JP6781204B2 - 高い炭水化物抗原密度を有するワクチン及び新規サポニンアジュバント - Google Patents
高い炭水化物抗原密度を有するワクチン及び新規サポニンアジュバント Download PDFInfo
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- JP6781204B2 JP6781204B2 JP2018117319A JP2018117319A JP6781204B2 JP 6781204 B2 JP6781204 B2 JP 6781204B2 JP 2018117319 A JP2018117319 A JP 2018117319A JP 2018117319 A JP2018117319 A JP 2018117319A JP 6781204 B2 JP6781204 B2 JP 6781204B2
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- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 229940126577 synthetic vaccine Drugs 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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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
- A61K39/02—Bacterial antigens
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001169—Tumor associated carbohydrates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
- A61K39/0016—Combination vaccines based on diphtheria-tetanus-pertussis
-
- 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
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/256—Polyterpene radicals
-
- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
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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
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
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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
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]
Description
本出願は、2013年1月4日出願の米国特許出願第61/748,880号の優先権を主張し、その全開示を参照により本明細書に組み入れることとする。
(先行技術文献)
(特許文献)
(特許文献1) 米国特許第8540964号明細書
(特許文献2) 国際公開第2013/142245号明細書
(特許文献3) 米国特許出願公開第2012/0328646号明細書
(特許文献4) 国際公開第2011/156774号明細書
(特許文献5) 国際公開第1996/040242号明細書
(特許文献6) 国際公開第2009/126737号明細書
(非特許文献)
(非特許文献1) Yen−Lin Huang et al.Carbohydrate−based vaccines with a glycolipid adjuvant for breast cancer PNAS February 12,2013 vol.110 no.7 2517−2522
なお、R1は、β−D−アピオース(β−D−Apiose)又はβ−D−キシロース(β−D−Xylose)から選択され、
R2及びR3は、H基、アルキル基(alkyl)又は
薬学的に許容される担体とを含む医薬組成物を提供し、
なお、R1は、β−D−アピオース又はβ−D−キシロースから選択され、
R2及びR3は、H基、アルキル基又は
腫瘍関連炭水化物抗原は、一般的に弱い免疫原性を示す。担体タンパク質と結合(コンジュゲート)させた炭水化物抗原を採用することによって、その炭水化物抗原の免疫原性を向上させる。例えば、約700個のGlobo H分子は1個の無毒性のキーホールリンペットヘモシニアン(KLH)タンパク質に結合され、平均約2〜4個のGlobo H分子はジフテリア毒素(DT)に結合され、約8個のGlobo H分子はウシ血清アルブミン(BSA)に結合され、且つ約6個のGlobo H分子は破傷風トキソイドに結合される(米国特許第8,268,969号の表1)。
本発明は、実質的に純粋なOBI−821サポニンを提供することができる。本発明は、実質的に純粋なOBI−821サポニンと、生物活性断片とを含むものである。本発明もまた、不純なOBI−821サポニンを含むことができる。精製したOBI−821サポニンは、本明細書に記載されたワクチンと共に投与する、或いはそれを他の実質的に純粋なサポニン又は非サポニンのジュバントと混合する場合、アジュバントの効果を高めることを示した。
