JPWO2021089588A5 - - Google Patents

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JPWO2021089588A5
JPWO2021089588A5 JP2022525630A JP2022525630A JPWO2021089588A5 JP WO2021089588 A5 JPWO2021089588 A5 JP WO2021089588A5 JP 2022525630 A JP2022525630 A JP 2022525630A JP 2022525630 A JP2022525630 A JP 2022525630A JP WO2021089588 A5 JPWO2021089588 A5 JP WO2021089588A5
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fusion protein
cancer
seq
inventions
once
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JP2023502876A (en
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Priority claimed from PCT/EP2020/080892 external-priority patent/WO2021089588A1/en
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本明細書において使用される場合、単数形「1つの(a)」、「1つの(an)」、および「その(the)」は、文脈によって明白に他の意味に定められない限り、複数の指示対象を含む。
[本発明1001]
対象においてHER2+腫瘍を治療する際に使用するための融合タンパク質であって、
該治療が、約2.5mg/kg～約27mg/kgの用量で該融合タンパク質を投与することを含み、
該融合タンパク質が、HER2に特異的な抗体を含み、該HER2に特異的な抗体が、両方の重鎖のC末端において、4-1BBに特異的なリポカリンムテインのN末端に融合されており、
該抗体が、
(i)SEQ ID NO: 40、SEQ ID NO: 41、およびSEQ ID NO: 42に示される3つの重鎖相補性決定領域(CDR)ならびにSEQ ID NO: 43、SEQ ID NO: 44、およびSEQ ID NO: 45に示される3つの軽鎖CDRと;
(ii)SEQ ID NO: 49に示されるアミノ酸配列に対して少なくとも95％の配列同一性を有する重鎖およびSEQ ID NO: 50に示されるアミノ酸配列に対して少なくとも95％の配列同一性を有する軽鎖と
を含み、かつ
該リポカリンムテインが、SEQ ID NO: 22に示されるアミノ酸配列に対して少なくとも95％の配列同一性を有する、
該融合タンパク質。
[本発明1002]
前記治療が以下に関連している、本発明1001の使用のための融合タンパク質:
a 全腫瘍組織中のCD8+T細胞数の少なくとも約1.5倍の増加;
b 腫瘍細胞中のCD8+T細胞数の少なくとも約1.5倍の増加;
c 全腫瘍組織中のCD8+Ki67+T細胞数の少なくとも約1.5倍の増加;
d 腫瘍細胞中のCD8+Ki67+T細胞数の少なくとも約1.5倍の増加;
e 測定領域1mm 2 当たり約500個未満である治療前レベルからのCD8+T細胞の増加であって、該測定領域が、全腫瘍組織、腫瘍間質、もしくは腫瘍細胞の領域である、該増加;
f 標的病変の少なくとも30％の減少;
g 病勢安定;
h 部分奏功;または
i 完全奏効。
[本発明1003]
前記治療が、PD-1系阻害物質を前記対象に投与することを含まない、本発明1001または1002の使用のための融合タンパク質。
[本発明1004]
前記治療が、3週ごとに1回程度、2週ごとに1回程度、または毎週1回程度の間隔で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1005]
前記治療が、毎週1回程度の間隔で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1006]
前記治療が、2週ごとに1回程度の間隔で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1007]
前記治療が、3週ごとに1回程度の間隔で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1008]
前記融合タンパク質をおよそ3週ごとの間隔で投与する場合と比べて、2週ごとに1回程度の間隔で投与された場合に、前記治療が、優れた腫瘍縮小効果に関連している、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1009]
前記優れた腫瘍縮小効果が、より長い奏効期間である、本発明1008の使用のための融合タンパク質。
[本発明1010]
前記治療が、約8mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1011]
前記治療が、3週ごとに1回程度～毎週1回程度の間隔において約2.5mg/kg～約27mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1012]
前記治療が、3週ごとに1回程度～毎週1回程度の間隔において約5mg/kg～約27mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1013]
前記治療が、3週ごとに1回程度～毎週1回程度の間隔において約8mg/kg～約27mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1014]
前記治療が、3週ごとに1回程度～毎週1回程度の間隔において約2.5mg/kg～約12mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1015]
前記治療が、3週ごとに1回程度～毎週1回程度の間隔において約5mg/kg～約12mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1016]
前記治療が、3週ごとに1回程度～毎週1回程度の間隔において約8mg/kg～約18mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1017]
前記治療が、3週ごとに1回程度～3週ごとに1回程度の間隔において約2.5mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1018]
前記治療が、3週ごとに1回程度～3週ごとに1回程度の間隔において約5mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1019]
前記治療が、3週ごとに1回程度～3週ごとに1回程度の間隔において約8mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1020]
前記治療が、3週ごとに1回程度～3週ごとに1回程度の間隔において約12mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1021]
前記治療が、3週ごとに1回程度～3週ごとに1回程度の間隔において約18mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1022]
前記治療が、3週ごとに1回程度の間隔において約2.5mg/kg～約27mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1023]
前記治療が、3週ごとに1回程度の間隔において約2.5mg/kg～約18mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1024]
前記治療が、3週ごとに1回程度の間隔において約5mg/kg～約18mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1025]
前記治療が、3週ごとに1回程度の間隔において約8mg/kg～約18mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1026]
前記治療が、3週ごとに1回程度の間隔において約2.5mg/kg～約12mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1027]
前記治療が、3週ごとに1回程度の間隔において約5mg/kg～約12mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1028]
前記治療が、3週ごとに1回程度の間隔において約8mg/kg～約18mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1029]
前記治療が、3週ごとに1回程度の間隔において約8mg/kg～約27mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1030]
前記治療が、3週ごとに1回程度の間隔において約2.5mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1031]
前記治療が、3週ごとに1回程度の間隔において約5mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1032]
前記治療が、3週ごとに1回程度の間隔において約8mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1033]
前記治療が、3週ごとに1回程度の間隔において約12mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1034]
前記治療が、3週ごとに1回程度の間隔において約18mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1035]
前記治療が、3週ごとに1回程度の間隔において約27mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1036]
前記治療が、2週ごとに1回程度の間隔において約2.5mg/kg～約27mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1037]
