JPWO2021050640A5 - - Google Patents

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JPWO2021050640A5
JPWO2021050640A5 JP2022515026A JP2022515026A JPWO2021050640A5 JP WO2021050640 A5 JPWO2021050640 A5 JP WO2021050640A5 JP 2022515026 A JP2022515026 A JP 2022515026A JP 2022515026 A JP2022515026 A JP 2022515026A JP WO2021050640 A5 JPWO2021050640 A5 JP WO2021050640A5
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cdr
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polypeptide
binding polypeptide
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Priority claimed from PCT/US2020/050063 external-priority patent/WO2021050640A1/en
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細胞表面抗原に結合する第１のドメインと、ヒト及びマカク（Ｍａｃａｃａ）ＣＤ３ε鎖の細胞外エピトープに結合する第２のドメインとを含む二重特異性抗原結合ポリペプチドを精製する方法であって、
（ａ）ポリマーマトリックス部分及びリガンド部分を含む分離樹脂を提供する工程であって、
ここで前記マトリックス部分がポリマーを含み、少なくとも１０μｍの粒径を有し、前記リガンド部分が組換えプロテインＬを含み、前記リガンド部分のプロテインＬが前記マトリックス部分の粒子に共有結合している工程、
（ｂ）前記二重特異性抗原結合ポリペプチドを含むプロセス流体を前記分離樹脂と接触させる工程、
（ｃ）前記分離樹脂の前記リガンド部分によって前記二重特異性抗原結合ポリペプチドを捕捉する工程であって、
ここで、前記二重特異性抗原結合ポリペプチドは前記分離樹脂の前記リガンド部分に可逆的に結合し、前記プロセス流体の残りは前記分離樹脂の前記リガンド部分に結合しない工程であって、
前記プロセス流体を前記分離樹脂に少なくとも１回通して（精製サイクル）、前記二重特異性抗原結合ポリペプチドの前記プロテインＬとの接触を可能にし（滞留時間）、ここで、溶出前の二重特異性抗原結合ポリペプチド滞留時間は、約２．５～４分である工程、
（ｄ）前記結合した二重特異性抗原結合ポリペプチドを、前記リガンド部分から前記二重特異性抗原結合ポリペプチドを溶出させない洗浄バッファで、洗浄する工程、並びに
（ｅ）酸性ｐＨの溶出バッファで前記リガンド部分から前記二重特異性抗原結合ポリペプチドを溶出する工程
を含む方法。 1. A method of purifying a bispecific antigen-binding polypeptide comprising a first domain that binds a cell surface antigen and a second domain that binds an extracellular epitope of human and macaque CD3ε chains, the method comprising:
(a) providing a separation resin comprising a polymer matrix portion and a ligand portion, the step comprising:
wherein the matrix portion comprises a polymer and has a particle size of at least 10 μm, the ligand portion comprises recombinant protein L, and the protein L of the ligand portion is covalently bonded to particles of the matrix portion. process ,
(b) contacting a process fluid containing the bispecific antigen binding polypeptide with the separation resin;
(c) capturing the bispecific antigen-binding polypeptide by the ligand portion of the separation resin ,
