JP7395463B2 - 腫瘍微小環境における免疫応答を増強するための治療剤および方法 - Google Patents
腫瘍微小環境における免疫応答を増強するための治療剤および方法 Download PDFInfo
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- 238000000108 ultra-filtration Methods 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
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- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
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Description
本出願は、米国特許法第119(e)条の下、2017年3月28日出願の米国仮出願第62/477,661号の利益を主張し、その全体が、参照により本明細書に組み込まれる。
その野生型対応物と比較して、FcγRIIBに対する増強した選択性を有するFcバリアントが、本明細書に記載される。FcγRIIBに対する選択性、FcγRIIBに対する選択的結合、またはFcγRIIBに対する特異的結合を有するFc断片は、当該技術分野においてよく理解されている用語である。分子は、それが代替的な標的(例えば、FcγRIII受容体)と反応するよりも、特定の標的抗原(例えば、FcγRIIB受容体)とより頻繁に、より迅速に、より長い持続時間、かつ/またはより大きな親和性で反応する場合に、「選択的結合」または「特異的結合」を呈すると言われる。Fc断片は、それが他のFc受容体に結合するよりも、より大きな親和性、結合力で、より迅速に、かつ/またはより長い持続時間で結合する場合に、Fc受容体に「特異的に結合する」。例えば、FcγRIIBに特異的に(または優先的に)結合するFc断片は、それが他のFc受容体に結合するよりも、より大きな親和性、結合力で、より迅速に、および/またはより長い持続時間でこのFc受容体に結合するFc断片である。この定義において、例えば、第1のFc受容体に選択的または特異的に結合するFc断片は、第2のFc受容体に特異的または優先的に結合してもしなくてもよいことが理解される。したがって、「選択的結合」、「特異的結合」、または「優先的結合」は、排他的結合を必ずしも必要としない(が、それを含んでもよい)。いくつかの例では、標的Fc受容体(例えば、FcγRIIB)に「選択的に結合する」または「特異的に結合する」Fc断片は、他のFc受容体に結合しなくてもよい(すなわち、通例の方法によっては検出不能な結合)。異なるFc受容体に対するIgG1、IgG2、およびIgG4の相対的な結合親和性を、以下の表1に示す。
[結合]=[遊離]/(Kd+[遊離])
野生型ヒトIgG1 Fc断片のアミノ酸配列:
VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号1)
野生型ヒトIgG2 Fc断片のアミノ酸配列:
VDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号2)
野生型ヒトIgG4 Fc断片のアミノ酸配列:
VDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号3)
ヒトIgG4 S228P Fcバリアントのアミノ酸配列:
VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号4)
例示的なヒトIgG1 Fcバリアントのアミノ酸配列:
G1m1:
VDKKVEPKSCDKTHTCPPCPAPELLSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号5)
G1m2:
VDKKVEPKSCDKTHTCPPCPAPELLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号6)
G1m-2:
VDKKVEPKCCVECPPCPAPELLSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号7)
G1m-4:
VDKKVEPKYGPPCPPCPAPELLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号8)
G1m5:
VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEEKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号9)
G1m7:
VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号10)
G1m8:
VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAFPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号11)
G1m9:
VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAFPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号12)
G1m15:
VDKKVEPKSCDKTHTCPPCPAPELLSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEEKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号13)
G1m17:
VDKKVEPKSCDKTHTCPPCPAPELLSVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号14)
G1m18:
VDKKVEPKSCDKTHTCPPCPAPELLSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAFPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号15)
G1m19:
VDKKVEPKSCDKTHTCPPCPAPELLSVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAFPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号16)
