JP2021527426A - ネオ抗原およびその使用 - Google Patents
ネオ抗原およびその使用 Download PDFInfo
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- JP2021527426A JP2021527426A JP2020570749A JP2020570749A JP2021527426A JP 2021527426 A JP2021527426 A JP 2021527426A JP 2020570749 A JP2020570749 A JP 2020570749A JP 2020570749 A JP2020570749 A JP 2020570749A JP 2021527426 A JP2021527426 A JP 2021527426A
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- hla
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Abstract
Description
本出願は、それらの全体が参照により本明細書に組み込まれる、2018年6月19日出願の米国仮特許出願第62/687,188号および2019年2月4日出願の米国仮特許出願第62/800,735号の利益を主張する。
参照による組み込み
一部の態様では、(a)DTAGHEEY、TAGHEEYSAM、DILDTAGHE、DILDTAGH、ILDTAGHEE、ILDTAGHE、DILDTAGHEEY、DTAGHEEYS、LLDILDTAGH、DILDTAGRE、DILDTAGR、ILDTAGREE、ILDTAGRE、CLLDILDTAGR、TAGREEYSAM、REEYSAMRD、DTAGKEEYSAM、CLLDILDTAGK、DTAGKEEY、LLDILDTAGK、ILDTAGKE、ILDTAGKEE、DTAGLEEY、ILDTAGLE、DILDTAGL、ILDTAGLEE、GLEEYSAMRDQY、LLDILDTAGLE、LDILDTAGL、DILDTAGLE、DILDTAGLEEY、AGVGKSAL、GAAGVGKSAL、AAGVGKSAL、CGVGKSAL、ACGVGKSAL、DGVGKSAL、ADGVGKSAL、DGVGKSALTI、GARGVGKSA、KLVVVGARGV、VVVGARGV、SGVGKSAL、VVVGASGVGK、GASGVGKSAL、VGVGKSAL、VVVGAGCVGK、KLVVVGAGC、GDVGKSAL、DVGKSALTI、VVVGAGDVGK、TAGKEEYSAM、DTAGHEEYSAM、TAGHEEYSA、DTAGREEYSAM、TAGKEEYSA、AAGVGKSA、AGCVGKSAL、AGDVGKSAL、AGKEEYSAMR、AGVGKSALTI、ARGVGKSAL、ASGVGKSA、ASGVGKSAL、AVGVGKSA、CVGKSALTI、DILDTAGK、DILDTAGREEY、DTAGHEEYSAMR、DTAGKEEYS、DTAGKEEYSAMR、DTAGLEEYS、DTAGLEEYSA、DTAGLEEYSAMR、DTAGREEYS、DTAGREEYSAMR、GAAGVGKSA、GACGVGKSA、GACGVGKSAL、GADGVGKS、GAGDVGKSA、GAGDVGKSAL、GASGVGKSA、GCVGKSAL、GCVGKSALTI、GHEEYSAM、GKEEYSAM、GLEEYSAMR、GREEYSAM、GREEYSAMR、HEEYSAMRD、KEEYSAMRD、KLVVVGASG、LDILDTAGR、LEEYSAMRD、LVVVGARGV、LVVVGASGV、REEYSAMRDQY、RGVGKSAL、TAGLEEYSA、TEYKLVVVGAA、VGAAGVGKSA、VGADGVGK、VGASGVGKSA、VGVGKSALTI、VVVGAAGV、VVVGAVGV、YKLVVVGAC、YKLVVVGAD、YKLVVVGAR、およびDILDTAGKEからなる群から選択される1つもしくは複数の変異型RASペプチド配列を含む少なくとも1つのポリペプチド;または(b)この少なくとも1つのポリペプチドをコードする少なくとも1つのポリヌクレオチドを含む組成物が、本明細書で提供される。
I.定義
II.ネオ抗原およびその使用
III.ペプチド
表1
2太字のAAは、2つの融合した遺伝子のうち2番目のものによってコードされるアミノ酸配列のネイティブAAを示す。
3太字かつ下線付きのAAは、フレームシフトに起因する、2つの融合した遺伝子のうち2番目のものによってコードされるアミノ酸配列の非ネイティブAAを示す。
表2
2太字のAAは、2つの融合した遺伝子のうち2番目のものによってコードされるアミノ酸配列のネイティブAAを示す。
3太字かつ下線付きのAAは、フレームシフトに起因する、2つの融合した遺伝子のうち2番目のものによってコードされるアミノ酸配列の非ネイティブAAを示す。
