JP6245985B2 - 安定で可溶性の抗体 - Google Patents
安定で可溶性の抗体 Download PDFInfo
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- JP6245985B2 JP6245985B2 JP2013534142A JP2013534142A JP6245985B2 JP 6245985 B2 JP6245985 B2 JP 6245985B2 JP 2013534142 A JP2013534142 A JP 2013534142A JP 2013534142 A JP2013534142 A JP 2013534142A JP 6245985 B2 JP6245985 B2 JP 6245985B2
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Description
本願は、米国特許法第119条の下、2010年10月22日に出願された米国仮特許出願第61/405,798号、および2011年5月11日に出願された米国仮特許出願第61/484,749号への優先権を主張し、この米国仮特許出願の全体の内容は、本明細書中に参考として援用される。
本発明は、抗体の凝集傾向を低減する方法、および凝集傾向を低減するように改変されている抗体に関する。本発明は、腫瘍壊死因子アルファ(TNFα)に結合する抗体にも関する。特に、本発明は、安定性、可溶性、および低免疫原性が最適化されている特異的な軽鎖および重鎖の配列を含む、scFv抗体およびFabフラグメントを含めた、凝集低減性の改変を含む安定で可溶性の抗体に関する。さらに、本発明は、TNF媒介性障害の診断および/または処置のための方法に関する。
腫瘍壊死因子アルファ(TNFα、カケクチンとしても公知である)は、内毒素または他の刺激に反応して、単球およびマクロファージを含めた多数の細胞型によって産生される、天然に存在する哺乳動物のサイトカインである。TNFαは、炎症反応、免疫反応、および病態生理学的反応の主要なメディエーターである(非特許文献1)。
本発明は、少なくとも1つの凝集低減性の変異を含む抗体、およびこのような抗体を生成するための方法を提供する。
本発明の好ましい実施形態において、例えば以下の項目が提供される。
(項目1)
a.配列番号2または配列番号14の配列を含む可変軽鎖、および
b.配列番号5の配列を含む可変重鎖
を含む、ヒトTNFαに特異的に結合する抗体。
(項目2)
前記可変軽鎖が配列番号2の配列を含む、項目1に記載の抗体。
(項目3)
前記可変軽鎖が配列番号14の配列を含む、項目1に記載の抗体。
(項目4)
配列番号7の配列を含むリンカーをさらに有する、項目1に記載の抗体。
(項目5)
配列番号10の配列を含む、項目1に記載の抗体。
(項目6)
配列番号17の配列を含む、項目1に記載の抗体。
(項目7)
治療有効量の項目1に記載の抗体および薬学的に許容される担体を含む、薬学的組成物。
(項目8)
項目7に記載の薬学的組成物を、TNFα媒介性疾患の処置を必要とする被験体に投与するステップを含む、TNFα媒介性疾患を処置する方法。
(項目9)
前記TNFα媒介性疾患が、ブドウ膜炎、ベーチェット病、網膜炎、眼球乾燥、緑内障、シェーグレン症候群、糖尿病性神経障害、強膜炎、加齢黄斑変性、および角膜炎からなる群から選択される眼障害である、項目8に記載の方法。
(項目10)
前記薬学的組成物が、眼投与、鼻腔内投与、耳投与、舌下投与、経皮投与、局所投与、経口投与、経鼻投与、直腸投与、または非経口投与によって投与される、項目8に記載の方法。
(項目11)
前記薬学的組成物が、抗体0.1mgから100mgを含む単一用量または分割用量で投与される、項目10に記載の方法。
(項目12)
前記TNFα媒介性疾患がブドウ膜炎であり、前記薬学的組成物が前記被験体の眼に対して局所投与される、項目8に記載の方法。
(項目13)
項目1に記載の抗体をコードする、単離された核酸分子。
(項目14)
項目13に記載の核酸分子を含むベクター。
(項目15)
項目14に記載のベクターを含む宿主細胞。
(項目16)
Fab、Fab’、F(ab)’ 2 、単鎖Fv(scFv)、Fvフラグメント、または直鎖抗体である、項目1に記載の抗体。
(項目17)
