JPWO2019198051A5 - - Google Patents

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JPWO2019198051A5
JPWO2019198051A5 JP2021504593A JP2021504593A JPWO2019198051A5 JP WO2019198051 A5 JPWO2019198051 A5 JP WO2019198051A5 JP 2021504593 A JP2021504593 A JP 2021504593A JP 2021504593 A JP2021504593 A JP 2021504593A JP WO2019198051 A5 JPWO2019198051 A5 JP WO2019198051A5
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amino acid
acid sequence
binding protein
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Priority claimed from PCT/IB2019/053040 external-priority patent/WO2019198051A2/en
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（ａ）それぞれ、Ｆａｂ断片及びＦｃ部分を含む、２つの標的抗原結合部分と、
（ｂ）それぞれ、重鎖可変領域（Ｖ Ｈ ）及び軽鎖可変領域（Ｖ Ｌ ）を含む一本鎖可変断片（ｓｃＦｖ）のフォーマットである、２つのＣＤ１６Ａ抗原結合部分と、
を含む、多重特異性抗原結合タンパク質であって、
前記２つのｓｃＦｖのそれぞれのＮ末端における前記可変領域が前記Ｖ Ｌ である、多重特異性抗原結合タンパク質。 (A) Two target antigen binding moieties, each containing a Fab fragment and an Fc moiety ,
(B) Two CD16A antigen binding moieties and two CD16A antigen binding moieties, which are in the form of a single chain variable fragment (scFv) containing a heavy chain variable region ( VH ) and a light chain variable region ( VL ), respectively.
A multispecific antigen-binding protein, including
A multispecific antigen-binding protein in which the variable region at the N-terminus of each of the two scFvs is the VL . 前記少なくとも２つのＣＤ１６Ａ抗原結合部分の前記可変領域が、ＶＬ－ＶＨ、ＶＬ－ＶＬ－ＶＨ－ＶＨ、又はＶＬ－ＶＨ－ＶＬ－ＶＨの順でＮ末端からＣ末端に位置する、請求項１に記載の多重特異性抗原結合タンパク質。 The variable region of the at least two CD16A antigen-binding portions is N-terminal in the order of VL - VH , VL - VL - VH - VH , or VL - VH - VL - VH . The multispecific antigen-binding protein according to claim 1 , which is located at the C-terminal to the above. 前記少なくとも２つのＣＤ１６Ａ抗原結合部分の前記可変領域が、ＶＬ－ＶＨの順でＮ末端からＣ末端に位置する、請求項１又は２に記載の多重特異性抗原結合タンパク質。 The multispecific antigen-binding protein according to claim 1 or 2 , wherein the variable regions of the at least two CD16A antigen-binding portions are located from the N-terminal to the C-terminal in the order of VL - VH . 前記ポリペプチド鎖中の前記少なくとも２つのＣＤ１６Ａ抗原結合部分の前記可変領域が、ＶＬ－ＶＨ－ＶＬ－ＶＨの順でＮ末端からＣ末端に位置する、請求項１又は２に記載の多重特異性抗原結合タンパク質。 The invention according to claim 1 or 2 , wherein the variable regions of the at least two CD16A antigen-binding portions in the polypeptide chain are located from the N-terminal to the C-terminal in the order of VL - VH - VL - VH . Multispecific antigen-binding protein. 前記２つのｓｃＦｖの第１のｓｃＦｖのＮ末端が、前記２つの標的抗原結合部分の第１の標的抗原結合部分の前記Ｆｃ部分のＣ末端に融合し、前記２つのｓｃＦｖの第２のｓｃＦｖのＮ末端が、前記２つの標的抗原結合部分の第２の標的抗原結合部分の前記Ｆｃ部分のＣ末端に融合する、請求項１～４のいずれか一項に記載の多重特異性抗原結合タンパク質。 The N-terminal of the first scFv of the two scFvs fuses with the C -terminal of the Fc portion of the first target antigen-binding portion of the two target antigen-binding portions, and the second scFv of the two scFvs. The multispecific antigen-binding protein according to any one of claims 1 to 4 , wherein the N-terminal fuses with the C-terminal of the Fc portion of the second target antigen-binding portion of the two target antigen-binding portions . ａ）前記Ｆｃ部分が、単量体ＣＨ２－ＣＨ３断片、ヘテロ二量体Ｆｃ領域、及びホモ二量体Ｆｃ領域から選択される、及び／又は、
ｂ）前記Ｆｃ部分がＦｃガンマ受容体に結合しないが、新生児型Ｆｃ受容体への結合を維持する、
請求項１～５のいずれか一項に記載の多重特異性抗原結合タンパク質。 a) The Fc moiety is selected from the monomeric CH2-CH3 fragment, the heterodimer Fc region, and the homodimer Fc region, and / or
b) The Fc moiety does not bind to the Fc gamma receptor but maintains its binding to the neonatal Fc receptor.
