JP2017505614A - P97融合タンパク質 - Google Patents
P97融合タンパク質 Download PDFInfo
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- JP2017505614A JP2017505614A JP2016548215A JP2016548215A JP2017505614A JP 2017505614 A JP2017505614 A JP 2017505614A JP 2016548215 A JP2016548215 A JP 2016548215A JP 2016548215 A JP2016548215 A JP 2016548215A JP 2017505614 A JP2017505614 A JP 2017505614A
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- trastuzumab
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- fusion protein
- heavy chain
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Abstract
Description
本出願は、米国特許法第119条(e)の下で、2014年2月3日に出願された米国出願第61/935,253号の優先権を主張し、この仮出願は、その全体が参照により組み込まれる。
本出願に関連付けられる配列一覧は、ハードコピーの代わりにテキスト形式で提供され、ここに参照により本明細書に組み込まれる。配列一覧を含むテキストファイルの名称は、BIOA_008_01WO_ST25.txtである。このテキストファイルは、約340KBであり、2015年2月3日に作成され、EFS−Webを介して電子的に提出されている。
技術分野
本発明の実施形態は、p97(メラノトランスフェリン)−トラスツズマブ融合タンパク質及び抗体融合タンパク質、ならびにその使用に関連する方法に関し、例えば、血液脳関門(BBB)を越えるトラスツズマブの送達を促進し、かつ/またはCNS及び末梢組織における抗体の組織浸透を向上させ、それによって中枢神経系(CNS)の癌を含むHER2陽性癌を治療及び/または診断する方法に関する。
脳の障害等の中枢神経系(CNS)の多くの障害の治療または診断に対する主要な課題を象徴するのは、治療剤または診断剤を脳の特定の領域に送達する困難の克服である。その神経保護の役割において、血液脳関門(BBB)は、潜在的に重要な多くの診断剤及び治療剤の脳への送達を阻害するように機能する。
a)配列番号82の重鎖及び配列番号83の軽鎖、
b)配列番号84の重鎖及び配列番号85の軽鎖、
c)配列番号86の重鎖及び配列番号87の軽鎖、
d)配列番号88の重鎖及び配列番号89の軽鎖、
e)配列番号90の重鎖及び配列番号91の軽鎖、
f)配列番号92の重鎖及び配列番号93の軽鎖、ならびに
g)配列番号94の重鎖及び配列番号95の軽鎖(前述のいずれかの、それらのフラグメント/変異型を含む)のうちの1つ以上から選択されるものが挙げられる。一部の実施形態において、p97−抗体融合物は、a)の2つのセット、b)の2つのセット、c)の2つのセット、d)の2つのセット、e)の2つのセット、f)の2つのセット、またはg)の2つのセットを含むホモ二量体である。一部の実施形態において、p97−抗体融合物は、上記a)〜g)の任意の組み合わせを含むヘテロ二量体である。特定の実施形態において、p97−抗体融合物は、上記a)〜g)から選択される重鎖及び軽鎖のセットの第1のセットと、トラスツズマブ(非融合)重鎖及び軽鎖の第2のセット、例えば、配列番号29〜35または122(重鎖)及び36または123(軽鎖)とを含むヘテロ二量体である。
