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- 125000003275 alpha amino acid group Chemical group 0.000 claims description 72
- 102000037240 fusion proteins Human genes 0.000 claims description 68
- 108020001507 fusion proteins Proteins 0.000 claims description 68
- 210000004027 cells Anatomy 0.000 claims description 39
- 102100004476 SIRPA Human genes 0.000 claims description 32
- 101710024246 SIRPA Proteins 0.000 claims description 32
- 229920001184 polypeptide Polymers 0.000 claims description 30
- 150000001413 amino acids Chemical class 0.000 claims description 24
- 102000002627 4-1BB Ligand Human genes 0.000 claims description 22
- 108010082808 4-1BB Ligand Proteins 0.000 claims description 22
- 102100013078 CD47 Human genes 0.000 claims description 16
- 101700033237 CD47 Proteins 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 14
- 229920000023 polynucleotide Polymers 0.000 claims description 14
- 239000002157 polynucleotide Substances 0.000 claims description 14
- 230000000875 corresponding Effects 0.000 claims description 12
- 210000002865 immune cell Anatomy 0.000 claims description 11
- 230000003213 activating Effects 0.000 claims description 7
- 230000004913 activation Effects 0.000 claims description 6
- 125000000539 amino acid group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 230000035772 mutation Effects 0.000 claims description 4
- 206010057249 Phagocytosis Diseases 0.000 claims description 3
- 230000002708 enhancing Effects 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 210000001539 phagocyte Anatomy 0.000 claims description 3
- 230000008782 phagocytosis Effects 0.000 claims description 3
- 230000019491 signal transduction Effects 0.000 claims description 3
- 102200028872 MMP7 V92A Human genes 0.000 claims description 2
- 108090001123 antibodies Proteins 0.000 description 7
- 102000004965 antibodies Human genes 0.000 description 7
- 108020004707 nucleic acids Proteins 0.000 description 7
- 150000007523 nucleic acids Chemical class 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000002147 killing Effects 0.000 description 4
- 230000001404 mediated Effects 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 230000000903 blocking Effects 0.000 description 3
- 102100007290 CD274 Human genes 0.000 description 2
- 101710012053 CD274 Proteins 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 230000001506 immunosuppresive Effects 0.000 description 2
- 230000036961 partial Effects 0.000 description 2
- 230000001717 pathogenic Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 108010090838 Alemtuzumab Proteins 0.000 description 1
- 108010022830 Cetuximab Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010073071 Hepatocellular carcinoma Diseases 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N Lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N Pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 108010001645 Rituximab Proteins 0.000 description 1
