JP2022031635A - Cd47に対するヒト化及びキメラモノクローナル抗体 - Google Patents
Cd47に対するヒト化及びキメラモノクローナル抗体 Download PDFInfo
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Abstract
Description
一態様において、本発明は、CD47と特異的に反応性で、CD47を中和するヒト化又はキメラモノクローナル抗体、及びこのような抗体を産生する細胞株を対象とする。例示的な抗体の可変領域が提供される。対象の抗体には、これらの提供される組み合わせ、及び適当な定常領域又は定常領域の断片への可変領域の融合物(例えば、F(ab)’抗体を作製するもの)が含まれる。対象の可変領域には、提供される抗CD47抗体の少なくとも1つのCDR配列が含まれ、CDRはアミノ酸が3個、4個、5個、6個、7個、8個、9個、10個、11個、12個又はそれ以上であることができる。或いは、対象の抗体には、提供される抗体において示される可変領域、又は本明細書中に示される可変領域配列の対が含まれる。
本発明のヒト化又はキメラモノクローナル抗体は、参照によって全体が本明細書中に具体的に組み込まれる国際出願US2009/000319に記載された方法を含む、食作用の調節に使用できる。例えば、抗体組成物は、CD47を発現するがん細胞の食作用を増加させるために投与することができる。
以下の実施例は、本発明の製造方法及び使用方法についての完全な開示及び説明を当業者に提供するために示すものであって、本発明者らが自身の発明と考えるものの範囲を限定することも、下記の実験が実施した実験の全て又は実施した唯一の実験であることを意味することも意図しない。使用する数値(例えば、量、温度など)に関しては精度を保証するよう努めたが、若干の実験誤差及び偏差は考慮に入れなければならない。特に明記しない限り、部は重量部であり、分子量は重量平均分子量であり、温度は摂氏度であり、圧力は大気圧又はほぼ大気圧である。
本発明者らはここで、ヒトCD47に対するモノクローナル抗体のクローニング、作製及び発現について説明する。ヒトCD47に対する機能的阻害抗体、B6H12を分泌するマウスハイブリドーマ細胞株から、総RNAを調製し、Ig特異的オリゴヌクレオチドを用いてcDNAに転換した。cDNA断片をコードする重鎖及び軽鎖を単離し、配列決定した。次いで、マウスV領域cDNA断片をヒト免疫グロブリン定常領域に連結することによって、キメラ遺伝子を作製した。競合FACS分析によれば、キメラB6H12は、CD47とのネイティブマウスB6H12抗体の結合を阻害した。これは、キメラ及びマウスB6H12抗体が、CD47の同じエピトープを認識することを立証している。さらにまた、本発明者らは、ヒト化B6H12抗体を設計し、CDR移植によって作製した。ヒト化B6H12抗体は、キメラB6H12に相当するCD47結合を示した。キメラ及びヒト化B6H12抗体はいずれも、インビトロでがん細胞の食作用を可能にする。本発明者らは、キメラ及びヒト化抗体は、抗がん療法の一部としてヒト患者に投与される場合に、ネイティブマウス抗体より免疫原性が低いと予想する。
抗体Vのクローニング及び配列決定。ここで使用したクローニングストラテジーは、ハイブリドーマ細胞(Qiagen)からのRNAの最初の単離及びcDNAの調製を含む。B6H12モノクローナル抗体の重鎖及び軽鎖可変領域をコードするcDNA配列を、5’RACE-PCR技術(Clontech)を用いて取得し、標準なDNA配列決定法を用いて配列決定した。
VHセンスプライマー、
5’CAGACCCGTCGACATGAACTTCGGGCTCAGCTTGATTTTCCTT3’
VHアンチセンスプライマー、
5’GCCCTTGGTGCTAGCTGAGGAGACGGTGACTGAGGTTCCTTGACC3’
VLセンスプライマー、
5’CGCCATCACAGATCTATGGTGTCCACTTCTCAGCTCCTTGGACTT3’
VLアンチセンスプライマー、
5’TGCAGCCACCGTACGTTTGATTTCCAGCTTGGTGCCTCCACCGAA3’。
次いで、クローン化pfu DNAポリメラーゼ(Invitrogen)を用いて、PCRを行った。これらのPCR産物を、VHについてはSalI/NheI及びVLについてはBglII/BsiwIによって切断し、それぞれSalI/NheI又はBglII/BsiwIによって消化されるヒトγ1及びκ定常領域をコードする発現ベクター中にライゲートさせた。全てのコンストラクトを配列決定して、配列適合度を確認した。