別途定義されない限り、本明細書で使用される全ての技術用語及び科学用語は、本発明が属する技術分野の当業者によって広く理解されているものと同じ意味を有する。本明細書に記載されるものに類似または同等の任意の方法及び材料を本発明の実践または試験において使用することができるが、好ましい方法及び材料を記載する。本発明の目的に関して、以下の用語を下に定義する。
本発明の実施形態は、概して、ヒトp97(メラノトランスフェリン、MTf)ポリペプチド配列、トラスツズマブ配列、またはそれらの抗原結合フラグメントを含む融合タンパク質、そのような融合タンパク質を含む抗体(すなわち、抗体融合物)、融合タンパク質をコードするポリヌクレオチド、融合タンパク質/抗体を生成する宿主細胞及び方法、ならびに関連する組成物及びその使用方法に関する。例示的なp97ポリペプチド配列及びトラスツズマブ配列が下に記載される。p97ポリペプチド配列をトラスツズマブ配列に連結するための例示的方法、及びそのためのリンカーペプチド等の構成要素もまた記載される。
a)配列番号82の重鎖及び配列番号83の軽鎖、
b)配列番号84の重鎖及び配列番号85の軽鎖、
c)配列番号86の重鎖及び配列番号87の軽鎖、
d)配列番号88の重鎖及び配列番号89の軽鎖、
e)配列番号90の重鎖及び配列番号91の軽鎖、
f)配列番号92の重鎖及び配列番号93の軽鎖、
g)配列番号94の重鎖及び配列番号95の軽鎖、
(それらのフラグメント/変異型を含む)のうちの1つ以上から選択される。一部の実施形態において、p97−抗体融合物は、a)の2つのセット、b)の2つのセット、c)の2つのセット、d)の2つのセット、e)の2つのセット、f)の2つのセット、またはg)の2つのセットを含むホモ二量体である。特定の実施形態において、p97−抗体融合物は、上記のa)〜g)から選択される重鎖及び軽鎖のセットのうちの第1のセット、本明細書に記載されるp97−トラスツズマブ重鎖もしくは軽鎖の任意の組み合わせで構成される重鎖及び軽鎖の第2のセット(例えば、上記のa)〜g)、配列番号37〜46、96〜109、及び110〜121)、ならびに/またはトラスツズマブ(非融合)重鎖及び軽鎖のうちのいずれか(例えば、配列番号29〜35もしくは122(重鎖)及び36もしくは123(軽鎖))を含むヘテロ二量体である。
ある特定の実施形態は、本明細書に記載されるp97−トラスツズマブ融合タンパク質及び/または関連する抗体融合タンパク質を使用する方法に関する。そのような方法の例としては、治療方法及び診断方法が挙げられ、後者としては例えば、中枢神経系の医用画像診断等、ある特定の器官/組織の医用画像診断が挙げられる。特定の実施形態は、中枢神経系(CNS)の障害もしくは病態、またはCNS構成要素を有する障害もしくは病態の治療及び/または診断の方法を含む。本明細書に記載されるp97−トラスツズマブ融合タンパク質及び/または関連する抗体融合タンパク質を含む薬学的組成物もまた含まれる。
p97−トラスツズマブ融合タンパク質のヒトHer2/Neuへの結合
ヒトp97(MTf)−トラスツズマブ融合構築物を調製し、活性について試験した。MTf−トラスツズマブ融合構築物のアミノ酸配列を、下の表E1に示す。
p97−トラスツズマブ融合タンパク質のADCC細胞致死活性
MTf−トラスツズマブ融合構築物を、それぞれ正の対照及び負の対照としてのHerceptin(登録商標)(トラスツズマブ)及びヒトIgG1 Fcと比較した、BT−474乳癌細胞における抗体依存性細胞介在性細胞傷害活性(ADCC)について試験した。
p97−トラスツズマブ融合タンパク質のインビボ抗腫瘍効率
p97−トラスツズマブ融合タンパク質を、ヒトBT−474乳腺腫瘍細胞を頭蓋内注射されたマウスにおける抗腫瘍効率及び生存への影響について試験する。具体的には、融合構築物、TZM HC−MTf及びMTfp NH−TZMを、Herceptin(登録商標)(トラスツズマブ、AMM:5621037,ROCHE)と比較して試験する。