表3. RAS Q61H突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表4. RAS Q61R突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表5. RAS Q61K突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表6. RAS Q61L突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表7. RAS G12A突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表8. RAS G12C突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表9. RAS G12D突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表10. RAS G12R突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表11. RAS G12S突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表12. RAS G12V突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表13. RAS G13C突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
表14. RAS G13D突然変異を含むペプチド配列、対応するHLA対立遺伝子、および結合潜在力のランク
B.ネオエピトープ
C.ポリヌクレオチド
IV.ベクター
V.T細胞受容体
VI.抗原提示細胞
VII.アジュバント
VIII.処置の方法および医薬組成物
IX.キット
(実施例1)
CD4+およびCD8+T細胞応答の誘導
(実施例2)
テトラマー染色アッセイ
(実施例3)
細胞内サイトカイン染色アッセイ
(実施例4)
ELISPOTアッセイ
(実施例5)
CD107染色アッセイ
(実施例6)
細胞傷害性アッセイ
(実施例7)
ロングマーおよびショートマーを順次使用してin vivoで増強されたCD8+T細胞応答
in vivo免疫原性アッセイ
ペプチド
ELISPOT
(実施例8)
質量分析による変異型RASペプチドの検出
(実施例9)
変異型KRASペプチドは、複数の対立遺伝子に対する強いエピトープを産生する。
(実施例10)
複数のネオエピトープが、CD8+T細胞応答を惹起する
誘導されたT細胞の細胞傷害性アッセイ
(実施例12)
変異型KRASペプチドステーブルマー(stablemer)は、複数の対立遺伝子に対する強いエピトープを産生する
Claims (96)
- (a)
(i)KLVVVGADGV、KLVVVGACGV、KLVVVGAVGV、LVVVGADGV、LVVVGACGV、LVVVGAVGV;
(ii)GADGVGKSAL、GACGVGKSAL、GAVGVGKSAL、GADGVGKSA、GACGVGKSA、GAVGVGKSA;および/または
(iii)VVGADGVGK、VVGACGVGK、VVGAVGVGK、VVVGADGVGK、VVVGACGVGK、VVVGAVGVGK
からなる群から選択される2つもしくはそれよりも多くの変異型RASペプチド配列を含む少なくとも1つのポリペプチドもしくはその薬学的に許容される塩;または
(b)前記少なくとも1つのポリペプチドをコードする少なくとも1つのポリヌクレオチド
を含む組成物。 - 3つまたはそれよりも多くの前記変異型RASペプチド配列の混合物を含む、請求項1に記載の組成物。
- (a)2つもしくはそれよりも多くの変異型RASペプチド配列を含む少なくとも1つのポリペプチドもしくはその薬学的に許容される塩であって、前記変異型RASペプチド配列は各々、
(i)G12における突然変異を含む変異型RASタンパク質の少なくとも8個連続するアミノ酸、および
(ii)G12における前記突然変異
を含み、
さらに、前記変異型RASタンパク質に対して異種の3つもしくはそれよりも多くのアミノ酸残基が、2つもしくはそれよりも多くの前記変異型RASペプチド配列のN末端もしくはC末端に連結され、3つもしくはそれよりも多くの前記アミノ酸残基が、細胞における前記変異型RASペプチド配列のプロセシングを増強するおよび/もしくは前記変異型RASペプチド配列のエピトープの提示を増強する、ポリペプチドもしくはその薬学的に許容される塩;または
(b)前記少なくとも1つのポリペプチドをコードする少なくとも1つのポリヌクレオチド
を含む組成物。 - 2つまたはそれよりも多くの前記変異型RASペプチド配列のN末端またはC末端に連結された、前記変異型RASタンパク質に対して異種の3つまたはそれよりも多くの前記アミノ酸残基が、CMVのタンパク質、例えば、pp65、HIVまたはMART−1のアミノ酸配列を含む、請求項3に記載の組成物。
- 2つまたはそれよりも多くの前記変異型RASペプチド配列のN末端またはC末端に連結された、前記変異型RASタンパク質に対して異種の3つまたはそれよりも多くの前記アミノ酸残基が、少なくとも3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39または40アミノ酸を含む、請求項3または4に記載の組成物。
- 2つまたはそれよりも多くの前記変異型RASペプチド配列のN末端またはC末端に連結された、前記変異型RASタンパク質に対して異種の3つまたはそれよりも多くの前記アミノ酸残基が、多くて5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、50、60、70、80、90または100アミノ酸を含む、請求項3から5のいずれか一項に記載の組成物。
- (a)式
(XaaN)N−(XaaRAS)P−(XaaC)C
の少なくとも1つのポリペプチドもしくはその薬学的に許容される塩であって、
式中、
Pが、7よりも大きい整数であり;
(XaaRAS)Pが、変異型RASタンパク質の少なくとも8個連続するアミノ酸を含む変異型RASペプチド配列であり;前記少なくとも8個連続するアミノ酸が、配列
Lys1 Leu2 Val3 Val4 Val5 Gly6 Ala7 Xaa8 Gly9 Val10 Gly11 Lys12 Ser13 Ala14 Leu15
のうち少なくとも8個連続するアミノ酸を含み、
Nが、(i)0、もしくは(ii)2よりも大きい整数であり;
