JP2020521798A - 治療法 - Google Patents
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- JP2020521798A JP2020521798A JP2019566227A JP2019566227A JP2020521798A JP 2020521798 A JP2020521798 A JP 2020521798A JP 2019566227 A JP2019566227 A JP 2019566227A JP 2019566227 A JP2019566227 A JP 2019566227A JP 2020521798 A JP2020521798 A JP 2020521798A
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Abstract
Description
(i)CD3に特異的に結合する第1の抗原結合部分であって、配列番号1の重鎖CDR(HCDR)1、配列番号2のHCDR2、及び配列番号3のHCDR3を含む重鎖可変領域;並びに配列番号4の軽鎖CDR(LCDR)1、配列番号5のLCDR2及び配列番号6のLCDR3を含む軽鎖可変領域を含む第1の抗原結合部分;と
(ii)CEAに特異的に結合する第2の抗原結合部分であって、(i)配列番号9の重鎖CDR(HCDR)1、配列番号10のHCDR2、及び配列番号11のHCDR3を含む重鎖可変領域;並びに配列番号12の軽鎖CDR(LCDR)1、配列番号13のLCDR2及び配列番号14のLCDR3を含む軽鎖可変領域;又は(ii)配列番号17の重鎖CDR(HCDR)1、配列番号18のHCDR2、及び配列番号19のHCDR3を含む重鎖可変領域;並びに配列番号20の軽鎖CDR(LCDR)1、配列番号21のLCDR2及び配列番号22のLCDR3を含む軽鎖可変領域を含む第2の抗原結合部分と
を含む二重特異性抗体である。
(a)アミノ酸残基26−32(L1)、50−52(L2)、91−96(L3)、26−32(H1)、53−55(H2)、及び96−101(H3)に生じる超可変ループ(Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));
(b)アミノ酸残基24−34(L1)、50−56(L2)、89−97(L3)、31−35b(H1)、50−65(H2)、及び95−102(H3)に生じるCDR(Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991));
(c)アミノ酸残基27c−36(L1)、46−55(L2)、89−96(L3)、30−35b(H1)、47−58(H2)、及び93−101(H3)に生じる抗原接触(MacCallum et al. J. Mol. Biol. 262: 732-745 (1996));及び
(d)HVRアミノ酸残基46−56(L2)、47−56(L2)、48−56(L2)、49−56(L2)、26−35(H1)、26−35b(H1)、49−65(H2)、93−102(H3)、及び94−102(H3)を含む(a),(b)、及び/又は(c)の組み合わせ
を含む。
特定の実施態様では、GCは、CD3抗体の(初回)投与の約3時間、約1日(24時間)、約2日(48時間)、及び約3日(72時間)後に投与される。他の特定の実施態様では、GCは、CD3抗体の(初回)投与の約3時間、約1日(24時間)、約2日(48時間)、約3日(72時間)、約4日(96時間)、約5日(120時間)、約6日(144時間)及び約7日(168時間)後に投与される。
(i)CD3に特異的に結合する第1の抗原結合部分であって、配列番号1の重鎖CDR(HCDR)1、配列番号2のHCDR2、及び配列番号3のHCDR3を含む重鎖可変領域;並びに配列番号4の軽鎖CDR(LCDR)1、配列番号5のLCDR2及び配列番号6のLCDR3を含む軽鎖可変領域を含む第1の抗原結合部分;と
(ii)CEAに特異的に結合する第2の抗原結合部分であって、(i)配列番号9の重鎖CDR(HCDR)1、配列番号10のHCDR2、及び配列番号11のHCDR3を含む重鎖可変領域;並びに配列番号12の軽鎖CDR(LCDR)1、配列番号13のLCDR2及び配列番号14のLCDR3を含む軽鎖可変領域;又は(ii)配列番号17の重鎖CDR(HCDR)1、配列番号18のHCDR2、及び配列番号19のHCDR3を含む重鎖可変領域;並びに配列番号20の軽鎖CDR(LCDR)1、配列番号21のLCDR2及び配列番号22のLCDR3を含む軽鎖可変領域を含む第2の抗原結合部分と