項目1に記載の抗体を含む、二価または二重特異性の分子。
(項目18)
抗体の凝集の傾向を低減するための方法であって、1つまたは複数のアミノ酸置換を、該抗体の可変軽鎖(VL)および可変重鎖(VH)の境界に導入するステップを含み、ここで、該1つまたは複数の置換が、該VLと該VHとの間の自由エネルギーを少なくとも0.5kcal/mol低減するように選択される残基位置であり、それによって親抗体に比べて該抗体の凝集傾向を低減する、方法。
(項目19)
前記抗体が、Fab、Fab’、F(ab)’ 2 、単鎖Fv(scFv)、Fvフラグメント、ダイアボディ、単鎖ダイアボディ、タンデム抗体、または直鎖抗体である、項目18に記載の方法。
(項目20)
前記抗体の可変軽鎖の配列が、配列番号1の配列に対して少なくとも65%の同一性を有する、項目18に記載の方法。
(項目21)
改変が、前記可変軽鎖のAHo50位および/またはAHo47位の置換を含む、項目20に記載の方法。
(項目22)
前記置換が、前記可変軽鎖のAHo50位のアルギニン(R)および/またはAHo47位のアルギニン(R)である、項目21に記載の方法。
(項目23)
前記可変軽鎖のAHo47位および/または50位のリジン(K)が、アルギニン(R)によって置換されている、項目22に記載の方法。
(項目24)
前記抗体が、配列番号1の配列に対して少なくとも85%の同一性を有する可変重鎖配列を有する、項目18に記載の方法。
(項目25)
前記抗体が、配列番号3の配列または配列番号4の配列に対して少なくとも85%の同一性を有する可変重鎖配列を有する、項目18に記載の方法。
(項目26)
前記可変重鎖のAHo12位、103位、および144位のアミノ酸置換をさらに含む、項目18に記載の方法。
(項目27)
項目18に記載の方法によって生成される抗体。
本発明の全体的な一目的は、溶液中で凝集する傾向が低減した、安定で可溶性の抗体を提供することである。好ましい一実施形態では、前記抗体はscFv抗体またはFabフラグメントである。本発明の抗体は、本明細書に開示する軽鎖および重鎖を含むことが好ましい。
重鎖可変領域番号付け
(i)可変軽鎖(VL)および可変重鎖(VH)を含む抗体を提供するステップと、
(ii)抗体の可変軽鎖(VL)と可変重鎖(VH)との間の境界に関与する1つまたは複数の残基位置を同定するステップと、
(iii)置換(複数可)がVLドメインとVHドメインとの間の自由エネルギーを少なくとも0.5kcal/mol、好ましくは少なくとも1.0kcal/mol、最も好ましくは少なくとも2.0kcal/mol低減するように、同定された残基位置(複数可)に置換を導入することによって抗体を改変し(すなわち、置換を有するVLドメインとVHドメインとの間の自由エネルギーは、アミノ酸置換を含まない対応するVLドメインとVHドメインとの間の自由エネルギーよりも少なくとも0.5kcal/mol少ない)、それによって改変された抗体の凝集傾向を親抗体の凝集傾向に比べて低減するステップと
を含む。
G境界=G(a)−G(b)−G(c)
である。
a)ヒトVH3ファミリー重鎖可変領域に対して、好ましいアミノ酸は、
(i)AHoまたはKabat番号付けシステムを用いたアミノ酸1位のグルタミン(Q)、
(ii)AHoまたはKabat番号付けシステムを用いたアミノ酸6位のグルタミン(Q)、
(iii)AHoまたはKabat番号付けシステムを用いたアミノ酸7位のスレオニン(T)またはアラニン(A)、
(iv)AHo番号付けシステムを用いたアミノ酸89位(Kabat番号付けシステムを用いたアミノ酸78位)のアラニン(A)、バリン(V)、またはフェニルアラニン(F)、ならびに/あるいは、
(v)AHo番号付けシステムを用いたアミノ酸103位(Kabat番号付けを用いたアミノ酸89位)のアルギニン(R)、グルタミン(Q)、イソロイシン(I)、ロイシン(L)、メチオニン(M)、またはフェニルアラニン(F)であり、
b)ヒトVH1aファミリー重鎖可変領域に対して、好ましいアミノ酸は、
(i)AHoまたはKabat番号付けシステムを用いたアミノ酸1位のグルタミン酸(E)、
(ii)AHoまたはKabat番号付けシステムを用いたアミノ酸6位のグルタミン酸(E)、
(iii)AHo番号付けシステムを用いたアミノ酸12位(Kabat番号付けシステムを用いたアミノ酸11位)のロイシン(L)、