- 229960003433 Thalidomide Drugs 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N Thalidomide Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000003463 hyperproliferative Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 210000004962 mammalian cells Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
Description
続いて、いくつかのＳＩＲＰα－４－１ＢＢＬバリアントを設計した。それらの選択の根拠及びそれらの３Ｄモデルを含む配列を、以下の表４並びに図４～図６、図３７Ａ及び図３７Ｂに示す。
Subsequently, several SIRPα-4-1BBL variants were designed. The rationale for their selection and the sequences containing their 3D models are shown in Table 4 below and FIGS. 4-6, 37A and 37B .
結果…膜におけるＣＤ４７の高発現は、ＣＨＯ－Ｋ１－ＣＤ４７過剰発現細胞、ＳＵＤＨＬ４細胞、及びＨＴ１０１８細胞では観察されたが、ＣＨＯ－Ｋ１細胞では観察されなかった（図１９Ａ～図１９Ｂ及び図２０）。ＣＨＯ－Ｋ１－ＣＤ４７上及びＤＳＰ１０７＿Ｖ２（配列番号１３）上のＣＤ４７に結合した、全ての被験融合タンパク質は、ＳＵＤＨＬ４細胞に結合し、用量依存的に４－１ＢＢを過剰発現するＨＴ１０８０細胞上の４－１ＢＢ及びＣＤ４７に結合した（図１０、図２１Ａ～図２１Ｂ、及び図２２のＡ～Ｆ）。前記結果は、ビオチン化ＤＳＰ１０７＿Ｖ２のＨＴ１０８０ ４－１ＢＢ ＯＸ細胞への総結合が、ＨＴ１０８０親細胞への結合と比べて高かったことを示している（図２２のＡ～Ｆ）。さらに、ＨＴ１０８０（ＷＴ）細胞への結合は、特異的ブロッキング抗体によるＣＤ４７遮断後に完全に無効となり、ＨＴ１０８０ ４－１ＢＢ ＯＸ細胞への結合の減少はごく部分的であった。同様に、抗４－１ＢＢ抗体によって誘導されたＨＴ１０８０ ４－１ＢＢ ＯＸ細胞へのブロッキングもごく部分的であった。両抗体を使用して、ＣＤ４７と４－１ＢＢの両方の対応物を二重遮断（ｄｕａｌ－ｂｌｏｃｋｉｎｇ）すると、ＤＳＰ１０７＿Ｖ２結合の完全な抑止が達成された（図２２のＡ～Ｆ）。タンパク質はＣＨＯ－Ｋ１－ＷＴ細胞には結合しなかった（図２１Ａ及び図２１Ｂ）。アイソタイプ対照は最高濃度のタンパク質とインキュベートしてもバックグラウンド染色を示さなかった。
Results ... High expression of CD47 in the membrane was observed in CHO-K1-CD47 overexpressing cells, SUDHL4 cells, and HT1018 cells, but not in CHO-K1 cells (FIGS. 19A-19B and 20). .. All test fusion proteins bound to CD47 on CHO-K1-CD47 and DSP107_V2 (SEQ ID NO: 13) bound to SUDHL4 cells and dose-dependently overexpressed 4-1BB 4-on HT1080 cells. It bound to 1BB and CD47 (FIGS. 10, 21A - 21B, and 22A -F ). The above results show that the total binding of biotinylated DSP107_V2 to HT1080 4-1BB OX cells was higher than that to HT1080 parent cells (FIGS. 22A to F ). Furthermore, binding to HT1080 (WT) cells was completely ineffective after CD47 blocking with a specific blocking antibody, and reduced binding to HT1080 4-1BB OX cells was only partial. Similarly, blocking to HT1080 4-1BB OX cells induced by anti-4-1BB antibody was also only partial. Double-blocking of both CD47 and 4-1BB counterparts using both antibodies achieved complete inhibition of DSP107_V2 binding (FIGS. 22A -F ). The protein did not bind to CHO-K1-WT cells (FIGS. 21A and 21B). Isotype controls showed no background staining when incubated with the highest concentrations of protein.
結果…ＤＳＰ１０７＿Ｖ２は、Ｔ細胞によって媒介される、肝細胞がん、卵巣がん、及び中皮腫のがん細胞株の殺滅を促進した（図３０Ａ～図３０Ｃ及び図３１Ａ～図３１Ｂ）。
Results ... DSP107_V2 promoted the killing of T cell-mediated cancer cell lines of hepatocellular carcinoma, ovarian cancer, and mesothelioma (FIGS. 30A - 30C and 31A-31B). ..
さらに、本出願の優先権書類は、その全体が参照により本明細書に援用される。
本発明の例示的な態様を以下に記載する。
＜１＞
ＳＩＲＰαアミノ酸配列及び４－１ＢＢＬアミノ酸配列を含むＳＩＲＰα－４－１ＢＢＬ融合タンパク質であって、
前記ＳＩＲＰαアミノ酸配列は、配列番号２４及び２６からなる群から選択されるアミノ酸配列と少なくとも９５％の同一性を有する１００～１１９アミノ酸長であり、及び／又は
前記４－１ＢＢＬアミノ酸配列は：
（ａ）配列番号２２、２３、２７、及び２８からなる群から選択されるアミノ酸配列と少なくとも９５％の同一性を有する１８５～２０２アミノ酸長であるか；配列番号７４及び７６からなる群から選択されるアミノ酸配列と少なくとも８０％の同一性を有する１７０～１９７アミノ酸長であり、ただし配列番号３に対応するアミノ酸セグメントＧ１９８－Ｅ２０５を含まないか；配列番号７２と少なくとも８０％の同一性を有する１７０～１８２アミノ酸長であり、ただし配列番号３に対応するアミノ酸セグメントＡ１－Ｅ２３を含まないか；又は配列番号７０と少なくとも８０％の同一性を有する１８４アミノ酸長であり、及び／又は