・グループ1のマウスは、6週間連続して週2回、ビヒクルのIV投与を受ける。
・グループ2のマウスは、6週間連続して週2回、30mg/kgのHerceptin(登録商標)と等価用量の、TZM HC−MTfのIV投与を受ける。
・グループ3のマウスは、6週間連続して週2回、30mg/kgのHerceptin(登録商標)と等価用量の、MTfp NH−TZMのIV投与を受ける。
・グループ4のマウスは、6週間連続して週2回、30mg/kgのHerceptin(登録商標)のIV投与を受ける。
・疼痛、苦しみ、または苦痛の兆候:疼痛姿勢、疼痛顔面、行動
・3日間連続で残存する20%の体重減少
・不良な体調、るいそう、悪液質、脱水症状
・外部刺激に対する自発的応答の長期に亘る欠如
・急速な呼吸困難、貧血、著しい出血
・神経性の兆候:周回、痙攣、麻痺
・体温の持続的低下
・腹部膨満
・動物の個々の体重及び平均体重
・平均体重変化(MBWC):治療される動物の平均重量変化のパーセント(B日目の重量−A日目の重量/A日目の重量)を計算する。MBWCを計算する時間間隔は、体重曲線と体重測定の日にちの関数として選択される。
Claims (64)
- p97配列に融合したトラスツズマブ重鎖または軽鎖配列と、それらの間の任意選択のリンカーとを含む、p97融合タンパク質。
- 配列番号84(MTfp NH−TZM)もしくは82(TZM HC−MTf)、またはその変異型/フラグメントを含む、請求項1に記載の前記p97融合タンパク質。
- 前記p97配列のN末端に融合したトラスツズマブ重鎖配列を含む、請求項1に記載の前記p97融合タンパク質。
- 前記p97配列のC末端に融合したトラスツズマブ重鎖配列を含む、請求項1に記載の前記p97融合タンパク質。
- 前記p97配列のC末端に融合した切断型トラスツズマブ重鎖配列を含む、請求項4に記載の前記p97融合タンパク質。
- 前記切断型トラスツズマブ重鎖配列が、前記重鎖の定常領域またはそのフラグメントから本質的になり、前記重鎖の可変領域を実質的もしくは完全に欠く、請求項5に記載の前記p97融合タンパク質。
- 前記切断型トラスツズマブ重鎖配列が、CH1ドメインまたはそのフラグメント、ヒンジ領域、CH2ドメイン、及びCH3ドメインから本質的になる、請求項6に記載の前記p97融合タンパク質。
- 前記切断型トラスツズマブ重鎖配列が、ヒンジ領域またはそのフラグメント、CH2ドメイン、及びCH3ドメインから本質的になる、請求項6に記載の前記p97融合タンパク質。
- (a)配列番号37〜46もしくは96〜109に示される重鎖アミノ酸配列、(b)配列番号37〜46もしくは96〜109に示される配列と少なくとも90%一致する重鎖アミノ酸配列、または(c)約1〜50アミノ酸の付加、置換、挿入、もしくは欠失で配列番号37〜46もしくは96〜109とは異なる重鎖アミノ酸配列を含む、請求項1〜8のいずれかに記載の前記p97融合タンパク質。
- 配列番号37〜46または96〜109に示されるアミノ酸配列を含む、請求項9に記載の前記p97融合タンパク質。
- 前記p97配列のN末端に融合したトラスツズマブ軽鎖配列を含む、請求項1に記載の前記p97融合タンパク質。
- 前記p97配列のC末端に融合したトラスツズマブ軽鎖配列を含む、請求項1に記載の前記p97融合タンパク質。
- (a)配列番号110〜121に示される軽アミノ酸配列、(b)配列番号110〜121に示される配列と少なくとも90%一致する軽鎖アミノ酸配列、または(c)約1〜50アミノ酸の付加、置換、挿入、もしくは欠失で配列番号110〜121とは異なる軽鎖アミノ酸配列を含む、請求項1または11〜12のいずれかに記載の前記p97融合タンパク質。
- 配列番号110〜121に示されるアミノ酸配列、またはその変異型/フラグメントを含む、請求項13に記載の前記p97融合タンパク質。
- 前記p97配列が、配列番号2もしくは14、またはその変異型/フラグメントを含む、請求項1〜14のいずれかに記載の前記p97融合タンパク質。