(iv)AHo番号付けシステムを用いたアミノ酸13位(Kabat番号付けシステムを用いたアミノ酸12位)のメチオニン(M)、
(v)AHo番号付けシステムを用いたアミノ酸14位(Kabat番号付けシステムを用いたアミノ酸13位)のグルタミン酸(E)、またはグルタミン(Q)、
(vi)AHo番号付けシステムを用いたアミノ酸19位(Kabat番号付けシステムを用いたアミノ酸18位)のロイシン(L)、
(vii)AHo番号付けシステムを用いたアミノ酸21位(Kabat番号付けシステムを用いたアミノ酸20位)のイソロイシン(I)、
(viii)AHo番号付けシステムを用いたアミノ酸90位(Kabat番号付けシステムを用いたアミノ酸79位)のフェニルアラニン(F)、セリン(S)、ヒスチジン(H)、またはアスパラギン酸(D)、
(ix)AHo番号付けシステムを用いたアミノ酸92位(Kabat番号付けシステムを用いたアミノ酸81位)のアスパラギン酸(D)またはグルタミン(Q)、
(x)AHo番号付けシステムを用いたアミノ酸95位(Kabat番号付けシステムを用いたアミノ酸82b位)のグリシン(G)、アスパラギン(N)、またはスレオニン(T)、ならびに/あるいは、
(xi)AHo番号付けを用いたアミノ酸98位(Kabat番号付けを用いたアミノ酸84位)のスレオニン(T)、アラニン(A)、プロリン(P)、またはフェニルアラニン(F)であり、
c)ヒトVH1bファミリー重鎖可変領域に対して、好ましいアミノ酸は、
(i)AHoまたはKabat番号付けシステムを用いたアミノ酸1位のグルタミン酸(E)、
(ii)AHo番号付けシステムを用いたアミノ酸10位(Kabat番号付けシステムを用いたアミノ酸9位)のスレオニン(T)、プロリン(P)、バリン(V)、またはアスパラギン酸(D)、
(iii)AHo番号付けシステムを用いたアミノ酸12位(Kabat番号付けシステムを用いたアミノ酸11位)のロイシン(L)、
(iv)AHo番号付けシステムを用いたアミノ酸13位(Kabat番号付けシステムを用いたアミノ酸12位)のバリン(V)、アルギニン(R)、グルタミン(Q)、またはメチオニン(M)、
(v)AHo番号付けシステムを用いたアミノ酸14位(Kabat番号付けシステムを用いたアミノ酸13位)のグルタミン酸(E)、アルギニン(R)、またはメチオニン(M)、
(vi)AHo番号付けシステムを用いたアミノ酸20位(Kabat番号付けシステムを用いたアミノ酸19位)のアルギニン(R)、スレオニン(T)、またはアスパラギン(N)、
(vii)AHo番号付けシステムを用いたアミノ酸21位(Kabat番号付けシステムを用いたアミノ酸20位)のイソロイシン(I)、フェニルアラニン(F)、またはロイシン(L)、
(viii)AHo番号付けシステムを用いたアミノ酸45位(Kabat番号付けシステムを用いたアミノ酸38位)のリジン(K)、
(ix)AHo番号付けシステムを用いたアミノ酸47位(Kabat番号付けシステムを用いたアミノ酸40位)のスレオニン(T)、プロリン(P)、バリン(V)、またはアルギニン(R)、
(x)AHo番号付けシステムを用いたアミノ酸50位(Kabat番号付けシステムを用いたアミノ酸43位)のリジン(K)、ヒスチジン(H)、またはグルタミン酸(E)、
(xi)AHo番号付けを用いたアミノ酸55位(Kabat番号付けを用いたアミノ酸48位)のイソロイシン(I)、
(xii)AHo番号付けを用いたアミノ酸77位(Kabat番号付けを用いたアミノ酸66位)のリジン(K)、
(xiii)AHo番号付けシステムを用いたアミノ酸78位(Kabat番号付けシステムを用いたアミノ酸67位)のアラニン(A)、ロイシン(L)、またはイソロイシン(I)、
(xiv)AHo番号付けシステムを用いたアミノ酸82位(Kabat番号付けシステムを用いたアミノ酸71位)のグルタミン酸(E)、スレオニン(T)、またはアラニン(A)、
(xv)AHo番号付けシステムを用いたアミノ酸86位(Kabat番号付けシステムを用いたアミノ酸75位)のスレオニン(T)、セリン(S)、またはロイシン(L)、
(xvi)AHo番号付けシステムを用いたアミノ酸87位(Kabat番号付けシステムを用いたアミノ酸76位)のアスパラギン酸(D)、アスパラギン(N)、またはグリシン(G)、ならびに/あるいは、