(XaaN)Nが、前記変異型RASタンパク質に対して異種の任意のアミノ酸配列であり;
Cが、(i)0、もしくは(ii)2よりも大きい整数であり;
(XaaC)Cが、前記変異型RASタンパク質に対して異種の任意のアミノ酸配列であり;
Xaa8が、Asp、Val、Cys、Ala、ArgおよびSerからなる群から選択され;
前記ポリペプチドが、KLVVVGAVGVGKSALTIQLではなく;
Nが0である場合にはCは0ではなく、Cが0である場合にはNは0ではない、少なくとも1つのポリペプチドもしくはその薬学的に許容される塩;または
(b)前記少なくとも1つのポリペプチドをコードする少なくとも1つのポリヌクレオチド
を含む組成物。 - (Xaa)Nおよび/または(XaaC)Cが、CMVのタンパク質、例えば、pp65、HIVまたはMART−1のアミノ酸配列を含む、請求項7に記載の組成物。
- Nおよび/またはCが、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39または40よりも大きい整数である、請求項7または8に記載の組成物。
- Nおよび/またはCが、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、50、60、70、80、90または100未満の整数である、請求項7から9のいずれか一項に記載の組成物。
- Nが0である、請求項7から10のいずれか一項に記載の組成物。
- Cが0である、請求項7から10のいずれか一項に記載の組成物。
- (a)Xaa1−Xaa2−Val3−Val4−Val5−Gly6−Ala7−Xaa8−Gly9−Xaa10
のアミノ酸配列を含む少なくとも1つのポリペプチドもしくはその薬学的に許容される塩であって、
式中、
Xaa1がAlaではなく;
ただし、Xaa1がLysではない場合、Xaa2はLeuであり、および/もしくはXaa10はGlyであり;
Xaa2がGluではなく;
ただし、Xaa2がLeuではない場合、Xaa1はLysであり、および/もしくはXaa10はGlyであり;
Xaa8が、Asp、Val、Cys、Ala、ArgおよびSerからなる群から選択され;
ただし、Xaa8がGluである場合、Xaa1はTyrではなく、および/もしくはXaa2はLeuではなく、
ただし、Xaa8がValである場合、Xaa1はLysではなく;
Xaa10が任意のアミノ酸であり;
ただし、Xaa10がGlyではない場合、Xaa1はLysであり、および/もしくはXaa2はLeuであり;
前記ポリペプチドが、HLA−A02:01、HLA−A03:01、HLA−A11:01、HLA−A03:02、HLA−A30:01、HLA−A31:01、HLA−A33:01、HLA−A33:03、HLA−A68:01および/もしくはHLA−A74:01分子に結合するHLA−A02:01拘束性T細胞エピトープ、HLA−A03:01拘束性T細胞エピトープ、HLA−A11:01拘束性T細胞エピトープ、HLA−A03:02拘束性T細胞エピトープ、HLA−A30:01拘束性T細胞エピトープ、HLA−A31:01拘束性T細胞エピトープ、HLA−A33:01拘束性T細胞エピトープ、HLA−A33:03拘束性T細胞エピトープ、HLA−A68:01拘束性T細胞エピトープもしくはHLA−A74:01拘束性T細胞エピトープを含み、
HLA−A02:01拘束性細胞傷害性T細胞応答、HLA−A02:01拘束性細胞傷害性T細胞応答、HLA−A03:01拘束性細胞傷害性T細胞応答、HLA−A11:01拘束性細胞傷害性T細胞応答、HLA−A03:02拘束性細胞傷害性T細胞応答、HLA−A30:01拘束性細胞傷害性T細胞応答、HLA−A31:01拘束性細胞傷害性T細胞応答、HLA−A33:01拘束性細胞傷害性T細胞応答、HLA−A33:03拘束性細胞傷害性T細胞応答、HLA−A68:01拘束性細胞傷害性T細胞応答もしくはHLA−A74:01拘束性細胞傷害性T細胞応答を誘導し;
HLA−A02:01、HLA−A03:01、HLA−A11:01、HLA−A03:02、HLA−A30:01、HLA−A31:01、HLA−A33:01、HLA−A33:03、HLA−A68:01および/もしくはHLA−A74:01に結合する、少なくとも1つのポリペプチドもしくはその薬学的に許容される塩;または
(b)前記少なくとも1つのポリペプチドをコードする少なくとも1つのポリヌクレオチド
を含む組成物。 - (a)1つもしくは複数の変異型RASペプチド配列を含む少なくとも1つのポリペプチドもしくはその薬学的に許容される塩であって、前記変異型RASペプチド配列は各々、
(i)G12A、G12C、G12D、G12R、G12SもしくはG12V突然変異を含む変異型RASタンパク質の少なくとも8個連続するアミノ酸、および
(ii)前記G12A、G12C、G12D、G12R、G12SもしくはG12V突然変異
を含み、
さらに、前記ペプチドが、
(i)がん細胞のゲノムによってコードされない突然変異を含み、HLA−A02:01対立遺伝子に対する150nMもしくはそれ未満の親和性もしくは予測された親和性および/または2時間もしくはそれよりも長い半減期を有する、あるいは
(j)2時間もしくはそれよりも長い半減期、ならびにHLA−A02:01対立遺伝子、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、もしくはHLA−A74:01対立遺伝子および/もしくはHLA−C08:02対立遺伝子に対する150nMもしくはそれ未満の親和性もしくは予測された親和性を有する、少なくとも1つのポリペプチドもしくはその薬学的に許容される塩;または
(b)前記少なくとも1つのポリペプチドをコードする少なくとも1つのポリヌクレオチド