前記治療が、2週ごとに1回程度の間隔において約2.5mg/kg～約18mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1038]
前記治療が、2週ごとに1回程度の間隔において約5mg/kg～約18mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1039]
前記治療が、2週ごとに1回程度の間隔において約8mg/kg～約18mg/kgの用量で前記融合タンパク質を投与することを含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1040]
前記治療が、2週ごとに1回程度の間隔の、約2.5mg/kg～約12mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1041]
前記治療が、2週ごとに1回程度の間隔の、約5mg/kg～約12mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1042]
前記治療が、2週ごとに1回程度の間隔の、約8mg/kg～約18mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1043]
前記治療が、2週ごとに1回程度の間隔の、約8mg/kg～約27mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1044]
前記治療が、2週ごとに1回程度の間隔の、約2.5mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1045]
前記治療が、2週ごとに1回程度の間隔の、約5mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1046]
前記治療が、2週ごとに1回程度の間隔の、約8mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1047]
前記治療が、2週ごとに1回程度の間隔の、約12mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1048]
前記治療が、2週ごとに1回程度の間隔の、約18mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1049]
前記治療が、2週ごとに1回程度の間隔の、約27mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1050]
前記治療が、毎週1回程度の間隔の、約2.5mg/kg～約27mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1051]
前記治療が、毎週1回程度の間隔の、約2.5mg/kg～約18mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1052]
前記治療が、毎週1回程度の間隔の、約5mg/kg～約18mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1053]
前記治療が、毎週1回程度の間隔の、約8mg/kg～約18mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1054]
前記治療が、毎週1回程度の間隔の、約2.5mg/kg～約12mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1055]
前記治療が、毎週1回程度の間隔の、約5mg/kg～約12mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1056]
前記治療が、毎週1回程度の間隔の、約8mg/kg～約18mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1057]
前記治療が、毎週1回程度の間隔の、約8mg/kg～約27mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1058]
前記治療が、毎週1回程度の間隔の、約2.5mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1059]
前記治療が、毎週1回程度の間隔の、約5mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1060]
前記治療が、毎週1回程度の間隔の、約8mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1061]
前記治療が、毎週1回程度の間隔の、約12mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1062]
前記治療が、毎週1回程度の間隔の、約18mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1063]
前記治療が、毎週1回程度の間隔の、約27mg/kgの用量での前記融合タンパク質の投与を含む、本発明1001～1003のいずれかの使用のための融合タンパク質。
[本発明1064]
前記治療が用量制限毒性を伴わない、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1065]
注入によって投与される、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1066]
前記対象が、HER2ターゲティング薬物または4-1BB/4-1BBL経路ターゲティング薬物で以前に治療されたことがある、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1067]
前記対象が抗HER2抗体で以前に治療されたことがある、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1068]
前記対象がトラスツズマブで以前に治療されたことがある、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1069]
前記対象がペルツズマブで以前に治療されたことがある、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1070]
前記対象が抗4-1BB抗体で以前に治療されたことがある、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1071]
前記腫瘍が、胃がん、婦人科がん(例えば、ファロピウス管がん、子宮内膜がん、または卵巣がん)、乳がん、肺がん、特に非小細胞肺がん、胆嚢がん、胆管がん、黒色腫、食道がん、胃食道がん(例えば、胃食道接合部のがん)、結腸直腸がん、直腸がん、結腸がん、膵臓がん、胆道がん、唾液腺管がん、膀胱がん、および原発不明がんからなる群より選択される、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1072]
前記腫瘍が、胃がん、胃食道がん、ファロピウス管がん、乳がん、胆嚢がん、および膀胱がんからなる群より選択される、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1073]
前記腫瘍が、胃がん、胃食道がん、ファロピウス管がん、乳がん、および肺がん、特に非小細胞肺がんからなる群より選択される、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1074]
前記腫瘍が胃がんまたは胃食道がんである、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1075]
前記腫瘍が胃がんである、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1076]
前記腫瘍がファロピウス管がんである、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1077]
前記腫瘍が乳がんである、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1078]
前記腫瘍が肺がんである、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1079]
前記腫瘍が非小細胞肺がんである、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1080]
前記腫瘍が胆嚢がんである、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1081]
前記腫瘍が黒色腫である、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1082]
前記腫瘍が食道がんである、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1083]
前記腫瘍が子宮内膜がんである、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1084]
前記腫瘍が直腸がんである、本発明1001～1070のいずれかの使用のための融合タンパク質。
[本発明1085]
前記対象が、前記融合タンパク質に対する抗薬物抗体を有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1086]
前記対象が、前記融合タンパク質による1回の治療サイクルの後に、該融合タンパク質に対する抗薬物抗体を有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1087]
前記対象が、前記融合タンパク質による2回の治療サイクルの後に、該融合タンパク質に対する抗薬物抗体を有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1088]
前記対象が、前記融合タンパク質による3回の治療サイクルの後に、該融合タンパク質に対する抗薬物抗体を有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1089]
前記対象がB細胞枯渇物質で治療されたことがある、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1090]
前記治療が、前記対象にB細胞枯渇物質を投与することを含む、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1091]