- 前記トラスツズマブ重鎖または軽鎖と前記p97配列との間にペプチドリンカーを含む、請求項1〜15のいずれかに記載の前記p97融合タンパク質。
- 請求項1〜16のいずれかに記載のp97融合タンパク質をコードする、単離ポリヌクレオチド。
- 宿主細胞における発現のためにコドン最適化される、請求項17に記載の前記単離ポリヌクレオチド。
- 前記宿主細胞が、哺乳動物細胞、昆虫細胞、酵母細胞、または細菌細胞である、請求項18に記載の前記単離ポリヌクレオチド。
- 請求項1〜19のいずれかに記載の単離ポリヌクレオチドを含み、前記単離ポリヌクレオチドが、1つ以上の調節エレメントと作動可能に連結される、組換え宿主細胞。
- 1つ以上の調節エレメントと作動可能に連結される、(非融合)トラスツズマブ軽鎖配列をコードする単離ポリヌクレオチドを更に含む、請求項20に記載の前記組換え宿主細胞。
- 1つ以上の調節エレメントと作動可能に連結される、(非融合)トラスツズマブ重鎖配列をコードする単離ポリヌクレオチドを更に含む、請求項20に記載の前記組換え宿主細胞。
- 1つ以上の調節エレメントと作動可能に連結される、(非融合)トラスツズマブ軽鎖配列をコードする単離ポリヌクレオチドと、(非融合)トラスツズマブ重鎖配列をコードする単離ポリヌクレオチドとを更に含む、請求項20に記載の前記組換え宿主細胞。
- 1つ以上の調節エレメントと作動可能に連結される、請求項1〜23のいずれかに記載のp97融合タンパク質をコードする単離ポリヌクレオチドを含む、ベクター。
- 1つ以上の調節エレメントと作動可能に連結される、(非融合)トラスツズマブ軽鎖配列をコードする単離ポリヌクレオチドを更に含む、請求項24に記載の前記ベクター。
- 1つ以上の調節エレメントと作動可能に連結される、(非融合)トラスツズマブ重鎖配列をコードする単離ポリヌクレオチドを更に含む、請求項24に記載の前記ベクター。
- 1つ以上の調節エレメントと作動可能に連結される、(非融合)トラスツズマブ軽鎖配列をコードする単離ポリヌクレオチドと、(非融合)トラスツズマブ重鎖配列をコードする単離ポリヌクレオチドとを更に含む、請求項24に記載の前記ベクター。
- 請求項1〜27のいずれかに記載のベクターを含む、組換え宿主細胞。
- 2つの(非融合)トラスツズマブ軽鎖配列と、請求項1〜28のいずれかに記載の1つまたは2つのp97−トラスツズマブ重鎖融合タンパク質とを含むp97−抗体融合タンパク質であって、前記1つまたは2つのp97−トラスツズマブ重鎖融合タンパク質が、p97配列のN末端またはC末端に融合したトラスツズマブ重鎖配列と、それらの間の任意選択のリンカーとを含む、前記p97−抗体融合タンパク質。
- 2つのp97−トラスツズマブ重鎖融合タンパク質を含む、請求項29に記載の前記p97−抗体融合タンパク質。
- 1つのp97−トラスツズマブ重鎖融合タンパク質及び1つの(非融合)トラスツズマブ重鎖配列を含む、請求項29に記載の前記p97−抗体融合タンパク質。
- 1つまたは2つのトラスツズマブ軽鎖配列と、1つのトラスツズマブ重鎖配列と、請求項1〜31のいずれかに記載の1つのp97−トラスツズマブ重鎖融合タンパク質とを含み、前記p97−トラスツズマブ重鎖融合タンパク質が、p97配列のC末端に融合したトラスツズマブ重鎖と、それらの間の任意選択のリンカーとを含む、p97−抗体融合タンパク質。
- 1つの軽鎖配列しか含まず、前記トラスツズマブ重鎖が、切断型トラスツズマブ重鎖である、請求項32に記載の前記p97−抗体融合タンパク質。
- 請求項1〜33のいずれかに記載の1つまたは2つのp97−トラスツズマブ軽鎖融合タンパク質と、2つのトラスツズマブ重鎖配列とを含み、前記1つまたは2つのp97−トラスツズマブ軽鎖融合タンパク質が、N末端p97配列に融合したトラスツズマブ軽鎖配列と、それらの間の任意選択のリンカーとを含む、p97−抗体融合タンパク質。