G1m25:
VDKKVEPKSCDKTHTCPPCPAPELLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEEKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号17)
G1m27:
VDKKVEPKSCDKTHTCPPCPAPELLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号18)
G1m28:
VDKKVEPKSCDKTHTCPPCPAPELLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAFPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号19)
G1m29:
VDKKVEPKSCDKTHTCPPCPAPELLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAFPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号20)
G1mAA:
VDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号21)
G1mAG:
VDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号22)
例示的なヒトIgG2 Fcバリアントのアミノ酸配列:
G2m1:
VDKTVERKCCVECPPCPAPPVASVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号23)
G2m-1:
VDKTVERKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号24)
G2m2:
VDKTVERKCCVECPPCPAPPFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号25)
G2m-4:
VDKTVERKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号26)
G2m5:
VDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEEQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号27)
G2m7:
VDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号28)
G2m8:
VDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGFPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号29)
G2m9:
VDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGFPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号30)
G2m10:
VDKTVERKCCVECPPCPAPEVSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGFPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号31)
G2m15:
VDKTVERKCCVECPPCPAPPVASVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEEQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号32)
G2m17:
VDKTVERKCCVECPPCPAPPVASVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号33)
G2m18:
VDKTVERKCCVECPPCPAPPVASVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGFPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号34)
G2m19:
VDKTVERKCCVECPPCPAPPVASVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGFPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号35)
G2m20:
VDKTVERKCCVECPPCPAPPVAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号36)
G2m27:
VDKTVERKCCVECPPCPAPPVAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号37)
G2m28:
VDKTVERKCCVECPPCPAPPVAPSVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号38)
例示的なヒトIgG4 Fcバリアントのアミノ酸配列:
G4m1:
VDKRVESKYGPPCPPCPAPEFLSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号39)
G4m-1:
VDKRVESKSCDKTHTPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号40)
G4m2:
VDKRVESKYGPPCPPCPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号41)
G4m-2:
VDKRVESKCCVEPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号42)
G4m3:
VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEEQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号43)
G4m4:
