JP2021517471A - 変異kras配列及び脂質を含む化合物並びにその使用 - Google Patents
変異kras配列及び脂質を含む化合物並びにその使用 Download PDFInfo
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Abstract
Description
本明細書で使用される「カルボニル」は、-C(O)-基を指す。
DSPE-アミド-dPEG24-アミド-dPEG24-MAL
投与される各KRASペプチドの用量は、ペプチドあたり100〜5000μgの範囲であり得る(例えば、700μg/ペプチド、これは7つのペプチドのグループに対して4900gのペプチド用量をもたらすであろう)。
免疫応答を誘発することに関して、可溶性-KRas(KRas)又はアンフィフィル-KRas(aKRas)(図6)変異配列、及びアンフィフィル-CpGアジュバント(aCpG)の有効性を調べた。この実験では、アンフィフィル-CKRasの5倍量のaCpGを使用したが、これはCpGの漸増試験から、この用量がより効果的であることが示唆されたためである。
1. KRas G12D + aCpG
2. aKRas G12D + aCpG
3. KRas G12D + pIC
4. 非免疫化
免疫応答を誘発することに関して、追加の可溶性-KRas(KRas)又はアンフィフィル-KRas(aKRas)変異配列、及びアンフィフィル-CpGアジュバント(aCpG)又は可溶性-CpG(CpG)の有効性を調べた。
1. KRas G12R + CpG
2. KRas G12V + CpG
3. KRas G12R + pIC
4. KRas G12V + pIC
5. aKRas G12R + aCpG
6. aKRas G12V + aCpG
7. 非免疫化
野生型B6マウスでは、KRas特異的CD8+ T細胞応答を引き起こすことは困難である。ヒトHLA遺伝子A2.1を導入したB6マウスを、KRas G12D抗原の可溶性又はアンフィフィル-コンジュゲート型、及びアジュバント(CpG又はaCpG)で免疫した。A2.1アレルは、ヒトにおいてKRasペプチドに対する応答をマウントすることが知られている。
1. KRas 野生型 + CpG
2. KRas 12D + CpG
3. aKRas 12D + aCpG
4. 非免疫化
抗原の濃度を20μgから50μgに増加させ、隔週(bw)又は毎週(w)の投与間隔で試験した。
1. KRas 12D + CpG1826 (bw)
2. KRas 12D + CpG1826 (w)
3. aKRas 12D + aCpG1826 (bw)
4. aKRas 12D + aCpG1826 (w)
5. 非免疫化
上記実施例に記載されているように、aCpGアジュバントを伴う変異KRASペプチド-アンフィルワクチンの潜在的な免疫原性は、C57BL/6マウスモデルにおいて実証されている。この研究及びさらなる研究は、表4に要約されており、MHC結合の種差に起因して、マウスは歴史的に変異型KRASペプチドに対する免疫学的応答がヒトよりも低いことを示している。
・変異KRAS Amph-ペプチド(G12D(図6)、G12R、及びG12V)の皮下投与は、ELISPOT及びサイトカインビーズアレイによって同定されるマウスのKRAS特異的脾臓T細胞の誘導に効果的である(図1、図2、図4、及び図5)、
・アジュバントとしてのaCpGと組み合わせた変異KRAS Amph-ペプチド(G12D、G12R、及びG12V)は、アジュバントとしての可溶性CpG又はポリイノシニック:ポリシチジリック酸(poly IC)と組み合わせた変異KRASペプチドよりも、KRAS特異的脾臓T細胞の誘導に効果的である(図1、図2、及び図5)、及び
・長い(18-mer)又は最小(9-mer)ペプチドエピトープで再刺激したときのエフェクターサイトカイン応答を通して実証されたように(図4)、aCpGと組み合わせた変異KRAS Amph-ペプチド(G12D)は、可溶性CpGと組み合わせた可溶性KRASペプチドよりも、CD4及びCD8の両方のT細胞応答を誘発するのに有効である。
本発明は、その特定の実施形態に関連して記載されてきたが、さらなる改変が可能であり、本願は、一般に、本発明の原理に従う本発明のあらゆる変形、使用、又は適応をカバーすることを意図していることが理解され得、本発明が属する技術分野における既知又は慣例の範囲内にある、本明細書の開示からのそのような逸脱を含むものであり、本明細書に先に述べた本質的な特徴に適用され得るものである。
Claims (22)
- 変異KRAS配列及び脂質を含む化合物であって、前記変異KRAS配列はリンカーによって脂質にコンジュゲートし、並びに(i)前記リンカーは1つ以上のポリエチレングリコールブロックを含み、(ii)前記脂質は1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミン(DSPE)であり、且つ(iii)前記変異KRAS配列はCYKLVVVGADGVGKSALTI(配列番号1)、CYKLVVVGAVGVGKSALTI(配列番号2)、CYKLVVVGARGVGKSALTI(配列番号3)、CYKLVVVGAAGVGKSALTI(配列番号4)、CYKLVVVGASGVGKSALTI(配列番号5)、CYKLVVVGACGVGKSALTI(配列番号6)、CYKLVVVGATGVGKSALTI(配列番号22)、及びCYKLVVVGAGDVGKSALTI(配列番号7)からなる群から選択されるアミノ酸配列からなる、化合物。