- 2つのp97−トラスツズマブ軽鎖融合タンパク質を含む、請求項34に記載の前記p97−抗体融合タンパク質。
- 1つのp97−トラスツズマブ軽鎖融合タンパク質及び1つの(非融合)トラスツズマブ軽鎖配列を含む、請求項34に記載の前記p97−抗体融合タンパク質。
- 請求項1〜36のいずれかに記載の1つまたは2つのp97−トラスツズマブ軽鎖融合タンパク質と、請求項1〜36のいずれかに記載の1つまたは2つのp97−トラスツズマブ重鎖融合タンパク質とを含み、前記1つまたは2つのp97−トラスツズマブ軽鎖融合タンパク質が、N末端p97配列に融合したトラスツズマブ軽鎖配列と、それらの間の任意選択のリンカーとを含み、かつ前記1つまたは2つのp97−トラスツズマブ重鎖融合タンパク質が、p97配列のN末端またはC末端に融合したトラスツズマブ重鎖配列と、それらの間の任意選択のリンカーとを含む、p97−抗体融合タンパク質。
- 2つのp97−トラスツズマブ軽鎖融合タンパク質と、2つのp97−トラスツズマブ重鎖融合タンパク質とを含み、前記2つのp97−トラスツズマブ重鎖融合タンパク質が、p97配列のN末端に融合したトラスツズマブ重鎖配列と、それらの間の任意選択のリンカーとを含む、請求項37に記載の前記p97−抗体融合タンパク質。
- 重鎖及び軽鎖の2つのセットを含むp97−抗体融合タンパク質であって、少なくとも1つのセットが、
a)配列番号82の重鎖及び配列番号83の軽鎖、
b)配列番号84の重鎖及び配列番号85の軽鎖、
c)配列番号86の重鎖及び配列番号87の軽鎖、
d)配列番号88の重鎖及び配列番号89の軽鎖、
e)配列番号90の重鎖及び配列番号91の軽鎖、
f)配列番号92の重鎖及び配列番号93の軽鎖、ならびに
g)配列番号94の重鎖及び配列番号95の軽鎖(それらのフラグメント/変異型を含む)のうちの1つ以上から選択される、前記p97−抗体融合タンパク質。 - 前記融合タンパク質が、a)の2つのセット、b)の2つのセット、c)の2つのセット、d)の2つのセット、e)の2つのセット、f)の2つのセット、またはg)の2つのセットを含むホモ二量体である、請求項39に記載の前記p97−抗体融合タンパク質。
- 前記融合タンパク質が、a)〜g)から選択される重鎖及び軽鎖の第1のセットと、(i)配列番号37〜46、82〜109、または110〜121の前記p97−トラスツズマブ重鎖及び軽鎖、ならびに(ii)配列番号29〜35または122(重鎖)及び36または123(軽鎖)の前記トラスツズマブ(非融合)重鎖及び軽鎖の任意の組み合わせから選択される重鎖及び軽鎖の第2のセットとを含むヘテロ二量体である、請求項39に記載の前記p97−抗体融合タンパク質。
- 請求項1〜41のいずれかに記載のp97−抗体融合タンパク質を含む、組換え宿主細胞。
- 前記宿主細胞が、哺乳動物細胞、昆虫細胞、酵母細胞、または細菌細胞である、請求項1〜42のいずれかに記載の前記組換え宿主細胞。
- 前記哺乳動物細胞が、チャイニーズハムスター卵巣(CHO)細胞またはHEK−293細胞である、請求項43に記載の前記組換え宿主細胞。
- 薬学的に許容される担体と、請求項1〜44のいずれかに記載のp97−抗体融合タンパク質とを含む、薬学的組成物。
- 治療を必要とする対象におけるHER2過剰発現癌を治療するための方法であって、請求項1〜45のいずれかに記載のp97−抗体融合タンパク質または薬学的組成物を、前記対象に投与することを含む、前記方法。
- 前記HER2過剰発現癌が、前記対象のCNSに転移する危険性がある、請求項46に記載の前記方法。
- 前記HER2過剰発現癌が、前記対象のCNSに転移している、請求項46に記載の前記方法。
- 前記HER2過剰発現癌が、乳癌、卵巣癌、胃癌、または子宮癌である、請求項1〜48のいずれかに記載の前記方法。
- 前記HER2過剰発現癌が、HER2過剰発現転移性乳癌である、請求項46〜48のいずれかに記載の前記方法。