(xvii)AHo番号付けシステムを用いたアミノ酸107位(Kabat番号付けシステムを用いたアミノ酸93位)のアスパラギン(N)またはセリン(S)であり、
d)ヒトVカッパ1ファミリー軽鎖可変領域に対して、好ましいアミノ酸は、
(i)AHoまたはKabat番号付けシステムを用いたアミノ酸1位のグルタミン酸(E)、またはイソロイシン(I)、
(ii)AHoまたはKabat番号付けシステムを用いたアミノ酸3位のバリン(V)、またはイソロイシン(I)、
(iii)AHoまたはKabat番号付けシステムを用いたアミノ酸4位のバリン(V)、ロイシン(L)、またはイソロイシン(I)、
(iv)AHoまたはKabat番号付けシステムを用いたアミノ酸24位のグルタミン(Q)、
(v)AHo番号付けシステムを用いたアミノ酸47位(Kabat番号付けシステムを用いたアミノ酸39位)のアルギニン(R)またはイソロイシン(I)、
(vi)AHo番号付けシステムを用いたアミノ酸50位(Kabat番号付けシステムを用いたアミノ酸42位)のアルギニン(R)、グルタミン酸(E)、スレオニン(T)、メチオニン(M)またはグルタミン(Q)、
(vii)AHo番号付けシステムを用いたアミノ酸57位(Kabat番号付けシステムを用いたアミノ酸49位)のヒスチジン(H)、セリン(S)、またはフェニルアラニン(F)、
(viii)AHo番号付けシステムを用いたアミノ酸91位(Kabat番号付けシステムを用いたアミノ酸73位)のフェニルアラニン(F)、ならびに/あるいは、
(ix)AHo番号付けシステムを用いたアミノ酸103位(Kabat番号付けシステムを用いたアミノ酸85位)のバリン(V)、セリン(S)、グリシン(G)、またはイソロイシン(I)であり、
e)ヒトVカッパ3ファミリー軽鎖可変領域に対して、好ましいアミノ酸は、
(i)AHoまたはKabat番号付けシステムを用いたアミノ酸2位のスレオニン(T)、
(ii)AHoまたはKabat番号付けシステムを用いたアミノ酸3位のスレオニン(T)、
(iii)AHoまたはKabat番号付けシステムを用いたアミノ酸10位のイソロイシン(I)、
(iv)AHoまたはKabat番号付けシステムを用いたアミノ酸12位のチロシン(Y)、
(v)AHoまたはKabat番号付けシステムを用いたアミノ酸18位のセリン(S)、
(vi)AHoまたはKabat番号付けシステムを用いたアミノ酸20位のアラニン(A)、
(vii)AHo番号付けシステムを用いたアミノ酸56位(Kabat番号付けシステムを用いたアミノ酸48位)のメチオニン(M)、
(viii)AHo番号付けシステムを用いたアミノ酸74位(Kabat番号付けシステムを用いたアミノ酸58位)のバリン(V)またはスレオニン(T)、
(ix)AHo番号付けシステムを用いたアミノ酸94位(Kabat番号付けシステムを用いたアミノ酸76位)のアスパラギン(N)、
(x)AHo番号付けシステムを用いたアミノ酸101位(Kabat番号付けシステムを用いたアミノ酸83位)のチロシン(Y)またはセリン(S)、ならびに/あるいは、
(xi)AHo番号付けを用いたアミノ酸103位(Kabat番号付けを用いたアミノ酸85位)のロイシン(L)またはアラニン(A)であり、
f)ヒトVラムダ1ファミリー軽鎖可変領域に対して、好ましいアミノ酸は、
(i)AHoまたはKabat番号付けシステムを用いたアミノ酸1位のロイシン(L)、セリン(S)、またはグルタミン酸(E)、
(ii)AHoまたはKabat番号付けシステムを用いたアミノ酸2位のアラニン(A)、プロリン(P)、イソロイシン(I)、またはチロシン(Y)、
(iii)AHoまたはKabat番号付けシステムを用いたアミノ酸4位のバリン(V)またはメチオニン(M)、
(iv)AHoまたはKabat番号付けシステムを用いたアミノ酸7位のグルタミン酸(E)、
(v)AHoまたはKabat番号付けシステムを用いたアミノ酸11位のアラニン(A)、
(vi)AHoまたはKabat番号付けシステムを用いたアミノ酸14位のスレオニン(T)またはセリン(S)、
(vii)AHo番号付けシステムを用いたアミノ酸46位(Kabat番号付けシステムを用いたアミノ酸38位)のヒスチジン(H)、