を含む組成物。 - (i)表3〜14のうちいずれか1つ中のペプチド配列を含むペプチド、または(ii)表3〜14中の配列を含む前記ペプチドをコードするポリヌクレオチドをさらに含む、請求項1から14のいずれか一項に記載の組成物。
- (a)DTAGHEEY、TAGHEEYSAM、DILDTAGHE、DILDTAGH、ILDTAGHEE、ILDTAGHE、DILDTAGHEEY、DTAGHEEYS、LLDILDTAGH、DILDTAGRE、DILDTAGR、ILDTAGREE、ILDTAGRE、CLLDILDTAGR、TAGREEYSAM、REEYSAMRD、DTAGKEEYSAM、CLLDILDTAGK、DTAGKEEY、LLDILDTAGK、ILDTAGKE、ILDTAGKEE、DTAGLEEY、ILDTAGLE、DILDTAGL、ILDTAGLEE、GLEEYSAMRDQY、LLDILDTAGLE、LDILDTAGL、DILDTAGLE、DILDTAGLEEY、AGVGKSAL、GAAGVGKSAL、AAGVGKSAL、CGVGKSAL、ACGVGKSAL、DGVGKSAL、ADGVGKSAL、DGVGKSALTI、GARGVGKSA、KLVVVGARGV、VVVGARGV、SGVGKSAL、VVVGASGVGK、GASGVGKSAL、VGVGKSAL、VVVGAGCVGK、KLVVVGAGC、GDVGKSAL、DVGKSALTI、VVVGAGDVGK、TAGKEEYSAM、DTAGHEEYSAM、TAGHEEYSA、DTAGREEYSAM、TAGKEEYSA、AAGVGKSA、AGCVGKSAL、AGDVGKSAL、AGKEEYSAMR、AGVGKSALTI、ARGVGKSAL、ASGVGKSA、ASGVGKSAL、AVGVGKSA、CVGKSALTI、DILDTAGK、DILDTAGREEY、DTAGHEEYSAMR、DTAGKEEYS、DTAGKEEYSAMR、DTAGLEEYS、DTAGLEEYSA、DTAGLEEYSAMR、DTAGREEYS、DTAGREEYSAMR、GAAGVGKSA、GACGVGKSA、GACGVGKSAL、GADGVGKS、GAGDVGKSA、GAGDVGKSAL、GASGVGKSA、GCVGKSAL、GCVGKSALTI、GHEEYSAM、GKEEYSAM、GLEEYSAMR、GREEYSAM、GREEYSAMR、HEEYSAMRD、KEEYSAMRD、KLVVVGASG、LDILDTAGR、LEEYSAMRD、LVVVGARGV、LVVVGASGV、REEYSAMRDQY、RGVGKSAL、TAGLEEYSA、TEYKLVVVGAA、VGAAGVGKSA、VGADGVGK、VGASGVGKSA、VGVGKSALTI、VVVGAAGV、VVVGAVGV、YKLVVVGAC、YKLVVVGAD、YKLVVVGAR、およびDILDTAGKEからなる群から選択される1つもしくは複数の変異型RASペプチド配列を含む少なくとも1つのポリペプチドもしくはその薬学的に許容される塩;または
(b)前記少なくとも1つのポリペプチドをコードする少なくとも1つのポリヌクレオチド
を含む組成物。 - (i)表1〜14のうちいずれか1つ中のペプチド配列を含むペプチド、または
(ii)表1〜14中の配列を含む前記ペプチドをコードするポリヌクレオチド
をさらに含む、請求項16に記載の組成物。 - 前記変異型RASペプチド配列のうち少なくとも1つが、少なくとも3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39または40アミノ酸のNまたはC末端アミノ酸配列延長を含み、前記NまたはC末端延長が、野生型RASアミノ酸配列または非異種RASアミノ酸配列である、請求項1から17のいずれか一項に記載の組成物。
- 前記少なくとも1つのポリペプチドが、少なくとも3、4、5、6、7、8、9または10個の変異型RASペプチド配列を含む、請求項1から18のいずれか一項に記載の組成物。
- 前記少なくとも1つのポリペプチドが、少なくとも2つのポリペプチドを含む、または前記少なくとも1つのポリヌクレオチドが、少なくとも2つのポリヌクレオチドを含む、請求項1から19のいずれか一項に記載の組成物。
- 前記変異型RASペプチド配列のうち少なくとも1つが、変異型RASタンパク質の少なくとも9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39または40個連続するアミノ酸を含む、請求項1から20のいずれか一項に記載の組成物。
- 前記変異型RASペプチド配列のうち少なくとも2、3、4、5、6、7、8、9または10個が、変異型RASタンパク質の少なくとも9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39または40個連続するアミノ酸を含む、請求項1から21のいずれか一項に記載の組成物。
- 前記変異型RASペプチド配列の各々または2つもしくはそれよりも多くの前記RASペプチド配列の各々が、変異型RASタンパク質の少なくとも9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39または40個連続するアミノ酸を含む、請求項1から22のいずれか一項に記載の組成物。
- 前記少なくとも1つのポリペプチドが、HLA−A02:01対立遺伝子、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子および/またはHLA−C08:02対立遺伝子によってコードされるタンパク質に結合するまたは結合すると予測される少なくとも1つの変異型RASペプチド配列を含む、請求項1から23のいずれか一項に記載の組成物。
- 前記少なくとも1つのポリペプチドが、