R2及びR3は、それぞれH基、アルキル基、
(i)約1モル%〜約15モル%の1857化合物の混合物、及び
(ii)約85モル%〜約99モル%の1989化合物の混合物。
を含み、
R2及びR3は、それぞれH基、アルキル基又は
炭水化物抗原と結合されたトキソイドタンパク質は、ジフテリア毒素(DT)又は破傷風トキソイド(TT)であってもよい。
本発明のもう一つの態様は、免疫応答を誘導する方法に関するものであり、それは本明細書に記載のワクチンを需要のある個体に投与するステップを含む。免疫応答は、NK細胞応答、ADCC及びCDC活性、及びIgMとIgGの産生を含むが、これらに限定されない。
Globo Hは、当該技術分野において公知の方法を通してKLH又はDTと結合され、例えば、米国特許第6,544,952号又は第8,268,969号に記載の方法に従って、その全開示を参照により本明細書に組み入れることとする。得られたワクチンは、Globo H:DT(Globo HとDTとの分子の比率=2〜4:1)を含む。
複合糖質は以下のように調製する。
(a)10ml〜25mlのGlobo H(OBI Pharmaから購入可能、台湾)及びp−ニトロフェニルエステルリンカー(p−nitrophenyl ester linker)(OBI Pharmaから購入可能である、台湾)を25μlのDMF(Sigma−Aldrichから購入可能、米国)に溶解する。
(b)25mgのDTを2.5mlのリン酸緩衝液(即ち、pH>8の塩基性緩衝液)で溶解する。
(c)ステップ(a)の混合物をステップ(g)の混合物に加えて室温で一晩置く。得られた混合物のpHが8〜9.2である。
OBI−821サポニンの調製は、下記ステップに従ってキラジャサポナリアモリナコルテックス樹抽出物から抽出する。
(a)大きい粒子径のC18の逆相クロマトグラフィーによってキラジャサポナリアモリナコルテックス樹抽出物を予め濾過し、そしてシリカ系の順相分取クロマトグラフィーによって精製する。上記によって、粗OBI−821を得る。
(b)続いて、大きい粒子径のC18の逆相クロマトグラフィーによってステップ(a)の粗OBI−821を予め濾過し、そして分取逆相HPLCを行う。OBI−821物質は脱塩及び凍結乾燥処理で順次に生成する。
CL57B/6マウスを用いて例1におけるGlobo H/DT(8:1)のワクチンのin vivo免疫原性及びOBI−821サポニンアジュバント効果の評価を行う。
ルイスラット(Lewis rats)の4群が表3におけるワクチンで免疫される。
CL57B/6マウス又はBalb/cマウスを用いて例1におけるGlobo H/DT(8:1)のワクチン及びGlobo H/DT(16:1)のワクチンと、OBI−821サポニンアジュバントとのin vivo評価を行う。
●17日目にG1ワクチン(OBI−821サポニン)のIgM力価は、G6ワクチン(C34)のIgM力価より有意に高い(p=0.03)、
●24日目にG3ワクチン(OBI−821サポニン)のIgM力価は、G5ワクチン(C34)のIgM力価より有意に高い(p=0.03)、
●17日目にG3ワクチン(OBI−821サポニン)のIgG力価は、G5ワクチン(C34)のIgG力価より有意に高い(p=0.001)、
●17日目にG1ワクチン(OBI−821サポニン)のIgG力価は、G6ワクチン(C34)のIgG力価より有意に高い(p=0.003)、
●24日目にG3ワクチン(OBI−821サポニン)のIgG力価は、G5ワクチン(C34)のIgG力価より有意に高い(p=0.003)、及び
●24日目にG1ワクチン(OBI−821サポニン)のIgG力価は、G6ワクチン(C34)のIgG力価より有意に高い(p=0.004)。
●24日目にG1ワクチン(KLH)のIgM力価は、G2ワクチン(DT)のIgM力価より有意に高い(p=0.03)、
●24日目にG1ワクチン(KLH)のIgG力価は、G2ワクチン(DT)のIgG力価より有意に高い(p=0.004)。
●17日目にG7ワクチン(Globo HとDTとの分子の比率が16:1)のIgM力価は、G2ワクチン(3:1の比率)のIgM力価より有意に高い(p=0.006)、
●17日目にG3ワクチン(Globo HとDTとの分子の比率が8:1)のIgG力価は、G2ワクチン(3:1の比率)のIgG力価より有意に高い(p=0.01)、
●17日目にG7ワクチン(Globo HとDTとの分子の比率が16:1)のIgG力価は、G2ワクチン(Globo HとDTとの分子の比率が3:1)のIgG力価より有意に高い(p=0.03)、
●24日目にG3ワクチン(Globo HとDTとの分子の比率が8:1)のIgG力価は、G2ワクチン(3:1の比率)のIgG力価より有意に高い(p=0.01)、
●24日目にG7ワクチン(Globo HとDTとの分子の比率が16:1)のIgG力価は、G2ワクチン(Globo HとDTとの分子の比率が3:1)のIgG力価より有意に高い(p=0.01)、
17日目及び25日目にGlobo H/DT(Globo HとDTとの分子の比率が8:1)/OBI−821サポニン(G3)及びGlobo H/DT(16:1)/OBI−821サポニン(G7)のIgM力価は、Globo H/DT(Globo HとDTとの分子の比率が3:1)/OBI−821サポニン(G2))のIgM力価より有意に高い(p<0.05)。
Claims (6)
- 単離された以下の式(I)で表される化合物(a)〜(d)の混合物を含む、サポニンアジュバント:
化合物(a):式(I)において、R1は、β−D−アピオースであり、R2は、
であり、R3は、H基である化合物;
化合物(b):式(I)において、R1は、β−D−アピオースであり、R2は、H基であり、R3は、
である化合物;
