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Description
本開示は、バリアントＩｇＭ重鎖定常領域であって、当該バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体の血清半減期を増加させることができる当該バリアントＩｇＭ重鎖定常領域を同定する方法を更に提供する。上記方法は、バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体を、それらのＦｃアルファ－ミュー受容体（ＦｃαμＲ）、Ｆｃミュー受容体（ＦｃμＲ）、多量体Ｉｇ受容体（ｐＩｇＲ）、上記受容体の任意の２つの組み合わせ、または上記受容体の３つ全てへの結合レベルについて試験することであって、当該バリアントＩｇＭ重鎖定常領域が、既定のアミノ酸挿入、欠失、または置換を含む、試験することと、バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体に、当該既定のアミノ酸挿入、欠失、または置換を除いて当該バリアントＩｇＭ重鎖定常領域と同一のＩｇＭ重鎖定常領域を含む参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して、減少したＦｃαμＲ結合能、減少したＦｃμＲ結合能、減少したｐＩｇＲ結合能、上記受容体の任意の２つへの減少した結合能、または上記受容体の３つ全てへの減少した結合能を付与する当該バリアントＩｇＭ重鎖定常領域を含む当該ＩｇＭ抗体またはＩｇＭ様抗体を回収すること、を含む。この方法は、バリアントＩｇＭ重鎖定常領域を含む回収されたＩｇＭ抗体またはＩｇＭ様抗体を、既定のアミノ酸挿入、欠失、または置換を除いてバリアントＩｇＭ重鎖定常領域と同一のＩｇＭ重鎖定常領域を含む参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して、対象動物において増加した血清半減期について試験することを更に含み得る。
[本発明1001]
5つの二価抗体の結合ユニットまたはそのバリアントもしくは断片及びバリアントＪ鎖またはその機能断片を含む、増強された血清半減期を有するＩｇＭ抗体またはＩｇＭ様抗体であって、
各結合ユニットが、各々が抗原結合ドメインまたはそのサブユニットと会合している2つのＩｇＭ重鎖定常領域またはその多量体化断片もしくはバリアントを含み、
前記バリアントＪ鎖またはその機能断片が、参照Ｊ鎖と比較して1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を含み、前記参照Ｊ鎖が、前記1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を除いて前記バリアントＪ鎖と同一であり、前記バリアントＪ鎖が、前記ＩｇＭ抗体またはＩｇＭ様抗体の血清半減期に影響を及ぼすことができ、
前記バリアントＪ鎖における前記1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を除いて同一でありかつ同一の動物種に同様に投与される参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して、前記ＩｇＭ抗体またはＩｇＭ様抗体が、対象動物に投与された際に、増加した血清半減期を示す、
前記ＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1002]
前記バリアントＪ鎖またはその機能断片が、前記参照Ｊ鎖と比較して1つ、2つ、3つ、または4つの単一アミノ酸置換、欠失、または挿入を含む、本発明1001のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1003]
前記バリアントＪ鎖またはその機能断片が、野生型ヒトＪ鎖（配列番号2）のアミノ酸Ｙ102に対応するアミノ酸位でのアミノ酸置換を含む、本発明1001または本発明1002のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1004]
配列番号2のＹ102に対応するアミノ酸が、アラニン（Ａ）、セリン（Ｓ）、またはアルギニン（Ｒ）で置換されている、本発明1003のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1005]
配列番号2のＹ102に対応するアミノ酸が、アラニン（Ａ）で置換されている、本発明1004のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1006]
前記Ｊ鎖が、バリアントヒトＪ鎖であり、かつ配列番号3のアミノ酸配列を含む、本発明1005のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1007]
配列番号2のＹ102に対応するアミノ酸が、セリン（Ｓ）で置換されている、本発明1004のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1008]
前記Ｊ鎖が、バリアントヒトＪ鎖であり、かつ配列番号4のアミノ酸配列を含む、本発明1007のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1009]
配列番号2のＹ102に対応するアミノ酸が、アルギニン（Ｒ）で置換されている、本発明1004のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1010]
前記Ｊ鎖が、バリアントヒトＪ鎖であり、かつ配列番号5のアミノ酸配列を含む、本発明1009のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1011]
前記バリアントＪ鎖またはその機能断片が、野生型ヒトＪ鎖（配列番号2）のアミノ酸Ｔ103に対応するアミノ酸位でのアミノ酸置換を含む、本発明1001または本発明1002のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1012]
配列番号2のＴ103に対応するアミノ酸が、アラニン（Ａ）で置換されている、本発明1011のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1013]
前記Ｊ鎖が、バリアントヒトＪ鎖であり、かつ配列番号6のアミノ酸配列を含む、本発明1012のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1014]
前記バリアントＪ鎖またはその機能断片が、ヒトＪ鎖（配列番号2）のアミノ酸Ｎ49またはアミノ酸Ｓ51に対応するアミノ酸位でのアミノ酸置換を含み、Ｓ51がトレオニン（Ｔ）で置換されていないか、または前記バリアントＪ鎖が、ヒトＪ鎖（配列番号2）のアミノ酸Ｎ49及びＳ51の両方に対応するアミノ酸位でのアミノ酸置換を含む、本発明1001または本発明1002のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1015]
配列番号2のＮ49に対応する位置が、アラニン（Ａ）、グリシン（Ｇ）、トレオニン（Ｔ）、セリン（Ｓ）、またはアスパラギン酸（Ｄ）で置換されている、本発明1014のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1016]
配列番号2のＮ49に対応する位置が、アラニン（Ａ）で置換されている、本発明1015のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1017]
前記Ｊ鎖が、バリアントヒトＪ鎖であり、かつ配列番号7のアミノ酸配列を含む、本発明1016のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1018]
配列番号2のＳ51に対応する位置が、アラニン（Ａ）またはグリシン（Ｇ）で置換されている、本発明1014のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1019]
配列番号2のＳ51に対応する位置が、アラニン（Ａ）で置換されている、本発明1018のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1020]
前記Ｊ鎖が、バリアントヒトＪ鎖であり、かつ配列番号8のアミノ酸配列を含む、本発明1019のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1021]
前記ＩｇＭ重鎖定常領域またはその多量体化断片が、参照ＩｇＭ重鎖定常領域と比較して1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を含むバリアントＩｇＭ重鎖定常領域であり、前記参照ＩｇＭ重鎖定常領域が、前記1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を除いて前記バリアントＩｇＭ重鎖定常領域と同一であり、
前記バリアントＩｇＭ重鎖定常領域が、前記ＩｇＭ抗体またはＩｇＭ様抗体の血清半減期に影響を及ぼすことができ、
前記ＩｇＭ重鎖定常領域における前記1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を除いて同一でありかつ同一の動物種に同様に投与される参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して、前記ＩｇＭ抗体またはＩｇＭ様抗体が、対象動物に投与された際に、更に増加した血清半減期を示す、
本発明1001～1020のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1022]
前記血清半減期の更なる増加が相加的である、本発明1021のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1023]
5つまたは6つの二価抗体の結合ユニットまたはそのバリアントもしくは断片を含む、増強された血清半減期を有するＩｇＭ抗体またはＩｇＭ様抗体であって、
各結合ユニットが、各々が抗原結合ドメインまたはそのサブユニットと会合している2つのバリアントＩｇＭ重鎖定常領域またはその多量体化断片を含み、
前記バリアントＩｇＭ重鎖定常領域またはその多量体化断片が、それぞれ、参照ＩｇＭ重鎖定常領域と比較して1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を含み、前記参照ＩｇＭ重鎖定常領域が、前記1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を除いて前記バリアントＩｇＭ重鎖定常領域と同一であり、前記バリアントＩｇＭ重鎖定常領域が、前記ＩｇＭ抗体またはＩｇＭ様抗体の血清半減期に影響を及ぼすことができ、
前記ＩｇＭ重鎖定常領域における前記1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を除いて同一でありかつ同一の動物種に同様に投与される参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して、前記ＩｇＭ抗体またはＩｇＭ様抗体が、対象動物に投与された際に、増加した血清半減期を示す、
ＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1024]
前記バリアントＩｇＭ重鎖定常領域が、前記参照ＩｇＭ重鎖定常領域と比較して1つ、2つ、3つ、または4つの単一アミノ酸置換、欠失、または挿入を含む、本発明1021～1023のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1025]