(a)HLA−A02:01対立遺伝子およびHLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、もしくはHLA−A74:01対立遺伝子;
(b)HLA−A02:01対立遺伝子およびHLA−C08:02対立遺伝子;
(c)HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、もしくはHLA−A74:01対立遺伝子およびHLA−C08:02対立遺伝子;または
(d)HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、もしくはHLA−A74:01対立遺伝子および対立遺伝子およびHLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、もしくはHLA−A74:01対立遺伝子
によってコードされるタンパク質に結合するまたは結合すると予測される少なくとも1つの変異型RASペプチド配列を含む、請求項1から24のいずれか一項に記載の組成物。 - 前記変異型RASペプチド配列が、
(a)HLA−A02:01対立遺伝子、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、HLA−A74:01対立遺伝子および/またはHLA−C08:02対立遺伝子によってコードされるタンパク質に結合するまたは結合すると予測される第1の変異型RASペプチド配列;ならびに
(b)HLA−A02:01対立遺伝子、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、HLA−A74:01対立遺伝子および/またはHLA−C08:02対立遺伝子によってコードされるタンパク質に結合するまたは結合すると予測される第2のRASペプチド配列
を含み、
前記第1の変異型RASペプチド配列が、前記第2の変異型RASペプチド配列とは異なるHLA対立遺伝子によってコードされるタンパク質に結合するまたは結合すると予測される、請求項1から25のいずれか一項に記載の組成物。 - 前記少なくとも1つのポリペプチドが、10μM未満、1μM未満、500nM未満、400nM未満、300nM未満、250nM未満、200nM未満、150nM未満、100nM未満または50nM未満の親和性でHLA対立遺伝子によってコードされるタンパク質に結合する、少なくとも1つの変異型RASペプチド配列を含む、請求項1から26のいずれか一項に記載の組成物。
- 前記少なくとも1つのポリペプチドが、24時間よりも長い、12時間よりも長い、9時間よりも長い、6時間よりも長い、5時間よりも長い、4時間よりも長い、3時間よりも長い、2時間よりも長い、1時間よりも長い、45分よりも長い、30分よりも長い、15分よりも長いまたは10分よりも長い安定性でHLA対立遺伝子によってコードされるタンパク質に結合する、少なくとも1つの変異型RASペプチド配列を含む、請求項1から27のいずれか一項に記載の組成物。
- 前記HLA対立遺伝子が、HLA−A02:01対立遺伝子、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、HLA−A74:01対立遺伝子および/またはHLA−C08:02対立遺伝子ならびにそれらの任意の組合せからなる群から選択される、請求項27または28に記載の組成物。
- 前記少なくとも1つのポリペプチドが、以下の配列:LVVVGACGV、KLVVVGACGV、LVVVGADGV、KLVVVGADGV、LVVVGAVGV、KLVVVGAVGV、VVGACGVGK、VVVGACGVGK、VVGADGVGK、VVVGADGVGK、VVGAVGVGK、VVVGAVGVGK、VVGACGVGK、VVGADGVGK、VVVGADGVGK、VVGAVGVGK、およびVVVGAVGVGKのうち少なくとも1つを含む、請求項1から29のいずれか一項に記載の組成物。
- 前記変異型RASペプチド配列が、以下の配列:KLVVVGACGV、FLVVVGACGL、FMVVVGACGI、FLVVVGACGI、FMVVVGACGV、FLVVVGACGV、MLVVVGACGV、FMVVVGACGL、YLVVVGACGV、KMVVVGACGV、YMVVVGACGV、およびMMVVVGACGVのうち少なくとも1つまたは2つを含む、請求項1から30のいずれか一項に記載の組成物。
- 前記変異型RASペプチド配列が、以下の配列:
(a)TEYKLVVVGAVGV;
(b)WQAGILARKLVVVGAVGVQGQNLKYQ;
(c)HSYTTAEKLVVVGAVGVILGVLLLI;
(d)PLTEEKIKKLVVVGAVGVEKEGKISK;
(e)GALHFKPGSRKLVVVGAVGVAASDFIFLVT;
(f)RRANKDATAEKLVVVGAVGVKELKQVASPF;
(g)KAFISHEEKRKLVVVGAVGVKKKLINEKKE;
(h)TDLSSRFSKSKLVVVGAVGVKKCDISLQFF;
(i)FDLGGGTFDVKLVVVGAVGVKSTAGDTHLG;または
(j)CLLLHYSVSKKLVVVGAVGVATFYVAVTVP
のうち少なくとも1つまたは2つを含む、請求項1から31のいずれか一項に記載の組成物。 - (Xaa)Nが、IDIIMKIRNA、FFFFFFFFFFFFFFFFFFFFIIFFIFFWMC、FFFFFFFFFFFFFFFFFFFFFFFFAAFWFW、IFFIFFIIFFFFFFFFFFFFIIIIIIIWEC、FIFFFIIFFFFFIFFFFFIFIIIIIIFWEC、TEY、WQAGILAR、HSYTTAE、PLTEEKIK、GALHFKPGSR、RRANKDATAE、KAFISHEEKR、TDLSSRFSKS、FDLGGGTFDV、CLLLHYSVSK、またはMTEYKLVVVのアミノ酸配列を含む、請求項1から32のいずれか一項に記載の組成物。