VDKRVESKYGPPCPPCPAPEFLSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEEQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号44)
G4m5:
VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEEQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号45)
G4m7:
VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号46)
G4m8:
VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGFPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号47)
G4m9:
VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGFPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号48)
G4m10:
VDKRVESKYGPPCPPCPAPEVSSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGFPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号49)
G4m15
VDKRVESKYGPPCPPCPAPEFLSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEEQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号128)
G4m17:
VDKRVESKYGPPCPPCPAPEFLSVFLFPPKPKDTLMISRTPEVTCVVVDVEQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号50)
G4m18:
VDKRVESKYGPPCPPCPAPEFLSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGFPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号51)
G4m19:
VDKRVESKYGPPCPPCPAPEFLSVFLFPPKPKDTLMISRTPEVTCVVVDVEQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGFPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号52)
G4m20:
VDKRVESKYGPPCPPCPAPEFLGSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号53)
G4m25:
VDKRVESKYGPPCPPCPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEEQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号54)
G4m27:
VDKRVESKYGPPCPPCPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号55)
G4m28:
VDKRVESKYGPPCPPCPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGFPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号56)
G4m29:
VDKRVESKYGPPCPPCPAPEFLGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGFPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号57)
G4m30:
VDKRVESKYGPPCPPCPAPEFLPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号58)
G4mPE:
VDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号59)
免疫受容体およびFcγRIIB受容体を架橋することができる治療剤もまた、本明細書に提供される。そのような治療剤は、癌および腫瘍流入領域リンパ節などの特定の微小環境におけるT細胞およびNK細胞などの免疫細胞を活性化するための、増強したアゴニスト効果を持つために、侵入病原体または罹患細胞に対する免疫応答を誘発または増強することが予想される。
本明細書に記載の治療剤は、少なくとも2つの結合部分を含有する。1つの結合部分は、細胞表面上に発現される免疫細胞受容体、例えば、TNFスーパーファミリーの受容体に結合することができる。例には、Fas受容体/FAS、TWEAK受容体/TNFRSF12A、4-1BB/TNFRSF9/CD137、TACI/TNFRSF13B、BAFF R/TNFRSF13C、CD27/TNFRSF7、CD30/TNFRSF8、CD40/TNFRSF5、DR3/TNFRSF25、DR4/TNFRSF10A、DR5/TNFRSF10B、DR6/TNFRSF21、GITR/TNFRSF18、HVEM/TNFRSF14、リンホトキシン-ベータ受容体/LTβR、OX40/TNFRSF4、TROY/TNFRSF19、RELT/TNFRSF19L、TNFRSF12A、TACI/TNFRSF13B、TL1A/TNFSF15、TNFRSF17、TNFR1/TNFRSF1A、TNFRSF11B、RANK/TNFRSF11A、TR1/TNFRSF11B、NGFR、EDA2R、およびTNFRII/TNFRSF1Bが含まれる。場合によっては、免疫細胞受容体に対する結合部分は、抗体結合断片(例えば、Fab断片または単鎖抗体断片)である。
本明細書に記載のTNFスーパーファミリーメンバーなどの免疫細胞受容体およびFcγRIIBの両方に結合することができる抗体は、以下のように作製することができる。免疫細胞受容体に結合する抗体は、当該技術分野において既知である任意の方法によって調製することができる。例えば、Harlow and Lane,(1998)Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory,New Yorkを参照されたい。