化合物(c):式(I)において、R1は、β−D−キシロースであり、R2は、
であり、R3は、H基である化合物;
化合物(d):R1は、β−D−キシロースであり、R2は、H基であり、R3は、
である化合物。 - 単離された以下の式(I)で表される化合物(e)〜(h)からなる群から選択される一つ又は複数の化合物をさらに含む、請求項1に記載のサポニンアジュバント:
化合物(e):式(I)において、R1は、β−D−アピオースであり、R2は、
であり、R3は、H基である化合物;
化合物(f):式(I)において、R1は、β−D−アピオースであり、R2は、H基であり、R3は、
である化合物;
化合物(g):式(I)において、R1は、β−D−キシロースであり、R2は、
であり、R3は、H基である化合物;
化合物(h):式(I)において、R1は、β−D−キシロースであり、R2は、H基であり、R3は、
である化合物。 - 1〜15モル%の第1の混合物と、85〜99モル%の第2の混合物とを含み、
前記第1の混合物は、60〜70モル%の以下の化合物(a)と、1〜5モル%の以下の化合物(b)と、30〜40モル%の以下の化合物(c)と、0.1〜3モル%の以下の化合物(d)とを含み、かつ、
前記第2の混合物は、60〜70モル%の以下の化合物(e)と、1〜5モル%の以下の化合物(f)と、30〜40モル%の以下の化合物(g)と、0.1〜3モル%の以下の化合物(h)とを含む、サポニンアジュバント:
化合物(a):式(I)において、R1は、β−D−アピオースであり、R2は、
であり、R3は、H基である化合物;
化合物(b):式(I)において、R1は、β−D−アピオースであり、R2は、H基であり、R3は、
である化合物;
化合物(c):式(I)において、R1は、β−D−キシロースであり、R2は、
であり、R3は、H基である化合物;
化合物(d):R1は、β−D−キシロースであり、R2は、H基であり、R3は、
である化合物;
化合物(e):式(I)において、R1は、β−D−アピオースであり、R2は、
であり、R3は、H基である化合物;
化合物(f):式(I)において、R1は、β−D−アピオースであり、R2は、H基であり、R3は、
である化合物;
化合物(g):式(I)において、R1は、β−D−キシロースであり、R2は、
であり、R3は、H基である化合物;
化合物(h):式(I)において、R1は、β−D−キシロースであり、R2は、H基であり、R3は、
である化合物。 - (a)Globo H又はその免疫原性断片と、
(b)ジフテリア毒素(DT)である担体タンパク質と、
(c)請求項1〜3のいずれか1項に記載のサポニンアジュバントと、
を含み、Globo HとDTとの比率が5:1〜39:1であるワクチンを含み、ヒトに投与されて用いられる、がん細胞の抑制剤。 - ヒトである患者におけるがん細胞を抑制するための医薬の製造における、
(a)Globo H又はその免疫原性断片と、
(b)ジフテリア毒素(DT)である担体タンパク質と、
(c)請求項1〜3のいずれか1項に記載のサポニンアジュバントと、
を含み、Globo HとDTとの比率が5:1〜39:1であるワクチンの使用。 - 前記がんが、乳癌、肺癌、胃癌、結腸癌、膵臓癌、前立腺癌、卵巣癌、子宮内膜癌、食道癌、直腸癌、胆管癌、肝癌、頬癌、鼻咽頭癌、腎臓癌、子宮頚部癌、睾丸癌、膀胱癌、頭頚部癌、口腔癌、神経内分泌癌、副腎癌、甲状腺癌、骨癌、皮膚癌、基底細胞癌、扁平上皮癌、黒色腫又は脳腫瘍である、請求項5に記載の使用。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014107652A2 (en) | 2013-01-04 | 2014-07-10 | Obi Pharma | Vaccines with higher carbohydrate antigen density and novel saponin adjuvant |
WO2015143123A2 (en) | 2014-03-19 | 2015-09-24 | Mackay Memorial Hospital Of Taiwan Presbyterian Church And Mackay Memorial Social Work Foundation | Antibodies against immunogenic glycopeptides, composition comprising the same and use thereof |
WO2016040369A2 (en) * | 2014-09-08 | 2016-03-17 | Academia Sinica | HUMAN iNKT CELL ACTIVATION USING GLYCOLIPIDS |
TWI726850B (zh) * | 2014-09-15 | 2021-05-11 | 台灣浩鼎生技股份有限公司 | 免疫/治療性醣共軛物組合物及其用途 |
WO2016044164A1 (en) * | 2014-09-15 | 2016-03-24 | Wayne State University | Novel synthetic anticancer, antifungal, and antibacterial vaccines |
JP2018532990A (ja) | 2015-09-04 | 2018-11-08 | オービーアイ ファーマ,インコーポレイテッド | グリカンアレイおよび使用の方法 |
US10980894B2 (en) | 2016-03-29 | 2021-04-20 | Obi Pharma, Inc. | Antibodies, pharmaceutical compositions and methods |
TWI780045B (zh) | 2016-03-29 | 2022-10-11 | 台灣浩鼎生技股份有限公司 | 抗體、醫藥組合物及方法 |