(viii)AHo番号付けシステムを用いたアミノ酸53位(Kabat番号付けシステムを用いたアミノ酸45位)のスレオニン(T)、セリン(S)、アスパラギン(N)、グルタミン(Q)、またはプロリン(P)、
(ix)AHo番号付けシステムを用いたアミノ酸82位(Kabat番号付けシステムを用いたアミノ酸66位)のアルギニン(R)またはグルタミン(Q)、
(x)AHo番号付けシステムを用いたアミノ酸92位(Kabat番号付けシステムを用いたアミノ酸74位)のグリシン(G)、スレオニン(T)、またはアスパラギン酸(D)、ならびに/あるいは、
(xi)AHo番号付けを用いたアミノ酸103位(Kabat番号付けを用いたアミノ酸85位)のバリン(V)、スレオニン(T)、ヒスチジン(H)、またはグルタミン酸(E)である。
したがって、本方法において行われる置換は、PCT/CH2008/000285の教示に従うことが好ましい。サブタイプの決定は当業者には公知である。
(1)重鎖および軽鎖の可変ドメインを含むヘテロ二量体複合体である抗体の凝集傾向を低減するための方法であって、
(a)抗体の完全な原子論的分子の提示を提供するステップと、
(b)両ドメイン間の境界の自由エネルギーを決定するステップと、
(c)選択された位置に1つまたは複数の置換を含む抗体の分子モデルを提供し、置換された分子提示の境界の自由エネルギーを決定することによって、置換のために境界で関与する1つまたは複数のアミノ酸残基を選択するステップと、
(d)置換された分子モデルの境界の自由エネルギーが、最初の分子モデルの境界の自由エネルギーよりも低い場合は、置換のためのアミノ酸残基を選択するステップと
を含む方法、
(2)境界の自由エネルギーが、複合体と、絶対的溶媒方法の状況において個々のドメインのエネルギーの合計との間のエネルギーの差を計算することによって決定される、(1)の方法、
(3)溶媒がGBMVまたはPBSAである、(2)の方法、
(4)(i)前記ステップをステップaおよびステップb内で行う、タンパク質の電荷分布をシミュレートするステップ
をさらに含む、上記(1)〜(3)のいずれか一つの方法、
(5)上記電荷分布が、静電力またはファンデルワールス力に基づいてシミュレートされる、(4)の方法、
(6)ステップ(c)が、変異周辺の領域におけるエネルギー最小化のさらなるステップを含む、上記(1)〜(5)のいずれか一つの方法、
(7)抗体が単鎖可変フラグメント(scFv)である、上記(1)〜(7)のいずれか一つの方法
を提供する。
(a)111In、99Tc、14C、131I、125I、3H、32Pまたは35Sなどの放射性同位元素。抗体は、例えばCurrent Protocols in Immunology、1および2巻、Coligenら編、Wiley−Interscience、New York、N.Y.、Pubs.(1991年)に記載の技法を用いて、放射性同位元素により標識でき、放射活性は、シンチレーション計数器を用いて測定することができる。
(i)西洋ワサビペルオキシダーゼ(HRPO)と、基質としての水素ペルオキシダーゼであり、水素ペルオキシダーゼが、色素前駆体(例えば、オルトフェニレンジアミン(OPD)または3,3’,5,5’−テトラメチルベンジジン塩酸塩(TMB))を酸化する、
(ii)アルカリホスファターゼ(AP)と、色素形成基質としてのパラ−ニトロフェニルホスフェート、および
(iii)β−D−ガラクトシダーゼ(β−D−Gal)と色素形成基質(例えば、P−ニトロフェニル−β−D−ガラクトシダーゼ)または蛍光発生基質4−メチルウンベリフェリル−β−D−ガラクトシダーゼ、が挙げられる。
本開示を、さらに限定するものと解釈すべきではない以下の実施例によってさらに説明する。全ての図ならびにこの出願全体にわたって引用される全ての参考文献、特許および公開された特許出願の内容は、それらの全体が参照により本明細書に明示的に援用される。
