의 짝지음 정도가 향상된 항체.
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AU2017298535B2 (en) * | 2016-07-19 | 2020-12-10 | Ibentrus, Inc. | Bispecific proteins and methods for preparing same |
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CN109476763B (zh) * | 2016-07-19 | 2023-11-07 | 伊班绰斯有限责任公司 | 双特异性蛋白质及其制备方法 |
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EP2975061A4 (en) | 2017-03-01 |
KR20160012151A (ko) | 2016-02-02 |
EP2975061A1 (en) | 2016-01-20 |
AU2014230291A1 (en) | 2015-11-05 |
CA3085446A1 (en) | 2014-09-18 |
EP3486255A2 (en) | 2019-05-22 |
EP3486255A3 (en) | 2019-11-13 |
US10118971B2 (en) | 2018-11-06 |
CA2918328C (en) | 2020-09-01 |
AU2014230291B2 (en) | 2018-02-22 |
CA2918328A1 (en) | 2014-09-18 |
CN105229036B (zh) | 2022-05-24 |
US20160152726A1 (en) | 2016-06-02 |
CN105229036A (zh) | 2016-01-06 |
CA3085446C (en) | 2022-08-09 |
KR101813708B1 (ko) | 2017-12-29 |
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