を含む二重特異性抗体である。
i)第1の抗原結合部分の定常ドメインCLにおいて124位のアミノ酸が正に帯電したアミノ酸により置換されており(Kabatによる番号付け)、第1の抗原結合部分の定常ドメインCH1において147位のアミノ酸又は213位のアミノ酸が負に帯電したアミノ酸により置換されているか(Kabat EUインデックスによる番号付け);或いは
ii)第2の抗原結合部分の定常ドメインCLにおいて124位のアミノ酸が正に帯電したアミノ酸により置換されており(Kabatによる番号付け)、第2の抗原結合部分の定常ドメインCH1において147位のアミノ酸又は213位のアミノ酸が負に帯電したアミノ酸により置換されている(Kabat EUインデックスによる番号付け)。
i)第1の抗原結合部分の定常ドメインCLにおいて124位のアミノ酸がリジン(K)、アルギニン(R)又はヒスチジン(H)により独立して置換されており(Kabatによる番号付け)、第1の抗原結合部分の定常ドメインCH1において147位のアミノ酸又は213位のアミノ酸がグルタミン酸(E)、又はアスパラギン酸(D)により独立して置換されているか(Kabat EUインデックスによる番号付け);或いは
ii)第2の抗原結合部分の定常ドメインCLにおいて124位のアミノ酸がリジン(K)、アルギニン(R)又はヒスチジン(H)により独立して置換されており(Kabatによる番号付け)、第2の抗原結合部分の定常ドメインCH1において147位のアミノ酸又は213位のアミノ酸がグルタミン酸(E)、又はアスパラギン酸(D)により独立して置換されている(Kabat EUインデックスによる番号付け)。
(i)CD3に特異的に結合する第1の抗原結合部分であって、配列番号1の重鎖CDR(HCDR)1、配列番号2のHCDR2、及び配列番号3のHCDR3を含む重鎖可変領域;並びに配列番号4の軽鎖CDR(LCDR)1、配列番号5のLCDR2及び配列番号6のLCDR3を含む軽鎖可変領域を含み、Fab軽鎖とFab重鎖の可変領域又は定常領域、特に定常領域が交換されている第1の抗原結合部分;と
(ii)CEAに特異的に結合する第2及び第3の抗原結合部分であって、配列番号9の重鎖CDR(HCDR)1、配列番号10のHCDR2、及び配列番号11のHCDR3を含む重鎖可変領域;並びに配列番号12の軽鎖CDR(LCDR)1、配列番号13のLCDR2及び配列番号14のLCDR3を含む軽鎖可変領域を含み、第2及び第3の抗原結合部分の各々がFab分子、特に一般的なFab分子である第2及び第3の抗原結合部分;と
(iii)第1及び第2のサブユニットから構成されるFcドメイン
を含む二重特異性抗体であり、
第2の抗原結合部分はFab重鎖のC末端において第1の抗原結合部分のFab重鎖のN末端に融合しており、第1の抗原結合部分はFab重鎖のC末端においてFcドメインの第1のサブユニットのN末端に融合しており、第3の抗原結合部分はFab重鎖のC末端においてFcドメインの第2のサブユニットのN末端に融合している。
(i)CD3に特異的に結合する第1の抗原結合部分であって、配列番号1の重鎖CDR(HCDR)1、配列番号2のHCDR2、及び配列番号3のHCDR3を含む重鎖可変領域;並びに配列番号4の軽鎖CDR(LCDR)1、配列番号5のLCDR2及び配列番号6のLCDR3を含む軽鎖可変領域を含み、Fab軽鎖とFab重鎖の可変領域又は定常領域、特に可変領域が交換されている第1の抗原結合部分;と
(ii)CEAに特異的に結合する第2及び第3の抗原結合部分であって、配列番号17の重鎖CDR(HCDR)1、配列番号18のHCDR2、及び配列番号19のHCDR3を含む重鎖可変領域;並びに配列番号20の軽鎖CDR(LCDR)1、配列番号21のLCDR2及び配列番号22のLCDR3を含む軽鎖可変領域を含み、第2及び第3の抗原結合部分の各々がFab分子、特に一般的なFab分子である第2及び第3の抗原結合部分;と
(iii)安定に会合することのできる第1のサブユニットと第2のサブユニットから構成されるFcドメイン
を含む二重特異性抗体であり、