マウスB6H12可変領域のクローニング。ユニバーサル抗体プライマーを用いて、抗CD47 B6H12ハイブリドーマから、重鎖及び軽鎖可変領域をコードするクローンを成功裏に単離した。各V遺伝子産物の複数のクローンを配列決定して、PCRによって誘発されたエラーをモニターした。VH配列及びVL配列はそれぞれ、図1A及び1Bに示される。産物のDNA配列分析により、B6H12の重鎖がIgh-v7183 VH5ファミリーのVセグメントを使用すること、及び軽鎖がIGKV23サブグループに属することが立証された。重鎖可変領域は、CDR1、CDR2及びCDR3配列を含み、軽鎖可変領域は、CDR1、CDR2及びCDR3配列を含む(図1)。
ユニバーサル抗体プライマーを用いて、抗CD47ハイブリドーマ5F9及び8B6から、重鎖及び軽鎖可変領域をコードするDNA断片を成功裏にクローニングした。各V遺伝子産物の複数のクローンを配列決定して、PCRによって誘発されたエラーをモニターした。5F9のVH配列及びVL配列はそれぞれ、図9A及び9Bに示される。産物のDNA配列分析により、5F9の重鎖がIgh-VJ558 VH1ファミリーのVセグメントを使用すること、及び軽鎖がIGKV1サブグループに属することが立証された。8B6のVH及びVL配列はそれぞれ、図10A及び10Bに示される。産物のDNA配列分析により、8B6の重鎖がIgh-VJ558 VH1ファミリーのVセグメントを使用すること、及び軽鎖がIGKV23サブグループに属することが立証された。重鎖可変領域は、CDR1、CDR2及びCDR3配列を含み、軽鎖可変領域は、CDR1、CDR2及びCDR3配列を含む(図9及び10)。
1. ヒトCD47に特異的に結合し、且つ配列番号3~8、配列番号20~25又は配列番号28~33に示される少なくとも1つのCDR配列を含む、単離キメラ又はヒト化抗体。
2. 抗体の軽鎖が、配列番号6~8、配列番号23~25又は配列番号31~33から選択される少なくとも1つのCDRを含む、実施形態1に記載の単離キメラ又はヒト化抗体。
3. 前記軽鎖が、配列番号6~8、配列番号23~25又は配列番号31~33に示されるCDR配列のそれぞれを含む、実施形態2に記載の抗体。
4. 前記軽鎖が、配列番号12又は図12Bに示されるアミノ酸配列を含む、実施形態3に記載の抗体。
5. 抗体の重鎖が、配列番号3~5、配列番号20~22又は配列番号28~30から選択される少なくとも1つのCDRを含む、実施形態1に記載の単離キメラ又はヒト化抗体。
6. 前記重鎖が、配列番号3~5、配列番号20~22又は配列番号28~30に示されるCDR配列のそれぞれを含む、実施形態5に記載の抗体。
7. 前記重鎖が、配列番号11、17又は図12Aに示されるアミノ酸配列を含む、実施形態6に記載の抗体。
8. 実施形態2から4のいずれかに記載の軽鎖と実施形態5から7のいずれか一項に記載の重鎖とを含む、実施形態1に記載の抗体。
9. 前記抗体が、配列番号2~5に示されるCDR配列のそれぞれを有する重鎖及び配列番号5~6に示されるCDR配列のそれぞれを有する軽鎖、又は配列番号20~22に示されるCDR配列のそれぞれを有する重鎖及び配列番号23~25に示されるCDR配列のそれぞれを有する軽鎖、又は配列番号28~30に示されるCDR配列のそれぞれを有する重鎖及び配列番号31~33に示されるCDR配列のそれぞれを有する軽鎖を含む、実施形態8に記載の抗体。
10. 結合時にCD47を活性化しない、実施形態1から8のいずれか一項に記載の抗体。
11. ヒト化モノクローナル抗体である、実施形態9に記載の抗体。
12. キメラ抗体である、実施形態9に記載の抗体。
13. 実施形態1から12のいずれか一項に記載の抗体をコードするポリヌクレオチド。
14. 実施形態1から12のいずれか一項に記載の抗体を産生する細胞。
15. 実施形態1から12のいずれか一項に記載の抗体を含む医薬組成物。
16. 実施形態1から12のいずれか一項に記載の抗体と、医薬として許容される賦形剤とを含む医薬組成物。
17. 実施形態1から12のいずれか一項に記載の抗体の治療有効量を、食作用を調節するのに有効な用量で対象に投与するステップを含む、食作用の調節方法。
18. 対象がヒトである、実施形態17に記載の方法。
19. 配列番号1~8、11~12又は17のいずれか1つに示されるアミノ酸配列を含む抗体。
20. 配列番号9、10又は13~16のいずれか1つに示されるヌクレオチド配列によってコードされる抗体。
21. 生体試料又は組織中のCD47の存在を検出する方法であって、前記試料又は組織を実施形態1に記載の抗体と接触させるステップと、前記組織又は試料に結合した抗体の存在を決定するステップとを含む方法。
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