前記B細胞枯渇物質が抗CD20抗体である、本発明1089または1090の使用のための融合タンパク質。
[本発明1092]
前記B細胞枯渇物質がオビヌツズマブである、本発明1089～1091のいずれかの使用のための融合タンパク質。
[本発明1093]
前記対象がオビヌツズマブで治療されたことがあるか、または
オビヌツズマブが、前記融合タンパク質の最初の投与の約3週前から当日までのある時点において、約1000mg～約2000mgの用量で該対象に投与される、
本発明1089～1092のいずれかの使用のための融合タンパク質。
[本発明1094]
オビヌツズマブが、前記融合タンパク質の最初の投与の約7日前に、約1000mg～約2000mgの用量で前記対象に投与される、本発明1089～1093のいずれかの使用のための融合タンパク質。
[本発明1095]
オビヌツズマブが、前記融合タンパク質の最初の投与の7日前に約2000mgの用量で、または該融合タンパク質の最初の投与の7日前および6日前に1000mgの用量で、前記対象に投与される、本発明1089～1094のいずれかの使用のための融合タンパク質。
[本発明1096]
前記B細胞枯渇物質がリツキシマブである、本発明1089～1091のいずれかの使用のための融合タンパク質。
[本発明1097]
前記B細胞枯渇物質がオクレリズマブである、本発明1089～1091のいずれかの使用のための融合タンパク質。
[本発明1098]
前記B細胞枯渇物質がベルツズマブである、本発明1089～1091のいずれかの使用のための融合タンパク質。
[本発明1099]
前記対象が、前記融合タンパク質による治療の開始時に末梢血において、約1:5またはそれより小さいB細胞対T細胞の比を有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1100]
前記対象が、前記融合タンパク質による治療の開始時にリンパ節において、約1:5またはそれより小さいB細胞対T細胞の比を有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1101]
前記対象が、前記融合タンパク質による治療の開始時に脾臓において、約1:5またはそれより小さいB細胞対T細胞の比を有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1102]
前記対象が、全腫瘍組織1mm 2 当たりのCD8+T細胞数が約500個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1103]
前記対象が、全腫瘍組織1mm 2 当たりのCD8+T細胞数が約400個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1104]
前記対象が、全腫瘍組織1mm 2 当たりのCD8+T細胞数が約300個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1105]
前記対象が、全腫瘍組織1mm 2 当たりのCD8+T細胞数が約250個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1106]
前記対象が、全腫瘍組織1mm 2 当たりのCD8+T細胞数が約200個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1107]
前記対象が、全腫瘍組織1mm 2 当たりのCD8+T細胞数が約150個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1108]
前記対象が、全腫瘍組織1mm 2 当たりのCD8+T細胞数が約100個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1109]
前記対象が、腫瘍細胞1mm 2 当たりのCD8+T細胞数が約500個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1110]
前記対象が、腫瘍細胞1mm 2 当たりのCD8+T細胞数が約400個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1111]
前記対象が、腫瘍細胞1mm 2 当たりのCD8+T細胞数が約300個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1112]
前記対象が、腫瘍細胞1mm 2 当たりのCD8+T細胞数が約250個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1113]
前記対象が、腫瘍細胞1mm 2 当たりのCD8+T細胞数が約200個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1114]
前記対象が、腫瘍細胞1mm 2 当たりのCD8+T細胞数が約150個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1115]
前記対象が、腫瘍細胞1mm 2 当たりのCD8+T細胞数が約100個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1116]
前記対象が、腫瘍間質1mm 2 当たりのCD8+T細胞数が約500個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1117]
前記対象が、腫瘍間質1mm 2 当たりのCD8+T細胞数が約400個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1118]
前記対象が、腫瘍間質1mm 2 当たりのCD8+T細胞数が約300個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1119]
前記対象が、腫瘍間質1mm 2 当たりのCD8+T細胞数が約250個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1120]
前記対象が、腫瘍間質1mm 2 当たりのCD8+T細胞数が約200個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1121]
前記対象が、腫瘍間質1mm 2 当たりのCD8+T細胞数が約150個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1122]
前記対象が、腫瘍間質1mm 2 当たりのCD8+T細胞数が約100個未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1123]
前記対象が、全免疫細胞に対するPD-L1 + 細胞のパーセンテージが約25％未満である治療前レベルを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1124]
前記対象が、(i)測定領域1mm 2 当たりのCD8+T細胞数が約250個未満である治療前レベルであって、該測定領域が、全腫瘍組織、腫瘍間質、または腫瘍細胞の領域である、該治療前レベルと、(ii)全免疫細胞に対するPD-L1 + 細胞のパーセンテージが約25％未満である治療前レベルとを有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1125]
SEQ ID NO: 50およびSEQ ID NO: 51に示されるアミノ酸配列に対して少なくとも約95％の配列同一性を有する、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1126]
SEQ ID NO: 51およびSEQ ID NO: 51に示されるアミノ酸配列を含む、前記本発明のいずれかの使用のための融合タンパク質。
[本発明1127]
SEQ ID NO: 50に示されるアミノ酸配列を有する2つの鎖とSEQ ID NO: 51に示されるアミノ酸配列を有する2つの鎖とを含む、前記本発明のいずれかの使用のための融合タンパク質。 As used herein, the singular forms "a,""an," and "the" refer to the plural, unless the context clearly dictates otherwise. contains the referent of.
[Invention 1001]
A fusion protein for use in treating a HER2+ tumor in a subject, the fusion protein comprising:
the treatment comprises administering the fusion protein at a dose of about 2.5 mg/kg to about 27 mg/kg;
the fusion protein comprises an antibody specific for HER2, the HER2-specific antibody fused at the C-terminus of both heavy chains to the N-terminus of a lipocalin mutein specific for 4-1BB;
The antibody is
(i) The three heavy chain complementarity determining regions (CDRs) shown in SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42 and SEQ ID NO: 43, SEQ ID NO: 44, and SEQ With the three light chain CDRs shown in ID NO: 45;
(ii) a heavy chain having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 49 and having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 50; light chain and
including, and
the lipocalin mutein has at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 22;
The fusion protein.