（ｂ）４－１ＢＢＬアミノ酸配列の３回の反復を含み、
前記融合タンパク質は、
（ｉ）ＣＤ４７及び４－１ＢＢに結合すること、
（ｉｉ）前記４－１ＢＢを発現する細胞において前記４－１ＢＢシグナル伝達経路を活性化すること、
（ｉｉｉ）前記４－１ＢＢを発現する免疫細胞を共刺激すること、及び／又は
（ｉｖ）前記ＳＩＲＰα－４－１ＢＢＬ融合タンパク質の非存在下と比較して、食細胞による前記ＣＤ４７を発現する病的細胞に対する食作用を増強すること、
の少なくとも１つが可能である、
ＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜２＞
ＳＩＲＰαアミノ酸配列及び４－１ＢＢＬアミノ酸配列を含むＳＩＲＰα－４－１ＢＢＬ融合タンパク質であって、
前記ＳＩＲＰαアミノ酸配列は、配列番号２４及び２６からなる群から選択されるアミノ酸配列と少なくとも９５％の同一性を有する１００～１１９アミノ酸長であり、及び／又は
前記４－１ＢＢＬアミノ酸配列は、配列番号２２、２３、２７、及び２８からなる群から選択されるアミノ酸配列と少なくとも９５％の同一性を有する１８５～２０２アミノ酸長であり、並びに
前記融合タンパク質は、
（ｉ）ＣＤ４７及び４－１ＢＢに結合すること、
（ｉｉ）前記４－１ＢＢを発現する細胞において前記４－１ＢＢシグナル伝達経路を活性化すること、
（ｉｉｉ）前記４－１ＢＢを発現する免疫細胞を共刺激すること、及び／又は
（ｉｖ）前記ＳＩＲＰα－４－１ＢＢＬ融合タンパク質の非存在下と比較して、食細胞による前記ＣＤ４７を発現する病的細胞に対する食作用を増強すること、
の少なくとも１つが可能である、
ＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜３＞
ＳＩＲＰαアミノ酸配列を含む単離ポリペプチドであって、
前記ＳＩＲＰαアミノ酸配列は、配列番号２４及び２６からなる群から選択されるアミノ酸配列と少なくとも９５％の同一性を有する１００～１１９アミノ酸長であり、前記ポリペプチドはＣＤ４７に結合可能である、ＳＩＲＰαアミノ酸配列を含む単離ポリペプチド。
＜４＞
前記ＳＩＲＰαアミノ酸配列は少なくとも１１５アミノ酸長である、＜１＞若しくは＜２＞に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質又は＜３＞に記載の単離ポリペプチド。
＜５＞
前記ＳＩＲＰαアミノ酸配列は１１６アミノ酸長である、＜１＞～＜３＞及び＜４＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質又は単離ポリペプチド。
＜６＞
前記ＳＩＲＰαアミノ酸配列は、配列番号２に対応するＬ４、Ａ２７、Ｅ４７、及びＶ９２からなる群から選択されるアミノ酸残基での変異を含む、＜３＞及び＜４＞～＜５＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質又は単離ポリペプチド。
＜７＞
前記変異は、配列番号２に対応するＬ４Ｉ、Ａ２７Ｉ、Ｅ４７Ｖ、及びＶ９２Ｉからなる群から選択される、＜６＞に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質又は単離ポリペプチド。
＜８＞
前記ＳＩＲＰαアミノ酸配列は、配列番号２に対応するアミノ酸残基Ｋ１１７－Ｙ３４３のいずれも含まない、＜１＞～＜３＞及び＜４＞～＜７＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質又は単離ポリペプチド。
＜９＞
前記ＳＩＲＰαアミノ酸配列は、配列番号２４又は２６を含む、＜１＞～＜３＞、＜４＞、及び＜８＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質又は単離ポリペプチド。
＜１０＞
前記ＳＩＲＰαアミノ酸配列は、配列番号２４又は２６からなる、＜１＞～＜３＞、＜４＞、＜５＞、及び＜８＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質又は単離ポリペプチド。
＜１１＞
前記４－１ＢＢＬアミノ酸配列は、配列番号３に対応するアミノ酸残基Ａ１－Ｖ６及びＡ１－Ｇ１４のいずれも含まない、＜１＞、＜２＞、及び＜４＞～＜１０＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜１２＞
前記４－１ＢＢＬアミノ酸配列は、配列番号２２、２３、２７、又は２８を含む、＜１＞、＜２＞、＜４＞～＜１０＞、及び＜１１＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜１３＞
前記４－１ＢＢＬアミノ酸配列は、配列番号２２、２３、２７、又は２８からなる、＜１＞、＜２＞、＜４＞～＜１０＞及び＜１１＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜１４＞
（ｉ）前記ＳＩＲＰαアミノ酸配列は、配列番号２又は２５に記載の通りであり、前記４－１ＢＢＬアミノ酸配列は、配列番号２２、２３、２７、又は２８に記載の通りであるか、又は
（ｉｉ）前記ＳＩＲＰαアミノ酸配列は、配列番号２４又は２６に記載の通りであり、前記４－１ＢＢＬアミノ酸配列は、配列番号３、２２、２３、２７、又は２８に記載の通りである、
＜１＞及び＜２＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜１５＞
（ｉ）前記ＳＩＲＰαアミノ酸配列は配列番号２に記載の通りであり、前記４－１ＢＢＬアミノ酸配列は配列番号２２又は２３に記載の通りであるか、又は
（ｉｉ）前記ＳＩＲＰαアミノ酸配列は配列番号２４に記載の通りであり、前記４－１ＢＢＬアミノ酸配列は配列番号２２に記載の通りである、
＜１＞及び＜２＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜１６＞
前記ＳＩＲＰα－４－１ＢＢＬ融合タンパク質は、前記ＳＩＲＰαと前記４－１ＢＢＬとの間にリンカーを含む、＜１＞、＜２＞、及び＜４＞～＜１５＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜１７＞
前記４－１ＢＢＬアミノ酸配列の３回の反復のそれぞれの間にリンカーを含む、＜１＞及び＜４＞～＜１５＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜１８＞
前記リンカーは単一アミノ酸リンカーである、＜１６＞及び＜１７＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜１９＞
