TW202304512A - 雙特異性t細胞銜接體之給藥 - Google Patents
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Abstract
本發明描述用於在患者中減少骨髓源性抑制細胞且活化T細胞及用於治療罹患實體腫瘤之患者的方法。該等方法需要投與CD3/CD33 T細胞銜接體。
Description
T細胞銜接體為一類特定雙特異性抗體,其介導靶細胞與T細胞之間的結合,引起T細胞定向裂解及T細胞活化、分化及增殖。雖然T細胞銜接體在一些情況下展現出令人印象深刻的效能及抗腫瘤活性,但在許多情形下,更廣泛治療成功之障礙係對表現所關注靶標之正常細胞的不良活性。此「中靶、脫瘤」毒性可為顯著的,且已廣泛報導用於工程化T細胞銜接體。
骨髓源性抑制細胞(MDSC)在局部及全身起作用,損害抗腫瘤免疫、抑制效應T細胞反應、促進免疫抑制調節T細胞的之形成、抑制樹突狀細胞之成熟及抗原呈遞且促進轉移瘤形成。MDSC引發一系列抑制功能,抑制正常細胞反應且導致對免疫檢查點阻斷無反應。MDSC之一個主要功能為以取決於病理學及環境之多種方式抑制T細胞活性。MDSC之存在被認為與不佳結果及對某些療法缺乏反應有關,該等療法例如活化T細胞之療法及涉及使用檢查點抑制劑之療法。
一些T細胞活化療法(例如免疫療法,諸如T細胞銜接體及CAR T細胞療法)與細胞介素釋放症候群(CRS)相關。CRS之發生可限制一些免疫療法之效用。T細胞活化驅動骨髓細胞活化及各種細胞介素及趨化介素之產生,包括IL-6。在一些情況下,細胞介素及趨化介素之含量為病理性的。MDSC屬於主要產生IL-6之骨髓細胞。
本文中描述使用與CD3及CD33結合之雙特異性、二價分子AMV564之方法。AMV564為均二聚蛋白(亦即,具有SEQ ID NO: 1之胺基酸序列之多肽的均二聚體),其具有四個單鏈可變片段(scFv)結合位點,其中兩者結合CD33且兩者結合CD3。理論上,二價設計可恢復對T細胞銜接體之選擇性,引導優先結合至高局部密度密度區域,諸如在活性信號傳遞部位發現或與高受體密度或表現相關之區域。儘管事實上,AMV564結合在整個骨髓譜系中廣泛表現之CD33,但其可以提供理想治療指數之方式給藥,且選擇性結合MDSC。重要地,已發現AMV564在廣泛劑量範圍內具有選擇性。不受任何特定理論束縛,此可歸因於以下某一組合:二價性、scFv之親和力及均二聚體之幾何形狀。例如,同樣不受任何特定理論束縛,AMV564之結構可允許其結合成群之二聚CD33。
AMV564具有雙重活性:其誘導T細胞介導之MDSC殺滅且驅動T細胞活化,促進有利的極化(例如,Th1 CD4 T細胞及效應CD8 T細胞)。AMV564對MDSC之EC50低於約3 pM。適當給藥後,AMV564在很大程度上避開嗜中性球、單核球及許多分化之骨髓細胞,同時引導MDSC殺滅,從而抑制MDSC驅動之抑制途徑。
AMV564適用於減少MDSC且可用以減少全身性免疫抑制,例如在實體腫瘤患者體內。AMV564亦可與各種免疫療法結合使用以控制CRS且減少免疫抑制。
周邊MDSC可在T細胞抑制及T細胞遷移至腫瘤部位中發揮重要作用,該MDSC為基於T細胞活化之療法的潛在速率限制因素。例如,在一些情況下,15 µg劑量之AMV564可達成MDSC群體之顯著耗竭。由於MDSC係自骨髓募集,因此周邊耗竭可使得能夠在超出組織駐留MDSC之有限壽命的給藥時間範圍內進行充分控制,以有利於抗腫瘤免疫。然而,AMV564在腫瘤微環境中之分佈可靶向腫瘤部位之MDSC,同時促進局部T細胞擴增。此外,AMV564遞送至或進入引流淋巴結外加周邊(例如,藉由CIV途徑以高達50 µg、75 µg及100 μg之劑量)可達成抗腫瘤T細胞去抑制且恢復抗原呈遞及免疫穩態。例如以5 µg、15 µg或50 μg之劑量皮下遞送AMV564提供淋巴系統(包括腫瘤引流淋巴結)中起始分佈之直接機制。在皮下投與之情況下,AMV564在較低劑量下有效,很可能係由於進入淋巴系統。