The multispecific antigen-binding protein according to any one of claims 1 to 5 . 前記抗原結合タンパク質が、四価である、請求項１～６のいずれか一項に記載の多重特異性抗原結合タンパク質。 The multispecific antigen-binding protein according to any one of claims 1 to 6 , wherein the antigen-binding protein is tetravalent. 前記２つのＣＤ１６Ａ抗原結合部分が、それぞれ、
（ｉ）配列番号５０に示されるアミノ酸配列を含むＣＤＲ１；配列番号５１に示されるアミノ酸配列を含むＣＤＲ２；及び配列番号５２に示されるアミノ酸配列を含むＣＤＲ３を含む重鎖可変領域、並びに／又は、
配列番号５３に示されるアミノ酸配列を含むＣＤＲ１；配列番号５４に示されるアミノ酸配列を含むＣＤＲ２；及び配列番号５５に示されるアミノ酸配列を含むＣＤＲ３を含む軽鎖可変領域；又は、
（ｉｉ）配列番号７３に示されるアミノ酸配列を含むＣＤＲ１；配列番号７４に示されるアミノ酸配列を含むＣＤＲ２；及び配列番号７５に示されるアミノ酸配列を含むＣＤＲ３を含む重鎖可変領域、並びに／又は、
配列番号７６に示されるアミノ酸配列を含むＣＤＲ１；配列番号７７に示されるアミノ酸配列を含むＣＤＲ２；及び配列番号７８に示されるアミノ酸配列を含むＣＤＲ３を含む軽鎖可変領域、
を含む、請求項１～７のいずれか一項に記載の多重特異性抗原結合タンパク質。 The two CD16A antigen-binding moieties are each
(I) CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 50; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 51; and a heavy chain variable region comprising CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 52, and / or.
CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 53; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 54; and a light chain variable region comprising CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 55 ;
(Ii) CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74; and a heavy chain variable region comprising CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75, and / or.
CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 76; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 77; and a light chain variable region comprising CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 78.
The multispecific antigen-binding protein according to any one of claims 1 to 7 , which comprises. 前記２つのＣＤ１６Ａ抗原結合部分が、それぞれ、（ｉ）配列番号３に示されるアミノ酸配列に対して少なくとも約８０％相同若しくは同一であるアミノ酸配列を含む重鎖可変領域、及び／又は（ｉｉ）配列番号２に示されるアミノ酸配列に対して少なくとも約８０％相同若しくは同一であるアミノ酸配列を含む軽鎖可変領域を含む、請求項１～８のいずれか一項に記載の多重特異性抗原結合タンパク質。 A heavy chain variable region and / or a sequence in which the two CD16A antigen-binding moieties contain an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in (i) SEQ ID NO: 3, respectively. The multispecific antigen-binding protein according to any one of claims 1 to 8 , which comprises a light chain variable region containing an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence shown in No. 2. 前記２つのＣＤ１６Ａ抗原結合部分が、それぞれ、（ｉ）配列番号３に示されるアミノ酸配列を含む重鎖可変領域、及び／又は（ｉｉ）配列番号２に示されるアミノ酸配列を含む軽鎖可変領域を含む、請求項１～９のいずれか一項に記載の多重特異性抗原結合タンパク質。 The two CD16A antigen-binding moieties each have a heavy chain variable region containing the amino acid sequence set forth in SEQ ID NO: 3 and / or a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 2. The multispecific antigen-binding protein according to any one of claims 1 to 9 , which comprises. 