[Present invention 1002]
Fusion protein for use according to the invention 1001, wherein said treatment relates to:
a At least approximately 1.5-fold increase in the number of CD8+ T cells in all tumor tissues;
b At least about a 1.5-fold increase in the number of CD8+ T cells in the tumor cells;
c At least approximately 1.5-fold increase in the number of CD8+Ki67+ T cells in all tumor tissues;
d at least about a 1.5-fold increase in the number of CD8+Ki67+ T cells in tumor cells;
e an increase in CD8+ T cells from a pre-treatment level of less than about 500 cells per mm2 of measurement area, where the measurement area is an area of whole tumor tissue, tumor stroma, or tumor cells ; ;
f at least 30% reduction in target lesion;
g Stable disease;
h partial response; or
i Complete response.
[Present invention 1003]
Fusion protein for use according to the invention 1001 or 1002, wherein said treatment does not include administering to said subject a PD-1 system inhibitor.
[Present invention 1004]
For the use of any of the inventions 1001 to 1003, wherein said treatment comprises administering said fusion protein at intervals of about once every three weeks, about once every two weeks, or about once every week. fusion protein.
[Present invention 1005]
The fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at intervals of about once weekly.
[Present invention 1006]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at intervals of about once every two weeks.
[Present invention 1007]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at intervals of about once every three weeks.
[Present invention 1008]
the treatment is associated with superior tumor reduction efficacy when the fusion protein is administered at intervals of approximately once every two weeks, as compared to approximately every three weeks; Fusion protein for use in any of inventions 1001-1003.
[Present invention 1009]
Fusion protein for use according to the invention 1008, wherein said superior tumor reduction effect is a longer duration of response.
[Present invention 1010]
A fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 8 mg/kg.
[Present invention 1011]
Any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 2.5 mg/kg to about 27 mg/kg at intervals of about once every three weeks to about once every week. Fusion proteins for use in.
[Invention 1012]
Any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 5 mg/kg to about 27 mg/kg at intervals of about once every three weeks to about once every week. Fusion proteins for use.
[Present invention 1013]
Any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 8 mg/kg to about 27 mg/kg at intervals of about once every three weeks to about once every week. Fusion proteins for use.
[Present invention 1014]
Any of Inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 2.5 mg/kg to about 12 mg/kg at intervals of about once every three weeks to about once every week. Fusion proteins for use in.
[Present invention 1015]
Any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 5 mg/kg to about 12 mg/kg at intervals of about once every three weeks to about once every week. Fusion proteins for use.
[Invention 1016]
Any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 8 mg/kg to about 18 mg/kg at intervals of about once every three weeks to about once every week. Fusion proteins for use.
[Invention 1017]
The use of any of the invention 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 2.5 mg/kg at intervals of about once every three weeks to about once every three weeks. fusion protein for.
[Invention 1018]
The use of any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 5 mg/kg at intervals of about once every three weeks to about once every three weeks. fusion protein for.
[Invention 1019]
The use of any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 8 mg/kg at intervals of about once every three weeks to about once every three weeks. fusion protein for.
[Invention 1020]
The use of any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 12 mg/kg at intervals of about once every three weeks to about once every three weeks. fusion protein for.
[Invention 1021]
The use of any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 18 mg/kg at intervals of about once every three weeks to about once every three weeks. fusion protein for.
[Invention 1022]
For the use of any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 2.5 mg/kg to about 27 mg/kg at intervals of about once every three weeks. fusion protein.
[Invention 1023]
For the use of any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 2.5 mg/kg to about 18 mg/kg at intervals of about once every three weeks. fusion protein.
[Invention 1024]
Fusion for use in any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 5 mg/kg to about 18 mg/kg at intervals of about once every three weeks. protein.
[Invention 1025]
The fusion for use in any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 8 mg/kg to about 18 mg/kg at intervals of about once every three weeks. protein.
[Invention 1026]
For the use of any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 2.5 mg/kg to about 12 mg/kg at intervals of about once every three weeks. fusion protein.
[Invention 1027]
The fusion for use in any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 5 mg/kg to about 12 mg/kg at intervals of about once every three weeks. protein.
[Invention 1028]
The fusion for use in any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 8 mg/kg to about 18 mg/kg at intervals of about once every three weeks. protein.
[Invention 1029]
The fusion for use in any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 8 mg/kg to about 27 mg/kg at intervals of about once every three weeks. protein.
[Invention 1030]
The fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 2.5 mg/kg at intervals of about once every three weeks.
[Present invention 1031]
A fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 5 mg/kg at intervals of about once every three weeks.
[Invention 1032]
The fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 8 mg/kg at intervals of about once every three weeks.
[Present invention 1033]
The fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 12 mg/kg at intervals of about once every three weeks.
[Present invention 1034]
The fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 18 mg/kg at intervals of about once every three weeks.
[Invention 1035]
The fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 27 mg/kg at intervals of about once every three weeks.
[Invention 1036]
For the use of any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 2.5 mg/kg to about 27 mg/kg at intervals of about once every two weeks. fusion protein.
[Present invention 1037]
For the use of any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 2.5 mg/kg to about 18 mg/kg at intervals of about once every two weeks. fusion protein.
[Invention 1038]
Fusion for use in any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 5 mg/kg to about 18 mg/kg at intervals of about once every two weeks. protein.
[Invention 1039]
The fusion for use in any of the inventions 1001-1003, wherein said treatment comprises administering said fusion protein at a dose of about 8 mg/kg to about 18 mg/kg at intervals of about once every two weeks. protein.
[Invention 1040]
For the use of any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 2.5 mg/kg to about 12 mg/kg at intervals of about once every two weeks. fusion protein.