本明細書に記載の抗体を薬学的に許容される担体(賦形剤)と混合して、標的疾患の治療に使用するための薬学的組成物を形成することができる。「許容される」は、担体が組成物の活性成分と適合し(かつ好ましくは活性成分を安定化することができ)、治療される対象にとって有害であってはならないことを意味する。緩衝液を含む薬学的に許容される賦形剤(担体)は、当該技術分野において周知である。例えば、Remington:The Science and Practice of Pharmacy20th Ed.(2000)Lippincott Williams and Wilkins,Ed.K.E.Hooverを参照されたい。
本明細書に記載の免疫細胞受容体およびFcγRIIBを架橋することができる治療剤(例えば、抗体)はいずれも、侵入病原体および/または罹患細胞(癌細胞など)に対する免疫応答を増強するのに有用である。
本開示はまた、本明細書に記載の治療剤のいずれか、例えば、FcγRIIBに選択的に結合する本明細書に記載のFcバリアントを含有する抗TNF抗体を使用して、所望の免疫応答の増強に使用するためのキットも提供する。
別段示されない限り、本発明の実施は、(組換え技術を含む)分子生物学、微生物学、細胞生物学、生化学、および免疫学の従来の技術を用い、これらは、当該技術分野の範囲内である。そのような技術は、Molecular Cloning:A Laboratory Manual,second edition(Sambrook,et al.,1989)Cold Spring Harbor Press、Oligonucleotide Synthesis(M.J.Gait,ed.,1984);Methods in Molecular Biology,Humana Press、Cell Biology:A Laboratory Notebook(J.E.Cellis,ed.,1998)Academic Press、Animal Cell Culture(R.I.Freshney,ed.,1987)、Introduction to Cell and Tissue Culture(J.P.Mather and P.E.Roberts,1998)Plenum Press、Cell and Tissue Culture:Laboratory Procedures(A.Doyle,J.B.Griffiths,and D.G.Newell,eds.,1993-8)J.Wiley and Sons、Methods in Enzymology(Academic Press,Inc.)、Handbook of Experimental Immunology(D.M.Weir and C.C.Blackwell,eds.)、Gene Transfer Vectors for Mammalian Cells(J.M.Miller and M.P.Calos,eds.,1987)、Current Protocols in Molecular Biology(F.M.Ausubel,et al.,eds.,1987)、PCR:The Polymerase Chain Reaction,(Mullis,et al.,eds.,1994)、Current Protocols in Immunology(J.E.Coligan et al.,eds.,1991)、Short Protocols in Molecular Biology(Wiley and Sons,1999)、Immunobiology(C.A.Janeway and P.Travers,1997)、Antibodies(P.Finch,1997)、Antibodies:a practical approach(D.Catty.,ed.,IRL Press,1988-1989)、Monoclonal antibodies:a practical approach(P.Shepherd and C.Dean,eds.,Oxford University Press,2000)、Using antibodies:a laboratory manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press,1999)、The Antibodies(M.Zanetti and J.D.Capra,eds.,Harwood Academic Publishers,1995)などの文献で完全に説明されている。
FcγR2b/CD32Bへの結合活性に対するヒトIgG1、IgG2、およびIgG4のヒンジドメイン内の変異の影響を検証するために、本明細書に開示されるヒトFcバリアントG1m1、G1m2、G2m1、G2m2、G2m10、G4m1、G4m2、G4m10、およびG4m20を、抗CD137抗体のVH断片ならびに対応するIgG1、G2、およびG4 CH1断片に連結させて、完全長IgG重鎖を生成した。これらの変異体IgG重鎖をクローニングし、抗CD137抗体の軽鎖と同時発現させ、標準的な分子生物学および抗体プロトコルを使用して精製した。VH-CH1断片(VHドメインが斜体になっている)および軽鎖のアミノ酸配列を、以下に提供する。
VH-CH1(IgG1):
EVQLVQSGAEVKKPGESLRISCKGSGYSFSTYWISWVRQMPGKGLEWMGKIYPGDSYTNYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGYGIFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK(配列番号60)
VH-CH1(IgG2):
EVQLVQSGAEVKKPGESLRISCKGSGYSFSTYWISWVRQMPGKGLEWMGKIYPGDSYTNYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGYGIFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTK(配列番号61)
VH-CH1(IgG4):
EVQLVQSGAEVKKPGESLRISCKGSGYSFSTYWISWVRQMPGKGLEWMGKIYPGDSYTNYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGYGIFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK(配列番号62)
軽鎖:
SYELTQPPSVSVSPGQTASITCSGDNIGDQYAHWYQQKPGQSPVLVIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYTGFGSLAVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(配列番号63)