前記標的抗原が、ＢＣＭＡ又はＥＧＦＲを含む、請求項１～１０のいずれか一項に記載の多重特異性抗原結合タンパク質。 The multispecific antigen-binding protein according to any one of claims 1 to 10 , wherein the target antigen comprises BCMA or EGFR. 前記標的抗原が、ＢＣＭＡを含む、請求項１１に記載の多重特異性抗原結合タンパク質。 The multispecific antigen-binding protein according to claim 11 , wherein the target antigen comprises BCMA. 前記タンパク質が、１つのＢＣＭＡ標的部分又は２つのＢＣＭＡ標的部分を含む、請求項１１又は１２に記載の多重特異性抗原結合タンパク質。The multispecific antigen-binding protein according to claim 11 or 12, wherein the protein comprises one BCMA target moiety or two BCMA target moieties. 前記タンパク質が、配列番号６１又は６３に示されるアミノ酸配列を含む第１のポリペプチド鎖と、配列番号６２又は６４に示されるアミノ酸配列を含む第２のポリペプチド鎖と、を含む四量体である、請求項１２に記載の多重特異性抗原結合タンパク質。 The protein is a tetramer comprising a first polypeptide chain comprising the amino acid sequence set forth in SEQ ID NO: 61 or 63 and a second polypeptide chain comprising the amino acid sequence set forth in SEQ ID NO: 62 or 64. The multispecific antigen-binding protein according to claim 12 . 前記第１のポリペプチド及び前記第２のポリペプチドが、
（ｉ）配列番号６１に示されるアミノ酸配列を含む第１のポリペプチド及び配列番号６２に示されるアミノ酸配列を含む第２のポリペプチド；
（ｉｉ）配列番号６１に示されるアミノ酸配列を含む第１のポリペプチド及び配列番号６４に示されるアミノ酸配列を含む第２のポリペプチド；
（ｉｉｉ）配列番号６３に示されるアミノ酸配列を含む第１のポリペプチド及び配列番号６２に示されるアミノ酸配列を含む第２のポリペプチド；及び
（ｉｖ）配列番号６３に示されるアミノ酸配列を含む第１のポリペプチド及び配列番号６４に示されるアミノ酸配列を含む第２のポリペプチド；
から選択される、請求項１４に記載の多重特異性抗原結合タンパク質。 The first polypeptide and the second polypeptide
(I) A first polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 61 and a second polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 62 ;
(Ii) A first polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 61 and a second polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 64 ;
(Iii) A first polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 63 and a second polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 62 ; and
(Iv) A first polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 63 and a second polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 64 ;
The multispecific antigen-binding protein according to claim 14 , which is selected from. 前記標的抗原がＢＣＭＡを含み、ＢＣＭＡ抗原結合部分が、
（ｉ）配列番号６７に示されるアミノ酸配列を含むＣＤＲ１；配列番号６８に示されるアミノ酸配列を含むＣＤＲ２；及び配列番号６９に示されるアミノ酸配列を含むＣＤＲ３を含む重鎖可変領域、並びに／又は、
（ｉｉ）配列番号７０に示されるアミノ酸配列を含むＣＤＲ１；配列番号７１に示されるアミノ酸配列を含むＣＤＲ２；及び配列番号７２に示されるアミノ酸配列を含むＣＤＲ３を含む軽鎖可変領域、
を含む、請求項１１又は１２に記載の多重特異性抗原結合タンパク質。 The target antigen contains BCMA, and the BCMA antigen-binding portion is
(I) CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 67; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 68; and a heavy chain variable region comprising CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 69, and / or.
(Ii) CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71; and a light chain variable region comprising CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72.