第2の抗原結合部分はFab重鎖のC末端において第1の抗原結合部分のFab重鎖のN末端に融合しており、第1の抗原結合部分はFab重鎖のC末端においてFcドメインの第1のサブユニットのN末端に融合しており、第3の抗原結合部分はFab重鎖のC末端においてFcドメインの第2のサブユニットのN末端に融合している。
単剤としての及びアテゾリズマブとの組み合わせでの新規がん胎児性抗原T細胞二重特異性抗体(CEA−TCB)抗体の第I相試験
背景:CEA−TCB(RG7802、RO6958688)は、腫瘍細胞上のCEA及びT細胞上のCD3を標的とする新規のT細胞二重特異性抗体である。前臨床的に、CEA−TCBは強力な抗腫瘍活性を有し、腫瘍内T細胞浸潤及び活性化の増大、T細胞媒介性腫瘍細胞殺傷及びPD−L1/PD−1の上方制御をもたらした。
Claims (21)
- がんの治療における使用のためのCD3抗体であって、前記治療が、CD3抗体(の投与)により引き起こされる腫瘍炎症関連の有害事象の改善、治療又は予防のためのグルココルチコイド(GC)の投与を含む、CD3抗体。
- CD3抗体及びグルココルチコイド(GC)の投与を含むがんの治療方法であって、GCがCD3抗体(の投与)により引き起こされる腫瘍炎症関連の有害事象の改善、治療又は予防のために投与される、方法。
- がんの治療のための医薬の製造におけるCD3抗体の使用であって、前記治療が、CD3抗体(の投与)により引き起こされる腫瘍炎症関連の有害事象の改善、治療又は予防のためのグルココルチコイド(GC)の投与を含む、使用。
- GCがメチルプレドニゾロン又はプレドニゾンである、請求項1から3のいずれか一項に記載のCD3抗体、方法又は使用。
- GCが約5から約60mg、特に約40mgの用量で投与される、請求項1から4のいずれか一項に記載のCD3抗体、方法又は使用。
- GCが、CD3抗体の投与の前に、同投与と同時に及び/又は同投与の後で投与される、請求項1から5のいずれか一項に記載のCD3抗体、方法又は使用。
- GCがCD3抗体の投与の後で投与される、請求項1から6のいずれか一項に記載のCD3抗体、方法又は使用。
- GCが、CD3抗体の投与後、特に初回投与後、約1時間から約7日の間に投与される、請求項1から7のいずれか一項に記載のCD3抗体、方法又は使用。
- GCが、CD3抗体の(初回)投与の、(i)約3時間、約1日(24時間)、約2日(48時間)及び約3日(72時間)後、又は(ii)約3時間、約1日(24時間)、約2日(48時間)、約3日(72時間)、約4日(96時間)、約5日(120時間)、約6日(144時間)及び約7日(168時間)後に投与される、請求項1から8のいずれか一項に記載のCD3抗体、方法又は使用。
- がんが固形腫瘍がんである、請求項1から9のいずれか一項に記載のCD3抗体、方法又は使用。
- がんが、結腸直腸がん、肺がん、膵臓がん、乳がん、及び胃がんからなる群より選択されるがんである、請求項1から10のいずれか一項に記載のCD3抗体、方法又は使用。
- CD3抗体が、配列番号1の重鎖CDR(HCDR)1、配列番号2のHCDR2、及び配列番号3のHCDR3を含む重鎖可変領域;並びに配列番号4の軽鎖CDR(LCDR)1、配列番号5のLCDR2及び配列番号6のLCDR3を含む軽鎖可変領域を含む、請求項1から11のいずれか一項に記載のCD3抗体、方法又は使用。
- CD3抗体が、CD3及び標的細胞抗原に特異的に結合する二重特異性抗体である、請求項1から12のいずれか一項に記載のCD3抗体、方法又は使用。
- CD3抗体が、CD3及びCEAに特異的に結合する二重特異性抗体である、請求項1から13のいずれか一項に記載のCD3抗体、方法又は使用。
- CD3抗体が、
(i)CD3に特異的に結合する第1の抗原結合部分であって、配列番号1の重鎖CDR(HCDR)1、配列番号2のHCDR2、及び配列番号3のHCDR3を含む重鎖可変領域;並びに配列番号4の軽鎖CDR(LCDR)1、配列番号5のLCDR2及び配列番号6のLCDR3を含む軽鎖可変領域を含む第1の抗原結合部分;と
(ii)CEAに特異的に結合する第2の抗原結合部分であって、(i)配列番号9の重鎖CDR(HCDR)1、配列番号10のHCDR2、及び配列番号11のHCDR3を含む重鎖可変領域;並びに配列番号12の軽鎖CDR(LCDR)1、配列番号13のLCDR2及び配列番号14のLCDR3を含む軽鎖可変領域;又は(ii)配列番号17の重鎖CDR(HCDR)1、配列番号18のHCDR2、及び配列番号19のHCDR3を含む重鎖可変領域;並びに配列番号20の軽鎖CDR(LCDR)1、配列番号21のLCDR2及び配列番号22のLCDR3を含む軽鎖可変領域を含む第2の抗原結合部分と
