JPS62175175A - Modified tryptophanase and production thereof - Google Patents
Modified tryptophanase and production thereofInfo
- Publication number
- JPS62175175A JPS62175175A JP61016357A JP1635786A JPS62175175A JP S62175175 A JPS62175175 A JP S62175175A JP 61016357 A JP61016357 A JP 61016357A JP 1635786 A JP1635786 A JP 1635786A JP S62175175 A JPS62175175 A JP S62175175A
- Authority
- JP
- Japan
- Prior art keywords
- tryptophanase
- modified
- triazine
- bis
- methoxypolyethylene glycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 102100040653 Tryptophan 2,3-dioxygenase Human genes 0.000 title claims abstract description 29
- 101710136122 Tryptophan 2,3-dioxygenase Proteins 0.000 title claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 18
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract description 12
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000003277 amino group Chemical group 0.000 claims abstract description 11
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 claims abstract description 6
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 claims abstract description 6
- 229960001327 pyridoxal phosphate Drugs 0.000 claims abstract description 6
- 150000001413 amino acids Chemical class 0.000 claims description 3
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical group C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 claims 1
- 230000003327 cancerostatic effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- 102000004142 Trypsin Human genes 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 229960004799 tryptophan Drugs 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229940122029 DNA synthesis inhibitor Drugs 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000000593 degrading effect Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 1
- HTSVYUUXJSMGQC-UHFFFAOYSA-N 2-chloro-1,3,5-triazine Chemical compound ClC1=NC=NC=N1 HTSVYUUXJSMGQC-UHFFFAOYSA-N 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
Landscapes
- Enzymes And Modification Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
【発明の詳細な説明】
（目的）
本発明は、抗原性を低下又は消失させた修飾１〜リプト
ファナーゼに関し、医薬としての安全性を高めたもので
ある。DETAILED DESCRIPTION OF THE INVENTION (Purpose) The present invention relates to a modified 1-lyptophanase whose antigenicity has been reduced or eliminated, and which has improved safety as a medicine.
抗がん剤の大量療法はその副作用の発現を抑制すること
が大きな課題である。近年アミノ酸分解酵素が抗がん剤
の副作用を抑制することがわかり、例えばＤＮＡ合成阻
害剤であるメトトレキセートとアスパラギナーゼとを併
用する方法（Ｃａｐｉｚｚｉ療法）により抗がん剤の大
量投与を可能にし、良好な治療成績を挙げている（リン
パ性白血病寛解率８０％）。トリプトファナーゼも、ピ
リドキサールりん酸の関与のもとに、Ｌ−トリプトファ
ンからピルビン酸、インドール、アンモニアを生成する
アミノ酸分解酵素であり、それ自体抗がん作用を有する
のみならず、ＤＮＡ合成阻害剤と併用することにより、
さらに一層の抗がん作用の強化が期待出来る。A major challenge in high-dose anticancer drug therapy is to suppress the occurrence of side effects. In recent years, amino acid degrading enzymes have been found to suppress the side effects of anticancer drugs. For example, the combination of methotrexate, a DNA synthesis inhibitor, and asparaginase (Capizzi therapy) has made it possible to administer large doses of anticancer drugs, and has shown good results. It has achieved excellent treatment results (lymphocytic leukemia remission rate of 80%). Tryptophanase is also an amino acid degrading enzyme that generates pyruvate, indole, and ammonia from L-tryptophan with the involvement of pyridoxal phosphate, and it not only has an anticancer effect itself but also is a DNA synthesis inhibitor. By using it in conjunction with
Further enhancement of anticancer effects can be expected.
ところが、これらのアミノ酸分解酵素は、紬菌由来で、
ヒトにとっては異種の蛋白質であるため、頻回投与によ
り抗体が生産され、アナフィラキシ−ショック等の危険
がある。However, these amino acid-degrading enzymes are derived from the pongee fungus,
Since it is a foreign protein to humans, repeated administration may lead to the production of antibodies, which poses a risk of anaphylactic shock.
本発明者は、トリプトファナーゼの分子表面をポリエチ
レングリコール鎖でヒゲ状に覆うことにより、酵素活性
を保持したま＼で抗原性を低下又は消失することを見い
出し、またその製法を確立した。The present inventors have discovered that antigenicity can be reduced or eliminated while retaining enzyme activity by covering the molecular surface of tryptophanase with polyethylene glycol chains in the form of whiskers, and have also established a method for producing the same.