The multispecific antigen-binding protein according to claim 11 or 12 . 前記ＢＣＭＡ抗原結合部分が、
（ｉ）配列番号６５に示されるアミノ酸配列に対して少なくとも約８０％相同若しくは同一であるアミノ酸配列を含む重鎖可変領域、及び／又は
（ｉｉ）配列番号６６に示されるアミノ酸配列に対して少なくとも約８０％相同又は同一であるアミノ酸配列を含む軽鎖可変領域、
を含む、請求項１１、１２及び１６のいずれか一項に記載の多重特異性抗原結合タンパク質。 The BCMA antigen-binding portion is
(I) A heavy chain variable region containing an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 65, and / or at least to the amino acid sequence set forth in (ii) SEQ ID NO: 66. A light chain variable region containing an amino acid sequence that is approximately 80% homologous or identical,
The multispecific antigen-binding protein according to any one of claims 11, 12 and 16 , which comprises. 前記ＢＣＭＡ抗原結合部分が、
（ｉ）配列番号６５に示されるアミノ酸配列を含む重鎖可変領域、及び／又は
（ｉｉ）配列番号６６に示されるアミノ酸配列を含む軽鎖可変領域、
を含む、請求項１１、１２、１６及び１７のいずれか一項に記載の多重特異性抗原結合タンパク質。 The BCMA antigen-binding portion is
(I) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 65, and / or (ii) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 66.
The multispecific antigen-binding protein according to any one of claims 11, 12, 16 and 17, which comprises. （ｉ）２つのＣＤ１６Ａ抗原結合部分は、それぞれ、
（ａ）配列番号７３に示されるアミノ酸配列を含むＣＤＲ１；配列番号７４に示されるアミノ酸配列を含むＣＤＲ２；及び配列番号７５に示されるアミノ酸配列を含むＣＤＲ３を含む重鎖可変領域、及び、
（ｂ）配列番号７６に示されるアミノ酸配列を含むＣＤＲ１；配列番号７７に示されるアミノ酸配列を含むＣＤＲ２；及び配列番号７８に示されるアミノ酸配列を含むＣＤＲ３を含む軽鎖可変領域、
を含み、並びに
（ｉｉ）前記標的抗原がＢＣＭＡを含み、ＢＣＭＡ抗原結合部分は、
（ａ）配列番号６７に示されるアミノ酸配列を含むＣＤＲ１；配列番号６８に示されるアミノ酸配列を含むＣＤＲ２；及び配列番号６９に示されるアミノ酸配列を含むＣＤＲ３を含む重鎖可変領域、及び、
（ｂ）配列番号７０に示されるアミノ酸配列を含むＣＤＲ１；配列番号７１に示されるアミノ酸配列を含むＣＤＲ２；及び配列番号７２に示されるアミノ酸配列を含むＣＤＲ３を含む軽鎖可変領域、
を含む、
請求項１１～１３及び１６～１８のいずれか一項に記載の多重特異性抗原結合タンパク質。 ( I) The two CD16A antigen-binding moieties are each
(A) CDR1 containing the amino acid sequence set forth in SEQ ID NO: 73; CDR2 containing the amino acid sequence set forth in SEQ ID NO: 74; and a heavy chain variable region containing CDR3 containing the amino acid sequence set forth in SEQ ID NO: 75, and
(B) CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 76; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 77; and a light chain variable region comprising CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 78 .
Including, and
(Ii) The target antigen contains BCMA, and the BCMA antigen-binding portion is
(A) CDR1 containing the amino acid sequence set forth in SEQ ID NO: 67; CDR2 containing the amino acid sequence set forth in SEQ ID NO: 68; and a heavy chain variable region containing CDR3 containing the amino acid sequence set forth in SEQ ID NO: 69, and
(B) CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71; and a light chain variable region comprising CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72.