前記リンカーはグリシンである、＜１８＞に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜２０＞
可溶性である、＜１＞～＜１９＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質又は単離ポリペプチド。
＜２１＞
前記融合タンパク質の産生収量は、同じ産生条件下での配列番号５の産生収量よりも１．５倍以上多く、
前記産生条件は、哺乳動物細胞での発現、並びに３２～３７℃及び５～１０％ＣＯ２で５～１３日間の培養を含む、＜１＞、＜２＞、及び＜４＞～＜２０＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜２２＞
前記ＳＩＲＰα－４－１ＢＢＬ融合タンパク質のアミノ酸配列は、配列番号１１、１３、１５、１６、１８～２１、及び４５～４９からなる群から選択されるアミノ酸配列と少なくとも９５％の同一性を有するアミノ酸配列を含む、＜１＞、＜２＞、及び＜１６＞～＜２１＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜２３＞
前記ＳＩＲＰα－４－１ＢＢＬ融合タンパク質のアミノ酸配列は、配列番号１１、１３、及び１６からなる群から選択されるアミノ酸配列と少なくとも９５％の同一性を有するアミノ酸配列を含む、＜１＞及び＜１６＞～＜２１＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜２４＞
前記ＳＩＲＰα－４－１ＢＢＬ融合タンパク質のアミノ酸配列は、配列番号１１、１３、１５、１６、１８～２１、及び４５～４９からなる群から選択されるアミノ酸配列を含む、＜１＞及び＜１６＞～＜２１＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜２５＞
前記ＳＩＲＰα－４－１ＢＢＬ融合タンパク質のアミノ酸配列は、配列番号１１、１３、及び１６からなる群から選択されるアミノ酸配列を含む、＜１＞及び＜１６＞～＜２１＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜２６＞
前記ＳＩＲＰα－４－１ＢＢＬ融合タンパク質のアミノ酸配列は、配列番号１１、１３、１５、１６、１８～２１、及び４５～４９からなる群から選択されるアミノ酸配列からなる、＜１＞及び＜１６＞～＜２１＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜２７＞
前記ＳＩＲＰα－４－１ＢＢＬ融合タンパク質のアミノ酸配列は、配列番号１１、１３、及び１６からなる群から選択されるアミノ酸配列からなる、＜１＞及び＜１６＞～＜２１＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。
＜２８＞
＜１＞～＜２７＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質又はポリペプチドをコードするポリヌクレオチド。
＜２９＞
＜２８＞に記載のポリヌクレオチドと、
宿主細胞における前記ポリヌクレオチドの発現を指示するための調節エレメントと、
を含む核酸構築物。
＜３０＞
＜１＞～＜２７＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質若しくはポリペプチド又は＜２８＞及び＜２９＞のいずれか一項に記載のポリヌクレオチド若しくは核酸構築物を含む宿主細胞。
＜３１＞
＜２８＞及び＜２９＞のいずれか一項に記載のポリヌクレオチド又は核酸構築物を宿主細胞において発現させることを含む、ＳＩＲＰα－４－１ＢＢＬ融合タンパク質又はポリペプチドを製造する方法。
＜３２＞
前記融合タンパク質又は前記ポリペプチドを単離することを含む、＜３１＞に記載の方法。
＜３３＞
＜１＞～＜２７＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質若しくは単離ポリペプチド、＜２８＞及び＜２９＞のいずれか一項に記載のポリヌクレオチド若しくは核酸構築物、又は＜３０＞に記載の宿主細胞を、処置を必要とする対象に投与することを含む、免疫細胞の活性化から恩恵を受け得る疾患を処置する方法。
＜３４＞
前記対象に、前記疾患を処置するための治療薬を投与することをさらに含む、＜３３＞に記載の方法。
＜３５＞
免疫細胞の活性化から恩恵を受け得る疾患の処置に使用するための、＜１＞～＜２７＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質若しくは単離ポリペプチド、＜２８＞及び＜２９＞のいずれか一項に記載のポリヌクレオチド若しくは核酸構築物、又は＜３０＞に記載の宿主細胞。
＜３６＞
前記疾患を処置するための治療薬をさらに含む、＜３５＞に記載の使用のための組成物。
＜３７＞
免疫細胞の活性化から恩恵を受け得る疾患を処置するための治療薬、及び＜１＞～＜２７＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質若しくは単離ポリペプチド、＜２８＞及び＜２９＞のいずれか一項に記載のポリヌクレオチド若しくは核酸構築物、又は＜３０＞に記載の宿主細胞を包装する包装材料を含む製品。
＜３８＞
前記疾患の細胞がＣＤ４７を発現する、＜３３＞及び＜３４＞のいずれか一項に記載の方法、＜３５＞及び＜３６＞のいずれか一項に記載の使用のための組成物、又は＜３７＞に記載の製品。
＜３９＞
前記疾患が過剰増殖性疾患を含む、＜３３＞～＜３８＞のいずれか一項に記載の方法、使用のための組成物、又は製品。
＜４０＞
前記過剰増殖性疾患ががんを含む、＜３９＞に記載の方法、使用のための組成物、又は製品。
＜４１＞
前記疾患が、免疫抑制、薬物誘発性免疫抑制、又は感染症に関連する疾患を含む、＜３３＞～＜３８＞のいずれか一項に記載の方法、使用のための組成物、又は製品。
＜４２＞
＜１＞～＜２７＞のいずれか一項に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質若しくは単離ポリペプチド、＜２８＞及び＜２９＞のいずれか一項に記載のポリヌクレオチド若しくは核酸構築物、又は＜３０＞に記載の宿主細胞の存在下において、インビトロで免疫細胞を活性化することを含む、免疫細胞を活性化する方法。
＜４３＞
前記活性化が、ＣＤ４７又は外因性ＣＤ４７を発現する細胞の存在下である、＜４２＞に記載の方法。
＜４４＞
前記活性化が抗がん剤の存在下である、＜４２＞及び＜４３＞のいずれか一項に記載の方法。
＜４５＞
前記疾患を処置するための前記治療薬又は前記抗がん剤が抗体を含む、＜３４＞、＜３６＞、＜３７＞～＜４１＞及び＜４４＞のいずれか一項に記載の方法、使用のための組成物、又は製品。
＜４６＞