- (XaaC)Cが、KKNKKDDIKD、AGNDDDDDDDDDDDDDDDDDKKDKDDDDDD、AGNKKKKKKKNNNNNNNNNNNNNNNNNNNN、AGRDDDDDDDDDDDDDDDDDDDDDDDDDDD、GKSALTIQL、GKSALTI、QGQNLKYQ、ILGVLLLI、EKEGKISK、AASDFIFLVT、KELKQVASPF、KKKLINEKKE、KKCDISLQFF、KSTAGDTHLG、ATFYVAVTVP、LTIQLIQNHFVDEYDPTIEDSYRKQVVIDG、またはTIQLIQNHFVDEYDPTIEDSYRKQVVIDGEのアミノ酸配列を含む、請求項1から33のいずれか一項に記載の組成物。
- 第1の変異型RASペプチド配列が変異型RASタンパク質の第1のネオエピトープを含み、第2の変異型RASペプチド配列が変異型RASタンパク質の第2のネオエピトープを含み、前記第1の変異型RASペプチド配列が前記変異型RASペプチド配列とは異なり、前記第1のネオエピトープが少なくとも1つの突然変異型アミノ酸を含み、前記第2のネオエピトープが同じ突然変異型アミノ酸を含む、請求項1から34のいずれか一項に記載の組成物。
- 前記変異型RASペプチド配列のうち少なくとも1つが、対象のがん細胞のゲノムによってコードされない突然変異型アミノ酸を含む、請求項1から35のいずれか一項に記載の組成物。
- 前記変異型RASペプチド配列の各々が、少なくとも1μg/mL、少なくとも10μg/mL、少なくとも25μg/mL、少なくとも50μg/mLまたは少なくとも100μg/mLの濃度で存在する、請求項1から36のいずれか一項に記載の組成物。
- 前記変異型RASペプチド配列の各々が、多くて5000μg/mL、多くて2500μg/mL、多くて1000μg/mL、多くて750μg/mL、多くて500μg/mL、多くて400μg/mLまたは多くて300μg/mLの濃度で存在する、請求項1から36のいずれか一項に記載の組成物。
- 前記変異型RASペプチド配列の各々が、10μg/mL〜5000μg/mL、10μg/mL〜4000μg/mL、10μg/mL〜3000μg/mL、10μg/mL〜2000μg/mL、10μg/mL〜1000μg/mL、25μg/mL〜500μg/mLまたは50μg/mL〜300μg/mLの濃度で存在する、請求項1から36のいずれか一項に記載の組成物。
- G13A、G13C、G13D、G13R、G13S、G13V、G12A、G12C、G12D、G12R、G12S、G12VまたはQ61突然変異を有する異なる変異型RASペプチド配列をさらに含む、請求項1から39のいずれか一項に記載の組成物。
- 免疫調節剤またはアジュバントをさらに含む、請求項1から40のいずれか一項に記載の組成物。
- 前記アジュバントがポリICLCである、請求項41に記載の組成物。
- (a)請求項1から42のいずれか一項に記載の組成物、および
(b)薬学的に許容される賦形剤
を含む医薬組成物。 - 1mM未満または1mMよりも高い濃度で存在するpH改変因子を含む、請求項43に記載の医薬組成物。
- ワクチン組成物である、請求項43または44に記載の医薬組成物。
- 水性である、請求項43から45のいずれか一項に記載の医薬組成物。
- 前記少なくとも1つのポリペプチドのうち1つまたは複数が、
(a)pI>5かつHYDRO>−6、
(b)pI>8かつHYDRO>−8、
(c)pI<5かつHYDRO>−5、
(d)pI>9かつHYDRO<−8、
(e)pI>7かつHYDRO値>−5.5、
(f)pI<4.3かつ−4≧HYDRO≧−8、
(g)pI>0かつHYDRO<−8、pI>0かつHYDRO>−4またはpI>4.3かつ−4≧HYDRO≧−8、
(h)pI>0かつHYDRO>−4またはpI>4.3かつHYDRO≦−4.、
(i)pI>0かつHYDRO>−4またはpI>4.3かつ−4≧HYDRO≧−9、
(j)5≧pI≧12かつ−4≧HYDRO≧−9
を境界とする、請求項43から46のいずれか一項に記載の医薬組成物。 - 前記pH改変因子が塩基である、請求項43から47のいずれか一項に記載の医薬組成物。
- 前記pH改変因子が、弱酸の共役塩基である、請求項43から48のいずれか一項に記載の医薬組成物。
- 前記pH改変因子が、薬学的に許容される塩である、請求項43から49のいずれか一項に記載の医薬組成物。
- 前記pH改変因子が、ジカルボン酸塩またはトリカルボン酸塩である、請求項43から50のいずれか一項に記載の医薬組成物。
- 前記pH改変因子が、クエン酸および/またはクエン酸塩である、請求項43から50のいずれか一項に記載の医薬組成物。
- 前記クエン酸塩が、クエン酸二ナトリウムおよび/またはクエン酸三ナトリウムである、請求項52に記載の医薬組成物。
- 前記pH改変因子が、コハク酸および/またはコハク酸塩である、請求項43から50のいずれか一項に記載の医薬組成物。
- 前記コハク酸塩が、コハク酸二ナトリウムおよび/またはコハク酸一ナトリウムである、請求項54に記載の医薬組成物。
- 前記コハク酸塩が、コハク酸二ナトリウム六水和物である、請求項55に記載の医薬組成物。
- 前記pH改変因子が、0.1mM〜1mMの濃度で存在する、請求項43から55のいずれか一項に記載の医薬組成物。
- 前記薬学的に許容される担体が、液体を含む、請求項43から57のいずれか一項に記載の医薬組成物。
- 前記薬学的に許容される担体が、水を含む、請求項43から58のいずれか一項に記載の医薬組成物。
- 前記薬学的に許容される担体が、糖を含む、請求項43から59のいずれか一項に記載の医薬組成物。