本明細書に開示されるヒトFcバリアントG1m5、G1m7、G1m8、G1m9、G2m5、G2m7、G2m8、G2m9、G4m5、G4m7、G4m8、およびG4m9を、抗CD137抗体のVH断片ならびに対応するIgG1、G2、およびG4 CH1断片に連結させて、完全長IgG重鎖を生成した。上記の実施例1を参照されたい。これらの変異体IgG重鎖をクローニングし、抗CD137抗体の軽鎖と同時発現させ(上記の実施例1を参照されたい)、標準的な分子生物学および抗体プロトコルを使用して精製した。結果を、以下の表7~9に示す。
本明細書に開示されるヒトFcバリアントG1m15、G1m17、G1m18、G1m19、G2m25、G2m27、G2m28、G4m15、G4m17、G4m18、およびG4m19、G4m25、G4m27、G4m28、およびG4m29を、抗CD137抗体のVH断片ならびに対応するIgG1、G2、およびG4 CH1断片に連結させて、完全長IgG重鎖を生成した。上記の実施例1を参照されたい。これらのFcバリアントは、ヒンジドメイン内の1つまたは変異と、CH2および/またはCH3ドメイン内の1つ以上の変異との組み合わせを含有する。これらの変異体IgG重鎖をクローニングし、抗CD137抗体の軽鎖と同時発現させ(上記の実施例1を参照されたい)、標準的な分子生物学および抗体プロトコルを使用して精製した。結果を、以下の表10~12に示す。
細胞性Fc受容体に対するヒトIgG変異体の結合活性を決定するために、当該技術分野において既知であるレンチウイルス送達系を使用してCHO細胞を遺伝子操作して、ヒトFcγR(FcγRI、FcγRIIA(H131)、FcγRIIA(R131)、FcγRIIB、FcγRIIC、およびFcγRIII)を発現させた。
細胞性FcγR2Bに対する結合がIgG変異体のアゴニスト活性を増強することを検証するために、FcγR2Bを発現するCHO細胞およびヒトCD8陽性T細胞に関与する共培養アッセイを開発した。CHO-FcγRIIB細胞を、96ウェル細胞培養プレートに2×104個/ウェルで播種し、一晩インキュベートした。ヒトCD8陽性T細胞を単離するために、健康なドナーからの新鮮な血液を等量のDPBSと穏やかに混合した。その後、血液試料をFicollの下敷きの上に置き、ブレーキをかけずに、室温、1000gで30分間遠心分離した。PBMCを含有するバフィーコートを新たな管に採取し、DPBSで洗浄した。EasySep(商標)ヒトCD8+T細胞単離キット(Stemcell番号17953)をキットのマニュアルに従って使用して、CD8陽性T細胞をPBMCから単離した。RPMI培地中に懸濁した単離されたCD8+T細胞を、CHO-FcγRIIB細胞とともにプレートに添加した。抗ヒトCD3抗体OKT3を、0.1ug/mlの最終濃度になるように添加し、その後、所望の濃度に希釈した試験抗体を添加した。プレートを3日間培養した後、培養上清を採取して、ヒトIFN-ガンマELISA Ready-SET-GOキット(EBIOSCIENCE、番号88-7316-88)を使用するELISAによってIFNg濃度を測定した。
マウス4-1BB(CD137)、LOB12.3、および3H3に対する2つの異なる抗体を、詳細に調査した。これら2つの抗体を、マウスIgG1、FcRに結合する能力が低下していることが既知であるマウスIgG1 N297A変異体(陰性対照として)、およびマウスIgG2aを含む、様々なマウスIgGアイソタイプとしてクローニングし、発現させた。
選択されたキメラ抗体の薬物動態を研究するために、インビボ研究を実行した。PBS中に製剤化した抗体を、尾静脈注射を介してC57BL/6マウス(生後6~7週間、19~20g、雄)に投与した。用量は、1~3mg/kgであった(1群あたりn=4匹のマウス)。
本明細書に開示される特徴の全ては、任意の組み合わせで組み合わせることができる。本明細書に開示される各特徴は、同じ、同等、または同様の目的を果たす代替的な特徴で置き換えることができる。したがって、別段明確に述べられない限り、開示される各特徴は、一般的な一連の同等または同様の特徴の例に過ぎない。
Claims (6)
- 腫瘍壊死因子受容体スーパーファミリー(TNFRSF)の受容体を結合する結合部分と、IgG1分子に由来するバリアントFc領域と、を含む抗体であって、
前記バリアントFc領域が、野生型の親Fc領域と比較して218位~329位のいずれかに変異を含み、ここで番号付けは、EUインデックスに従うものであり、
前記変異は、(i)236位での欠失であるか、または(ii)236位での欠失およびS267Eである267位でのアミノ酸置換である、
抗体。 - 前記バリアントFc領域が、配列番号6または配列番号18のアミノ酸配列を有する、請求項1に記載の抗体。
- 前記TNFRSFの受容体が、FAS、TNFRSF12A、4-1BB/CD137、TNFRSF13B、TNFRSF13C、CD27/TNFRSF7、CD30/TNFRSF8、CD40/TNFRSF5、DR3/TNFRSF25、DR4/TNFRSF10A、DR5/TNFRSF10B、DR6/TNFRSF21、GITR/TNFRSF18、HVEM/TNFRSF14、LTβR、OX40/TNFRSF4、TROY/TNFRSF19、RELT/TNFRSF19L、TNFRSF12A、TNFRSF13B、TL1A/TNFSF15、TNFRSF17、TNFRSF1A、TNFRSF11B、RANK/TNFRSF11A、TNFRSF11B、NGFR、EDA2R、およびTNFRSF1Bからなる群より選択される、請求項1または2に記載の抗体。
- 対象において免疫応答を選択的に活性化するのに使用するための薬学的組成物であって、
前記薬学的組成物は、有効量の請求項1~3のいずれか1項に記載の抗体と、薬学的に許容される担体と、を含み、
前記抗体は、前記TNFRSFの受容体およびFcγRIIBを結合し、
前記抗体は、請求項1の(ii)で規定されるバリアントFc領域を含むか、または配列番号18のアミノ酸配列を含む、
薬学的組成物。 - 癌を有するか癌を有することが疑われるヒト患者において癌を治療するのに使用するための、請求項4に記載の薬学的組成物。
- 前記癌が、肺癌、胃癌、肝臓癌、乳癌、皮膚癌、膵臓癌、脳癌、前立腺癌、膀胱癌、結腸直腸癌、肉腫、骨癌、リンパ腫、および血液癌からなる群から選択される、請求項5に記載の薬学的組成物。
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