前記抗体は、リツキシマブ、セツキシマブ、及びアレムツズマブからなる群から選択される、＜４５＞に記載の方法、使用のための組成物、又は製品。
＜４７＞
前記疾患を処置するための前記治療薬又は前記抗がん剤は、ＩＭｉＤ（例えば、サリドマイド、レナリドミド、ポマリドミド）を含む、＜３４＞、＜３６＞、＜３７＞～＜４１＞、及び＜４４＞のいずれか一項に記載の方法、使用のための組成物、又は製品。
In addition, the priority documents of this application are incorporated herein by reference in their entirety.
Exemplary embodiments of the present invention are described below.
<1>
A SIRPα-4-1BBL fusion protein comprising a SIRPα amino acid sequence and a 4-1BBL amino acid sequence.
The SIRPα amino acid sequence is 100-119 amino acids long and / or has at least 95% identity with the amino acid sequence selected from the group consisting of SEQ ID NOs: 24 and 26.
The 4-1BBL amino acid sequence is:
(A) Is it 185-202 amino acid length with at least 95% identity with the amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 23, 27, and 28; selected from the group consisting of SEQ ID NOs: 74 and 76? Is 170-197 amino acids long with at least 80% identity with the amino acid sequence to be, but does not contain the amino acid segment G198-E205 corresponding to SEQ ID NO: 3; has at least 80% identity with SEQ ID NO: 72? It is 170-182 amino acids long, but does not contain the amino acid segments A1-E23 corresponding to SEQ ID NO: 3; or is 184 amino acids long and / or has at least 80% identity with SEQ ID NO: 70.
(B) Containing three iterations of the 4-1BBL amino acid sequence.
The fusion protein is
(I) binding to CD47 and 4-1BB,
(Ii) Activating the 4-1BB signaling pathway in cells expressing the 4-1BB.
(Iii) Co-stimulating immune cells expressing the 4-1BB and / or
(Iv) enhancing phagocytosis of phagocytic cells on pathogenic cells expressing the CD47 as compared to the absence of the SIRPα-4-1BBL fusion protein.
At least one of is possible,
SIRPα-4-1BBL fusion protein.
<2>
A SIRPα-4-1BBL fusion protein comprising a SIRPα amino acid sequence and a 4-1BBL amino acid sequence.
The SIRPα amino acid sequence is 100-119 amino acids long and / or has at least 95% identity with the amino acid sequence selected from the group consisting of SEQ ID NOs: 24 and 26.
The 4-1BBL amino acid sequence is 185 to 202 amino acids long and has at least 95% identity with the amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 23, 27, and 28, and
The fusion protein is
(I) binding to CD47 and 4-1BB,
(Ii) Activating the 4-1BB signaling pathway in cells expressing the 4-1BB.
(Iii) Co-stimulating immune cells expressing the 4-1BB and / or
(Iv) enhancing phagocytosis of phagocytic cells on pathogenic cells expressing the CD47 as compared to the absence of the SIRPα-4-1BBL fusion protein.
At least one of is possible,
SIRPα-4-1BBL fusion protein.
<3>
An isolated polypeptide containing the SIRPα amino acid sequence,
The SIRPα amino acid sequence has a length of 100 to 119 amino acids having at least 95% identity with the amino acid sequence selected from the group consisting of SEQ ID NOs: 24 and 26, and the polypeptide is capable of binding to CD47, SIRPα amino acid. An isolated polypeptide containing a sequence.