一般的に、本発明の実施では、特に示さない限り、化学、分子生物学、組換えDNA技術、免疫学(特に、例えば抗体技術)の従来技法、およびポリペプチド調製の標準技法を採用する。例えば、Sambrook、FritschおよびManiatis、Molecular Cloning: Cold Spring Harbor Laboratory Press(1989年);Antibody Engineering Protocols(Methods in Molecular Biology)、510巻、Paul, S.、Humana Pr(1996年);Antibody Engineering: A Practical Approach(Practical Approach Series、169巻)、McCafferty編、Irl Pr(1996年);Antibodies: A Laboratory Manual、Harlowら、C.S.H.L. Press, Pub.(1999年);およびCurrent Protocols in Molecular Biology、Ausubelら編、John Wiley & Sons(1992年)を参照されたい。
減衰全反射フーリエ変換IR(FTIR−ATR)スペクトルを、Tensor BrukerにおけるFT−IR Bio−ATRセルを使用して、様々な単鎖および追加の分子に関して入手した。分子を、3mg/mlまで濃縮し、PBS(pH6.5)に対して4℃で一晩中透析し、緩衝液のフロースルー(flow through)をブランクとして採取した。変性プロファイルを、5℃ステップ(25から95℃)の広範な温度で分子を熱チャレンジ(challenge)することによって入手した。全てのスペクトルの操作は、OPUSソフトウェアを用いて行った。主な緩衝液および一過性の雰囲気(CO2およびH2O)のバックグラウンドは、タンパク質スペクトルから差し引いた。結果のタンパク質スペクトルを、次いでベースライン補正し、タンパク質アミドIスペクトルを、期待される領域における最大幅の分解可能なピークの幅から決定した。第2の誘導体スペクトルを、平滑関数による3次多項式関数を用いて、アミドIバンドスペクトルに関して入手した。タンパク質構造における変化を、3つの低度測定に関して0%の変性、および3つの高度測定に関して100%変性と仮定する、初期カーブフィット(curve−fit)計算についての直線検定曲線を用いて、アミドIの第2誘導体分析によって、推定した。変性プロファイルを、ボルツマンシグモイドモデル(Boltzmann sigmoidal model)に適用する改変体毎の熱アンフォールディング転移(TM)の中間点を概算するのに使用した。
様々なscFv分子の相対的な可溶性を、硫酸アンモニウムの存在下でタンパク質の凝集および沈殿を増強させた後、測定した。硫酸アンモニウムを水溶液中のタンパク質に添加し、塩−タンパク質の最終混合物における飽和を5%増加させた。動的な範囲における沈殿を実験的に決定し、飽和間隔は、最終混合物において2.5%の飽和間隔までこの範囲で減少した。硫酸アンモニウムの添加後、試料を静かに混合し、6000rpmで30分遠心分離した。上清中に残ったタンパク質を、硫酸アンモニウムの飽和のパーセント毎に回収した。溶解曲線を、NanoDropTM1000 Spectrophotometerを使用して、上清中のタンパク質濃度を測定することによって決定した。上清中に残った可溶性タンパク質の測定を正規化し、ボルツマンシグモイドモデルに適用する改変体毎の相対的な可溶性の中間点を推定するのに使用した。
タンパク質を、可溶性凝集物および分解産物に関して、40℃で2週間インキュベーションした後、調べた。10mg/mlの濃度のタンパク質を、広範なpH(3.5、4.5、5.5、6.5、7.0、7.5および8.5)のPBSに対して4℃で一晩中透析した。標準緩衝液PBS(pH6.5)中の同じ濃度の対照タンパク質を、2週間の間−80℃で保管した。SDS−PAGEによる分解のバンドの決定は、t=0およびt=14d時点で行い、可溶性凝集物をSEC−HPLCにおいて評価した。40℃で2週間後、残った活性の決定を、Biacoreを使用して行った。
凝集を低減するための、抗TNFα scFv抗体である34rFW1.4の最適化
34rFW1.4抗体は、溶液中でのpH依存性凝集の傾向を示す。578rFW1.4抗体(国際特許出願第WO2009155724を参照されたい)は、34rFW1.4と同じフレームワーク構造を共有するが、凝集の傾向を示さない。ホモロジーモデルを生成して、以下の通りその凝集傾向を低減するように改変され得る34rFW1.4における潜在的な残基を同定した。
好ましい置換の導入