AMV564可在癌症患者中緩解免疫抑制,且活化T細胞效應功能。AMV564可藉由經由靶向耗竭骨髓源性抑制細胞(MDSC)緩解免疫抑制且藉由直接活化/再極化T細胞及改善T效應功能來達成此點。
重要地,皮下投與AMV564藉由靶向淋巴系統促進免疫活化。
本文中描述用於在患者(例如,進行免疫療法之患者)中減少骨髓源性抑制細胞且活化T細胞之方法,該方法包含向患者投與AMV564 (具有SEQ ID NO: 1之胺基酸序列之多肽)。在各種實施例中:AMV564係藉由皮下注射投與;注射之AMV564之劑量為5 µg至150 µg (micrograms);在14天時間內投與AMV564至少7天(8、9、10、11、12、13或14天);每天皮下投與AMV564 (例如,以5、10、15、20、25、30、35、40、45、50 μg/劑);在14天時間內的10天投與AMV564;在14天時間內分兩個時段連續投與5天AMV564;連續投與5天AMV564,在隨後的兩天不投與,且隨後連續投與5天;在21天週期內投與AMV564,其中在14天時間內投與至少7天AMV564且在隨後的7天時間內不投與;21天週期重複至少兩次;在14天時間內投與至少10天AMV564,其中連續投與5天,隨後2天不投與,隨後連續投與5天;投與時每天投與之AMV564劑量為5、10、15、20、25、30、35、40、45、50 μg;正用活化T細胞之療法治療患者(例如,該療法為CAR T細胞療法;該療法為CTL療法;該療法為抗體療法;該療法係用包含CD3結合域且活化T細胞之T細胞銜接體治療);患者罹患白血病(急性骨髓白血病或骨髓發育不良症候群)或正在接受白血病治療;患者罹患實體腫瘤或正在接受實體腫瘤治療;該實體腫瘤係選自由以下組成之群:胰臟癌、卵巢癌、大腸癌、直腸癌、非小細胞肺癌、尿道上皮癌、鱗狀細胞癌、直腸癌、陰莖癌、子宮內膜癌、小腸癌、闌尾癌;AMV564之投與達成0.1 pM 至5 pM (例如,0.1、0.2、0.3、0.4、0.5、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5或5.0 pm) AMV564之穩態暴露。
亦描述一種用於治療患者之實體腫瘤之方法,該方法包含向患者投與AMV564 (具有SEQ ID NO: 1之胺基酸序列之多肽)。在各種實施例中:AMV564係藉由皮下注射投與;注射之AMV564之劑量為5 µg至150 µg (mcg或micrograms);在14天時間內的至少7天(8、9、10、11、12、13或14天)投與AMV564;每天皮下投與AMV564 (例如,以5、10、15、20、25、30、35、40、45、50 μg/劑);在14天時間內的10天投與AMV564;在14天時間內分兩個時段連續投與5天AMV564;連續投與5天AMV564,在隨後的兩天不投與,且隨後連續投與5天;在21天週期內投與AMV564,其中在14天時間內投與至少7天AMV564且在隨後的7天時間內不投與;21天週期重複至少兩次;在14天時間內投與至少10天AMV564,其中連續投與5天,隨後2天不投與,隨後連續投與5天;投與時每天投與之AMV564劑量為5、10、15、20、25、30、35、40、45、50 μg; 正用活化T細胞之療法治療患者(例如,該療法為CAR T細胞療法;該療法為CTL療法;該療法為抗體療法;該療法係用包含CD3結合域及活化T細胞之T細胞銜接體治療);患者患有白血病(急性骨髓白血病或骨髓發育不良症候群)或正在接受白血病治療;患者罹患實體腫瘤或正在接受實體腫瘤治療;該實體腫瘤係選自由以下組成之群:胰臟癌、卵巢癌、大腸癌、直腸癌、非小細胞肺癌、尿道上皮癌、鱗狀細胞癌、直腸癌、陰莖癌、子宮內膜癌、小腸癌、闌尾癌;AMV564之投與達成0.1 pM 至5 pM AMV564之穩態暴露;。