JP2020509067A - 糖尿病の治療のためのペプチド及び方法 - Google Patents
糖尿病の治療のためのペプチド及び方法 Download PDFInfo
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- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003906 phosphoinositides Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000007921 solubility assay Methods 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003760 tallow Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 108060008226 thioredoxin Proteins 0.000 description 1
- 229940094937 thioredoxin Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
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Abstract
Description
Cxx[CST]SLQPLALEGSLQK[配列番号4]、
[CST]xxCSLQPLALEGSLQK[配列番号5]、
CxxCSLQPLALEGSLQK[配列番号6]、
HCxx[CST]SLQPLALEGSLQK[配列番号7]、
H[CST]xxCSLQPLALEGSLQK[配列番号8]、又は
HCxxCSLQPLALEGSLQK[配列番号9]
からなる。
Cxx[CST]SLQPLALEGSLQKRG[配列番号10]、
[CST]xxCSLQPLALEGSLQKRG[配列番号11]、
CxxCSLQPLALEGSLQKRG[配列番号12]、
HCxx[CST]SLQPLALEGSLQKRG[配列番号13]、
H[CST]xxCSLQPLALEGSLQKRG[配列番号14]、又は
HCxxCSLQPLALEGSLQKRG[配列番号15]
からなる。
- 末梢血細胞を提供する工程と、
- 前記細胞を、上記で開示される免疫原性ペプチドのうちいずれか1つとインビトロで接触させる工程と、
- 前記細胞をIL-2の存在下で拡大する工程と
を含むインビトロ方法に関する。
- 2回の別個の注射各25μg(各100μL)でのペプチド50μgのSC投与、その後、2回の別個の注射各12.5μg(各50μL)としてのペプチド25μgの3回の連続した注射を含む低用量計画。
- 2回の別個の注射各75μg(各300μL)でのペプチド150μgのSC投与、その後、2回の別個の注射各37.5μg(各150μL)としてのペプチド75μgの3回の連続した投与を含む中用量計画。
- 2回の別個の注射各225μg(各900μL)でのペプチド450μgのSC投与、その後、2回の別個の注射各112.5μg(各450μL)としてのペプチド225μgの3回の連続した投与を含む高用量計画。
MHC-クラスII分子により提示される抗原由来のペプチドとの同種の相互作用から生じる、抗原特異的T細胞の活性化;
レダクターゼ配列は、第2のドメインが拘束されたジスルフィド架橋を含むCD4分子等のT細胞表面タンパク質を還元する。これにより、シグナルがT細胞に伝達される。酸化経路の増大に関連する一連の結果の中でも、重要なイベントはカルシウム流入及びNF-kB転写因子の核への移行の増大である。後者は、IFN-ガンマ及びグランザイムの転写増大をもたらし、これにより細胞はアポトーシス誘導機構による細胞溶解特性を獲得することができる。細胞溶解特性は、グランザイムB分泌、及びFas-FasL相互作用を必要とする機構により、ペプチドを提示する細胞に影響を及ぼす。細胞死滅効果がアポトーシス経路を介して得られることから、これらの細胞にとっては細胞溶解性細胞が細胞毒性細胞よりも適切な用語である。抗原提示標的細胞の破壊は、同じ抗原、又は同じ抗原提示細胞によりプロセシングされると予想される無関係の抗原に位置するエピトープに特異的なその他のT細胞の活性化を予防する。T細胞活性化の更なる結果は、細胞-細胞接触依存性機構によるバイスタンダーT細胞の活性化を抑制することである。そのような場合、細胞溶解性細胞及びバイスタンダーT細胞の両方がすぐ近くにある、すなわち同じ抗原提示細胞表面で活性化されるという条件で、異なる抗原提示細胞により提示される抗原により活性化されたT細胞も抑制される。