- 前記糖が、デキストロースを含む、請求項60に記載の医薬組成物。
- 前記デキストロースが、1〜10%w/vの濃度で存在する、請求項61に記載の医薬組成物。
- 前記糖が、トレハロースを含む、請求項60から62のいずれか一項に記載の医薬組成物。
- 前記糖が、スクロースを含む、請求項60から63のいずれか一項に記載の医薬組成物。
- 前記薬学的に許容される担体が、ジメチルスルホキシド(DMSO)を含む、請求項43から64のいずれか一項に記載の医薬組成物。
- 前記DMSOが、0.1%〜10%、0.5%〜5%または1%〜3%の濃度で存在する、請求項65に記載の医薬組成物。
- 前記薬学的に許容される担体が、ジメチルスルホキシド(DMSO)を含まない、請求項43から64のいずれか一項に記載の医薬組成物。
- 凍結乾燥可能である、請求項43から67のいずれか一項に記載の医薬組成物。
- 免疫調節因子またはアジュバントをさらに含む、請求項43から68のいずれか一項に記載の医薬組成物。
- 前記免疫調節因子またはアジュバントが、ポリ−ICLC、1018 ISS、アルミニウム塩、Amplivax、AS15、BCG、CP−870,893、CpG7909、CyaA、ARNAX、STINGアゴニスト、dSLIM、GM−CSF、FLT−3L、IC30、IC31、イミキモド、ImuFact IMP321、IS Patch、ISS、ISCOMATRIX、Juvlmmune、LipoVac、MF59、モノホスホリルリピドA、Montanide IMS 1312、Montanide ISA 206、Montanide ISA 50V、Montanide ISA−51、OK−432、OM−174、OM−197−MP−EC、ONTAK、PepTel(登録商標)、ベクターシステム、PLGAマイクロ粒子、レシキモド、SRL172、ビロソームおよび他のウイルス様粒子、YF−17D、VEGF trap、R848、ベータ−グルカン、Pam3Cys、ならびにAquila’s QS21 stimulonからなる群から選択される、請求項69に記載の医薬組成物。
- 前記免疫調節因子またはアジュバントが、ポリ−ICLCを含む、請求項69または70に記載の医薬組成物。
- 前記医薬組成物中のポリ−ICLCのペプチドに対する比が、2:1〜1:10 v:vである、請求項71に記載の医薬組成物。
- 前記医薬組成物中のポリ−ICLCのペプチドに対する前記比が、約1:1、1:2、1:3、1:4または1:5 v:vである、請求項72に記載の医薬組成物。
- 前記医薬組成物中のポリ−ICLCのペプチドに対する前記比が、約1:3 v:vである、請求項73に記載の医薬組成物。
- がんを有する対象を処置する方法であって、前記対象に、請求項43から74のいずれか一項に記載の医薬組成物を投与するステップを含む、方法。
- がんを有する対象を処置する方法であって、前記対象に、VVGADGVGK、VVGACGVGK、VVGAVGVGK、VVVGADGVGK、VVVGACGVGK、VVVGAVGVGKの配列を有するペプチドを投与するステップを含み、前記対象が、前記対象のゲノムのHLA−A02:01対立遺伝子、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、HLA−A74:01対立遺伝子またはHLA−C08:02対立遺伝子によってコードされるタンパク質を発現する、方法。
- がんを有する対象を処置する方法であって、
前記対象に、変異型RASペプチドまたは前記変異型RASペプチドをコードする核酸を投与するステップを含み、前記変異型RASペプチドが、G12における突然変異を含む変異型RASタンパク質の少なくとも8個連続するアミノ酸を含み、前記ペプチドが、G12における前記突然変異を含み、HLA−A11:01またはHLA−A03:01に結合し、前記対象が、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子またはHLA−A74:01対立遺伝子によってコードされるタンパク質を発現すると同定される、方法。 - がんを有する対象を処置する方法であって、前記対象に、配列GADGVGKSAL、GACGVGKSAL、GAVGVGKSAL、GADGVGKSA、GACGVGKSAまたはGAVGVGKSAを含むペプチドを投与するステップを含み;
前記対象が、前記ペプチドに結合する前記対象のゲノムのHLA−A02:01対立遺伝子、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、HLA−A74:01対立遺伝子またはHLA−C08:02対立遺伝子によってコードされるタンパク質を発現する、方法。 - がんを有する対象を処置する方法であって、前記対象に、第1および第2のペプチドまたは前記第1および第2のペプチドをコードする核酸を投与するステップを含み、前記第1および第2のペプチドが、(1)KLVVVGADGV、KLVVVGACGV、KLVVVGAVGV、LVVVGADGV、LVVVGACGV、LVVVGAVGV;(2)GADGVGKSAL、GACGVGKSAL、GAVGVGKSAL、GADGVGKSA、GACGVGKSA、GAVGVGKSA;および(3)VVGADGVGK、VVGACGVGK、VVGAVGVGK、VVVGADGVGK、VVVGACGVGK、VVVGAVGVGKのうち少なくとも2つを含み;前記対象のHLA対立遺伝子発現が、投与の時点では未知である、方法。
