JP2001505059A - 複数のV▲下H▼およびV▲下κ▼領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 - Google Patents
複数のV▲下H▼およびV▲下κ▼領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体Info
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.以下の改変を含むゲノムを有するトランスジェニック非ヒト哺乳動物: その哺乳動物が正常なB細胞発生を呈しないように不活性化された内因性免疫 グロブリン(Ig)遺伝子座; 挿入されるVHおよびVκ遺伝子の数がその哺乳動物における正常なB細胞発生が 実質的に再現されるように選択される、 実質的な生殖細胞系コンフィギュレーションとして挿入されたヒト重鎖Ig遺伝 子座であって、ヒトμ定常領域ならびにそれに対する調節およびスイッチ配列、 複数のヒトJH遺伝子、複数のヒトDH遺伝子、ならびに複数のヒトVH遺伝子を含む ヒト重鎖Ig遺伝子座;ならびに 実質的な生殖細胞系コンフィギュレーションとして挿入されたヒトκ軽鎖Ig遺 伝子座であって、ヒトκ定常領域、複数のJκ遺伝子、および複数のVκ遺伝子を 含むヒトκ軽鎖Ig遺伝子座。 2.重鎖Ig遺伝子座がヒトγ1、ヒトγ2、ヒトγ3、ヒトγ4、α、εおよびδか らなる群より選択される第2の定常領域を含む、請求項1記載の哺乳動物。 3.VH遺伝子の数が約20よりも多い、請求項1記載の哺乳動物。 4.Vκ遺伝子の数が約15よりも多い、請求項1記載の哺乳動物。 5.DH遺伝子の数が約25よりも多く、JH遺伝子の数が約4よりも多く、VH遺伝子の 数が約20よりも多く、Jκ遺伝子の数が約4よりも多く、Vκ遺伝子の数が約15よ りも多い、請求項1記載の哺乳動物。 6.DH遺伝子の数、JH遺伝子の数、VH遺伝子の数、Jκ遺伝子の数、およびVκ遺 伝子の数が、Ig遺伝子座が約1×105種を超える異なる機能的な抗体配列の組み合 わせをコードするように選択される、請求項1記載の哺乳動物。 7.哺乳動物の1つの集団において野生型と比べて平均で約50%を超えるB細胞の 機能が再構成される、請求項1記載の哺乳動物。 8.哺乳動物を、ヒト免疫グロブリン分子を産生しうるが機能的な内因性抗体分 子を実質的に産生しえないようにする、以下の改変を含むゲノムを有するトラン スジェニック非ヒト哺乳動物: 接合点多様性または体細胞変異事象に寄与することなく、その哺乳動物が約1 × 106種を超える異なる機能的なヒト免疫グロブリン配列の組み合わせをコードし うるために十分なヒトVH、DH、JH、VκおよびJκ遺伝子の、哺乳動物ゲノムへの 挿入。 9.哺乳動物を、ヒト免疫グロブリン分子を産生しうるが機能的な内因性抗体分 子を実質的に産生しえないようにする改変であって、その哺乳動物が機能的な内 因性抗体分子を産生する能力をもたないことに関してその哺乳動物が正常なB細 胞発生を行えないようにするような以下の改変を含むゲノムを有するトランスジ ェニック非ヒト哺乳動物: その哺乳動物が約1×106種を超える異なる機能的なヒト免疫グロブリン配列の 組み合わせをコードしうるために十分なヒトVH、DH、JH、VκおよびJκ遺伝子、 ならびに哺乳動物において正常なB細胞発生が実質的に再現されるのに十分なVH およびVκ遺伝子の、哺乳動物ゲノムへの挿入。 10.哺乳動物の1つの集団において野生型と比べて平均で約50%を超えるB細胞の 機能が再構成される、請求項9記載の哺乳動物。 11.以下の改変を含むゲノムを有するトランスジェニック非ヒト哺乳動物: 不活性化された内因性重鎖免疫グロブリン(Ig)遺伝子座; 不活性化された内因性κ軽鎖Ig遺伝子座; yH2のヌクレオチド配列に実質的に対応するヌクレオチド配列を含む、挿入さ れたヒト重鎖Ig遺伝子座;および yK2のヌクレオチド配列に実質的に対応するヌクレオチド配列を含む、挿入さ れたヒトκ軽鎖Ig遺伝子座。 12.以下の改変を含むゲノムを有するトランスジェニック非ヒト哺乳動物: 不活性化された内因性重鎖免疫グロブリン(Ig)遺伝子座; yH2のヌクレオチド配列に実質的に対応するヌクレオチド配列を含む、挿入さ れたヒト重鎖Ig遺伝子座;および yK2のヌクレオチド配列に実質的に対応するヌクレオチド配列を含む、挿入さ れたヒトκ軽鎖Ig遺伝子座。 13.以下の改変を含むゲノムを有するトランスジェニック非ヒト哺乳動物: 不活性化された内因性重鎖免疫グロブリン(Ig)遺伝子座; 不活性化された内因性κ軽鎖Ig遺伝子座; ヒトγ2定常領域が存在しないyH2のヌクレオチド配列に実質的に対応するヌク レオチド配列を含む、挿入されたヒト重鎖Ig遺伝子座;および yK2のヌクレオチド配列に実質的に対応するヌクレオチド配列を含む、挿入さ れたヒトκ軽鎖Ig遺伝子座。 14.以下の改変を含むゲノムを有するトランスジェニック非ヒト哺乳動物: 不活性化された内因性重鎖免疫グロブリン(Ig)遺伝子座; ヒトγ2定常領域が存在しないyH2のヌクレオチド配列に実質的に対応するヌク レオチド配列を含む、挿入されたヒト重鎖Ig遺伝子座;および yK2のヌクレオチド配列に実質的に対応するヌクレオチド配列を含む、挿入さ れたヒトκ軽鎖Ig遺伝子座。 15.以下の改変を含むゲノムを有するトランスジェニック非ヒト哺乳動物: 不活性化された内因性重鎖免疫グロブリン(Ig)遺伝子座; ヒトγ2定常領域が存在しないyH2のヌクレオチド配列に実質的に対応するヌク レオチド配列を含む、挿入されたヒト重鎖Ig遺伝子座;および yK2のヌクレオチド配列に実質的に対応するヌクレオチド配列を含む、挿入さ れたヒトκ軽鎖Ig遺伝子座。 16.以下の段階を含む、ヒト抗体を製造するための方法: 請求項1〜10のいずれか一項記載の哺乳動物への抗原の接種; 109M-1よりも大きい親和性で抗原と特異的に結合するヒト抗体を分泌する不死 化細胞系を得るためのリンパ球細胞の回収および不死化;ならびに 不死化細胞系からの抗体の単離。 