CN109379889A (zh) * | 2016-04-22 | 2019-02-22 | 台湾浩鼎生技股份有限公司 | 通过经由globo系列抗原的免疫激活或免疫调节的癌症免疫疗法 |
BR112019001656A2 (pt) | 2016-07-27 | 2019-05-28 | Obi Pharma Inc | composição, composição farmacêutica, vacina, método para induzir anticorpos em um indivíduo, método para tratar câncer em um paciente necessitando do mesmo e método para induzir ou melhorar a reação imune em um indivíduo necessitando do mesmo |
CN110062767B (zh) | 2016-07-29 | 2023-07-11 | 台湾浩鼎生技股份有限公司 | 人抗体、药物组合物和方法 |
CN110290800A (zh) | 2016-11-21 | 2019-09-27 | 台湾浩鼎生技股份有限公司 | 缀合生物分子、医药组合物及方法 |
EP3775894B1 (en) * | 2018-05-11 | 2024-04-24 | OBI Pharma, Inc. | Method for predicting human immune response |
WO2020006176A1 (en) | 2018-06-27 | 2020-01-02 | Obi Pharma, Inc. | Glycosynthase variants for glycoprotein engineering and methods of use |
CN114805454B (zh) * | 2021-01-21 | 2023-07-18 | 中国科学院生态环境研究中心 | α-半乳糖神经酰胺类化合物及其制备方法和用途 |
CN114259559B (zh) * | 2021-12-28 | 2024-03-19 | 天津科技大学 | 一种含有α-GalCer内源性佐剂的合成肿瘤疫苗 |
CN114306586A (zh) * | 2022-01-04 | 2022-04-12 | 天津科技大学 | 基于tf抗原和壳寡糖内源性佐剂的肿瘤疫苗、方法和应用 |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
US5332583A (en) | 1987-11-24 | 1994-07-26 | Connaught Laboratories Limited | Vaccine containing genetically-detoxified pertussis holotoxin |
US5244657A (en) | 1987-11-24 | 1993-09-14 | Connaught Laboratories Limited | Genetic detoxification of pertussis toxin |
US5221618A (en) | 1987-11-24 | 1993-06-22 | Connaught Laboratories Limited | Genetic detoxification of pertussis toxin |
US5358868A (en) | 1987-11-24 | 1994-10-25 | Connaught Laboratories Limited | Genetic detoxification of pertussis toxin |
GB8727489D0 (en) | 1987-11-24 | 1987-12-23 | Connaught Lab | Detoxification of pertussis toxin |
DK0616034T3 (da) | 1993-03-05 | 2005-02-21 | Wyeth Corp | Plasmid til fremstilling af CRM-protein og diphtheria toxin |
US6544952B1 (en) * | 1994-03-15 | 2003-04-08 | Sloan-Kettering Institute For Cancer Research | Synthesis of glycoconjugates of the globo-H epitope and uses thereof |
CA2221511C (en) * | 1995-06-07 | 2013-01-08 | Smithkline Beecham Biologicals S.A. | Vaccine comprising a polysaccharide antigen-carrier protein conjugate and free carrier protein |
CN1215337A (zh) * | 1995-06-23 | 1999-04-28 | 史密斯克莱·比奇曼生物公司 | 包含一种多糖抗原-载体蛋白共轭物和游离载体蛋白的疫苗 |
US6231859B1 (en) | 1996-12-02 | 2001-05-15 | Aquila Biopharmaceuticals, Inc. | Saponin adjuvant compositions |
ES2235330T3 (es) | 1997-05-20 | 2005-07-01 | Galenica Pharmaceuticals, Inc. | Analogos de saponionas triterpenicas que tienen actividad ayuvante. |