前記バリアントＩｇＭ重鎖定常領域が、野生型ヒトＩｇＭ定常領域である配列番号12のアミノ酸Ｒ344に対応するアミノ酸位でのアミノ酸置換を含む、本発明1021～1024のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1026]
配列番号12のＲ344に対応するアミノ酸が、アラニン（Ａ）で置換されている、本発明1025のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1027]
前記バリアントＩｇＭ重鎖定常領域が、バリアントヒトＩｇＭ重鎖定常領域であり、配列番号31のアミノ酸配列を含む、本発明1026のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1028]
前記バリアントＩｇＭ重鎖定常領域が、野生型ヒトＩｇＭ定常領域である配列番号12のアミノ酸Ｅ345に対応するアミノ酸位でのアミノ酸置換を含む、本発明1021～1024のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1029]
配列番号12のＥ345に対応するアミノ酸が、アラニン（Ａ）で置換されている、本発明1028のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1030]
前記バリアントＩｇＭ重鎖定常領域が、バリアントヒトＩｇＭ重鎖定常領域であり、配列番号32のアミノ酸配列を含む、本発明1029のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1031]
前記バリアントＩｇＭ重鎖定常領域が、野生型ヒトＩｇＭ定常領域である配列番号12のアミノ酸Ｓ401に対応するアミノ酸位でのアミノ酸置換を含む、本発明1021～1024のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1032]
配列番号12のＳ401に対応するアミノ酸が、アラニン（Ａ）で置換されている、本発明1031のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1033]
前記バリアントＩｇＭ重鎖定常領域が、バリアントヒトＩｇＭ重鎖定常領域であり、かつ配列番号13のアミノ酸配列を含む、本発明1032のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1034]
前記バリアントＩｇＭ重鎖定常領域が、野生型ヒトＩｇＭ定常領域である配列番号12のアミノ酸Ｅ402に対応するアミノ酸位でのアミノ酸置換を含む、本発明1021～1024のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1035]
配列番号12のＥ402に対応するアミノ酸が、アラニン（Ａ）で置換されている、本発明1034のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1036]
前記バリアントＩｇＭ重鎖定常領域が、バリアントヒトＩｇＭ重鎖定常領域であり、かつ配列番号14のアミノ酸配列を含む、本発明1035のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1037]
前記バリアントＩｇＭ重鎖定常領域が、野生型ヒトＩｇＭ定常領域である配列番号12のアミノ酸Ｅ403に対応するアミノ酸位でのアミノ酸置換を含む、本発明1021～1024のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1038]
配列番号12のＥ403に対応するアミノ酸が、アラニン（Ａ）で置換されている、本発明1037のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1039]
前記バリアントＩｇＭ重鎖定常領域がバリアントヒトＩｇＭ重鎖定常領域であり、かつ配列番号34のアミノ酸配列を含む、本発明1038のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1040]
前記増加した血清半減期が、増加したアルファ半減期（ｔ
1／2
α）、増加したベータ半減期（ｔ
1／2
β）、または増加したｔ
1／2
α及び増加したｔ
1／2
βを含む、本発明1001～1039のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1041]
前記参照抗体と比較して、増加したピーク血漿濃度（Ｃｍａｘ）、増加した曲線下面積（ＡＵＣ）、改変されたクリアランス時間、またはそれらの任意の組み合わせを更に示す、本発明1001～1040のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1042]
前記ＩｇＭ重鎖定常領域またはその多量体化断片もしくはバリアントが、それぞれ、Ｃμ4ドメイン及びＩｇＭ尾部（ｔｐ）ドメインを含む、本発明1001～1041のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1043]
前記ＩｇＭ重鎖定常領域またはその多量体化断片もしくはバリアントが、それぞれ、Ｃμ3ドメイン、Ｃμ2ドメイン、Ｃμ1ドメイン、またはそれらの任意の組み合わせを更に含む、本発明1042のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1044]
前記抗原結合ドメインが、単鎖Ｆｖ（ＳｃＦｖ）断片または単一ドメイン可変領域（ＶＨＨ）を含む、本発明1001～1043のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1045]
前記抗原結合ドメインのサブユニットが重鎖可変領域（ＶＨ）を含む、本発明1001～1043のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1046]
各結合ユニットが、各々が抗原結合ドメインまたはそのサブユニットと会合している2つの軽鎖定常領域またはその断片もしくはバリアントを更に含む、本発明1001～1045のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1047]
前記軽鎖定常領域が、カッパもしくはラムダ軽鎖定常領域またはそれらの断片もしくはバリアントであり、抗原結合ドメインがＳｃＦｖ断片を含むか、または前記抗原結合ドメインのサブユニットが軽鎖可変領域（ＶＬ）を含む、本発明1046のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1048]
前記Ｊ鎖またはその機能的断片もしくはバリアントが、直接または間接的に前記Ｊ鎖またはその機能的断片もしくはバリアントに融合された1つまたはそれ以上の異種ポリペプチドを更に含む、本発明1001～1047のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1049]
前記1つまたはそれ以上の異種ポリペプチドが、ペプチドリンカーを介して前記Ｊ鎖またはその断片に融合されている、本発明1048のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1050]
前記ペプチドリンカーが、少なくとも5アミノ酸であるが25アミノ酸以下を含む、本発明1049のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1051]
前記ペプチドリンカーが、
[本発明1052]
前記1つまたはそれ以上の異種ポリペプチドが、前記Ｊ鎖またはその断片もしくはバリアントのＮ末端に融合されているか、前記Ｊ鎖またはその断片もしくはバリアントのＣ末端に融合されているか、または異種ポリペプチドが、前記Ｊ鎖またはその断片もしくはバリアントのＮ末端及びＣ末端の両方に融合されており、前記異種ポリペプチドが、同一であるか、または異なり得る、本発明1048～1051のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1053]
少なくとも1つの異種ポリペプチドが結合ドメインを含む、本発明1048～1052のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1054]
前記異種ポリペプチドの前記結合ドメインが、抗体またはその抗原結合断片である、本発明1053のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1055]
前記抗原結合断片が、Ｆａｂ断片、Ｆａｂ´断片、Ｆ（ａｂ´）2断片、Ｆｄ断片、Ｆｖ断片、単鎖Ｆｖ（ｓｃＦｖ）断片、ジスルフィド結合Ｆｖ（ｓｄＦｖ）断片、またはそれらの任意の組み合わせを含む、本発明1054のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1056]
前記抗原結合断片がｓｃＦｖ断片である、本発明1055のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1057]
少なくとも1つの異種ポリペプチドが、ＣＤ3εに特異的に結合することができる、本発明1053～1056のいずれかのＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1058]
前記Ｊ鎖が配列番号9の改変Ｊ鎖（Ｖ15Ｊ）のバリアントである、本発明1057のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1059]
前記改変Ｊ鎖が配列番号10（Ｖ15Ｊ－Ｙ102Ａ）のアミノ酸配列を含む、本発明1058のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1060]
前記改変Ｊ鎖が配列番号23（Ｖ15Ｊ－Ｔ103Ａ）のアミノ酸配列を含む、本発明1058のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1061]
前記改変Ｊ鎖が配列番号24（Ｖ15Ｊ－Ｎ49Ａ）のアミノ酸配列を含む、本発明1058のＩｇＭ抗体またはＩｇＭ様抗体。
[本発明1062]
本発明1001～1061のいずれかのＩｇＭ抗体またはＩｇＭ様抗体及び薬学的に許容される担体を含む、組成物。
[本発明1063]
参照Ｊ鎖と比較して1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を含むバリアントＪ鎖またはその機能断片であって、前記参照Ｊ鎖が前記1つまたはそれ以上の単一アミノ酸置換、欠失、または挿入を除いて前記バリアントＪ鎖と同一であり、前記バリアントＪ鎖が、前記バリアントＪ鎖を含むＩｇＭ抗体またはＩｇＭ様抗体の血清半減期に影響を及ぼすことができる、前記バリアントＪ鎖またはその機能断片。
[本発明1064]
配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号10、配列番号23、配列番号24のアミノ酸配列、またはそれらの任意の組み合わせを含む、本発明1063のバリアントＪ鎖。
[本発明1065]
本発明1001～1061のいずれかのＩｇＭまたはＩｇＭ様抗体のサブユニットポリペプチドをコードする核酸を含む単離ポリヌクレオチドであって、前記サブユニットポリペプチドが、（ａ）ＩｇＭもしくはＩｇＭ様重鎖定常領域またはそれらの多量体化断片、（ｂ）抗体軽鎖、または（ｃ）Ｊ鎖、改変Ｊ鎖、またはそれらの機能断片もしくはバリアント、または（ｄ）それらの任意の組み合わせを含む、前記単離ポリヌクレオチド。
[本発明1066]
前記サブユニットポリペプチドが、ＩｇＭまたはＩｇＭ様重鎖定常領域もしくはその多量体化断片を含む、本発明1065のポリヌクレオチド。