活性化した際の、CD103、CTLA-4、Fasl及びICOSを含む表面マーカーの発現増大、
CD25の中間体発現、
CD4、ICOS、CTLA-4、GITRが発現し、CD127(IL7-R)の発現が小さいか見られず、CD27の発現が見られないこと、
転写因子T-bet及びegr-2(Krox-20)が発現するが転写リプレッサーFoxp3の発現が見られないこと、
IFN-ガンマが高産生され、IL-10、IL-4、IL-5、IL-13又はTGF-ベータが見られないか微量しかないこと。
ペプチド設計
WO2016059236で開示されるペプチドと比較して、以下に示されるアラインメントに示すように、インスリンのCドメインのT細胞エピトープを含み、インスリン配列には存在しないVRジペプチド配列が除去されたペプチドを合成する:
P17 001:HCPYC VR SLQPLALEGSLQKRG[配列番号25]
P17 003:HCPYC- SLQPLALEGSLQKRG[配列番号26]
ペプチドの還元活性を評価するための方法論
ペプチドのレダクターゼ活性は、Tomazzolliら(2006) Anal. Biochem. 350、105〜112頁に記載された蛍光を用いて決定する。FITC標識を有する2つのペプチドは、ジスルフィド架橋を介して互いに共有結合すると自己消光になる。本発明によるペプチドにより還元すると、還元された個々のペプチドは再び蛍光になる。
細胞溶解性CD4+T細胞株によるインターフェロンガンマ放出
インターフェロンガンマは、細胞溶解性CD4+T細胞の特徴を示すための重要なマーカーである。T1D患者(T1D07)由来のナイーブCD4+T細胞を、ペプチドp17-001でプライミング及び刺激することにより、特異的CD4+T細胞株を得た。12回の刺激の後、ペプチドp17-001又はp17-003がローディングされた自己LCL B細胞(2μM)と細胞を共培養した。24時間後、上清を採取し、マルチプレックスアッセイによりIFN-ガンマを測定した(以下のtable 1(表1)を参照のこと)。
細胞溶解性CD4+T細胞株によるFasL放出
上記の実施例3に記載されるようにp17 001により最初に生成されたT細胞株を分け、自己LCL B細胞株をAPCとして使用して、4回の連続したインビトロ刺激にわたって、ペプチドP17 003又はP17 001で刺激した。各刺激(計4回)から11日目に、自己B細胞により提示される対応するペプチドでの再刺激後のFasLについて、細胞を試験した。24h(刺激1及び2)又は72h(刺激3及び4)の共培養後に上清を採取した。
T1D-患者のPBMCにおけるsFasL放出及びサイトカイン産生
T1D-患者T1D018由来のPBMCを、P17001ペプチド又はP17003ペプチドのいずれかによりインビトロで刺激した。これら2つの集団は、抗原による活性化後にIl-5を特異的に放出する。ペプチドによる6回の刺激サイクル後に、サイトカイン捕捉ビーズにより、両細胞株はIL-5産生細胞が豊富となった。インターロイキン-5陰性細胞の2集団は、対照として使用した。
4つの細胞株のsFasLレベルを図1に示す。これは、ペプチドp17-003又はp17-001に特異的な特定の細胞において豊富なIL5陽性画分(黒のヒストグラム)が、陰性画分(白のヒストグラム)と比較してより多くのsFasLを放出することを示し、効率的で特異的な細胞精製であることがわかる。
効率的で特異的な細胞精製の尺度として、ペプチドp17-003又はp17-001に特異的な特定の細胞において豊富なIL5陽性画分を、IL5陰性画分と比較してのより多いグランザイムB放出について試験する。