wherein the bispecific antigen binding polypeptide reversibly binds to the ligand portion of the separation resin, and the remainder of the process fluid does not bind to the ligand portion of the separation resin ;
Passing the process fluid through the separation resin at least once (purification cycle) to allow contact of the bispecific antigen-binding polypeptide with the Protein L (residence time), where the the specific antigen binding polypeptide residence time is about 2.5 to 4 minutes ;
(d) washing the bound bispecific antigen-binding polypeptide with a wash buffer that does not elute the bispecific antigen-binding polypeptide from the ligand moiety; and (e) washing the bound bispecific antigen-binding polypeptide with an elution buffer at an acidic pH. A method comprising the step of eluting said bispecific antigen binding polypeptide from said ligand moiety. 前記マトリックス部分が、約４５μｍの粒径を有する、請求項１に記載の方法。 2. The method of claim 1, wherein the matrix portion has a particle size of about 45 [mu]m. 前記組換えプロテインＬが、複数のカップリング部位を有するアルカリ安定性四量体リガンドを有する修飾Ｂ４ドメインを含む、請求項１に記載の方法。 2. The method of claim 1, wherein the recombinant Protein L comprises a modified B4 domain with an alkaline stable tetrameric ligand with multiple coupling sites. 前記組換プロテインＬが、二重特異性抗原結合ポリペプチドの抗原結合部位の外側のκ軽鎖に可逆的に結合する、請求項１に記載の方法。 2. The method of claim 1, wherein the recombinant protein L reversibly binds to the kappa light chain outside the antigen binding site of the bispecific antigen binding polypeptide. 前記洗浄バッファが、０．０１～１倍の濃度範囲のリン酸緩衝生理食塩水（ＰＢＳ）、０～３０ｍＭの範囲の３－（Ｎ－モルフォリノ）プロパンスルホン酸（ＭＯＰＳ）、５０～１５０ｍＭの範囲のＮａＣｌ、１５～３５ｍＭの範囲のトリス、０．２５～１Ｍの範囲のアルギニン、及び４０～６０ｍＭの範囲の酢酸塩からなる群からなる群から選択される少なくとも１つの化合物を含み、ｐＨが５～８の範囲である、請求項１に記載の方法。 The washing buffer may include phosphate buffered saline (PBS) in a concentration range of 0.01 to 1 times , 3-(N-morpholino)propanesulfonic acid (MOPS) in a range of 0 to 30 mM , and 50 to 150 mM. of NaCl , Tris in the range of 15-35mM , arginine in the range of 0.25-1M, and acetate in the range of 40-60mM, and the pH is 5. The method according to claim 1, which ranges from 5 to 8. 前記溶出バッファが、１５～３５ｍＭの範囲のトリス、０．２５～１Ｍの範囲のアルギニン、５０～１５０ｍＭの範囲のグリシン、及び５０～１５０ｍＭの範囲の酢酸塩からなる群から選択される少なくとも１つの化合物を含み、３～７．５の範囲のｐＨを有する、請求項１に記載の方法。 The elution buffer contains at least one selected from the group consisting of Tris in the range of 15-35mM , arginine in the range of 0.25-1M , glycine in the range of 50-150mM, and acetate in the range of 50-150mM. 2. The method of claim 1, comprising a compound having a pH in the range of 3 to 7.5. 