[本発明1067]
前記サブユニットポリペプチドが、配列番号12、配列番号13、配列番号14、配列番号15、配列番号31、配列番号32、または配列番号34のアミノ酸配列を含む、本発明1066のポリヌクレオチド。
[本発明1068]
前記サブユニットポリペプチドが抗体軽鎖を含む、本発明1065のポリヌクレオチド。
[本発明1069]
前記サブユニットポリペプチドが、Ｊ鎖、改変Ｊ鎖、またはそれらの任意の機能的断片もしくはバリアントを含む、本発明1065のポリヌクレオチド。
[本発明1070]
前記サブユニットが、配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号23、または配列番号24のアミノ酸配列を含む、本発明1069のポリヌクレオチド。
[本発明1071]
2種、3種、またはそれ以上のサブユニットポリペプチドをコードする2種、3種、またはそれ以上の核酸配列を含む、本発明1065～1070のいずれかのポリヌクレオチド。
[本発明1072]
本発明1065～1071のいずれかのポリヌクレオチドを含む、発現ベクター。
[本発明1073]
本発明1065～1071のいずれかのポリヌクレオチドまたは本発明1072の発現ベクターを含む、宿主細胞。
[本発明1074]
バリアントＪ鎖を含む五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体の血清半減期を増加させることができる前記バリアントＪ鎖を同定する方法であって、
（ａ）バリアントＪ鎖またはその断片を含む五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体を、参照五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体と比較して対象動物において増加した血清半減期について試験する工程であって、前記バリアントＪ鎖またはその断片が、既定のアミノ酸挿入、欠失、または置換を含み、前記参照五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体が、前記既定のアミノ酸挿入、欠失、または置換を除いて前記バリアントＪ鎖と同一のＪ鎖またはその断片を含む、試験する工程と、
（ｂ）前記五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体に、参照五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体と比較して増加した血清半減期を付与するバリアントＪ鎖またはその断片を回収する工程と
を含む、前記方法。
[本発明1075]
バリアントＪ鎖を含む五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体の血清半減期を増加させることができる前記バリアントＪ鎖を同定する方法であって、
（ａ）バリアントＪ鎖またはその断片を含む五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体を、それらのＦｃアルファ－ミュー受容体（ＦｃαμＲ）、多量体Ｉｇ受容体（ｐＩｇＲ）、またはＦｃαμＲ及びｐＩｇＲの両方への結合レベルについて試験する工程であって、前記バリアントＪ鎖またはその断片が既定のアミノ酸挿入、欠失、または置換を含む、試験する工程と、
（ｂ）前記既定のアミノ酸挿入、欠失、または置換を除いて前記バリアントＪ鎖と同一のＪ鎖またはその断片を含む参照五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体と比較して減少したＦｃαμＲ結合能、減少したｐＩｇＲ結合能、または減少したＦｃαμＲ及びｐＩｇＲ結合能を、前記五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体に付与するバリアントＪ鎖またはその断片を回収する工程と
を含む、前記方法。
[本発明1076]
回収されたバリアントＪ鎖またはその断片を含む五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体を、前記既定のアミノ酸挿入、欠失、または置換を除いて回収されたバリアントＪ鎖またはその断片と同一のＪ鎖またはその断片を含む参照五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体と比較して対象動物において増加した血清半減期について試験する工程を更に含む、本発明1075の方法。
[本発明1077]
バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体の血清半減期を増加させることができる前記バリアントＩｇＭ重鎖定常領域を同定する方法であって、
（ａ）バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体を、参照5量体ＩｇＭ抗体または5量体ＩｇＭ様抗体と比較して対象動物において増加した血清半減期について試験する工程であって、前記バリアントＩｇＭ重鎖定常領域が、既定のアミノ酸挿入、欠失、または置換を含み、前記参照ＩｇＭ抗体またはＩｇＭ様抗体が、前記既定のアミノ酸挿入、欠失、または置換を除いて前記バリアントＩｇＭ重鎖定常領域と同じＩｇＭ重鎖定常領域を含む、試験する工程と、
（ｂ）バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体に、前記参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して増加した血清半減期を付与する前記バリアントＩｇＭ重鎖定常領域を含む前記ＩｇＭ抗体またはＩｇＭ様抗体を回収する工程と
を含む、前記方法。
[本発明1078]
バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体の血清半減期を増加させることができる前記バリアントＩｇＭ重鎖定常領域を同定する方法であって、
（ａ）バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体を、それらのＦｃアルファ－ミュー受容体（ＦｃαμＲ）、Ｆｃミュー受容体（ＦｃμＲ）、多量体Ｉｇ受容体（ｐＩｇＲ）、前記受容体の任意の2つの組み合わせ、または前記受容体の3つ全てへの結合レベルについて試験する工程であって、前記バリアントＩｇＭ重鎖定常領域が、既定のアミノ酸挿入、欠失、または置換を含む、試験する工程と、
（ｂ）前記既定のアミノ酸挿入、欠失、または置換を除いて前記バリアントＩｇＭ重鎖定常領域と同一のＩｇＭ重鎖定常領域を含む参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して、減少したＦｃαμＲ結合能、減少したＦｃμＲ結合能、減少したｐＩｇＲ結合能、前記受容体の任意の2つへの減少した結合能、または前記受容体の3つ全てへの減少した結合能を、バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体に付与する前記バリアントＩｇＭ重鎖定常領域を含む前記ＩｇＭ抗体またはＩｇＭ様抗体を回収する工程と
を含む、前記方法。
[本発明1079]
前記バリアントＩｇＭ重鎖定常領域を含む回収されたＩｇＭ抗体またはＩｇＭ様抗体を、前記既定のアミノ酸挿入、欠失、または置換を除いて前記バリアントＩｇＭ重鎖定常領域と同一のＩｇＭ重鎖定常領域を含む参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して対象動物において増加した血清半減期について試験する工程を更に含む、本発明1078の方法。
The present disclosure is a method for identifying a variant IgM heavy chain constant region that can increase the serum half-life of an IgM antibody or IgM-like antibody comprising the variant IgM heavy chain constant region. Further provide. In the above method, an IgM antibody or an IgM-like antibody containing a variant IgM heavy chain constant region thereof is subjected to Fcalpha-mu receptor (FcαμR), Fcmu receptor (FcμR), multimer Ig receptor (pIgR), and the above. Testing for any combination of two receptors, or levels of binding to all three of the above receptors, wherein the variant IgM heavy chain constant region comprises a predetermined amino acid insertion, deletion, or substitution. , And to the IgM antibody or IgM-like antibody containing the variant IgM heavy chain constant region, the same IgM heavy chain constant as the variant IgM heavy chain constant region except for the predetermined amino acid insertion, deletion, or substitution. Reduced FcαμR binding ability, decreased FcμR binding ability, decreased pIgR binding ability, reduced binding ability of the above receptors to any two, or the above, as compared to a reference IgM antibody or IgM-like antibody containing a region. Retrieving the IgM or IgM-like antibody containing the variant IgM heavy chain constant region that imparts reduced binding ability to all three of the receptors. In this method, a recovered IgM antibody or IgM-like antibody containing a variant IgM heavy chain constant region is subjected to the same IgM heavy chain constant region as the variant IgM heavy chain constant region except for predetermined amino acid insertion, deletion, or substitution. It may further comprise testing for an increased serum half-life in a subject animal as compared to a reference IgM antibody or IgM-like antibody comprising.