- がんを有する対象を処置する方法であって、前記対象に、変異型RASペプチドまたは前記変異型RASペプチドをコードする核酸を投与するステップを含み、前記変異型RASペプチドが、G12C突然変異を含む変異型RASタンパク質の少なくとも8個連続するアミノ酸を含み、前記ペプチドが、前記G12C突然変異を含み、さらに、前記ペプチドが、がん細胞のゲノムによってコードされない安定化突然変異を含み、前記対象が、HLA−A02:01対立遺伝子、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子、HLA−A74:01対立遺伝子またはHLA−C08:02対立遺伝子によってコードされるタンパク質を発現する、方法。
- がんを有する対象を治療薬の候補として同定する方法であって、前記対象を、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子またはHLA−A74:01対立遺伝子によってコードされるタンパク質を発現する対象として同定するステップを含み、前記治療薬が、変異型RASペプチドまたは前記変異型RASペプチドをコードする核酸であり、前記変異型RASペプチドが、G12における突然変異を含む変異型RASタンパク質の少なくとも8個連続するアミノ酸を含み、前記ペプチドが、G12における前記突然変異を含み、HLA−A03:01対立遺伝子、HLA−A11:01対立遺伝子、HLA−A03:02対立遺伝子、HLA−A30:01対立遺伝子、HLA−A31:01対立遺伝子、HLA−A33:01対立遺伝子、HLA−A33:03対立遺伝子、HLA−A68:01対立遺伝子またはHLA−A74:01対立遺伝子によってコードされるタンパク質に結合する、方法。
- 前記対象に前記治療薬を投与するステップをさらに含む、請求項81に記載の方法。
- がんを有する対象を処置する方法であって、
(a)前記対象によって発現される第1のタンパク質を同定するステップであって、前記第1のタンパク質が、前記対象の第1のHLA対立遺伝子によってコードされ、前記第1のHLA対立遺伝子が、表1〜14のうちいずれか1つ中に提供されるHLA対立遺伝子である、ステップ;および
(b)前記対象に、(i)表1〜14のうちいずれか1つ中に提供される前記第1のHLA対立遺伝子に対するペプチドである第1の変異型RASペプチド、または(ii)前記第1の変異型RASペプチドをコードするポリ核酸を投与するステップ
を含む、方法。 - 前記対象によって発現される第2のタンパク質を同定するステップであって、前記第2のタンパク質が、前記対象の第2のHLA対立遺伝子によってコードされ、前記第2のHLA対立遺伝子が、表1〜14のうちいずれか1つ中に提供されるHLA対立遺伝子である、ステップをさらに含む、請求項83に記載の方法。
- 前記対象に、(i)表1〜14のうちいずれか1つ中に提供される前記第2のHLA対立遺伝子に対するペプチドである、第2の変異型RASペプチド、または(ii)前記第2の変異型RASペプチドをコードするポリ核酸を投与するステップをさらに含む、請求項84に記載の方法。
- 前記第1のHLA対立遺伝子が、前記第2のHLA対立遺伝子とは異なる、請求項84または85に記載の方法。
- 前記第1の変異型RASペプチドが、前記第2の変異型RASペプチドとは異なる、請求項84または85に記載の方法。
- 免疫応答が前記対象において惹起される、請求項75から87のいずれか一項に記載の方法。
- 前記免疫応答が体液性応答である、請求項88に記載の方法。
- 前記変異型RASペプチド配列が、同時に、別々にまたは順次投与される、請求項75から89のいずれか一項に記載の方法。
- 前記第1のペプチドが、前記第2のペプチドが第2のT細胞を活性化するのに十分な期間の後に順次投与される、請求項90に記載の方法。
- 前記がんが、肺がん、非小細胞肺がん、膵がん、結腸直腸がん、子宮がんおよび肝臓がんからなる群から選択される、請求項75から91のいずれか一項に記載の方法。
- 少なくとも1つのさらなる治療剤またはモダリティを投与するステップをさらに含む、請求項75から92のいずれか一項に記載の方法。
- 前記少なくとも1つのさらなる治療剤またはモダリティが、手術、チェックポイント阻害剤、抗体もしくはその断片、化学療法剤、放射線、ワクチン、小分子、T細胞、ベクター、およびAPC、ポリヌクレオチド、腫瘍溶解性ウイルスまたはそれらの任意の組合せである、請求項93に記載の方法。
- 前記少なくとも1つのさらなる治療剤が、抗PD−1剤および抗PD−L1剤、抗CTLA−4剤、または抗CD40剤である、請求項94に記載の方法。
- 前記さらなる治療剤が、前記変異型RASペプチド配列を投与するステップの前に、それと同時に、またはその後に投与される、請求項94または95に記載の方法。
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US11421015B2 (en) | 2020-12-07 | 2022-08-23 | Think Therapeutics, Inc. | Method of compact peptide vaccines using residue optimization |
US11058751B1 (en) | 2020-11-20 | 2021-07-13 | Think Therapeutics, Inc. | Compositions for optimized RAS peptide vaccines |
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US11464842B1 (en) | 2021-04-28 | 2022-10-11 | Think Therapeutics, Inc. | Compositions and method for optimized peptide vaccines using residue optimization |
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