（構成）
本発明は、トリプトファナーゼ分子中のアミノ基に２，
４−ビス（Ｏ−メトキシポリエチレングリコール）−６
−クロル−Ｓ−トリアジン（Ｔ）が部分的に結合した修
飾トリプトファナーゼである。(Structure) The present invention provides 2,
4-bis(O-methoxypolyethylene glycol)-6
- It is a modified tryptophanase with partially bound chloro-S-triazine (T).
また、本発明は、補酵素であるピリドキサールりん酸が
結合するアミノ基が修飾されないように、反応系にピリ
ドキサールりん酸の存在下に、トリゾｉ・ファナーゼに
２，４−ビス（Ｏ−メトキシポリエチレングリコール）
−６−クロル−３−トリアジンを反応させることを特徴
とする前述修飾トリプトファナーゼの製法そある。Furthermore, in the present invention, 2,4-bis(O-methoxypolyethylene glycol)
There is a method for producing the above-mentioned modified tryptophanase, which is characterized by reacting with -6-chloro-3-triazine.
原料の２．４−ビス（Ｏ−メトキシポリエチレングリコ
ール）−６−クロル−８−トリアジンは、モノメトキシ
ポリエチレングリコール（分子ＩＪ２０００〜８０００
）と２． ４． ６−１−リクロル−Ｓ−トリアジンと
を反応させることによって行われる。The raw material 2,4-bis(O-methoxypolyethylene glycol)-6-chloro-8-triazine is monomethoxypolyethylene glycol (molecule IJ 2000-8000
) and 2. 4. It is carried out by reacting with 6-1-lichloro-S-triazine.
修飾トリプトファナーゼを製造するには、ピリドキサー
ルりん酸１〜１０倍モル及びトリプトファナーゼを含む
ｐＨ９，０〜９．５の緩衝溶液に２゜４−ビス（Ｏ−メ
トキシポリエチレングリコール）−６−クロル−５−ト
リアジンをトリジ１−フアナーゼ分子中に存在するアミ
ノ基当り１．８〜１８倍量（モル比）加え、３７℃で１
時間反応させることにより、アミノ基に修飾基（＋）が
部分的に結合した修飾トリプトファナーゼが得られる。To produce modified tryptophanase, 2°4-bis(O-methoxypolyethylene glycol)-6- Chlor-5-triazine was added in an amount of 1.8 to 18 times (molar ratio) per amino group present in the tridi-1-phanase molecule, and the
By reacting for a period of time, a modified tryptophanase in which a modifying group (+) is partially bound to an amino group can be obtained.
（効果）
本発明の修飾トリプトファナーゼについて、酵素活性及
び抗体との結合能を測定した結果は次表の通りである。(Effects) The results of measuring the enzyme activity and antibody binding ability of the modified tryptophanase of the present invention are shown in the following table.
ａ））リプトファナーゼ分子中のアミノ基に対する修飾
基（１）のモル比。a)) Molar ratio of modifying group (1) to amino groups in the liptophanase molecule.
ｂ）修飾率は、トリプトファナーゼ分子中の全アミノ基
のうち修飾基（Ｉ）が結合したアミノ基の割合であり、
未反応のアミノ基をトリニトロベンゼンスルホン酸を用
いて測定して算出した。b) Modification rate is the proportion of amino groups to which modifying group (I) is bonded among all amino groups in the tryptophanase molecule,
It was calculated by measuring unreacted amino groups using trinitrobenzenesulfonic acid.
Ｃ）酵素活性は、合成基質５−Ｏ−ニトロフェニル−し
−システィンを用いて分光学的に測定した。またトリプ
トファンに対しては、生成するインドールをエールリッ
ヒ・アルデヒド試薬により比色定量した。C) Enzyme activity was measured spectroscopically using the synthetic substrate 5-O-nitrophenyl-cysteine. Regarding tryptophan, the produced indole was determined colorimetrically using Ehrlich aldehyde reagent.
ｄ）抗体との結合能は、ウサギをトリプトファナーゼで
免疫した抗血清を用い、抗原−抗体反応により生ずる沈
澱量を測定した。d) The ability to bind to the antibody was determined by measuring the amount of precipitate produced by the antigen-antibody reaction using antiserum obtained by immunizing a rabbit with tryptophanase.