[Invention 1001]
An IgM antibody or IgM-like antibody having an enhanced serum half-life, comprising a binding unit of five divalent antibodies or a variant or fragment thereof and a variant J chain or a functional fragment thereof.
Each binding unit comprises two IgM heavy chain constant regions or multimerized fragments or variants thereof, each associated with an antigen binding domain or its subunit.
The variant J chain or functional fragment thereof comprises one or more single amino acid substitutions, deletions, or insertions as compared to the reference J chain, and the reference J chain is said one or more singles. It is identical to the variant J chain except for one amino acid substitution, deletion, or insertion, and the variant J chain can affect the serum half-life of the IgM antibody or IgM-like antibody.
Compared to a reference IgM antibody or IgM-like antibody that is identical and similarly administered to the same animal species except for the one or more single amino acid substitutions, deletions, or insertions in the variant J chain. When the IgM antibody or IgM-like antibody is administered to a target animal, it shows an increased serum half-life.
The IgM antibody or IgM-like antibody.
[Invention 1002]
The IgM antibody of the invention 1001 or a functional fragment thereof comprising one, two, three, or four single amino acid substitutions, deletions, or insertions as compared to the reference J chain. IgM-like antibody.
[Invention 1003]
The IgM antibody or IgM-like antibody of the present invention 1001 or the present invention 1002, wherein the variant J chain or a functional fragment thereof comprises an amino acid substitution at the amino acid position corresponding to the amino acid Y102 of the wild-type human J chain (SEQ ID NO: 2).
[Invention 1004]
The IgM antibody or IgM-like antibody of the present invention 1003, wherein the amino acid corresponding to Y102 of SEQ ID NO: 2 is replaced with alanine (A), serine (S), or arginine (R).
[Invention 1005]
The IgM antibody or IgM-like antibody of the present invention 1004, wherein the amino acid corresponding to Y102 of SEQ ID NO: 2 is substituted with alanine (A).
[Invention 1006]
The IgM antibody or IgM-like antibody of the present invention 1005, wherein the J chain is a variant human J chain and contains the amino acid sequence of SEQ ID NO: 3.
[Invention 1007]
The IgM antibody or IgM-like antibody of the present invention 1004, wherein the amino acid corresponding to Y102 of SEQ ID NO: 2 is substituted with serine (S).
[Invention 1008]
The IgM antibody or IgM-like antibody of the present invention 1007, wherein the J chain is a variant human J chain and contains the amino acid sequence of SEQ ID NO: 4.
[Invention 1009]
The IgM antibody or IgM-like antibody of the present invention 1004, wherein the amino acid corresponding to Y102 of SEQ ID NO: 2 is substituted with arginine (R).
[Invention 1010]
The IgM antibody or IgM-like antibody of the present invention 1009, wherein the J chain is a variant human J chain and contains the amino acid sequence of SEQ ID NO: 5.
[Invention 1011]
The IgM antibody or IgM-like antibody of the present invention 1001 or the present invention 1002, wherein the variant J chain or a functional fragment thereof comprises an amino acid substitution at the amino acid position corresponding to the amino acid T103 of the wild human J chain (SEQ ID NO: 2).
[Invention 1012]
The IgM antibody or IgM-like antibody of the present invention 1011 in which the amino acid corresponding to T103 of SEQ ID NO: 2 is substituted with alanine (A).
[Invention 1013]
The IgM antibody or IgM-like antibody of the present invention 1012, wherein the J chain is a variant human J chain and comprises the amino acid sequence of SEQ ID NO: 6.
[Invention 1014]
The variant J chain or a functional fragment thereof comprises an amino acid substitution at the amino acid position corresponding to amino acid N49 or amino acid S51 of human J chain (SEQ ID NO: 2), and S51 is not substituted with treonine (T) or. The IgM or IgM-like antibody of the invention 1001 or the invention 1002, wherein the variant J chain comprises an amino acid substitution at the amino acid position corresponding to both amino acids N49 and S51 of the human J chain (SEQ ID NO: 2).
[Invention 1015]
The IgM antibody of the present invention 1014 or the position corresponding to N49 of SEQ ID NO: 2 is substituted with alanine (A), glycine (G), threonine (T), serine (S), or aspartic acid (D). IgM-like antibody.
[Invention 1016]
The IgM antibody or IgM-like antibody of the present invention 1015, wherein the position corresponding to N49 of SEQ ID NO: 2 is substituted with alanine (A).
[Invention 1017]
The IgM antibody or IgM-like antibody of the present invention 1016, wherein the J chain is a variant human J chain and comprises the amino acid sequence of SEQ ID NO: 7.
[Invention 1018]
The IgM antibody or IgM-like antibody of the present invention 1014, wherein the position corresponding to S51 of SEQ ID NO: 2 is substituted with alanine (A) or glycine (G).
[Invention 1019]
The IgM antibody or IgM-like antibody of the present invention 1018, wherein the position corresponding to S51 of SEQ ID NO: 2 is substituted with alanine (A).
[Invention 1020]
The IgM antibody or IgM-like antibody of the present invention 1019, wherein the J chain is a variant human J chain and comprises the amino acid sequence of SEQ ID NO: 8.
[Invention 1021]
The IgM heavy chain constant region or a multimerized fragment thereof is a variant IgM heavy chain constant region containing one or more single amino acid substitutions, deletions, or insertions as compared to the reference IgM heavy chain constant region. , The reference IgM heavy chain constant region is identical to the variant IgM heavy chain constant region except for the one or more single amino acid substitutions, deletions, or insertions.
The variant IgM heavy chain constant region can affect the serum half-life of the IgM antibody or IgM-like antibody.
Compared to reference IgM or IgM-like antibodies that are identical and similarly administered to the same animal species except for the one or more single amino acid substitutions, deletions, or insertions in the IgM heavy chain constant region. When the IgM antibody or IgM-like antibody is administered to a target animal, the serum half-life is further increased.
The IgM antibody or IgM-like antibody according to any one of 1001 to 1020 of the present invention.
[Invention 1022]
The IgM or IgM-like antibody of 1021 of the present invention, wherein the further increase in serum half-life is additive.
[Invention 1023]
An IgM antibody or IgM-like antibody having an enhanced serum half-life, comprising a binding unit of 5 or 6 divalent antibodies or a variant or fragment thereof.
Each binding unit comprises two variant IgM heavy chain constant regions or multimerized fragments thereof, each associated with an antigen binding domain or its subunit.