を含む二重特異性抗体である、請求項1から14のいずれか一項に記載のCD3抗体、方法又は使用。 - CD3抗体がCEA−TCBである、請求項1から15のいずれか一項に記載のCD3抗体、方法又は使用。
- CD3抗体が約60mgから約1200mgの用量で投与される、請求項1から16のいずれか一項に記載のCD3抗体、方法又は使用。
- CD3抗体が毎週/週に一回(QW)投与される、請求項1から17のいずれか一項に記載のCD3抗体、方法又は使用。
- CD3抗体がPD−1軸結合アンタゴニストと組み合わせて使用される、請求項1から18のいずれか一項に記載のCD3抗体、方法又は使用。
- CD3抗体がアテゾリズマブと組み合わせて使用される、請求項1から19のいずれか一項に記載のCD3抗体、方法又は使用。
- アテゾリズマブが約1200mgの用量で三週に一回に投与される、請求項20に記載のCD3抗体、方法又は使用。
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2018
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- 2018-05-29 AU AU2018276345A patent/AU2018276345B2/en active Active
- 2018-05-29 WO PCT/EP2018/063996 patent/WO2018219901A1/en active Application Filing
- 2018-05-29 BR BR112019025062-0A patent/BR112019025062A2/pt unknown
- 2018-05-29 EP EP18728846.9A patent/EP3630290A1/en active Pending
- 2018-05-29 JP JP2019566227A patent/JP2020521798A/ja active Pending
- 2018-05-29 CN CN201880034781.2A patent/CN110678228A/zh active Pending
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- 2018-05-29 KR KR1020197038296A patent/KR20200014345A/ko not_active Application Discontinuation
- 2018-05-31 TW TW107118608A patent/TW201902513A/zh unknown
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2019
- 2019-11-22 US US16/693,056 patent/US20200199230A1/en not_active Abandoned
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IL270867A (en) | 2020-01-30 |
TW201902513A (zh) | 2019-01-16 |
AU2018276345B2 (en) | 2024-02-29 |
CA3064668A1 (en) | 2018-12-06 |
CN110678228A (zh) | 2020-01-10 |
WO2018219901A1 (en) | 2018-12-06 |
US20200199230A1 (en) | 2020-06-25 |
MX2019014291A (es) | 2020-01-27 |
BR112019025062A2 (pt) | 2020-06-30 |
EP3630290A1 (en) | 2020-04-08 |
AU2018276345A1 (en) | 2019-12-05 |
KR20200014345A (ko) | 2020-02-10 |
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