本発明の修飾トリプトファナーゼは、前述のとおり、酵
素活性を保持しながら、抗原性が低下又は消失している
ので、医療としての安全性は高い。さらに、修飾トリプ
トファナーゼはＬ−トリプトファンに対するミカエリス
定数、ｐｌ＋及び温度に対する依存性がほぼ未修飾トリ
プトファナーゼと変わらず、蛋白質分解酵素トリプシン
による分解に対しては抵抗性が増している。As mentioned above, the modified tryptophanase of the present invention has reduced or eliminated antigenicity while retaining enzymatic activity, and therefore has high medical safety. Furthermore, modified tryptophanase has almost the same Michaelis constant for L-tryptophan, pl+, and temperature dependence as unmodified tryptophanase, and has increased resistance to degradation by the proteolytic enzyme trypsin.
実施例１
０．０４ｍＭピリドキサールリン酸及び６０１塩化カリ
ウムを含む０．１Ｍはう酸緩衝液ｐ Ｈ９，０に、トリ
プトファナーゼを５ ｍｇ／ｍ Ｉ！になるように用意
し、この溶液に２，４−ビス（Ｏ−メトキシポリエチレ
ングリコール）−６−クロル−８−トリアジンを、トリ
プトファナーゼ分子中のアミノ基に対して１４倍量（モ
ル比）加え、３７°Ｃ１時間反応させた後、常法により
精製し、修飾トリプトファナーゼを調製した。アミノ基
の分析の結果、４１％のアミノ基が修飾されていた。そ
して、この修飾酵素は、抗体との結合能は完全に消失し
ているが、酵素活性はＬ−１−リプトファンに対して１
０％保持していた。Example 1 Tryptophanase was added at 5 mg/m I! in 0.1 M phosphate buffer pH 9.0 containing 0.04 mM pyridoxal phosphate and 601 potassium chloride. To this solution, add 2,4-bis(O-methoxypolyethylene glycol)-6-chloro-8-triazine in an amount 14 times the amino group in the tryptophanase molecule (mole ratio). After adding the mixture and reacting at 37°C for 1 hour, it was purified by a conventional method to prepare modified tryptophanase. As a result of amino group analysis, 41% of the amino groups were modified. Although this modified enzyme has completely lost its ability to bind to antibodies, its enzymatic activity is 1 for L-1-lyptophan.
It was held at 0%.
実施例２
実施例１の方法で調製した修飾トリプトファナーゼのＬ
−トリプトファンに対する動力学的性質を解析した。Example 2 Modified tryptophanase L prepared by the method of Example 1
-The kinetic properties for tryptophan were analyzed.
０．０６ｍＭピリドキサールリン酸を含む０．１２Ｍリ
ン酸カリウム緩衝液（ｐ Ｈ７，８）中において、生成
されるインドールを、エールリッヒ・アルデヒド試薬を
用いて比色定量し、次表のような、ミカエリス定数（Ｋ
ｍ）及び最大速度（Ｖｍａｘ）を得た。In 0.12M potassium phosphate buffer (pH 7,8) containing 0.06mM pyridoxal phosphate, the produced indole was colorimetrically determined using Ehrlich aldehyde reagent, and the following Michaelis Constant (K
m) and maximum velocity (Vmax) were obtained.
実施例３
修飾トリプトファナーゼの蛋白質分解酵素トリプシンに
対する抵抗性を調べた。Example 3 The resistance of modified tryptophanase to the proteolytic enzyme trypsin was investigated.
修飾トリプトファンゼの酵素溶液（ｐＨ７，８）に、ト
リプシンを加た後、３７°Ｃで保温し、経時的に反応を
トリプシンインヒイビイターで止め、残存するトリプト
ファナーゼ活性を、合成５質５−０−ニトロフェニル−
し−システィンを用いて分光学的に測定した。その結果
、３０分間保温すると未修飾トリプトファナーゼは、そ
の酵素活性が５％以下になるのに対し、修飾酵素は約４
０％も残存していた。After adding trypsin to the modified tryptophanase enzyme solution (pH 7, 8), it was kept at 37°C, the reaction was stopped with a trypsin inhibitor over time, and the remaining tryptophanase activity was inhibited by synthetic 5 -0-nitrophenyl-
It was measured spectroscopically using cysteine. As a result, when kept warm for 30 minutes, the enzyme activity of unmodified tryptophanase decreases to less than 5%, while the enzyme activity of modified enzyme decreases to about 4%.
0% remained.