The variant IgM heavy chain constant region or a multimerized fragment thereof each comprises one or more single amino acid substitutions, deletions, or insertions as compared to the reference IgM heavy chain constant region, said reference IgM weight. The chain constant region is identical to the variant IgM heavy chain constant region except for the one or more single amino acid substitutions, deletions, or insertions, and the variant IgM heavy chain constant region is the IgM antibody or Can affect the serum half-life of IgM-like antibodies,
Compared to reference IgM or IgM-like antibodies that are identical and similarly administered to the same animal species except for the one or more single amino acid substitutions, deletions, or insertions in the IgM heavy chain constant region. When the IgM antibody or IgM-like antibody is administered to a target animal, the serum half-life is increased.
IgM antibody or IgM-like antibody.
[Invention 1024]
1021-1023 of the present invention, wherein the variant IgM heavy chain constant region comprises one, two, three, or four single amino acid substitutions, deletions, or insertions as compared to the reference IgM heavy chain constant region. IgM antibody or IgM-like antibody.
[Invention 1025]
The IgM antibody or IgM-like antibody according to any one of 1021 to 1024 of the present invention, wherein the variant IgM heavy chain constant region comprises an amino acid substitution at the amino acid position corresponding to amino acid R344 of SEQ ID NO: 12, which is a wild-type human IgM constant region. ..
[Invention 1026]
The IgM antibody or IgM-like antibody of the present invention 1025, wherein the amino acid corresponding to R344 of SEQ ID NO: 12 is substituted with alanine (A).
[Invention 1027]
The IgM antibody or IgM-like antibody of the present invention 1026, wherein the variant IgM heavy chain constant region is a variant human IgM heavy chain constant region and comprises the amino acid sequence of SEQ ID NO: 31.
[Invention 1028]
The IgM antibody or IgM-like antibody according to any one of 1021 to 1024 of the present invention, wherein the variant IgM heavy chain constant region comprises an amino acid substitution at the amino acid position corresponding to amino acid E345 of SEQ ID NO: 12, which is a wild-type human IgM constant region. ..
[Invention 1029]
The IgM antibody or IgM-like antibody of the present invention 1028, wherein the amino acid corresponding to E345 of SEQ ID NO: 12 is substituted with alanine (A).
[Invention 1030]
The IgM antibody or IgM-like antibody of the present invention 1029, wherein the variant IgM heavy chain constant region is a variant human IgM heavy chain constant region and comprises the amino acid sequence of SEQ ID NO: 32.
[Invention 1031]
The IgM antibody or IgM-like antibody according to any one of 1021 to 1024 of the present invention, wherein the variant IgM heavy chain constant region comprises an amino acid substitution at the amino acid position corresponding to amino acid S401 of SEQ ID NO: 12, which is a wild-type human IgM constant region. ..
[Invention 1032]
The IgM antibody or IgM-like antibody of the present invention 1031 in which the amino acid corresponding to S401 of SEQ ID NO: 12 is substituted with alanine (A).
[Invention 1033]
The IgM antibody or IgM-like antibody of the present invention 1032, wherein the variant IgM heavy chain constant region is a variant human IgM heavy chain constant region and comprises the amino acid sequence of SEQ ID NO: 13.
[Invention 1034]
The IgM antibody or IgM-like antibody according to any one of 1021 to 1024 of the present invention, wherein the variant IgM heavy chain constant region comprises an amino acid substitution at the amino acid position corresponding to amino acid E402 of SEQ ID NO: 12, which is a wild-type human IgM constant region. ..
[Invention 1035]
The IgM antibody or IgM-like antibody of the present invention 1034 in which the amino acid corresponding to E402 of SEQ ID NO: 12 is substituted with alanine (A).
[Invention 1036]
The IgM antibody or IgM-like antibody of the present invention 1035, wherein the variant IgM heavy chain constant region is a variant human IgM heavy chain constant region and comprises the amino acid sequence of SEQ ID NO: 14.
[Invention 1037]
The IgM antibody or IgM-like antibody according to any one of 1021 to 1024 of the present invention, wherein the variant IgM heavy chain constant region comprises an amino acid substitution at the amino acid position corresponding to amino acid E403 of SEQ ID NO: 12, which is a wild-type human IgM constant region. ..
[Invention 1038]
The IgM antibody or IgM-like antibody of the present invention 1037, wherein the amino acid corresponding to E403 of SEQ ID NO: 12 is substituted with alanine (A).
[Invention 1039]
The IgM antibody or IgM-like antibody of the present invention 1038, wherein the variant IgM heavy chain constant region is a variant human IgM heavy chain constant region and comprises the amino acid sequence of SEQ ID NO: 34.
[Invention 1040]
The increased serum half-life is an increased alpha half-life (t 1/2 α), an increased beta half-life (t 1/2 β), or an increased t 1/2 α and an increased t 1/2 β . IgM antibody or IgM-like antibody according to any one of the present inventions 1001 to 1039.
[Invention 1041]
Any of 1001-1040 of the invention further indicating increased peak plasma concentration (Cmax), increased area under the curve (AUC), modified clearance time, or any combination thereof as compared to the reference antibody. IgM antibody or IgM-like antibody.
[Invention 1042]
The IgM antibody or IgM-like antibody of any of 1001 to 1041 of the present invention, wherein the IgM heavy chain constant region or a multimerized fragment or variant thereof comprises a Cμ4 domain and an IgM tail (tp) domain, respectively.
[Invention 1043]
The IgM antibody or IgM-like antibody of the invention 1042, wherein the IgM heavy chain constant region or a multimerized fragment or variant thereof further comprises a Cμ3 domain, a Cμ2 domain, a Cμ1 domain, or any combination thereof, respectively.
[Invention 1044]
The IgM antibody or IgM-like antibody of any of 1001 to 1043 of the present invention, wherein the antigen binding domain comprises a single chain Fv (ScFv) fragment or a single domain variable region (VHH).
[Invention 1045]
The IgM antibody or IgM-like antibody according to any one of 1001 to 1043 of the present invention, wherein the subunit of the antigen-binding domain comprises a heavy chain variable region (VH).
[Invention 1046]
The IgM or IgM-like antibody of any of 1001-1045 of the invention, wherein each binding unit further comprises two light chain constant regions or fragments or variants thereof, each associated with an antigen binding domain or subunit thereof.
[Invention 1047]
The light chain constant region is a kappa or lambda light chain constant region or a fragment or variant thereof, and the antigen-binding domain contains a ScFv fragment, or a subunit of the antigen-binding domain forms a light chain variable region (VL). The IgM antibody or IgM-like antibody of the present invention 1046, which comprises.
[Invention 1048]
1001-1047 of the present invention, wherein the J chain or a functional fragment or variant thereof further comprises one or more heterologous polypeptides directly or indirectly fused to the J chain or a functional fragment or variant thereof. Any IgM antibody or IgM-like antibody.
[Invention 1049]
The IgM or IgM-like antibody of the invention 1048, wherein the one or more heterologous polypeptides are fused to the J chain or fragments thereof via a peptide linker.
[Invention 1050]
The IgM antibody or IgM-like antibody of the present invention 1049, wherein the peptide linker contains at least 5 amino acids but 25 amino acids or less.
[Invention 1051]
The peptide linker
[Invention 1052]
The one or more heterologous polypeptide is fused to the N-terminus of the J-chain or fragment or variant thereof, or to the C-terminus of the J-chain or fragment or variant thereof, or the heterologous polypeptide. Is fused to both the N-terminus and the C-terminus of the J chain or fragment or variant thereof, and the heterologous polypeptide may be the same or different, like the IgM antibody or IgM of the invention 1048-1051. antibody.
[Invention 1053]
The IgM antibody or IgM-like antibody according to any one of the present inventions 1048 to 1052, wherein at least one heterologous polypeptide comprises a binding domain.
[Invention 1054]
The IgM antibody or IgM-like antibody of the present invention 1053, wherein the binding domain of the heterologous polypeptide is an antibody or an antigen-binding fragment thereof.