動的負荷容量は、少なくとも１０ｍｇ／ｍｌ樹脂である、請求項１に記載の方法。 2. The method of claim 1, wherein the dynamic loading capacity is at least 10 mg/ml resin . 溶出結合能力は、少なくとも７．５ｍｇ／ｍｌ樹脂である、請求項１に記載の方法。 2. The method of claim 1, wherein the elution binding capacity is at least 7.5 mg/ml resin . 前記抗原結合ポリペプチドが、一本鎖抗原結合ポリペプチドである、請求項１に記載の方法。 2. The method of claim 1, wherein the antigen binding polypeptide is a single chain antigen binding polypeptide. 二重特異性抗原結合ポリペプチドが、それぞれヒンジ、ＣＨ２ドメイン及びＣＨ３ドメインを含む２つのポリペプチド単量体を含む第３のドメインをさらに含み、前記２つのポリペプチド単量体が、ペプチドリンカーを介して互いに融合されている、請求項１に記載の方法。 The bispecific antigen binding polypeptide further comprises a third domain comprising two polypeptide monomers each comprising a hinge, a CH2 domain and a CH3 domain, said two polypeptide monomers comprising a peptide linker. 2. The method of claim 1, wherein the fused to each other via. 前記第３のドメインが、アミノからカルボキシルの順に、
ヒンジ－ＣＨ２－ＣＨ３－リンカー－ヒンジ－ＣＨ２－ＣＨ３
を含む、請求項１０に記載の方法。 The third domain is in the order of amino to carboxyl,
Hinge-CH2-CH3-Linker-Hinge-CH2-CH3
11. The method of claim 10 , comprising: 前記第３のドメインにおける前記ポリペプチド単量体のそれぞれが、配列番号２０３～２１０からなる群から選択される配列と少なくとも９０％同一であるアミノ酸配列を有する、請求項１０に記載の方法。 11. The method of claim 10 , wherein each of the polypeptide monomers in the third domain has an amino acid sequence that is at least 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 203-210. 前記ポリペプチド単量体のそれぞれが、配列番号２０３～２１０から選択されるアミノ酸配列を有する、請求項１０に記載の方法。 11. The method of claim 10 , wherein each of the polypeptide monomers has an amino acid sequence selected from SEQ ID NOs: 203-210. 前記ＣＨ２ドメインが、ドメイン内システインジスルフィド架橋を含む、請求項１１に記載の方法。 12. The method of claim 11 , wherein the CH2 domain comprises an intradomain cysteine disulfide bridge. （ｉ）前記第１のドメインが２つの抗体可変ドメインを含み、前記第２のドメインが２つの抗体可変ドメインを含むか；
（ｉｉ）前記第１のドメインが１つの抗体可変ドメインを含み、前記第２のドメインが２つの抗体可変ドメインを含むか；
（ｉｉｉ）前記第１のドメインが２つの抗体可変ドメインを含み、前記第２のドメインが１つの抗体可変ドメインを含むか；又は
（ｉｖ）前記第１のドメインが１つの抗体可変ドメインを含み、前記第２のドメインが１つの抗体可変ドメインを含み、
前記第１及び第２のドメインが、ペプチドリンカーを介して前記第３のドメインに融合されている、請求項１に記載の方法。 (i) said first domain comprises two antibody variable domains and said second domain comprises two antibody variable domains;