17.抗原がIL-8である、請求項11記載の方法。 18.抗原がEGFRである、請求項11記載の方法。 19.抗原がTNF-αである、請求項11記載の方法。 20.請求項11記載の方法によって製造される抗体。 21.請求項12記載の方法によって製造される抗IL-8抗体。 22.請求項13記載の方法によって製造される抗EGFR抗体。 23.請求項14記載の方法によって製造される抗TNF-α抗体。 24.複数のヒト可変領域の挿入が含まれる以下の改変を含むゲノムを有するトラ ンスジェニックマウスを製造するための方法: 酵母人工染色体からのヒト可変領域の挿入。 25.請求項19記載の改善の使用を通じて製造されたトランスジェニックマウスお よびそれらに由来するトランスジェニック子孫。 26.挿入されたヒト重鎖免疫グロブリン導入遺伝子が含まれ、以下の改変を含む ゲノムを有するトランスジェニック哺乳動物: ヒト様の接合点多様性およびヒト様の相補性決定領域3(CDR3)の長さを可能 とするヒト可変領域遺伝子の選択された組(set)を含む導入遺伝子。 27.ヒト様の接合点多様性が平均7.7塩基のN付加長を含む、請求項26記載の改変 。 28.ヒト様CDR3の長さが約2から約25残基の間、平均すると約14残基を含む、請 求項26記載の改変。
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US75962096A | 1996-12-03 | 1996-12-03 | |
US08/759,620 | 1996-12-03 | ||
PCT/US1997/023091 WO1998024893A2 (en) | 1996-12-03 | 1997-12-03 | TRANSGENIC MAMMALS HAVING HUMAN IG LOCI INCLUDING PLURAL VH AND Vλ REGIONS AND ANTIBODIES PRODUCED THEREFROM |
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JP2005021414A Division JP4808412B2 (ja) | 1996-12-03 | 2005-01-28 | 複数のVHおよびVκ領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
JP2008132621A Division JP4195077B1 (ja) | 1996-12-03 | 2008-05-21 | 複数のVHおよびVκ領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
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JP52590998A Expired - Lifetime JP4215172B2 (ja) | 1996-12-03 | 1997-12-03 | 複数のV▲下H▼およびV▲下κ▼領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
JP2005021414A Expired - Lifetime JP4808412B2 (ja) | 1996-12-03 | 2005-01-28 | 複数のVHおよびVκ領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
JP2008124406A Withdrawn JP2008194058A (ja) | 1996-12-03 | 2008-05-12 | 複数のVHおよびVκ領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
JP2008132621A Expired - Lifetime JP4195077B1 (ja) | 1996-12-03 | 2008-05-21 | 複数のVHおよびVκ領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
JP2011146571A Withdrawn JP2011212019A (ja) | 1996-12-03 | 2011-06-30 | 複数のVHおよびVκ領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
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JP2005021414A Expired - Lifetime JP4808412B2 (ja) | 1996-12-03 | 2005-01-28 | 複数のVHおよびVκ領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
JP2008124406A Withdrawn JP2008194058A (ja) | 1996-12-03 | 2008-05-12 | 複数のVHおよびVκ領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
JP2008132621A Expired - Lifetime JP4195077B1 (ja) | 1996-12-03 | 2008-05-21 | 複数のVHおよびVκ領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
JP2011146571A Withdrawn JP2011212019A (ja) | 1996-12-03 | 2011-06-30 | 複数のVHおよびVκ領域を含むヒトIg遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体 |
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