インビトロで培養されたT1Dドナー由来の細胞がペプチドP17001又はP17003に特異的であるかどうかを決定するため、ペプチド刺激した際の細胞活性化の特徴であるサイトカイン放出について、MACSplex Cytokine 12キット(Miltenyi社、130-099-169)を使用して研究した。ペプチド非存在又は存在下で、T1DドナーPBMCの培養物から上清を24h後に採取した。生物学的に2度繰り返してサイトカイン濃度を決定し、pg/mLで示した。刺激10終了時(休息日)に特異性試験を行った。ペプチドなし及びありの条件で、各サイトカイン濃度の差として結果を提示する。
臨床試験
投与の前に本発明のペプチドを、アジュバントを含む希釈剤でもどす。産物は即座にもどすべきであり、好ましくはもどした後3時間未満内で使用される。
低用量(コホート1)は、2回の別個の注射各25μg(各100μL)でのペプチド50μgのSC投与、その後、2回の別個の注射各12.5μg(各50μL)としてのペプチド25μgの3回の連続した注射を含み得る。
中用量(コホート2)は、2回の別個の注射各75μg(各300μL)でのペプチド150μgのSC投与、その後、2回の別個の注射各37.5μg(各150μL)としてのペプチド75μgの3回の連続した投与を含み得る。
高用量(コホート3)は、2回の別個の注射各225μg(各900μL)でのペプチド450μgのSC投与、その後、2回の別個の注射各112.5μg(各450μL)としてのペプチド225μgの3回の連続した投与を含み得る。
Claims (15)
- アミノ酸配列HCPYCSLQPLALEGSLQKRG[配列番号26]からなる単離免疫原性ペプチド。
- 医薬としての使用のための、請求項1に記載のペプチド。
- 1型糖尿病の治療又は予防における使用のための、請求項1に記載のペプチド。
- 請求項1に記載のペプチド及び薬学的に許容可能な担体を含む医薬組成物。
- インスリンエピトープを提示するAPCに対する細胞溶解性CD4+T細胞の集団の生成のためのインビトロ方法であって、
- 末梢血細胞を提供する工程と、
- 前記細胞を、請求項1に記載のペプチドとインビトロで接触させる工程と、
- 前記細胞をIL-2の存在下で拡大する工程と
を含むインビトロ方法。 - 請求項5に記載の方法により得られる、インスリンエピトープを提示するAPCに対する細胞溶解性CD4+T細胞の集団。
- 医薬としての使用のための、請求項5に記載の方法により得られる、インスリンエピトープを提示するAPCに対する細胞溶解性CD4+T細胞の集団。
- 1型糖尿病の治療又は予防における使用のための、請求項5に記載の方法により得られる、インスリンエピトープを提示するAPCに対する細胞溶解性CD4+T細胞の集団。
- 1型糖尿病の治療若しくは予防における使用のための、又は1型糖尿病の症状を低減するための、請求項1から3のいずれか一項に記載の単離免疫原性ペプチド、又は請求項4に記載の医薬組成物。
- テトラペプチド配列Cxx[CST][配列番号1]又は[CST]xxC[配列番号2]、及びこのテトラペプチドから0〜4アミノ酸隔てられた配列LALEGSLQK[配列番号3]を含む、12〜50アミノ酸の長さを有するペプチド。
- 配列Cxx[CST]SLQPLALEGSLQK[配列番号4]又は[CST]xxCSLQPLALEGSLQK[配列番号5]を含む、請求項10に記載のペプチド。
- 配列CxxCSLQPLALEGSLQK[配列番号6]を含む、請求項10又は11に記載のペプチド。
- 配列HCxx[CST]SLQPLALEGSLQK[配列番号7]又はH[CST]xxCSLQPLALEGSLQK[配列番号8]を含む、請求項10から12のいずれか一項に記載のペプチド。
- 配列HCxxCSLQPLALEGSLQK[配列番号9]を含む、請求項10から13のいずれか一項に記載のペプチド。
- 配列Cxx[CST][配列番号1]又は[CST]xxC[配列番号2]レドックスモチーフ配列、及び配列SLQPLALEGSLQKRG[配列番号20]を含む、請求項10から14のいずれか一項に記載のペプチド。
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