(ii) said first domain comprises one antibody variable domain and said second domain comprises two antibody variable domains;
(iii) said first domain comprises two antibody variable domains and said second domain comprises one antibody variable domain; or (iv) said first domain comprises one antibody variable domain; the second domain comprises one antibody variable domain;
2. The method of claim 1, wherein the first and second domains are fused to the third domain via a peptide linker. 前記ポリペプチドが、アミノからカルボキシルの順に、
（ａ）第１のドメイン；
（ｂ）配列番号１８７～１８９からなる群から選択されるアミノ酸配列を有するペプチドリンカー；
（ｃ）第２のドメイン
を含む、又は、
前記ポリペプチドが、さらに、アミノからカルボキシルの順に、
（ｄ）配列番号１８７、１８８、１８９、１９５、１９６、１９７及び１９８からなる群から選択されるアミノ酸配列を有するペプチドリンカー；
（ｅ）第３のドメインの第１のポリペプチド単量体；
（ｆ）配列番号１９１、１９２、１９３及び１９４からなる群から選択されるアミノ酸配列を有するペプチドリンカー；並びに
（ｇ）前記第３のドメインの前記第２のポリペプチド単量体
を含む、請求項１に記載の方法。 The polypeptide is in the order of amino to carboxyl,
(a) first domain;
(b ) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 187 to 189;
(c) comprises a second domain; or
The polypeptide further comprises, in the order of amino to carboxyl,
(d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 187, 188, 189, 195, 196, 197 and 198;
(e) a first polypeptide monomer of a third domain;
(f) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 191, 192, 193 and 194; and
(g) said second polypeptide monomer of said third domain;
2. The method of claim 1, comprising : 前記ポリペプチドの前記第１のドメインが、ＣＤ３３、ＣＤ１９、ＢＣＭＡ、ＰＳＭＡ、ＭＳＬＮ、ＥＧＦＲｖＩＩＩ、ＭＵＣ１７、ＣＤ７０又はＥｐＣＡＭのエピトープに結合する、請求項１に記載の方法。 2. The method of claim 1, wherein the first domain of the polypeptide binds to an epitope of CD33, CD19, BCMA, PSMA, MSLN, EGFRvIII, MUC17 , CD70 or EpCAM . 前記第１の結合ドメインが、
（ａ）配列番号１に示されるとおりのＣＤＲ－Ｈ１、配列番号２に示されるとおりのＣＤＲ－Ｈ２、配列番号３に示されるとおりのＣＤＲ－Ｈ３、配列番号４に示されるとおりのＣＤＲ－Ｌ１、配列番号５に示されるとおりのＣＤＲ－Ｌ２及び配列番号６に示されるとおりのＣＤＲ－Ｌ３、
（ｂ）配列番号２９に示されるとおりのＣＤＲ－Ｈ１、配列番号３０に示されるとおりのＣＤＲ－Ｈ２、配列番号３１に示されるとおりのＣＤＲ－Ｈ３、配列番号３４に示されるとおりのＣＤＲ－Ｌ１、配列番号３５に示されるとおりのＣＤＲ－Ｌ２及び配列番号３６に示されるとおりのＣＤＲ－Ｌ３、
（ｃ）配列番号４２に示されるとおりのＣＤＲ－Ｈ１、配列番号４３に示されるとおりのＣＤＲ－Ｈ２、配列番号４４に示されるとおりのＣＤＲ－Ｈ３、配列番号４５に示されるとおりのＣＤＲ－Ｌ１、配列番号４６に示されるとおりのＣＤＲ－Ｌ２及び配列番号４７に示されるとおりのＣＤＲ－Ｌ３、
（ｄ）配列番号５３に示されるとおりのＣＤＲ－Ｈ１、配列番号５４に示されるとおりのＣＤＲ－Ｈ２、配列番号５５に示されるとおりのＣＤＲ－Ｈ３、配列番号５６に示されるとおりのＣＤＲ－Ｌ１、配列番号５７に示されるとおりのＣＤＲ－Ｌ２及び配列番号５８に示されるとおりのＣＤＲ－Ｌ３、
（ｅ）配列番号６５に示されるとおりのＣＤＲ－Ｈ１、配列番号６６に示されるとおりのＣＤＲ－Ｈ２、配列番号６７に示されるとおりのＣＤＲ－Ｈ３、配列番号６８に示されるとおりのＣＤＲ－Ｌ１、配列番号６９に示されるとおりのＣＤＲ－Ｌ２及び配列番号７０に示されるとおりのＣＤＲ－Ｌ３、