- 前記変異KRAS配列が、YKLVVVGADGVGKSALTI(配列番号23)、YKLVVVGAVGVGKSALTI(配列番号24)、YKLVVVGARGVGKSALTI(配列番号25)、YKLVVVGAAGVGKSALTI(配列番号26)、YKLVVVGASGVGKSALTI(配列番号27)、YKLVVVGACGVGKSALTI(配列番号28)、YKLVVVGATGVGKSALTI(配列番号29)、及びYKLVVVGAGDVGKSALTI(配列番号30)からなる群から選択されるアミノ酸配列からなる、請求項1の化合物。
- 前記変異KRAS配列が、そのN末端で、システイン-マレイミド連結を介してリンカーにコンジュゲートしている、請求項1又は2の化合物。
- 前記リンカーが、ポリエチレングリコールの48の繰り返し単位を含む、請求項1又は2の化合物。
- 請求項1又は2の1つ以上の化合物、及び薬学的に許容される担体を含む、組成物。
- 前記組成物が、(1)アミノ酸配列YKLVVVGADGVGKSALTI(配列番号23)を含む化合物、(2)アミノ酸配列YKLVVVGAVGVGKSALTI(配列番号24)を含む化合物、(3)アミノ酸配列YKLVVVGARGVGKSALTI(配列番号25)を含む化合物、(4)アミノ酸配列YKLVVVGAAGVGKSALTI(配列番号26)を含む化合物、(5)アミノ酸配列YKLVVVGASGVGKSALTI(配列番号27)を含む化合物、(6)アミノ酸配列YKLVVVGACGVGKSALTI(配列番号28)を含む化合物、又はアミノ酸配列YKLVVVGATGVGKSALTI(配列番号29)を含む化合物、及び(7)アミノ酸配列YKLVVVGAGDVGKSALTI(配列番号30)を含む化合物を含む、請求項6の組成物。
- 前記組成物が、(1)アミノ酸配列CYKLVVVGADGVGKSALTI(配列番号1)を含む化合物、(2)アミノ酸配列CYKLVVVGAVGVGKSALTI(配列番号2)を含む化合物、(3)アミノ酸配列CYKLVVVGARGVGKSALTI(配列番号3)を含む化合物、(4)アミノ酸配列CYKLVVVGAAGVGKSALTI(配列番号4)を含む化合物、(5)アミノ酸配列CYKLVVVGASGVGKSALTI(配列番号5)を含む化合物、(6)アミノ酸配列CYKLVVVGACGVGKSALTI(配列番号6)を含む化合物、又はアミノ酸配列CYKLVVVGATGVGKSALTI(配列番号22)を含む化合物、及び(7)アミノ酸配列CYKLVVVGAGDVGKSALTI(配列番号7)を含む化合物を含む、請求項6の組成物。
- 前記組成物が、700μgの各化合物を含む、請求項6の組成物。
- 前記ヌクレオチド配列が、前記脂質に結合している、請求項9の組成物。
- ヒト患者のがんの治療方法であって、請求項6の組成物を前記患者に投与する工程を含む、方法。
- アジュバントを投与する工程をさらに含む、請求項12の方法。
- 前記アジュバントが、CpGヌクレオチド配列を含む、請求項13の方法。
- 前記CpGヌクレオチド配列が、5'-TCGTCGTTTTGTCGTTTTGTCGTT-3'(配列番号8)を含む、請求項14の方法。
- 0.1mg、0.5mg、又は2.5mgの前記アジュバントを投与する、請求項12の方法。
- 前記ヌクレオチド配列が、前記脂質に結合している、請求項17の方法。
- 前記がんが、膵臓がん、肺がん、又は大腸がんである、請求項12の方法。
- 5'-TCGTCGTTTTGTCGTTTTGTCGTT-3'(配列番号8)のヌクレオシドを連結する全てのインターヌクレオシド基がホスホロチオエート類である、請求項12の方法。
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KR20230068628A (ko) | 2021-11-11 | 2023-05-18 | 의료법인 명지의료재단 | Kras 특이적 활성화 t 세포 유도용 항원 조성물 |
KR20230068627A (ko) | 2021-11-11 | 2023-05-18 | 의료법인 명지의료재단 | Kras 특이적 활성화 t 세포 유도용 항원 조성물을 이용한 항원 특이적 t 세포 유도방법 |
KR20230101284A (ko) | 2021-12-29 | 2023-07-06 | 의료법인 명지의료재단 | K-ras 특이적 활성화 T 세포를 포함하는 대장암의 예방 및 치료용 약제학적 조성물 및 이의 제조방법 |
KR20230101283A (ko) | 2021-12-29 | 2023-07-06 | 의료법인 명지의료재단 | K-ras 특이적 활성화 T 세포를 포함하는 폐 유두상 선암종의 예방 및 치료용 약제학적 조성물 및 이의 제조방법 |
KR20230101287A (ko) | 2021-12-29 | 2023-07-06 | 의료법인 명지의료재단 | K-ras 특이적 활성화 T 세포를 포함하는 흑색종의 예방 및 치료용 약제학적 조성물 및 이의 제조방법 |
KR20230101286A (ko) | 2021-12-29 | 2023-07-06 | 의료법인 명지의료재단 | K-ras 특이적 활성화 T 세포를 포함하는 폐 선암종의 예방 및 치료용 약제학적 조성물 및 이의 제조방법 |
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