- 前記HER2過剰発現転移性乳癌が、前記対象のCNSに転移する危険性がある、請求項50に記載の前記方法。
- 前記HER2過剰発現乳癌が、前記対象のCNSに転移している、請求項50に記載の前記方法。
- 前記HER2過剰発現癌が、HER2過剰発現転移性胃腺癌または胃食道接合部腺癌である、請求項46〜48のいずれかに記載の前記方法。
- 前記HER2過剰発現転移性胃腺癌または胃食道接合部腺癌が、前記対象のCNSに転移する危険性がある、請求項53に記載の前記方法。
- 前記HER2過剰発現転移性胃腺癌または胃食道接合部腺癌が、前記対象のCNSに転移している、請求項53に記載の前記方法。
- 前記HER2過剰発現癌が、HER2過剰発現子宮漿液性腺癌(USC)である、請求項46〜48のいずれかに記載の前記方法。
- 前記HER2過剰発現USCが、前記対象のCNSに転移する危険性がある、請求項56に記載の前記方法。
- 前記HER2過剰発現USCが、前記対象のCNSに転移している、請求項56に記載の前記方法。
- HER2過剰発現乳癌のための補助治療剤の一部として、前記p97−抗体融合タンパク質または薬学的組成物を投与することを含む、請求項46〜48のいずれかに記載の前記方法。
- 前記補助治療剤が、ドキソルビシン、シクロホスファミド、及びパクリタキセルまたはドセタキセルのいずれかを含む、請求項59に記載の前記方法。
- 前記補助治療剤が、ドセタキセル及びカルボプラチンを含む、請求項59に記載の前記方法。
- 多様式アントラサイクリン系療法後に、単剤として、前記p97−抗体融合タンパク質または薬学的組成物を投与することを含む、請求項59に記載の前記方法。
- 前記対象が、ヒトの女性である、請求項1〜62のいずれかに記載の前記方法。
- 静脈内(IV)注入によって、前記p97−抗体融合タンパク質または薬学的組成物を投与することを含む、請求項1〜63のいずれかに記載の前記方法。
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AU2003222568B2 (en) | 2002-01-11 | 2009-05-07 | Bioasis Technologies, Inc. | Use of P97 as an enzyme delivery system for the delivery of therapeutic lysosomal enzymes |
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US20160347821A1 (en) | 2014-02-03 | 2016-12-01 | Bioasis Technologies, Inc. | P97 fusion proteins |
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JP6847664B2 (ja) | 2014-05-01 | 2021-03-24 | バイオアシス テクノロジーズ インコーポレイテッド | P97−ポリヌクレオチド複合体 |
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US11643454B2 (en) | 2023-05-09 |
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BR112016017933A2 (pt) | 2017-10-10 |
AU2015210612B2 (en) | 2020-04-09 |
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WO2015117121A1 (en) | 2015-08-06 |
IL246348B (en) | 2022-03-01 |
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