（ｆ）配列番号８３に示されるとおりのＣＤＲ－Ｈ１、配列番号８４に示されるとおりのＣＤＲ－Ｈ２、配列番号８５に示されるとおりのＣＤＲ－Ｈ３、配列番号８６に示されるとおりのＣＤＲ－Ｌ１、配列番号８７に示されるとおりのＣＤＲ－Ｌ２及び配列番号８８に示されるとおりのＣＤＲ－Ｌ３、
（ｇ）配列番号９４に示されるとおりのＣＤＲ－Ｈ１、配列番号９５に示されるとおりのＣＤＲ－Ｈ２、配列番号９６に示されるとおりのＣＤＲ－Ｈ３、配列番号９７に示されるとおりのＣＤＲ－Ｌ１、配列番号９８に示されるとおりのＣＤＲ－Ｌ２及び配列番号９９に示されるとおりのＣＤＲ－Ｌ３、
（ｈ）配列番号１０５に示されるとおりのＣＤＲ－Ｈ１、配列番号１０６に示されるとおりのＣＤＲ－Ｈ２、配列番号１０７に示されるとおりのＣＤＲ－Ｈ３、配列番号１０９に示されるとおりのＣＤＲ－Ｌ１、配列番号１１０に示されるとおりのＣＤＲ－Ｌ２及び配列番号１１１に示されるとおりのＣＤＲ－Ｌ３、
（ｉ）配列番号１１５に示されるとおりのＣＤＲ－Ｈ１、配列番号１１６に示されるとおりのＣＤＲ－Ｈ２、配列番号１１７に示されるとおりのＣＤＲ－Ｈ３、配列番号１１８に示されるとおりのＣＤＲ－Ｌ１、配列番号１１９に示されるとおりのＣＤＲ－Ｌ２及び配列番号１２０に示されるとおりのＣＤＲ－Ｌ３、
（ｊ）配列番号１２６に示されるとおりのＣＤＲ－Ｈ１、配列番号１２７に示されるとおりのＣＤＲ－Ｈ２、配列番号１２８に示されるとおりのＣＤＲ－Ｈ３、配列番号１２９に示されるとおりのＣＤＲ－Ｌ１、配列番号１３０に示されるとおりのＣＤＲ－Ｌ２及び配列番号１３１に示されるとおりのＣＤＲ－Ｌ３、
（ｋ）配列番号１３７に示されるとおりのＣＤＲ－Ｈ１、配列番号１３８に示されるとおりのＣＤＲ－Ｈ２、配列番号１３９に示されるとおりのＣＤＲ－Ｈ３、配列番号１４０に示されるとおりのＣＤＲ－Ｌ１、配列番号１４１に示されるとおりのＣＤＲ－Ｌ２及び配列番号１４２に示されるとおりのＣＤＲ－Ｌ３、
（ｌ）配列番号１５２に示されるとおりのＣＤＲ－Ｈ１、配列番号１５３に示されるとおりのＣＤＲ－Ｈ２、配列番号１５４に示されるとおりのＣＤＲ－Ｈ３、配列番号１５５に示されるとおりのＣＤＲ－Ｌ１、配列番号１５６に示されるとおりのＣＤＲ－Ｌ２及び配列番号１５７に示されるとおりのＣＤＲ－Ｌ３、並びに
（ｍ）配列番号１６７に示されるとおりのＣＤＲ－Ｈ１、配列番号１６８に示されるとおりのＣＤＲ－Ｈ２、配列番号１６９に示されるとおりのＣＤＲ－Ｈ３、配列番号１７０に示されるとおりのＣＤＲ－Ｌ１、配列番号１７１に示されるとおりのＣＤＲ－Ｌ２及び配列番号１７２に示されるとおりのＣＤＲ－Ｌ３、
から選択されるＣＤＲ－Ｈ１、ＣＤＲ－Ｈ２及びＣＤＲ－Ｈ３を含むＶＨ領域を含む、請求項１に記載の方法。 The first binding domain is
(a) CDR-H1 as shown in SEQ ID NO: 1, CDR-H2 as shown in SEQ ID NO: 2, CDR-H3 as shown in SEQ ID NO: 3, CDR-L1 as shown in SEQ ID NO: 4 , CDR-L2 as shown in SEQ ID NO: 5 and CDR-L3 as shown in SEQ ID NO: 6,
(b) CDR-H1 as shown in SEQ ID NO: 29, CDR-H2 as shown in SEQ ID NO: 30, CDR-H3 as shown in SEQ ID NO: 31, CDR-L1 as shown in SEQ ID NO: 34; , CDR-L2 as shown in SEQ ID NO: 35 and CDR-L3 as shown in SEQ ID NO: 36,
(c) CDR-H1 as shown in SEQ ID NO:42, CDR-H2 as shown in SEQ ID NO:43, CDR-H3 as shown in SEQ ID NO:44, CDR-L1 as shown in SEQ ID NO:45 , CDR-L2 as shown in SEQ ID NO: 46 and CDR-L3 as shown in SEQ ID NO: 47,
(d) CDR-H1 as shown in SEQ ID NO:53, CDR-H2 as shown in SEQ ID NO:54, CDR-H3 as shown in SEQ ID NO:55, CDR-L1 as shown in SEQ ID NO:56 , CDR-L2 as shown in SEQ ID NO: 57 and CDR-L3 as shown in SEQ ID NO: 58,
(e) CDR-H1 as shown in SEQ ID NO: 65, CDR-H2 as shown in SEQ ID NO: 66, CDR-H3 as shown in SEQ ID NO: 67, CDR-L1 as shown in SEQ ID NO: 68; , CDR-L2 as shown in SEQ ID NO: 69 and CDR-L3 as shown in SEQ ID NO: 70,