[Present invention 1041]
A fusion for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 5 mg/kg to about 12 mg/kg at intervals of about once every two weeks. protein.
[Present invention 1042]
The fusion for use in any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 8 mg/kg to about 18 mg/kg at intervals of about once every two weeks. protein.
[Invention 1043]
The fusion for use in any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 8 mg/kg to about 27 mg/kg at intervals of about once every two weeks. protein.
[Present invention 1044]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 2.5 mg/kg at intervals of about once every two weeks.
[Invention 1045]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 5 mg/kg at intervals of about once every two weeks.
[Invention 1046]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 8 mg/kg at intervals of about once every two weeks.
[Invention 1047]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 12 mg/kg at intervals of about once every two weeks.
[Invention 1048]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 18 mg/kg at intervals of about once every two weeks.
[Invention 1049]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 27 mg/kg at intervals of about once every two weeks.
[Invention 1050]
A fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 2.5 mg/kg to about 27 mg/kg at intervals of about once weekly.
[Present invention 1051]
A fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 2.5 mg/kg to about 18 mg/kg at intervals of about once weekly.
[Invention 1052]
A fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 5 mg/kg to about 18 mg/kg at intervals of about once weekly.
[Present invention 1053]
A fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 8 mg/kg to about 18 mg/kg at intervals of about once weekly.
[Invention 1054]
A fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 2.5 mg/kg to about 12 mg/kg at intervals of about once weekly.
[Present invention 1055]
A fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 5 mg/kg to about 12 mg/kg at intervals of about once weekly.
[Invention 1056]
A fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 8 mg/kg to about 18 mg/kg at intervals of about once weekly.
[Present invention 1057]
A fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 8 mg/kg to about 27 mg/kg at intervals of about once weekly.
[Invention 1058]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 2.5 mg/kg at intervals of about once weekly.
[Invention 1059]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 5 mg/kg at intervals of about once weekly.
[Invention 1060]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 8 mg/kg at intervals of about once weekly.
[Present invention 1061]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 12 mg/kg at intervals of about once weekly.
[Invention 1062]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 18 mg/kg at intervals of about once weekly.
[Invention 1063]
Fusion protein for use according to any of the inventions 1001-1003, wherein said treatment comprises administration of said fusion protein at a dose of about 27 mg/kg at intervals of about once weekly.
[Present invention 1064]
A fusion protein for use in any of the inventions as described above, wherein said treatment is not accompanied by dose-limiting toxicity.
[Invention 1065]
A fusion protein for use in any of the above inventions, administered by injection.
[Invention 1066]
Fusion protein for use in any of the inventions, wherein said subject has been previously treated with a HER2 targeting drug or a 4-1BB/4-1BBL pathway targeting drug.
[Invention 1067]
Fusion protein for use in any of the inventions as described above, wherein said subject has been previously treated with an anti-HER2 antibody.
[Invention 1068]
A fusion protein for use in any of the above inventions, wherein said subject has been previously treated with trastuzumab.
[Invention 1069]
A fusion protein for use in any of the inventions as described above, wherein said subject has been previously treated with pertuzumab.
[Invention 1070]
Fusion protein for use in any of the inventions as described above, wherein said subject has been previously treated with an anti-4-1BB antibody.
[Present invention 1071]
The tumor is gastric cancer, gynecological cancer (e.g. fallopian tube cancer, endometrial cancer, or ovarian cancer), breast cancer, lung cancer, especially non-small cell lung cancer, gallbladder cancer, bile duct cancer, melanoma. , esophageal cancer, gastroesophageal cancer (e.g. cancer of the gastroesophageal junction), colorectal cancer, rectal cancer, colon cancer, pancreatic cancer, biliary tract cancer, salivary duct cancer, bladder cancer , and cancer of unknown primary origin for use in any of the above inventions.
[Invention 1072]
Fusion protein for use in any of the inventions 1001-1070, wherein said tumor is selected from the group consisting of gastric cancer, gastroesophageal cancer, fallopian tube cancer, breast cancer, gallbladder cancer, and bladder cancer.
[Invention 1073]
Fusion protein for use according to any of the inventions 1001 to 1070, wherein said tumor is selected from the group consisting of gastric cancer, gastroesophageal cancer, fallopian tube cancer, breast cancer, and lung cancer, especially non-small cell lung cancer.
[Present invention 1074]
Fusion protein for use in any of the inventions 1001-1070, wherein said tumor is gastric cancer or gastroesophageal cancer.
[Present invention 1075]
Fusion protein for use according to any of the inventions 1001-1070, wherein said tumor is gastric cancer.
[Invention 1076]
Fusion protein for use in any of the inventions 1001-1070, wherein said tumor is fallopian tube carcinoma.
[Invention 1077]
Fusion protein for use in any of the inventions 1001-1070, wherein said tumor is breast cancer.
[Invention 1078]
Fusion protein for use in any of the inventions 1001-1070, wherein said tumor is lung cancer.
[Invention 1079]
Fusion protein for use in any of the inventions 1001-1070, wherein said tumor is non-small cell lung cancer.
[Invention 1080]
Fusion protein for use in any of the inventions 1001-1070, wherein said tumor is gallbladder cancer.
[Present invention 1081]
Fusion protein for use in any of the inventions 1001-1070, wherein said tumor is melanoma.
[Present invention 1082]
Fusion protein for use in any of the inventions 1001-1070, wherein said tumor is esophageal cancer.
[Present invention 1083]
Fusion protein for use in any of the inventions 1001-1070, wherein said tumor is endometrial cancer.
[Present invention 1084]
Fusion protein for use according to any of the inventions 1001-1070, wherein said tumor is rectal cancer.
[Invention 1085]
A fusion protein for use in any of the above inventions, wherein said subject has anti-drug antibodies against said fusion protein.