including,
The multispecific antigen-binding protein according to any one of claims 11 to 13 and 16 to 18 . 前記Ｆｃ部分が、少なくとも１つのエフェクタレス（ｅｆｆｅｃｔｏｒ－ｌｅｓｓ）突然変異を含む、請求項１～１９のいずれか一項に記載の多重特異性抗原結合タンパク質。 The multispecific antigen-binding protein according to any one of claims 1 to 19 , wherein the Fc moiety comprises at least one effector-less mutation. 前記少なくとも１つのエフェクタレス突然変異が、（ｉ）Ｃ２２０Ｓ、Ｃ２２９Ｓ、Ｅ２３３Ｐ、Ｌ２３４Ａ、Ｌ２３４Ｖ、Ｌ２３４Ｆ、Ｌ２３５Ａ、Ｌ２３５Ｅ、Ｐ２３８Ｓ、Ｄ２６５Ａ、Ｎ２９７Ａ、Ｎ２９７Ｑ、及びＰ３３１Ｓ;（ｉｉ）Ｌ２３４Ａ、Ｌ２３４Ｖ、Ｌ２３４Ｆ、Ｌ２３５Ａ、Ｌ２３５Ｅ、Ｐ２３８Ｓ、及びＤ２６５Ａ；又は（ｉｉｉ）Ｌ２３４Ｆ、Ｌ２３５Ｅ、及びＤ２６５Ａから選択される、請求項２０に記載の多重特異性抗原結合タンパク質。 The at least one effectorless mutation is (i) C220S, C229S, E233P, L234A, L234V, L234F, L235A, L235E, P238S, D265A, N297A, N297Q, and P331S ; (ii) L234A, L234V, L234. , L235E, P238S, and D265A; or (iii) the multispecific antigen binding protein of claim 20, selected from L234F, L235E, and D265A . 前記Ｆｃ部分が、２つのエフェクタレス突然変異を有する、請求項１～２１のいずれか一項に記載の多重特異性抗原結合タンパク質。 The multispecific antigen-binding protein according to any one of claims 1 to 21 , wherein the Fc moiety has two effectorless mutations. 前記２つのエフェクタレス突然変異が、Ｌ２３４Ｆ及びＬ２３５Ｅである、請求項２２に記載の多重特異性抗原結合タンパク質。 The multispecific antigen-binding protein according to claim 22 , wherein the two effectorless mutations are L234F and L235E. 前記Ｆｃ部分が、３つのエフェクタレス突然変異を有する、請求項１～２１のいずれか一項に記載の多重特異性抗原結合タンパク質。 The multispecific antigen-binding protein according to any one of claims 1 to 21 , wherein the Fc moiety has three effectorless mutations. 前記３つのエフェクタレス突然変異が、Ｌ２３４Ｆ、Ｌ２３５Ｅ、及びＤ２６５Ａである、請求項２４に記載の多重特異性抗原結合タンパク質。 The multispecific antigen-binding protein according to claim 24 , wherein the three effectorless mutations are L234F, L235E, and D265A. 二重特異性抗原結合タンパク質である、請求項１～２５のいずれか一項に記載の多重特異性抗原結合タンパク質。The multispecific antigen-binding protein according to any one of claims 1 to 25, which is a bispecific antigen-binding protein. 二重特異性抗原結合タンパク質が、ＣＤ１６Ａと、ＢＣＭＡに結合する、請求項２６に記載の多重特異性抗原結合タンパク質。The multispecific antigen-binding protein according to claim 26, wherein the bispecific antigen-binding protein binds to CD16A and BCMA. 請求項１～２７のいずれか一項に記載の多重特異性抗原結合タンパク質と、薬学的に許容される担体と、を含む、医薬組成物。 A pharmaceutical composition comprising the multispecific antigen-binding protein according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier. 医薬として使用するための、請求項１～２７のいずれか一項に記載の多重特異性抗原結合タンパク質。 The multispecific antigen-binding protein according to any one of claims 1 to 27 for use as a pharmaceutical . 医薬として使用するための、請求項２８に記載の医薬組成物。 28. The pharmaceutical composition for use as a medicine. 対象における疾患の治療、改善及び／又は予防における使用のための、請求項１～２７のいずれか一項に記載の多重特異性抗原結合タンパク質又は請求項２８に記載の医薬組成物。 The multispecific antigen-binding protein according to any one of claims 1 to 27 or the pharmaceutical composition according to claim 28 for use in the treatment, amelioration and / or prevention of a disease in a subject . 前記疾患が、がんである、請求項３１に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to claim 31 , wherein the disease is cancer. 前記疾患が、血液のがんである、請求項３１又は３２に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to claim 31 or 32 , wherein the disease is blood cancer. 前記疾患が、多発骨髄腫である、請求項３１～３３のいずれか一項に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to any one of claims 31 to 33 , wherein the disease is multiple myeloma. 前記多重特異性抗原結合タンパク質又は医薬組成物は、静脈内に投与される、請求項３１～３４のいずれか一項に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to any one of claims 31 to 34 , wherein the multispecific antigen-binding protein or pharmaceutical composition is administered intravenously . 