<4>
The SIRPα-4-1BBL fusion protein according to <1> or <2> or the isolated polypeptide according to <3>, wherein the SIRPα amino acid sequence is at least 115 amino acids long.
<5>
The SIRPα-4-1BBL fusion protein or isolated polypeptide according to any one of <1> to <3> and <4>, wherein the SIRPα amino acid sequence is 116 amino acids long.
<6>
The SIRPα amino acid sequence is any one of <3> and <4> to <5>, which comprises a mutation at an amino acid residue selected from the group consisting of L4, A27, E47, and V92 corresponding to SEQ ID NO: 2. The SIRPα-4-1BBL fusion protein or isolated polypeptide according to paragraph 1.
<7>
The SIRPα-4-1BBL fusion protein or isolated polypeptide according to <6>, wherein the mutation is selected from the group consisting of L4I, A27I, E47V, and V92I corresponding to SEQ ID NO: 2.
<8>
SIRPα-4 according to any one of <1> to <3> and <4> to <7>, wherein the SIRPα amino acid sequence does not contain any of the amino acid residues K117-Y343 corresponding to SEQ ID NO: 2. -1BBL fusion protein or isolated polypeptide.
<9>
The SIRPα-4-1BBL fusion protein or isolated polypeptide according to any one of <1> to <3>, <4>, and <8>, wherein the SIRPα amino acid sequence comprises SEQ ID NO: 24 or 26. ..
<10>
The SIRPα-4-1BBL fusion protein according to any one of <1> to <3>, <4>, <5>, and <8>, wherein the SIRPα amino acid sequence comprises SEQ ID NO: 24 or 26. Isolated polypeptide.
<11>
The 4-1BBL amino acid sequence does not contain any of the amino acid residues A1-V6 and A1-G14 corresponding to SEQ ID NO: 3, any one of <1>, <2>, and <4> to <10>. SIRPα-4-1BBL fusion protein according to the section.
<12>
The SIRPα according to any one of <1>, <2>, <4> to <10>, and <11>, wherein the 4-1BBL amino acid sequence comprises SEQ ID NO: 22, 23, 27, or 28. 4-1 BBL fusion protein.
<13>
The SIRPα- 4-1BBL fusion protein.
<14>
(I) The SIRPα amino acid sequence is as set forth in SEQ ID NO: 2 or 25, and the 4-1BBL amino acid sequence is as set forth in SEQ ID NO: 22, 23, 27, or 28, or
(Ii) The SIRPα amino acid sequence is as set forth in SEQ ID NO: 24 or 26, and the 4-1BBL amino acid sequence is as set forth in SEQ ID NO: 3, 22, 23, 27, or 28.
The SIRPα-4-1BBL fusion protein according to any one of <1> and <2>.
<15>
(I) The SIRPα amino acid sequence is as set forth in SEQ ID NO: 2, and the 4-1BBL amino acid sequence is as set forth in SEQ ID NO: 22 or 23, or
(Ii) The SIRPα amino acid sequence is as set forth in SEQ ID NO: 24, and the 4-1BBL amino acid sequence is as set forth in SEQ ID NO: 22.
The SIRPα-4-1BBL fusion protein according to any one of <1> and <2>.
<16>
The SIRPα according to any one of <1>, <2>, and <4> to <15>, wherein the SIRPα-4-1BBL fusion protein contains a linker between the SIRPα and the 4-1BBL. 4-1 BBL fusion protein.
<17>
The SIRPα-4-1BBL fusion protein according to any one of <1> and <4> to <15>, which comprises a linker between each of the three iterations of the 4-1BBL amino acid sequence.
<18>
The SIRPα-4-1BBL fusion protein according to any one of <16> and <17>, wherein the linker is a single amino acid linker.
<19>
The SIRPα-4-1BBL fusion protein according to <18>, wherein the linker is glycine.
<20>
The SIRPα-4-1BBL fusion protein or isolated polypeptide according to any one of <1> to <19>, which is soluble.
<21>
The production yield of the fusion protein was 1.5 times or more higher than the production yield of SEQ ID NO: 5 under the same production conditions.
The production conditions of <1>, <2>, and <4> to <20> include expression in mammalian cells and culture at 32 to 37 ° C. and 5 to 10% CO2 for 5 to 13 days. The SIRPα-4-1BBL fusion protein according to any one of the above.
<22>
The amino acid sequence of the SIRPα-4-1BBL fusion protein has at least 95% identity with the amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 13, 15, 16, 18-21, and 45-49. The SIRPα-4-1BBL fusion protein according to any one of <1>, <2>, and <16> to <21>, which comprises a sequence.
<23>
The amino acid sequence of the SIRPα-4-1BBL fusion protein comprises an amino acid sequence having at least 95% identity with the amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 13, and 16. <1> and <16. > The SIRPα-4-1BBL fusion protein according to any one of <21>.