Discovery Studioソフトウェアを用いて分子ダイナミクスシミュレーションを行って、VLとVHとの間の相互作用親和性を改善する変異を予測し、それによってドメインが分解し、オリゴマーおよび/またはより高次の凝集物を形成するのを防いだ。34rFW1.4抗体のVL/VH境界の安定性を、自由エネルギーGとしてエネルギー関係として推定した。CHARMMプロトコール適合(DS2.5.5にも含まれる)を用いて、scFvヘテロ二量体複合体全体と、個々の各可変ドメインのエネルギーの合計との間のエネルギーの差を計算した。計算は、Generalized Born with Molecular Volume integration(GBMV)を用いて、絶対的溶媒方法の状況で行った。両方のドメインおよび複合体のエネルギーを計算し、出力を、複合体と以下の計算による個々のドメインの合計との間のエネルギーにおける差として決定した:G境界=G(a)−G(b)−G(c)
[式中、G(a)は抗体のエネルギーであり、G(b)はVLのエネルギーであり、G(c)はVHのエネルギーである]。
最適化した34rFW1.4抗体の安定性分析
K50R変異体およびK47R変異体を、34rFW1.4抗体(その内容が全体において参照によって本明細書に組み入れられる、2009年6月25日出願の、同時係属中の国際特許出願第PCT/CH2009/000219において開示されている)において産生した。インビボにおけるその免疫原性を低減するためのさらなる置換を有する34rFW1.4の別の変異体を、米国特許出願第12/973,968号に記載されている方法にしたがって調製した。特に、34rFW1.4_VLK50R_DHPと呼ばれる第3の変異体は、重鎖12位(AHo番号付け)にセリン(S)、重鎖103位(AHo番号付け)にスレオニン(T)、および重鎖144位(AHo番号付け)にスレオニン(T)を含んでいた。親および変異体34rFW1.4抗体の安定性試験を、以下の通り加速条件下で行った。
前述の記載を考慮すると、本発明の多くの修正および代替の実施形態が、当業者に明らかである。したがって、この記載は、単なる例示として解釈すべきであり、本発明を実施するのに最良の様式を当業者に教示するためのものである。構造の詳細は、本発明の精神から逸脱することなく実質的に変えることができ、添付の特許請求の範囲内となる全ての修正の独占的使用権を保有する。本発明は、添付の特許請求の範囲および適用可能な法律の規則によって要求される程度にのみ制限されるものであると意図する。
Claims (14)
- a.配列番号2の配列を含む可変軽鎖、および
b.配列番号5の配列を含む可変重鎖
を含む、ヒトTNFαに特異的に結合する抗体。 - 前記可変軽鎖を前記可変重鎖と連結するための、配列番号7の配列を含むリンカーをさらに有する、請求項1に記載の抗体。
- 配列番号10の配列を含む、請求項1に記載の抗体。
- 治療有効量の請求項1に記載の抗体および薬学的に許容される担体を含む、薬学的組成物。
- TNFα媒介性疾患を処置するための、請求項4に記載の薬学的組成物。
- 前記TNFα媒介性疾患が、ブドウ膜炎、ベーチェット病、網膜炎、眼球乾燥、緑内障、シェーグレン症候群、糖尿病性神経障害、強膜炎、加齢黄斑変性、および角膜炎からなる群から選択される眼障害である、請求項5に記載の薬学的組成物。
- 眼投与、鼻腔内投与、耳投与、舌下投与、経皮投与、局所投与、経口投与、経鼻投与、直腸投与、または非経口投与によって投与されることを特徴とする、請求項5に記載の薬学的組成物。
- 抗体0.1mgから100mgを含む単一用量または分割用量で投与されることを特徴とする、請求項7に記載の薬学的組成物。
- 前記TNFα媒介性疾患がブドウ膜炎であり、前記薬学的組成物が被験体の眼に対して局所投与されることを特徴とする、請求項5に記載の薬学的組成物。
- 請求項1に記載の抗体をコードする、単離された核酸分子。
- 請求項10に記載の核酸分子を含むベクター。
- 請求項11に記載のベクターを含む宿主細胞。
- Fab、Fab’、F(ab)’2、単鎖Fv(scFv)、Fvフラグメント、または直鎖抗体である、請求項1に記載の抗体。
- 請求項1に記載の抗体を含む、二価または二重特異性の分子。
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