US6080725A (en) | 1997-05-20 | 2000-06-27 | Galenica Pharmaceuticals, Inc. | Immunostimulating and vaccine compositions employing saponin analog adjuvants and uses thereof |
US7018637B2 (en) | 1998-02-23 | 2006-03-28 | Aventis Pasteur, Inc | Multi-oligosaccharide glycoconjugate bacterial meningitis vaccines |
DE10130545A1 (de) | 2001-06-25 | 2003-01-09 | Bosch Gmbh Robert | Verfahren zum Betrieb einer Klimaanlage |
EP1458242A4 (en) | 2001-07-06 | 2006-06-07 | Sloan Kettering Inst Cancer | COMPREHENSIVE CONJUGATED VACCINE AGAINST CANCER |
JP5153990B2 (ja) * | 2001-12-21 | 2013-02-27 | シーエスエル、リミテッド | 免疫反応性試薬およびサポニンを含有する組成物、およびその使用方法 |
US20060035267A1 (en) | 2003-04-09 | 2006-02-16 | Livingston Philip O | Optimal polyvalent vaccine for cancer |
CA2531023C (en) | 2003-07-04 | 2013-04-30 | Institut Pasteur | Glycoconjugates and their use as potential vaccines against infection by shigella flexneri |
GB0323965D0 (en) * | 2003-10-13 | 2003-11-19 | Glaxosmithkline Biolog Sa | Immunogenic compositions |
US8551920B2 (en) | 2005-02-01 | 2013-10-08 | Morpho Sys AG | Libraries and methods for isolating antibodies |
US20080260774A1 (en) | 2007-04-13 | 2008-10-23 | Chi-Huey Wong | Alpha-galactosyl ceramide analogs and their use as immunotherapies |
US8324742B2 (en) * | 2008-04-01 | 2012-12-04 | Texas Instruments Incorporated | Alignment mark for opaque layer |
CN104710487A (zh) | 2008-04-08 | 2015-06-17 | 索隆-基特林癌症研究协会 | 三萜皂苷、其合成方法和用途 |
JP2011524375A (ja) * | 2008-06-16 | 2011-09-01 | アカデミア シニカ | GloboHおよびSSEA3に特異的な免疫反応を誘起する組成物および癌治療におけるその使用 |
US7928077B2 (en) | 2008-07-11 | 2011-04-19 | Academia Sinica | Alpha-galactosyl ceramide analogs and their use as immunotherapies |
CN105535955B (zh) * | 2009-06-16 | 2019-04-23 | 中央研究院 | Globo h及含新颖糖脂质佐剂的相关抗癌疫苗 |
JP6050227B2 (ja) | 2010-06-11 | 2016-12-21 | スローン − ケタリング・インスティテュート・フォー・キャンサー・リサーチ | 多価糖ペプチド構築物およびその使用 |
AU2013235479A1 (en) | 2012-03-23 | 2014-10-02 | Memorial Sloan-Kettering Cancer Center | Potentiating antibody-induced complement-mediated cytotoxicity via PI3K inhibition |
WO2014107652A2 (en) | 2013-01-04 | 2014-07-10 | Obi Pharma | Vaccines with higher carbohydrate antigen density and novel saponin adjuvant |
ITMI20130142A1 (it) | 2013-01-31 | 2014-08-01 | Biosynth Srl | Vaccini glicoconiugati comprendenti unita' di base di un costrutto molecolare esprimente epitopi multipli incorporati |
CN104693305A (zh) | 2013-12-04 | 2015-06-10 | 苏州中赢医疗科技有限公司 | 一种抗人鞘糖脂Globo-H单克隆抗体、其制备方法及应用 |
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