<24>
The amino acid sequence of the SIRPα-4-1BBL fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 13, 15, 16, 18-21, and 45-49, <1> and <16>. The SIRPα-4-1BBL fusion protein according to any one of <21>.
<25>
The amino acid sequence of the SIRPα-4-1BBL fusion protein includes the amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 13, and 16, according to any one of <1> and <16> to <21>. The SIRPα-4-1BBL fusion protein described.
<26>
The amino acid sequence of the SIRPα-4-1BBL fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 13, 15, 16, 18-21, and 45-49, <1> and <16>. The SIRPα-4-1BBL fusion protein according to any one of <21>.
<27>
The amino acid sequence of the SIRPα-4-1BBL fusion protein comprises any one of <1> and <16> to <21>, which comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 13, and 16. The SIRPα-4-1BBL fusion protein described.
<28>
The polynucleotide encoding the SIRPα-4-1BBL fusion protein or polypeptide according to any one of <1> to <27>.
<29>
The polynucleotide according to <28> and
A regulatory element for directing the expression of the polynucleotide in a host cell,
Nucleic acid construct containing.
<30>
Host cell containing the SIRPα-4-1BBL fusion protein or polypeptide according to any one of <1> to <27> or the polynucleotide or nucleic acid construct according to any one of <28> and <29>. ..
<31>
A method for producing a SIRPα-4-1BBL fusion protein or polypeptide, which comprises expressing the polynucleotide or nucleic acid construct according to any one of <28> and <29> in a host cell.
<32>
31. The method of <31>, comprising isolating the fusion protein or the polypeptide.
<33>
The SIRPα-4-1BBL fusion protein or isolated polypeptide according to any one of <1> to <27>, the polynucleotide or nucleic acid construct according to any one of <28> and <29>, or A method of treating a disease that may benefit from activation of immune cells, comprising administering the host cell according to <30> to a subject in need of treatment.
<34>
33. The method of <33>, further comprising administering to the subject a therapeutic agent for treating the disease.
<35>
SIRPα-4-1BBL fusion protein or isolated polypeptide according to any one of <1> to <27>, <28> for use in the treatment of diseases that may benefit from activation of immune cells. And the polynucleotide or nucleic acid construct according to any one of <29>, or the host cell according to <30>.
<36>
35. The composition for use according to <35>, further comprising a therapeutic agent for treating the disease.
<37>
A therapeutic agent for treating a disease that may benefit from activation of immune cells, and the SIRPα-4-1BBL fusion protein or isolated polypeptide according to any one of <1> to <27>, <28. A product comprising the polynucleotide or nucleic acid construct according to any one of <29> and the packaging material for packaging the host cell according to <30>.
<38>
The method according to any one of <33> and <34>, the composition for use according to any one of <35> and <36>, or the composition for use according to any one of <35> and <36>, wherein the diseased cell expresses CD47. The product described in <37>.
<39>
The method, composition or product for use according to any one of <33> to <38>, wherein the disease comprises an overproliferative disease.
<40>
39. The method, composition or product for use, wherein the hyperproliferative disorder comprises cancer.
<41>
The method, composition or product for use according to any one of <33> to <38>, wherein the disease comprises a disease associated with immunosuppression, drug-induced immunosuppression, or an infectious disease.
<42>
The SIRPα-4-1BBL fusion protein or isolated polypeptide according to any one of <1> to <27>, the polynucleotide or nucleic acid construct according to any one of <28> and <29>, or <30> A method for activating an immune cell, which comprises activating the immune cell in vitro in the presence of the host cell.
<43>
42. The method of <42>, wherein the activation is in the presence of cells expressing CD47 or exogenous CD47.
<44>
The method according to any one of <42> and <43>, wherein the activation is in the presence of an anticancer agent.
<45>
The method according to any one of <34>, <36>, <37> to <41> and <44>, wherein the therapeutic agent or the anticancer agent for treating the disease contains an antibody. A composition or product for use.
<46>
The method, composition or product for use, wherein the antibody is selected from the group consisting of rituximab, cetuximab, and alemtuzumab.
<47>
The therapeutic or anti-cancer agent for treating the disease comprises IMiD (eg, thalidomide, lenalidomide, pomalidomide), <34>, <36>, <37> to <41>, and <44. > The method, composition or product for use according to any one of the paragraphs.