[Invention 1055]
The antigen-binding fragment may be a Fab fragment, a Fab'fragment, an F (ab') 2 fragment, an Fd fragment, an Fv fragment, a single chain Fv (scFv) fragment, a disulfide bond Fv (sdFv) fragment, or any combination thereof. The IgM antibody or IgM-like antibody of the present invention 1054, which comprises.
[Invention 1056]
The IgM antibody or IgM-like antibody of the present invention 1055, wherein the antigen-binding fragment is a scFv fragment.
[Invention 1057]
The IgM antibody or IgM-like antibody according to any one of 1053 to 1056 of the present invention, wherein at least one heterologous polypeptide can specifically bind to CD3ε.
[Invention 1058]
The IgM antibody or IgM-like antibody of the present invention 1057, wherein the J chain is a variant of the modified J chain (V15J) of SEQ ID NO: 9.
[Invention 1059]
The IgM antibody or IgM-like antibody of the present invention 1058, wherein the modified J chain comprises the amino acid sequence of SEQ ID NO: 10 (V15J-Y102A).
[Invention 1060]
The IgM antibody or IgM-like antibody of the present invention 1058, wherein the modified J chain comprises the amino acid sequence of SEQ ID NO: 23 (V15J-T103A).
[Invention 1061]
The IgM antibody or IgM-like antibody of the present invention 1058, wherein the modified J chain comprises the amino acid sequence of SEQ ID NO: 24 (V15J-N49A).
[Invention 1062]
A composition comprising an IgM antibody or IgM-like antibody according to any one of 1001 to 1061 of the present invention and a pharmaceutically acceptable carrier.
[Invention 1063]
A variant J chain or functional fragment thereof comprising one or more single amino acid substitutions, deletions, or insertions relative to the reference J chain, wherein the reference J chain is one or more single. Except for amino acid substitutions, deletions, or insertions, the variant J chain is identical and the variant J chain can affect the serum half-life of an IgM or IgM-like antibody comprising the variant J chain. The variant J chain or a functional fragment thereof.
[Invention 1064]
The present invention comprises the amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 23, SEQ ID NO: 24, or any combination thereof. Variant J chain of 1063.
[Invention 1065]
An isolated polynucleotide comprising a nucleic acid encoding a subunit polypeptide of any IgM or IgM-like antibody of the present invention, wherein the subunit polypeptide is (a) IgM or IgM-like heavy chain constant. Said isolation comprising regions or multimerized fragments thereof, (b) antibody light chains, or (c) J chains, modified J chains, or functional fragments or variants thereof, or (d) any combination thereof. Polynucleotide.
[Invention 1066]
The polynucleotide of the invention 1065, wherein the subunit polypeptide comprises an IgM or IgM-like heavy chain constant region or a multimerized fragment thereof.
[Invention 1067]
The polynucleotide of the invention 1066, wherein the subunit polypeptide comprises the amino acid sequence of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 31, SEQ ID NO: 32, or SEQ ID NO: 34.
[Invention 1068]
The polynucleotide of the invention 1065, wherein the subunit polypeptide comprises an antibody light chain.
[Invention 1069]
The polynucleotide of the invention 1065, wherein the subunit polypeptide comprises a J chain, a modified J chain, or any functional fragment or variant thereof.
[Invention 1070]
The subunits are SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 23, or The polynucleotide of the invention 1069 comprising the amino acid sequence of SEQ ID NO: 24.
[Invention 1071]
The polynucleotide of any of the present invention 1065-1070 comprising, 3 or more nucleic acid sequences encoding 2, 3 or more subunit polypeptides.
[Invention 1072]
An expression vector comprising any of the polynucleotides of the present invention 1065 to 1071.
[Invention 1073]
A host cell comprising any of the polynucleotides of the invention 1065-1071 or the expression vector of the invention 1072.
[Invention 1074]
A method for identifying the variant J chain that can increase the serum half-life of a pentameric IgM antibody or a pentameric IgM-like antibody comprising a variant J chain.
(A) Increased serum half-life in a subject animal comparing a pentameric IgM antibody or a pentameric IgM-like antibody comprising a variant J chain or a fragment thereof to a reference pentameric IgM antibody or pentameric IgM-like antibody. The variant J chain or fragment thereof comprises a predetermined amino acid insertion, deletion, or substitution, and the reference pentameric IgM antibody or pentameric IgM-like antibody comprises the predetermined amino acid. A step of testing, comprising the same J-chain or fragment thereof as the variant J-chain except for insertions, deletions, or substitutions.
(B) A variant J chain or a fragment thereof that imparts an increased serum half-life to the pentameric IgM antibody or pentameric IgM-like antibody as compared with the reference pentameric IgM antibody or pentameric IgM-like antibody. With the process of collecting
The method described above.
[Invention 1075]
A method for identifying the variant J chain that can increase the serum half-life of a pentameric IgM antibody or a pentameric IgM-like antibody comprising a variant J chain.
(A) Pentamer IgM antibodies or pentameric IgM-like antibodies containing variant J chains or fragments thereof can be used with their Fcalpha-mu receptors (FcαμR), multimeric Igreceptors (pIgR), or FcαμR and pIgR. A step of testing for the level of binding to both, wherein the variant J chain or fragment thereof comprises a predetermined amino acid insertion, deletion, or substitution.
(B) Reduced compared to a reference pentameric IgM antibody or pentameric IgM-like antibody containing the same J chain or fragment thereof as the variant J chain except for the predetermined amino acid insertion, deletion, or substitution. A step of recovering a variant J chain or a fragment thereof that imparts FcαμR binding ability, reduced pIgR binding ability, or reduced FcαμR and pIgR binding ability to the pentameric IgM antibody or pentameric IgM-like antibody.
The method described above.
[Invention 1076]
A pentameric IgM antibody or pentameric IgM-like antibody containing the recovered variant J chain or fragment thereof is identical to the recovered variant J chain or fragment thereof except for the predetermined amino acid insertion, deletion, or substitution. The method of the invention 1075, further comprising testing for increased serum half-life in a subject animal as compared to a reference pentameric IgM antibody or pentameric IgM-like antibody comprising a J chain or fragment thereof.
[Invention 1077]
A method for identifying said variant IgM heavy chain constant region capable of increasing the serum half-life of an IgM antibody or IgM-like antibody comprising a variant IgM heavy chain constant region.
(A) A step of testing an IgM antibody or IgM-like antibody containing a variant IgM heavy chain constant region for increased serum half-life in a subject animal compared to a reference pentameric IgM antibody or pentameric IgM-like antibody. The variant IgM heavy chain constant region comprises a predetermined amino acid insertion, deletion, or substitution, and the reference IgM antibody or IgM-like antibody is the variant except for the predetermined amino acid insertion, deletion, or substitution. A step of testing and comprising the same IgM heavy chain constant region as the IgM heavy chain constant region.
(B) The IgM comprising the variant IgM heavy chain constant region that imparts an increased serum half-life to the IgM antibody or IgM-like antibody comprising the variant IgM heavy chain constant region as compared to the reference IgM antibody or IgM-like antibody. With the step of recovering the antibody or IgM-like antibody
The method described above.
[Invention 1078]
A method for identifying said variant IgM heavy chain constant region capable of increasing the serum half-life of an IgM antibody or IgM-like antibody comprising a variant IgM heavy chain constant region.