(f) CDR-H1 as shown in SEQ ID NO: 83, CDR-H2 as shown in SEQ ID NO: 84, CDR-H3 as shown in SEQ ID NO: 85, CDR-L1 as shown in SEQ ID NO: 86; , CDR-L2 as shown in SEQ ID NO:87 and CDR-L3 as shown in SEQ ID NO:88,
(g) CDR-H1 as shown in SEQ ID NO: 94, CDR-H2 as shown in SEQ ID NO: 95, CDR-H3 as shown in SEQ ID NO: 96, CDR-L1 as shown in SEQ ID NO: 97; , CDR-L2 as shown in SEQ ID NO:98 and CDR-L3 as shown in SEQ ID NO:99,
(h) CDR-H1 as shown in SEQ ID NO: 105, CDR-H2 as shown in SEQ ID NO: 106, CDR-H3 as shown in SEQ ID NO: 107, CDR-L1 as shown in SEQ ID NO: 109; , CDR-L2 as shown in SEQ ID NO: 110 and CDR-L3 as shown in SEQ ID NO: 111,
(i) CDR-H1 as shown in SEQ ID NO: 115, CDR-H2 as shown in SEQ ID NO: 116, CDR-H3 as shown in SEQ ID NO: 117, CDR-L1 as shown in SEQ ID NO: 118; , CDR-L2 as shown in SEQ ID NO: 119 and CDR-L3 as shown in SEQ ID NO: 120,
(j) CDR-H1 as shown in SEQ ID NO: 126, CDR-H2 as shown in SEQ ID NO: 127, CDR-H3 as shown in SEQ ID NO: 128, CDR-L1 as shown in SEQ ID NO: 129 , CDR-L2 as shown in SEQ ID NO: 130 and CDR-L3 as shown in SEQ ID NO: 131,
(k) CDR-H1 as shown in SEQ ID NO: 137, CDR-H2 as shown in SEQ ID NO: 138, CDR-H3 as shown in SEQ ID NO: 139, CDR-L1 as shown in SEQ ID NO: 140; , CDR-L2 as shown in SEQ ID NO: 141 and CDR-L3 as shown in SEQ ID NO: 142,
(l) CDR-H1 as shown in SEQ ID NO: 152, CDR-H2 as shown in SEQ ID NO: 153, CDR-H3 as shown in SEQ ID NO: 154, CDR-L1 as shown in SEQ ID NO: 155 , CDR-L2 as shown in SEQ ID NO: 156 and CDR-L3 as shown in SEQ ID NO: 157, and (m) CDR-H1 as shown in SEQ ID NO: 167, CDR as shown in SEQ ID NO: 168. -H2, CDR-H3 as shown in SEQ ID NO: 169, CDR-L1 as shown in SEQ ID NO: 170, CDR-L2 as shown in SEQ ID NO: 171 and CDR-L3 as shown in SEQ ID NO: 172. ,
2. The method of claim 1, comprising a VH region comprising CDR-H1, CDR-H2 and CDR-H3 selected from. 二重特異性抗原結合ポリペプチドの製造プロセスの収率を改善するための方法であって、ダウンストリームプロセスにおいて、請求項１に記載の方法が適用される方法。 A method for improving the yield of a process for producing bispecific antigen-binding polypeptides, wherein the method according to claim 1 is applied in a downstream process. マトリックス部分が、ポリメタクリレートであるポリマーを含む、請求項１に記載の方法。2. The method of claim 1, wherein the matrix portion comprises a polymer that is a polymethacrylate.
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