[Invention 1086]
A fusion protein for use in any of the preceding inventions, wherein said subject has anti-drug antibodies against said fusion protein after one cycle of treatment with said fusion protein.
[Present invention 1087]
A fusion protein for use in any of the above inventions, wherein said subject has anti-drug antibodies against said fusion protein after two cycles of treatment with said fusion protein.
[Present invention 1088]
A fusion protein for use in any of the above inventions, wherein said subject has anti-drug antibodies against said fusion protein after three cycles of treatment with said fusion protein.
[Invention 1089]
Fusion protein for use in any of the above inventions, wherein said subject has been treated with a B cell depleting agent.
[Invention 1090]
A fusion protein for use in any of the preceding inventions, wherein said treatment comprises administering to said subject a B cell depleting agent.
[Present invention 1091]
A fusion protein for use in the invention 1089 or 1090, wherein the B cell depleting substance is an anti-CD20 antibody.
[Invention 1092]
Fusion protein for use in any of the inventions 1089-1091, wherein said B cell depleting agent is obinutuzumab.
[Present invention 1093]
the subject has been treated with obinutuzumab, or
obinutuzumab is administered to the subject at a dose of about 1000 mg to about 2000 mg at some time from about 3 weeks prior to the day of the first administration of the fusion protein;
Fusion protein for use in any of the invention 1089-1092.
[Present invention 1094]
Fusion protein for use in any of the inventions 1089-1093, wherein obinutuzumab is administered to said subject at a dose of about 1000 mg to about 2000 mg about 7 days before the first administration of said fusion protein.
[Present invention 1095]
The invention 1089 wherein obinutuzumab is administered to said subject at a dose of about 2000 mg 7 days before the first administration of said fusion protein, or at a dose of 1000 mg 7 days and 6 days before the first administration of said fusion protein. Fusion proteins for use with any of ~1094.
[Invention 1096]
Fusion protein for use in any of the inventions 1089-1091, wherein said B cell depleting agent is rituximab.
[Invention 1097]
Fusion protein for use in any of the inventions 1089-1091, wherein said B cell depleting agent is ocrelizumab.
[Present invention 1098]
Fusion protein for use in any of the inventions 1089-1091, wherein said B cell depleting agent is veltuzumab.
[Invention 1099]
A fusion protein for use in any of the preceding inventions, wherein said subject has a B cell to T cell ratio of about 1:5 or less in peripheral blood at the start of treatment with said fusion protein.
[Invention 1100]
A fusion protein for use in any of the foregoing inventions, wherein said subject has a B cell to T cell ratio of about 1:5 or less in the lymph nodes at the start of treatment with said fusion protein.
[Present invention 1101]
A fusion protein for use in any of the preceding inventions, wherein said subject has a B cell to T cell ratio of about 1:5 or less in the spleen at the beginning of treatment with said fusion protein.
[Present invention 1102]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 500 CD8+ T cells per mm 2 of total tumor tissue .
[Present invention 1103]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 400 CD8+ T cells per mm 2 of total tumor tissue .
[Present invention 1104]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 300 CD8+ T cells per mm 2 of total tumor tissue .
[Present invention 1105]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 250 CD8+ T cells per mm 2 of total tumor tissue .
[Present invention 1106]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 200 CD8+ T cells per mm 2 of total tumor tissue .
[Present invention 1107]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 150 CD8+ T cells per mm 2 of total tumor tissue .
[Present invention 1108]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 100 CD8+ T cells per mm 2 of total tumor tissue .
[Present invention 1109]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 500 CD8+ T cells per mm 2 of tumor cells .
[Present invention 1110]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 400 CD8+ T cells per mm 2 of tumor cells .
[Present invention 1111]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 300 CD8+ T cells per mm 2 of tumor cells .
[Present invention 1112]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 250 CD8+ T cells per mm 2 of tumor cells .
[Present invention 1113]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 200 CD8+ T cells per mm 2 of tumor cells .
[Present invention 1114]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 150 CD8+ T cells per mm 2 of tumor cells .
[Present invention 1115]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 100 CD8+ T cells per mm 2 of tumor cells .
[Present invention 1116]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 500 CD8+ T cells per mm 2 of tumor stroma .
[Present invention 1117]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 400 CD8+ T cells per mm 2 of tumor stroma .
[Present invention 1118]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 300 CD8+ T cells per mm 2 of tumor stroma .
[Present invention 1119]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 250 CD8+ T cells per mm 2 of tumor stroma .
[Invention 1120]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 200 CD8+ T cells per mm 2 of tumor stroma .
[Present invention 1121]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 150 CD8+ T cells per mm 2 of tumor stroma .
[Invention 1122]
A fusion protein for use in any of the preceding inventions, wherein said subject has a pre-therapeutic level of less than about 100 CD8+ T cells per mm 2 of tumor stroma .
[Invention 1123]
A fusion protein for use in any of the above inventions, wherein said subject has a pre-therapeutic level where the percentage of PD-L1 + cells to total immune cells is less than about 25%.
[Present invention 1124]
The subject has (i) a pre-treatment level of less than about 250 CD8+ T cells per mm 2 of the measurement area, and the measurement area is an area of whole tumor tissue, tumor stroma, or tumor cells ; and (ii) the percentage of PD-L1 + cells to total immune cells is less than about 25%. .
[Invention 1125]
A fusion protein for use in any of the above inventions having at least about 95% sequence identity to the amino acid sequences set forth in SEQ ID NO: 50 and SEQ ID NO: 51.
[Present invention 1126]
A fusion protein for use in any of the above inventions comprising SEQ ID NO: 51 and the amino acid sequence set forth in SEQ ID NO: 51.
