JP2021526830A - 複数のジスルフィド架橋によって安定化され、遺伝子変換によって多様化された長いcdr−h3sで抗体を作製するトランスジェニックニワトリ - Google Patents
複数のジスルフィド架橋によって安定化され、遺伝子変換によって多様化された長いcdr−h3sで抗体を作製するトランスジェニックニワトリ Download PDFInfo
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Abstract
【選択図】図2
Description
本出願は、2018年7月13日に出願された米国仮特許出願第62/684,669号の優先権を主張し、この出願は参照により本明細書に組み込まれる。
「決定する」、「測定する」、「評価する(evaluating)」、「評価する(assessing)」、および「アッセイする」という用語は、任意の形態の測定を指すために本明細書において互換的に使用され、ある要素が存在するかどうかを決定することを含む。これらの用語は、定量的および/または定性的決定の両方を含む。評価は、相対的または絶対的であってもよい。「〜の存在を決定すること」は、存在する何かの量を決定すること、ならびにそれが存在するのかどうかを決定することを含む。
本主題発明をさらに説明する前に、本発明は、記載される特定の実施形態に限定されるものではなく、当然のことながら、それ自体変化し得ることを理解されたい。本発明の範囲は、添付の特許請求の範囲のみによって限定されるため、本明細書で使用される用語は、特定の実施形態を説明する目的のみのものであり、限定的であることは意図されないこともまた理解されたい。
Claims (26)
- トランスジェニックニワトリであって、内因性免疫グロブリン重鎖遺伝子座が、
(a)CDR3が、30〜60アミノ酸長さの範囲にあり、少なくとも2つのシステイン残基を含む重鎖可変ドメインをコードする核酸を含む機能的免疫グロブリン重鎖遺伝子と、
(b)前記機能的免疫グロブリン重鎖遺伝子に作動可能に連結され、遺伝子変換によって、ヌクレオチド配列を(a)の前記重鎖可変ドメインをコードする核酸に供与する複数の偽遺伝子と、を含み、前記偽遺伝子が、前記機能的免疫グロブリン重鎖遺伝子の上流または下流にある、B細胞を含む、トランスジェニックニワトリ。 - 前記ニワトリの非B細胞が、VHセグメント、Dクラスター、Jセグメント、および複数の上流偽遺伝子を含む内因性免疫グロブリン重鎖遺伝子座を含み、前記Dクラスター内の各Dセグメントが、30〜60アミノ酸長さの範囲内の異なる配列をコードし、少なくとも2つ)のシステイン残基を含む、請求項1に記載のトランスジェニックニワトリ。
- 前記ニワトリの非B細胞が、(a)の前記機能的免疫グロブリン重鎖遺伝子および(b)の前記偽遺伝子を含む、請求項1または2に記載のトランスジェニックニワトリ。
- 前記偽遺伝子が、(a)の前記重鎖可変ドメインのCDR3領域に対応する配列を含まない、請求項1〜3のいずれかに記載のトランスジェニックニワトリ。
- 前記偽遺伝子が、遺伝子変換によって、(a)の前記重鎖可変ドメインのCDR3領域のコード配列を多様化する配列を含む、請求項1〜4のいずれかに記載のトランスジェニックニワトリ。
- 遺伝子変換によって、(a)の前記重鎖可変ドメインのCDR3領域のコード配列を多様化する前記偽遺伝子の配列が、30〜60アミノ酸配列長さの範囲内にあるアミノ酸配列をコードし、少なくとも2つのシステイン残基を含む、請求項1〜5のいずれかに記載のトランスジェニックニワトリ。
- (a)の前記重鎖可変ドメインが、自律型重鎖(AHC)可変ドメインである、請求項1〜6に記載のトランスジェニックニワトリ。
- (a)の前記AHC可変ドメインが、30〜60アミノ酸長さであり、少なくとも2つのシステイン残基を含むCDR3を有するラクダ化ヒト重鎖可変ドメインである、請求項7に記載のトランスジェニックニワトリ。
- (a)の前記AHC可変ドメインが、ラクダ化ヒトモノクローナル抗体である、請求項7に記載のトランスジェニックニワトリ。
- (a)の前記AHC可変ドメインが、ヒト生殖系列重鎖Vセグメント、30〜60アミノ酸長さの範囲内のアミノ酸配列をコードし、少なくとも2つのシステイン残基を含むDセグメントによってコードされ、前記AHC可変ドメインが、最大10のラクダ化アミノ酸置換を含む、請求項7に記載のトランスジェニックニワトリ。
- (b)の前記偽遺伝子が、ヒト生殖系列抗体配列をコードする、請求項1〜10のいずれかに記載のトランスジェニックニワトリ。
- 前記偽遺伝子が、600ヌクレオチド未満の長さである、請求項11に記載のトランスジェニックニワトリ。
- 前記偽遺伝子が、300〜600ヌクレオチドの長さである、請求項1〜12のいずれかに記載のトランスジェニックニワトリ。
- 前記内因性免疫グロブリン重鎖遺伝子座が、CH1欠失を含む重鎖をコードする、請求項1〜13のいずれかに記載のトランスジェニックニワトリ。
- 前記ニワトリのゲノムが、ノックアウトされた軽鎖免疫グロブリン遺伝子を含む、請求項1〜14のいずれかに記載のトランスジェニックニワトリ。
- 前記動物のゲノムが、定常領域を含むが可変領域を含まない短縮型軽鎖をコードする軽鎖免疫グロブリン遺伝子を含む、請求項1〜15のいずれかに記載のトランスジェニックニワトリ。
- 動物が、前記遺伝子座についてホモ接合性である、請求項1〜16のいずれかに記載のトランスジェニックニワトリ。
- 動物が、前記遺伝子座についてヘテロ接合性である、請求項1〜17のいずれかに記載のトランスジェニックニワトリ。
- (a)請求項1〜18のいずれかに記載のトランスジェニック動物を抗原で免疫化することと、
(b)前記動物から、前記抗原に特異的に結合する抗体を得ることと、を含む、方法。 - 前記抗体が、ポリクローナルである、請求項19に記載の方法。
- 前記抗体が、モノクローナルである、請求項19に記載の方法。
- (c)前記トランスジェニック動物のB細胞を使用してハイブリドーマを作製することと、
(d)前記ハイブリドーマをスクリーニングして、前記抗原に特異的に結合する抗体を産生するハイブリドーマを同定することと、をさらに含む、請求項19〜21のいずれかに記載の方法。 - (c)ハイブリドーマを作製せずにB細胞をスクリーニングして、前記抗原に特異的に結合する抗体を産生するB細胞を同定することをさらに含む、請求項19〜21のいずれかに記載の方法。
- PCRを使用して、前記トランスジェニック動物のB細胞から少なくとも前記重鎖可変領域をコードする核酸を増幅することと、前記増幅された核酸を使用して組換え抗体を発現させることと、をさらに含む、請求項19〜23のいずれかに記載の方法。
- 前記抗体が、自律型重鎖(AHC)可変ドメイン抗体である、請求項1〜18のいずれかに記載のトランスジェニック動物によって産生される、モノクローナルまたはポリクローナル抗体。
- 請求項1〜18のいずれかに記載の動物から単離された、B細胞。
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