實體腫瘤係選自由以下組成之群:小細胞肺癌(NSCLC) (例如,轉移性非鱗狀NSCLC、III NSCLC、表現PD-L1之轉移性NSCLC)、黑色素瘤、梅克爾細胞癌(Merkel cell)、高微星體不穩定性癌(例如,不可切除性或轉移性、高微星體不穩定性(MSI-H)或錯配修復缺陷);接受檢查點阻斷後病情進展的患者;AMV564之投與達成0.1 pM 至5 pM AMV564之穩態暴露;該方法包含藉由連續靜脈內輸注投與5 µg至50 µg AMV564。
亦描述用於藉由投與AMV564以達到30 pM至70 pM AMV564之穩態暴露來治療AML的方法。
CD33亦稱為Siglec-3,為表現於骨髓譜系細胞上之跨膜蛋白。由於在白血病胚細胞上之高流行率及高表現,CD33長久以來被視為急性骨髓白血病(AML)之吸引人的靶標。尚未充分理解CD33之功能,但已展示,CD33信號傳遞在早期譜系骨髓細胞,諸如免疫抑制性骨髓源性抑制細胞(MDSC)上之活化引起MDSC擴增及抑制細胞介素及因子之產生。CD33表現被用作細胞表面標記組之一種組分以識別此等免疫抑制性單核球及顆粒球細胞(例如,藉由使用流動式細胞測量術進行細胞免疫表現型分型)。尚不清楚CD33在更分化之骨髓譜系細胞,諸如成熟單核球、嗜中性球、巨噬細胞及樹突狀細胞上起何種作用(若存在)。實際上,使用CRISPR技術在人類細胞中基因剔除CD33已表明CD33並非譜系分化所必需的,但其仍然持續以不同量表現於此等細胞之大部分中,使其在安全性及功效性方面均成為非選擇性T細胞銜接體之具有挑戰性的靶標。
T細胞銜接體藉由充當靶細胞上之抗原與T細胞上之不同抗原之間的橋樑而作用,以在藥物與兩種不同細胞類型之間形成三元複合物,由此模擬在適應性免疫反應過程中產生之天然T細胞-靶細胞突觸之形成。認為必須適當結合10與100個分子之間的藥物以便活化T細胞殺滅,且T細胞亦必須為可獲得的。因此,此活性狀態為受體佔有率及給藥帶來超出標準模型之額外考慮因素,例如經由生物藥物結合抑制配位體或受體,其中給藥策略旨在達成最大目標覆蓋率,直至達到不可接受之毒性。對於靶向廣泛表現之抗原(諸如CD33)的T細胞銜接體,仍有更多因素需要考慮。除了與骨髓譜系細胞(其帶來有價值的感染防護)之廣泛耗竭相關的潛在安全風險外,此細胞群可為極大的(例如,人體內每天存在高達1000億個嗜中性球),且功效可能因此受損,此係由於藥物分佈不夠合適及T細胞供應不足以完成殺滅。因此,靶向其他細胞群,諸如白血病胚細胞或甚至更罕見的免疫抑制MDSC可能因此受到藥物在CD33陽性正常骨髓細胞中之廣泛分佈及需要足夠相關T細胞以達成殺滅的阻礙。由於此等原因,確定T細胞銜接體之適當劑量、劑量方案及投與途徑異常具有挑戰性,遠超過單價、單特異性藥劑。
AMV564 之結合特性及劑量選擇 AMV564之二價設計反映於其物理特性中。AMV564係極有效的且在低受體佔有率下表現出細胞殺滅,離體或活體外以皮莫耳(picomolar)或次皮莫耳(sub-picomolar) EC50值表現出CD33靶細胞之消除。AMV564為有效促效劑,其可在低受體佔有率或低靶標結合水準下誘導生物活性。使用流動式細胞測量術之結合研究表明,與在1 pM或10 pM AMV564下均有效結合之MDSC及白血病胚細胞株KG1相比,在1 pM或10 pM AMV564下不存在嗜中性球、多形核(PMN)白血球或單核球之結合(圖1F至圖1G)。在1 pM及10 pM之濃度下,與其他豐富的CD33表現細胞相比,AMV564似乎對MDSC具有高選擇性。