[Present invention 1127]
A fusion protein for use in any of the above inventions, comprising two chains having the amino acid sequence shown in SEQ ID NO: 50 and two chains having the amino acid sequence shown in SEQ ID NO: 51.

Claims (16)

対象においてHER2+腫瘍を治療する際に使用するための、融合タンパク質を含む医薬であって、
該医薬が、約2.5mg/kg～約27mg/kgの用量で該融合タンパク質が投与されるように用いられることを特徴とし、
該融合タンパク質が、HER2に特異的な抗体を含み、該HER2に特異的な抗体が、両方の重鎖のC末端において、4-1BBに特異的なリポカリンムテインのN末端に融合されており、
該抗体が、
(i)SEQ ID NO: 40、SEQ ID NO: 41、およびSEQ ID NO: 42に示される3つの重鎖相補性決定領域(CDR)ならびにSEQ ID NO: 43、SEQ ID NO: 44、およびSEQ ID NO: 45に示される3つの軽鎖CDRと;
(ii)SEQ ID NO: 49に示されるアミノ酸配列に対して少なくとも95％の配列同一性を有する重鎖およびSEQ ID NO: 50に示されるアミノ酸配列に対して少なくとも95％の配列同一性を有する軽鎖と
を含み、かつ
該リポカリンムテインが、SEQ ID NO: 22に示されるアミノ酸配列に対して少なくとも95％の配列同一性を有する、
該医薬。 A medicament comprising a fusion protein for use in treating a HER2+ tumor in a subject, the medicament comprising :
characterized in that the medicament is used such that the fusion protein is administered at a dose of about 2.5 mg/kg to about 27 mg/kg;
the fusion protein comprises an antibody specific for HER2, the HER2-specific antibody fused at the C-terminus of both heavy chains to the N-terminus of a lipocalin mutein specific for 4-1BB;
The antibody is
(i) The three heavy chain complementarity determining regions (CDRs) shown in SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42 and SEQ ID NO: 43, SEQ ID NO: 44, and SEQ With the three light chain CDRs shown in ID NO: 45;
(ii) a heavy chain having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 49 and having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 50; a light chain; and the lipocalin mutein has at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 22.
The medicine . 前記治療が以下に関連している、請求項1記載の医薬:
a 全腫瘍組織中のCD8+T細胞数の少なくとも約1.5倍の増加;
b 腫瘍細胞中のCD8+T細胞数の少なくとも約1.5倍の増加;
c 全腫瘍組織中のCD8+Ki67+T細胞数の少なくとも約1.5倍の増加;
d 腫瘍細胞中のCD8+Ki67+T細胞数の少なくとも約1.5倍の増加;
e 測定領域1mm2当たり約500個未満である治療前レベルからのCD8+T細胞の増加であって、該測定領域が、全腫瘍組織、腫瘍間質、もしくは腫瘍細胞の領域である、該増加;
f 標的病変の少なくとも30％の減少;
g 病勢安定;
h 部分奏功;または
i 完全奏効。 The medicament according to claim 1, wherein the treatment is associated with:
a At least approximately 1.5-fold increase in the number of CD8+ T cells in all tumor tissues;
b At least about a 1.5-fold increase in the number of CD8+ T cells in the tumor cells;
c At least approximately 1.5-fold increase in the number of CD8+Ki67+ T cells in all tumor tissues;
d at least about a 1.5-fold increase in the number of CD8+Ki67+ T cells in tumor cells;
e an increase in CD8+ T cells from a pre-treatment level of less than about 500 cells per mm2 of measurement area, where the measurement area is an area of whole tumor tissue, tumor stroma, or tumor cells; ;
f at least 30% reduction in target lesion;
g Stable disease;
h partial response; or
i Complete response. PD-1系阻害物質と組み合わせて用いられないことを特徴とする、請求項1または2記載の医薬。 3. The medicament according to claim 1 or 2, which is not used in combination with a PD -1 system inhibitor. 3週ごとに1回程度、2週ごとに1回程度、または毎週1回程度の間隔で前記融合タンパク質が投与されるように用いられることを特徴とする、請求項1～3のいずれか一項記載の医薬。 Any one of claims 1 to 3 , wherein the fusion protein is administered at intervals of about once every 3 weeks, about once every 2 weeks, or about once every week. Medicines listed in section. 2週ごとに1回程度の間隔で前記融合タンパク質が投与されるように用いられることを特徴とする、請求項1～3のいずれか一項記載の医薬。 4. The medicament according to claim 1, wherein the fusion protein is administered at intervals of about once every two weeks. 約8mg/kgの用量で前記融合タンパク質が投与されるように用いられることを特徴とする、請求項1～3のいずれか一項記載の医薬。 Medicament according to any one of claims 1 to 3, characterized in that the fusion protein is used to be administered at a dose of about 8 mg/kg. 前記医薬が、約18mg/kgの用量で前記融合タンパク質が投与されるように用いられることを特徴とし、 characterized in that said medicament is used such that said fusion protein is administered at a dose of about 18 mg/kg;
(i)該融合タンパク質が、SEQ ID NO:50および51に示されるアミノ酸配列を含むか、または (i) the fusion protein comprises the amino acid sequences shown in SEQ ID NO:50 and 51, or
(ii)該融合タンパク質の投与によって、20μg/mL以上の該融合タンパク質の血清濃度がもたらされる、 (ii) administration of the fusion protein results in a serum concentration of the fusion protein of 20 μg/mL or greater;