Claims (1)
ス（Ｏ−メトキシポリエチレングリコール）−Ｓ−トリ
アジンが部分的に結合した修飾トリプトファナーゼ。 ２、トリプトファナーゼに、ピリドキサールりん酸の存
在下に、２，４−ビス（Ｏ−メトキシポリエチレングリ
コール）−６−クロル−Ｓ−トリアジンを反応させるこ
とを特徴とするトリプトファナーゼ分子中のアミノ基に
２，４−ビス（Ｏ−メトキシポリエチレングリコール）
−Ｓ−トリアジンが部分的に結合した修飾トリプトファ
ナーゼの製法。[Claims] 1. A modified tryptophanase in which 2,4-bis(O-methoxypolyethylene glycol)-S-triazine is partially bound to the amino group in the tryptophanase molecule. 2. Amino acid in tryptophanase molecules characterized by reacting tryptophanase with 2,4-bis(O-methoxypolyethylene glycol)-6-chloro-S-triazine in the presence of pyridoxal phosphate. Based on 2,4-bis(O-methoxypolyethylene glycol)
- A method for producing a modified tryptophanase partially bound to S-triazine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61016357A JPS62175175A (en) | 1986-01-28 | 1986-01-28 | Modified tryptophanase and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61016357A JPS62175175A (en) | 1986-01-28 | 1986-01-28 | Modified tryptophanase and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62175175A true JPS62175175A (en) | 1987-07-31 |
Family
ID=11914096
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61016357A Pending JPS62175175A (en) | 1986-01-28 | 1986-01-28 | Modified tryptophanase and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62175175A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0488982A (en) * | 1990-07-30 | 1992-03-23 | Kanebo Ltd | Production of modified protease |
| US5342940A (en) * | 1989-05-27 | 1994-08-30 | Sumitomo Pharmaceuticals Company, Limited | Polyethylene glycol derivatives, process for preparing the same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55135590A (en) * | 1979-04-05 | 1980-10-22 | Mihama Hisaharu | Modified asparaginase and uricase and their preparation |
-
1986
- 1986-01-28 JP JP61016357A patent/JPS62175175A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55135590A (en) * | 1979-04-05 | 1980-10-22 | Mihama Hisaharu | Modified asparaginase and uricase and their preparation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5342940A (en) * | 1989-05-27 | 1994-08-30 | Sumitomo Pharmaceuticals Company, Limited | Polyethylene glycol derivatives, process for preparing the same |
| JPH0488982A (en) * | 1990-07-30 | 1992-03-23 | Kanebo Ltd | Production of modified protease |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6955042B2 (en) | Uniform antibody drug conjugate by enzymatic method | |
| EP0800829B2 (en) | Use of a pm-1 antibody or of a mh 166 antibody for enhancing the anti-tumor effect of cisplatin or carboplatin | |
| US4762707A (en) | New conjugates associating, by covalent bond, an enzyme with an antibody, and medicinal associations using the said conjugates | |
| CN112999362B (en) | Stable antibody drug coupling and preparation method and application thereof | |
| JPH02503088A (en) | Method for preparing antibody fragment complexes | |
| Lukasheva et al. | L-Lysine α-oxidase: physicochemical and biological properties | |
| JPS5843926A (en) | Selective carcinostatic agent | |
| CN1272136A (en) | Stimulation of hematopoietic cells in vitro | |
| Putnam | N-terminal groups of normal human gamma globulin and of myeloma proteins | |
| JPS58135821A (en) | Anticancer agent comprising chain portion a of retine and idiosyncratic monoclonal antibody | |
| CN106061496A (en) | Cd44 binding peptides | |
| EP0056322B1 (en) | Immunoglobulin conjugates | |
| IE56211B1 (en) | Therapeutic compounds of platinum and palladium and their preparation | |
| EP0325270A2 (en) | Anticancer conjugates | |
| JP2007500696A (en) | Use PLP with PEG-rMETase in vivo to increase efficacy | |
| EP1725583B1 (en) | Methods for increasing protein polyethylene glycol (peg) conjugation | |
| US10633429B2 (en) | Human antibody κ type light chain complex-containing composition and method for producing same | |
| JPS6142558B2 (en) | ||
| Allan et al. | Inhibition of the interaction between the complement component Clq and immune complexes | |
| CN107531720A (en) | Anticancer drug candidate | |
| US20260021196A1 (en) | Homogeneous antibody-conjugates with high payload loading | |
| JPS62175175A (en) | Modified tryptophanase and production thereof | |
| AU2022208654B2 (en) | Compound or salt thereof, and antibody produced using same | |
| Qian et al. | Chemical modification of L-asparaginase with N, O-carboxymethyl chitosan and its effects on plasma half-life and other properties | |
| US20250059215A1 (en) | Trifluoroborate (BF3) Compositions For Use In Boron Neutron Capture Therapy and Methods Thereof |