前記多重特異性抗原結合タンパク質又は医薬組成物は、皮下に投与される、請求項３１～３４のいずれか一項に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to any one of claims 31 to 34 , wherein the multispecific antigen-binding protein or pharmaceutical composition is administered subcutaneously . 対象に第２の治療法が投与される、請求項３１～３６のいずれか一項に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to any one of claims 31 to 36 , wherein a second treatment is administered to the subject . 前記第２の治療法が、抗ＰＤ－１抗体を含む治療法、抗ＰＤ－Ｌ１抗体を含む治療法、ＣＤ３二重特異性抗体を含む治療法、抗ＴＩＧＩＴ抗体を含む治療法、抗ＶＥＧＦ抗体を含む治療法、及び抗ＦｃＲＨ５抗体を含む治療法から選択される、請求項３７に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The second treatment method includes a treatment method containing an anti-PD-1 antibody, a treatment method containing an anti-PD-L1 antibody, a treatment method containing a CD3 bispecific antibody, a treatment method containing an anti-TIGIT antibody, and an anti-VEGF antibody. 37. A multispecific antigen-binding protein or composition for use, which is selected from a treatment method comprising, and a treatment method comprising an anti-FcRH5 antibody. 前記第２の治療法が、サイトカイン療法である、請求項３７に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to claim 37 , wherein the second treatment is cytokine therapy. 前記サイトカインが、ＩＬ－１５、ＩＬ－２、ＩＬ－１２、ＩＬ－２１、及びＩＬ－６から選択される、請求項３９に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen binding protein for use according to claim 39 , wherein the cytokine is selected from IL-15, IL-2, IL-12, IL-21 , and IL-6. Or the composition . 前記サイトカインが、ＩＬ－２を含む、請求項４０に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to claim 40 , wherein the cytokine comprises IL -2 . 前記サイトカインが、ＩＬ－１５を含む、請求項４０に記載の使用のための多重特異性抗原結合タンパク質又は組成物。The multispecific antigen-binding protein or composition for use according to claim 40, wherein the cytokine comprises IL-15. 多発骨髄腫が、再発した／難治性の多発骨髄腫（ＲＲＭＭ）である、請求項３４に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen binding protein or composition for use according to claim 34 , wherein the multiple myeloma is a relapsed / refractory multiple myeloma (RRMM) . 前記対象が、抗ＣＤ３８療法を受けたことがある、請求項３１～４３のいずれか一項に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to any one of claims 31 to 43 , wherein the subject has received anti-CD38 therapy. 前記抗ＣＤ３８療法が、ダラツムマブを含む、請求項４４に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen binding protein or composition for use according to claim 44, wherein the anti - CD38 therapy comprises daratumumab. 前記対象が、ダラツムマブナイーブ、ダラツムマブ抵抗性、ダラツムマブ難治性、又はダラツムマブ再発性である、請求項３１～４５のいずれか一項に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to any one of claims 31 to 45 , wherein the subject is daratumumab naive, daratumumab resistant, daratumumab refractory, or daratumumab relapse. .. 前記対象が、ダラツムマブ抵抗性、ダラツムマブ難治性、又はダラツムマブ再発性である、請求項４６に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to claim 46 , wherein the subject is daratumumab resistant, daratumumab refractory, or daratumumab relapsed. 前記対象が、ＣＤ１６Ａ多型を発現する、請求項３１～４７のいずれか一項に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to any one of claims 31 to 47 , wherein the subject expresses a CD16A polymorphism. 前記ＣＤ１６Ａ多型が、ＣＤ１６Ａ－１５８Ｖ／Ｆ多型である、請求項４８に記載の使用のための多重特異性抗原結合タンパク質又は組成物。 The multispecific antigen-binding protein or composition for use according to claim 48 , wherein the CD16A polymorphism is a CD16A-158V / F polymorphism. 枯渇又は減少したＮＫ細胞集団を有する対象の治療における使用のための、請求項１～２７のいずれか一項に記載の多重特異性抗原結合タンパク質又は請求項２８に記載の医薬組成物。 The multispecific antigen-binding protein according to any one of claims 1 to 27 or the pharmaceutical composition according to claim 28 for use in the treatment of a subject having a depleted or reduced NK cell population .
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