請求項1～3のいずれか一項記載の医薬。The medicament according to any one of claims 1 to 3. 2週ごとに1回程度の間隔において約8mg/kg～約18mg/kgの用量で前記融合タンパク質が投与されるように用いられることを特徴とする、請求項1～3のいずれか一項記載の医薬。 4. The fusion protein according to claim 1, wherein the fusion protein is administered at a dose of about 8 mg/kg to about 18 mg/kg at intervals of about once every two weeks. medicine . 2週ごとに1回程度の間隔において約8mg/kgの用量で前記融合タンパク質が投与されるように用いられることを特徴とする、請求項1～3のいずれか一項記載の医薬。 4. The medicament according to claim 1, wherein the fusion protein is administered at a dose of about 8 mg/kg at intervals of about once every two weeks. 2週ごとに1回程度の間隔において約18mg/kgの用量で前記融合タンパク質が投与されるように用いられることを特徴とする、請求項1～3のいずれか一項記載の医薬。 The medicament according to any one of claims 1 to 3 , characterized in that the fusion protein is administered at a dose of about 18 mg/kg at intervals of about once every two weeks. 前記腫瘍が、胃がん、婦人科がん(例えば、ファロピウス管がん、子宮内膜がん、または卵巣がん)、乳がん、肺がん、特に非小細胞肺がん、胆嚢がん、胆管がん、黒色腫、食道がん、胃食道がん(例えば、胃食道接合部のがん)、結腸直腸がん、直腸がん、結腸がん、膵臓がん、胆道がん、唾液腺管がん、膀胱がん、および原発不明がんからなる群より選択される、請求項1～10のいずれか一項記載の医薬。 The tumor is gastric cancer, gynecological cancer (e.g. fallopian tube cancer, endometrial cancer, or ovarian cancer), breast cancer, lung cancer, especially non-small cell lung cancer, gallbladder cancer, bile duct cancer, melanoma. , esophageal cancer, gastroesophageal cancer (e.g. cancer of the gastroesophageal junction), colorectal cancer, rectal cancer, colon cancer, pancreatic cancer, biliary tract cancer, salivary duct cancer, bladder cancer , and cancer of unknown primary origin. 前記腫瘍が胃がんまたは胃食道がんである、請求項1～11のいずれか一項記載の医薬。 12. The medicament according to any one of claims 1 to 11 , wherein the tumor is gastric cancer or gastroesophageal cancer. 前記対象が、(i)測定領域1mm2当たりCD8+T細胞が約250個未満である治療前レベルであって、該測定領域が、全腫瘍組織、腫瘍間質、または腫瘍細胞の領域である、該治療前レベルと、(ii)全免疫細胞に対するPD-L1+細胞が約25％未満である治療前レベルとを有する、請求項1～12のいずれか一項記載の医薬。 The subject has (i) a pre-treatment level of less than about 250 CD8 + T cells per mm 2 of the measurement area, and the measurement area is a region of whole tumor tissue, tumor stroma, or tumor cells; and (ii) less than about 25% PD-L1 + cells to total immune cells . 前記融合タンパク質が、SEQ ID NO: 50およびSEQ ID NO: 51に示されるアミノ酸配列に対して少なくとも約95％の配列同一性を有する、請求項1～13のいずれか一項記載の医薬。 14. A medicament according to any one of claims 1 to 13 , wherein the fusion protein has at least about 95% sequence identity to the amino acid sequences set forth in SEQ ID NO: 50 and SEQ ID NO: 51. 前記融合タンパク質が、SEQ ID NO: 50およびSEQ ID NO: 51に示されるアミノ酸配列を含む、請求項1～14のいずれか一項記載の医薬。 The medicament according to any one of claims 1 to 14 , wherein the fusion protein comprises the amino acid sequences shown in SEQ ID NO: 50 and SEQ ID NO: 51. 前記融合タンパク質が、SEQ ID NO: 50に示されるアミノ酸配列を有する2つの鎖とSEQ ID NO: 51に示されるアミノ酸配列を有する2つの鎖とを含む、請求項1～15のいずれか一項記載の医薬。 16. Any one of claims 1 to 15 , wherein the fusion protein comprises two chains having the amino acid sequence shown in SEQ ID NO: 50 and two chains having the amino acid sequence shown in SEQ ID NO: 51. Medications listed.
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Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3920358A1 (en) 1989-06-22 1991-01-17 Behringwerke Ag BISPECIFIC AND OLIGO-SPECIFIC, MONO- AND OLIGOVALENT ANTI-BODY CONSTRUCTS, THEIR PRODUCTION AND USE
ES2165851T3 (en) 1991-11-25 2002-04-01 Enzon Inc MULTIVALENT PROTEINS THAT JOIN ANTIGENS.
DE19742706B4 (en) 1997-09-26 2013-07-25 Pieris Proteolab Ag lipocalin muteins
DE19926068C1 (en) 1999-06-08 2001-01-11 Arne Skerra Muteins of the bilin binding protein
US7118915B2 (en) 2001-09-27 2006-10-10 Pieris Proteolab Ag Muteins of apolipoprotein D
WO2003029462A1 (en) 2001-09-27 2003-04-10 Pieris Proteolab Ag Muteins of human neutrophil gelatinase-associated lipocalin and related proteins
AU2003275958A1 (en) 2003-08-25 2005-03-10 Pieris Proteolab Ag Muteins of tear lipocalin
AU2015205530B8 (en) * 2014-01-13 2019-09-19 Pieris Pharmaceuticals Gmbh Multi-specific polypeptide useful for localized tumor immunomodulation
BR112017020434A2 (en) 2015-05-04 2018-06-26 Pieris Pharmaceuticals Gmbh fusion polypeptides, nucleic acid molecule, host cell, method for producing a fusion polypeptide, uses of fusion polypeptide, methods for activating signaling pathways, for costimulating cells, for inducing t lymphocyte proliferation, for directing assembly cd137, to induce a local t-cell response, to induce a local nk cell response, and to induce il-2 production
DK3292137T3 (en) 2015-05-04 2022-10-17 Pieris Pharmaceuticals Gmbh PROTEINS SPECIFIC FOR CD137

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