Claims (16)
前記ＳＩＲＰαアミノ酸配列は、配列番号２４及び２６からなる群から選択されるアミノ酸配列と少なくとも９５％の同一性を有する１００～１１９アミノ酸長であり、及び／又は
前記４－１ＢＢＬアミノ酸配列は：
（ａ）配列番号２２、２３、２７、及び２８からなる群から選択されるアミノ酸配列と少なくとも９５％の同一性を有する１８５～２０２アミノ酸長であるか；配列番号７４及び７６からなる群から選択されるアミノ酸配列と少なくとも８０％の同一性を有する１７０～１９７アミノ酸長であり、ただし配列番号３に対応するアミノ酸セグメントＧ１９８－Ｅ２０５を含まないか；配列番号７２と少なくとも８０％の同一性を有する１７０～１８２アミノ酸長であり、ただし配列番号３に対応するアミノ酸セグメントＡ１－Ｅ２３を含まないか；又は配列番号７０と少なくとも８０％の同一性を有する１８４アミノ酸長であり、及び／又は
（ｂ）４－１ＢＢＬアミノ酸配列の３回の反復を含み、
前記融合タンパク質は、
（ｉ）ＣＤ４７及び４－１ＢＢに結合すること、
（ｉｉ）前記４－１ＢＢを発現する細胞において前記４－１ＢＢシグナル伝達経路を活性化すること、
（ｉｉｉ）前記４－１ＢＢを発現する免疫細胞を共刺激すること、及び／又は
（ｉｖ）前記ＳＩＲＰα－４－１ＢＢＬ融合タンパク質の非存在下と比較して、食細胞による前記ＣＤ４７を発現する病的細胞に対する食作用を増強すること、
の少なくとも１つが可能である、
ＳＩＲＰα－４－１ＢＢＬ融合タンパク質。 A SIRPα-4-1BBL fusion protein comprising a SIRPα amino acid sequence and a 4-1BBL amino acid sequence.
The SIRPα amino acid sequence is 100-119 amino acids long with at least 95% identity with the amino acid sequence selected from the group consisting of SEQ ID NOs: 24 and 26, and / or the 4-1BBL amino acid sequence is:
(A) Is it 185-202 amino acid length with at least 95% identity with the amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 23, 27, and 28; selected from the group consisting of SEQ ID NOs: 74 and 76? Is 170-197 amino acid length with at least 80% identity with the amino acid sequence to be, but does not contain the amino acid segment G198-E205 corresponding to SEQ ID NO: 3; has at least 80% identity with SEQ ID NO: 72? It is 170-182 amino acids long, but does not contain the amino acid segments A1-E23 corresponding to SEQ ID NO: 3; or is 184 amino acids long with at least 80% identity with SEQ ID NO: 70 and / or (b). Includes 3 iterations of the 4-1BBL amino acid sequence, including 3 iterations
The fusion protein is
(I) binding to CD47 and 4-1BB,
(Ii) Activating the 4-1BB signaling pathway in cells expressing the 4-1BB.
(Iii) Co-stimulating immune cells expressing the 4-1BB and / or (iv) Diseases expressing the CD47 by phagocytic cells as compared to in the absence of the SIRPα-4-1BBL fusion protein. Enhancing phagocytosis on target cells,
At least one of is possible,
SIRPα-4-1BBL fusion protein.
前記ＳＩＲＰαアミノ酸配列は、配列番号２４及び２６からなる群から選択されるアミノ酸配列と少なくとも９５％の同一性を有する１００～１１９アミノ酸長であり、前記ポリペプチドはＣＤ４７に結合可能である、ＳＩＲＰαアミノ酸配列を含む単離ポリペプチド。 An isolated polypeptide containing the SIRPα amino acid sequence,
The SIRPα amino acid sequence has a length of 100 to 119 amino acids having at least 95% identity with the amino acid sequence selected from the group consisting of SEQ ID NOs: 24 and 26, and the polypeptide is capable of binding to CD47, SIRPα amino acid. An isolated polypeptide containing a sequence.
（ｉｉ）前記ＳＩＲＰαアミノ酸配列は、配列番号２４又は２６に記載の通りであり、前記４－１ＢＢＬアミノ酸配列は、配列番号３、２２、２３、２７、又は２８に記載の通りである、
請求項１に記載のＳＩＲＰα－４－１ＢＢＬ融合タンパク質。 (I) The SIRPα amino acid sequence is as set forth in SEQ ID NO: 2 or 25, and the 4-1BBL amino acid sequence is as set forth in SEQ ID NO: 22, 23, 27, or 28, or (ii). The SIRPα amino acid sequence is as set forth in SEQ ID NO: 24 or 26, and the 4-1BBL amino acid sequence is as set forth in SEQ ID NO: 3, 22, 23, 27, or 28.
The SIRPα-4-1BBL fusion protein according to claim 1 .
In the presence of the SIRPα-4-1BBL fusion protein or isolated polypeptide according to any one of claims 1 to 11 , the polynucleotide according to claim 12, or the host cell according to claim 13 . In, a method of activating an immune cell, comprising activating the immune cell in vitro.
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| US62/696,362 | 2018-07-11 | ||
| PCT/IL2019/050783 WO2020012486A1 (en) | 2018-07-11 | 2019-07-11 | SIRPalpha-4-1BBL VARIANT FUSION PROTEIN AND METHODS OF USE THEREOF |
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