(A) IgM antibody or IgM-like antibody containing a variant IgM heavy chain constant region thereof, Fcalpha-mu receptor (FcαμR), Fcmu receptor (FcμR), multimer Ig receptor (pIgR), said receptor. A step of testing for any combination of two bodies, or the level of binding of the receptor to all three, wherein the variant IgM heavy chain constant region comprises a predetermined amino acid insertion, deletion, or substitution. The process of testing and
(B) Reduced FcαμR binding compared to a reference IgM antibody or IgM-like antibody that contains the same IgM heavy chain constant region as the variant IgM heavy chain constant region except for the predetermined amino acid insertion, deletion, or substitution. Variant IgM heavy chain constant with reduced FcμR binding ability, reduced pIgR binding ability, reduced binding ability to any two of the receptors, or reduced binding ability to all three of the receptors. A step of recovering the IgM antibody or IgM-like antibody containing the variant IgM heavy chain constant region to be imparted to the IgM antibody or IgM-like antibody containing the region.
The method described above.
[Invention 1079]
The recovered IgM antibody or IgM-like antibody containing the variant IgM heavy chain constant region is subjected to the same IgM heavy chain constant region as the variant IgM heavy chain constant region except for the predetermined amino acid insertion, deletion, or substitution. The method of the invention 1078 comprising further testing for increased serum half-life in a subject animal as compared to a reference IgM antibody or IgM-like antibody comprising.
Claims (29)
各結合ユニットが、各々が抗原結合ドメインまたはそのサブユニットと会合している２つのＩｇＭ重鎖定常領域またはその多量体化断片もしくはバリアントを含み、
前記バリアントＪ鎖またはその機能断片が、参照Ｊ鎖と比較して１つ、２つ、３つ、または４つの単一アミノ酸置換、欠失、または挿入を含み、前記参照Ｊ鎖が、前記１つ、２つ、３つ、または４つの単一アミノ酸置換、欠失、または挿入を除いて前記バリアントＪ鎖と同一であり、前記バリアントＪ鎖が、前記ＩｇＭ抗体またはＩｇＭ様抗体の血清半減期に影響を及ぼすことができ、
前記バリアントＪ鎖における前記１つ、２つ、３つ、または４つの単一アミノ酸置換、欠失、または挿入を除いて同一でありかつ同一の動物種に同様に投与される参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して、前記ＩｇＭ抗体またはＩｇＭ様抗体が、対象動物に投与された際に、増加した血清半減期を示す、
前記ＩｇＭ抗体またはＩｇＭ様抗体。 An IgM antibody or IgM-like antibody having an enhanced serum half-life, comprising a binding unit of five divalent antibodies or a variant or fragment thereof and a variant J chain or a functional fragment thereof.
Each binding unit comprises two IgM heavy chain constant regions or multimerized fragments or variants thereof, each associated with an antigen binding domain or subunit thereof.
The variant J chain or a functional fragment thereof comprises one , two, three, or four single amino acid substitutions, deletions, or insertions as compared to the reference J chain. It is identical to the variant J chain except for one, two, three, or four single amino acid substitutions, deletions, or insertions, where the variant J chain is the serum of the IgM or IgM-like antibody. Can affect the half-life,
A reference IgM antibody or a reference IgM antibody that is identical and similarly administered to the same animal species except for the one, two, three, or four single amino acid substitutions, deletions, or insertions in the variant J chain. The IgM antibody or IgM-like antibody exhibits an increased serum half-life when administered to a subject animal as compared to an IgM-like antibody.
The IgM antibody or IgM-like antibody.
前記バリアントＩｇＭ重鎖定常領域が、前記ＩｇＭ抗体またはＩｇＭ様抗体の血清半減期に影響を及ぼすことができ、
前記ＩｇＭ重鎖定常領域における前記１つ、２つ、３つ、または４つの単一アミノ酸置換、欠失、または挿入を除いて同一でありかつ同一の動物種に同様に投与される参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して、前記ＩｇＭ抗体またはＩｇＭ様抗体が、対象動物に投与された際に、更に増加した血清半減期を示す、
請求項１～６のいずれか一項に記載のＩｇＭ抗体またはＩｇＭ様抗体。 Variants in which the IgM heavy chain constant region or a multimerized fragment thereof comprises one , two, three, or four single amino acid substitutions, deletions, or insertions as compared to the reference IgM heavy chain constant region. The IgM heavy chain constant region, wherein the reference IgM heavy chain constant region is the variant IgM heavy chain constant except for the one, two, three, or four single amino acid substitutions, deletions, or insertions. Same as the area,
The variant IgM heavy chain constant region can affect the serum half-life of the IgM antibody or IgM-like antibody.
Reference IgM that is identical and similarly administered to the same animal species except for the one, two, three, or four single amino acid substitutions, deletions, or insertions in the IgM heavy chain constant region. When the IgM antibody or IgM-like antibody is administered to a target animal, the serum half-life is further increased as compared with the antibody or IgM-like antibody.
The IgM antibody or IgM-like antibody according to any one of claims 1 to 6 .
各結合ユニットが、各々が抗原結合ドメインまたはそのサブユニットと会合している２つのバリアントＩｇＭ重鎖定常領域またはその多量体化断片を含み、
前記バリアントＩｇＭ重鎖定常領域またはその多量体化断片が、それぞれ、参照ＩｇＭ重鎖定常領域と比較して１つ、２つ、３つ、または４つの単一アミノ酸置換、欠失、または挿入を含み、前記参照ＩｇＭ重鎖定常領域が、前記１つ、２つ、３つ、または４つの単一アミノ酸置換、欠失、または挿入を除いて前記バリアントＩｇＭ重鎖定常領域と同一であり、前記バリアントＩｇＭ重鎖定常領域が、前記ＩｇＭ抗体またはＩｇＭ様抗体の血清半減期に影響を及ぼすことができ、
前記ＩｇＭ重鎖定常領域における前記１つ、２つ、３つ、または４つの単一アミノ酸置換、欠失、または挿入を除いて同一でありかつ同一の動物種に同様に投与される参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して、前記ＩｇＭ抗体またはＩｇＭ様抗体が、対象動物に投与された際に、増加した血清半減期を示す、
ＩｇＭ抗体またはＩｇＭ様抗体。 An IgM antibody or IgM-like antibody having an enhanced serum half-life, comprising a binding unit of 5 or 6 divalent antibodies or a variant or fragment thereof.
Each binding unit comprises two variant IgM heavy chain constant regions or multimerized fragments thereof, each associated with an antigen binding domain or subunit thereof.
The variant IgM heavy chain constant region or a multimerized fragment thereof has one , two, three, or four single amino acid substitutions, deletions, or insertions as compared to the reference IgM heavy chain constant region, respectively. The reference IgM heavy chain constant region comprises the same as the variant IgM heavy chain constant region except for the one, two, three, or four single amino acid substitutions, deletions, or insertions. , The variant IgM heavy chain constant region can affect the serum half-life of the IgM antibody or IgM-like antibody.
Reference IgM that is identical and similarly administered to the same animal species except for the one, two, three, or four single amino acid substitutions, deletions, or insertions in the IgM heavy chain constant region. The IgM or IgM-like antibody exhibits an increased serum half-life when administered to a subject animal as compared to the antibody or IgM-like antibody.
IgM antibody or IgM-like antibody.
ＩｇＭ抗体またはＩｇＭ様抗体が、前記参照抗体と比較して、増加したピーク血漿濃度（Ｃｍａｘ）、増加した曲線下面積（ＡＵＣ）、改変されたクリアランス時間、もしくはそれらの任意の組み合わせをさらに示す、
請求項１～１１のいずれか一項に記載のＩｇＭ抗体またはＩｇＭ様抗体。 The increased serum half-life is an increased alpha half -life (t 1 / 2α), an increased beta half -life (t 1 / 2β), or an increased t 1 / 2α and an increased t 1 / 1. Containing 2 β and / or
IgM or IgM-like antibodies further indicate increased peak plasma concentration (Cmax), increased subcurve area (AUC), modified clearance time, or any combination thereof compared to the reference antibody.
The IgM antibody or IgM-like antibody according to any one of claims 1 to 11 .
（１）
（ａ）バリアントＪ鎖またはその断片を含む五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体を、参照五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体と比較して対象動物において増加した血清半減期について試験する工程であって、前記バリアントＪ鎖またはその断片が、既定のアミノ酸挿入、欠失、または置換を含み、前記参照五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体が、前記既定のアミノ酸挿入、欠失、または置換を除いて前記バリアントＪ鎖と同一のＪ鎖またはその断片を含む、試験する工程と、
（ｂ）前記五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体に、参照五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体と比較して増加した血清半減期を付与するバリアントＪ鎖またはその断片を回収する工程と
を含む、あるいは
（２）
（ａ）バリアントＪ鎖またはその断片を含む五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体を、それらのＦｃアルファ－ミュー受容体（ＦｃαμＲ）、多量体Ｉｇ受容体（ｐＩｇＲ）、またはＦｃαμＲ及びｐＩｇＲの両方への結合レベルについて試験する工程であって、前記バリアントＪ鎖またはその断片が既定のアミノ酸挿入、欠失、または置換を含む、試験する工程と、
（ｂ）前記既定のアミノ酸挿入、欠失、または置換を除いて前記バリアントＪ鎖と同一のＪ鎖またはその断片を含む参照五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体と比較して減少したＦｃαμＲ結合能、減少したｐＩｇＲ結合能、または減少したＦｃαμＲ及びｐＩｇＲ結合能を、前記五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体に付与するバリアントＪ鎖またはその断片を回収する工程と
を含む、
前記方法。 A method for identifying the variant J chain that can increase the serum half-life of a pentameric IgM antibody or a pentameric IgM-like antibody comprising a variant J chain.
(1)
(A) Increased serum half-life in a subject animal comparing a pentameric IgM antibody or a pentameric IgM-like antibody comprising a variant J chain or a fragment thereof to a reference pentameric IgM antibody or pentameric IgM-like antibody. The variant J chain or fragment thereof comprises a predetermined amino acid insertion, deletion, or substitution, and the reference pentameric IgM antibody or pentameric IgM-like antibody comprises the predetermined amino acid. A step of testing, comprising the same J-chain or fragment thereof as the variant J-chain except for insertions, deletions, or substitutions.
(B) A variant J chain or a fragment thereof that imparts an increased serum half-life to the pentameric IgM antibody or pentameric IgM-like antibody as compared with the reference pentameric IgM antibody or pentameric IgM-like antibody. Including or including the process of recovery
(2)
(A) Pentamer IgM antibodies or pentameric IgM-like antibodies containing variant J chains or fragments thereof can be used with their Fcalpha-mu receptors (FcαμR), multimeric Igreceptors (pIgR), or FcαμR and pIgR. A step of testing for the level of binding to both, wherein the variant J chain or fragment thereof comprises a predetermined amino acid insertion, deletion, or substitution.
(B) Reduced compared to a reference pentameric IgM antibody or pentameric IgM-like antibody containing the same J chain or fragment thereof as the variant J chain except for the predetermined amino acid insertion, deletion, or substitution. A step of recovering a variant J chain or a fragment thereof that imparts FcαμR binding ability, reduced pIgR binding ability, or reduced FcαμR and pIgR binding ability to the pentameric IgM antibody or pentameric IgM-like antibody.
including,
The method.
（１）
（ａ）バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体を、参照五量体ＩｇＭ抗体または五量体ＩｇＭ様抗体と比較して対象動物において増加した血清半減期について試験する工程であって、前記バリアントＩｇＭ重鎖定常領域が、既定のアミノ酸挿入、欠失、または置換を含み、前記参照ＩｇＭ抗体またはＩｇＭ様抗体が、前記既定のアミノ酸挿入、欠失、または置換を除いて前記バリアントＩｇＭ重鎖定常領域と同じＩｇＭ重鎖定常領域を含む、試験する工程と、
（ｂ）バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体に、前記参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して増加した血清半減期を付与する前記バリアントＩｇＭ重鎖定常領域を含む前記ＩｇＭ抗体またはＩｇＭ様抗体を回収する工程と
を含む、あるいは
（２）
（ａ）バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体を、それらのＦｃアルファ－ミュー受容体（ＦｃαμＲ）、Ｆｃミュー受容体（ＦｃμＲ）、多量体Ｉｇ受容体（ｐＩｇＲ）、前記受容体の任意の２つの組み合わせ、または前記受容体の３つ全てへの結合レベルについて試験する工程であって、前記バリアントＩｇＭ重鎖定常領域が、既定のアミノ酸挿入、欠失、または置換を含む、試験する工程と、
（ｂ）前記既定のアミノ酸挿入、欠失、または置換を除いて前記バリアントＩｇＭ重鎖定常領域と同一のＩｇＭ重鎖定常領域を含む参照ＩｇＭ抗体またはＩｇＭ様抗体と比較して、減少したＦｃαμＲ結合能、減少したＦｃμＲ結合能、減少したｐＩｇＲ結合能、前記受容体の任意の２つへの減少した結合能、または前記受容体の３つ全てへの減少した結合能を、バリアントＩｇＭ重鎖定常領域を含むＩｇＭ抗体またはＩｇＭ様抗体に付与する前記バリアントＩｇＭ重鎖定常領域を含む前記ＩｇＭ抗体またはＩｇＭ様抗体を回収する工程と
を含む、
前記方法。 A method for identifying said variant IgM heavy chain constant region capable of increasing the serum half-life of an IgM antibody or IgM-like antibody comprising a variant IgM heavy chain constant region.
(1)
(A) A step of testing an IgM antibody or IgM-like antibody containing a variant IgM heavy chain constant region for increased serum half-life in a subject animal compared to a reference pentameric IgM antibody or pentameric IgM-like antibody. The variant IgM heavy chain constant region comprises a predetermined amino acid insertion, deletion, or substitution, and the reference IgM antibody or IgM-like antibody is the variant except for the predetermined amino acid insertion, deletion, or substitution. A step of testing and comprising the same IgM heavy chain constant region as the IgM heavy chain constant region.
(B) The IgM comprising the variant IgM heavy chain constant region that imparts an increased serum half-life to the IgM antibody or IgM-like antibody comprising the variant IgM heavy chain constant region as compared to the reference IgM antibody or IgM-like antibody. Including, or including, a step of recovering an antibody or an IgM-like antibody.
(2)
(A) IgM antibody or IgM-like antibody containing a variant IgM heavy chain constant region thereof, Fcalpha-mu receptor (FcαμR), Fcmu receptor (FcμR), multimer Ig receptor (pIgR), said receptor. A step of testing for any combination of two bodies, or the level of binding of the receptor to all three, wherein the variant IgM heavy chain constant region comprises a predetermined amino acid insertion, deletion, or substitution. The process of testing and
(B) Reduced FcαμR binding compared to a reference IgM antibody or IgM-like antibody that contains the same IgM heavy chain constant region as the variant IgM heavy chain constant region except for the predetermined amino acid insertion, deletion, or substitution. Variant IgM heavy chain constant with reduced ability, reduced FcμR binding ability, decreased pIgR binding ability, reduced binding ability to any two of the receptors, or reduced binding ability to all three of the receptors. A step of recovering the IgM antibody or IgM-like antibody containing the variant IgM heavy chain constant region to be imparted to the IgM antibody or IgM-like antibody containing the region.
including,
The method.
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-
2019
- 2019-03-01 KR KR1020207023441A patent/KR20200128391A/en not_active Application Discontinuation
- 2019-03-01 WO PCT/US2019/020374 patent/WO2019169314A1/en active Application Filing
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-
2020
- 2020-03-23 US US16/827,100 patent/US10899835B2/en active Active
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- 2020-12-03 US US17/110,550 patent/US20210087273A1/en not_active Abandoned
-
2023
- 2023-10-26 JP JP2023183845A patent/JP2024016093A/en active Pending
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