因此,當靶細胞與AMV564之銜接足以發揮活性,但與其他骨髓細胞之結合最小時,可獲得安全性及抗腫瘤(例如白血病胚細胞)及/或抗抑制(MDSC)細胞活性之理想治療窗。除安全考慮因素外,過度銜接包含正常骨髓譜系之大細胞群可能導致功效降低,此係由於藥物分佈欠佳及可用的T細胞不足,無法形成模擬天然T細胞突觸以促進細胞殺滅之必要三元複合物。殺滅
MDSC 之耗竭及劑量選擇 克服抑制性腫瘤微環境係免疫療法中之主要挑戰。抑制性腫瘤微環境之關鍵細胞效應物為MDSC,其與免疫功能障礙、抗腫瘤免疫抑制及對免疫療法之不佳反應有關。MDSC經由各種細胞介素、活性物種及途徑抑制T細胞及NK細胞反應。此外,其抑制腫瘤引流淋巴結中樹突狀細胞之有效抗原呈遞。在本發明之另一態樣中,AMV564以低劑量耗竭AML患者之周邊及骨髓中之MDSC。在低引入劑量之AMV546下觀測到的快速下降表明單核球及顆粒球MDSC群兩者之有效結合及耗竭。MDSC在健康成年人之周邊中係罕見的且在癌症患者中變得顯著升高。然而,與一般成熟骨髓譜系相比,其仍為相對稀有細胞,且當總受體佔有率不利於二價T細胞銜接體(諸如AMV564)之選擇性時,其耗竭及控制之功效在較高劑量下可能降低。
在實體腫瘤患者患者中,以5 µg至50 μg之劑量投與AMV564產生範圍介於0.1 pM至5 pM之近似穩態暴露,可有效耗竭MDSC且促進有利的CD4及CD8 T細胞活化分佈及細胞介素環境以促進抗腫瘤免疫之修復。50 µg至75 µg或75 µg至150 µg之較高劑量亦將產生保持在MDSC耗竭之選擇性範圍內的暴露。
循環MDSC為AMV564及T細胞反應之藥效學生物標記。由於已知MDSC係藉由T細胞活化誘導,因此其係由於藉由AMV564刺激之T細胞活化而誘導。MDSC反映AMV564與靶細胞(MDSC)之銜接及此類細胞之耗乏,且與二價、雙特異性T細胞銜接體(諸如AMV564)之劑量相關,其反映藥物最佳治療指數內之有效劑量,以使得與CD33陽性骨髓譜系之其餘部分相比,能夠有效耗竭此等相對稀有細胞。
因為AMV564耗竭MDSC,因此例如根據本文中所述之給藥方案用AMV564治療可適用於在多種情況下耗竭MDSC。例如,AMV564可用於耗竭正在用活化T細胞或涉及活化T細胞投與之療法治療之患者的MDSC。
細胞介素釋放症候群 ( CRS ) 之處理 雖然未完全理解,但CRS似乎涉及T細胞活化及巨噬細胞與其他骨髓細胞之後續活化,以產生及分泌IL-6、IL-1B及其他細胞介素。CRS通常與T細胞銜接療法,諸如T細胞銜接雙特異性抗體及CAR-T療法有關。CRS在開始給藥時最為明顯。如下文所示,在實體腫瘤患者中藉由皮下途徑投與例如15 µg至50 μg劑量之AMV564可產生穩固T細胞活化,如藉由各種量度所評定,包括在第一給藥週期中可偵測周邊干擾素γ (IFNγ)相對於基線增加高達10至40倍。然而,IL-6之增加相對少量(兩種細胞介素約為1:1或有利於較高IFNγ) (參見圖7A至圖7E),且未偵測到顯著含量之IL-1B。此有利型態與本臨床研究中未在患者中觀測到CRS一致。此明顯強力T細胞活化且缺乏CRS之有利型態可能反映特徵之組合,該等特徵包括MDSC之耗竭(可產生發炎性細胞介素)、二價T細胞與AMV564之銜接(可更近似於更原始T細胞受體銜接)及與皮下注射AMV564相關之淋巴遞送及分佈動力學。AMV564具有適合長期給藥之有利治療指數,此等特性亦應有助於在完成引入給藥至目標劑量後緩解CRS。
組合療法 常經由組合療法來達成有效治療腫瘤形成。可以最大化功效及安全性(特別是正常骨髓細胞未顯著消耗)之劑量範圍下的AMV564之功能治療指數使AMV564適用於組合療法。在實體腫瘤中,組合策略包括但不限於檢查點阻斷(PD-1或PDL-1阻斷劑);T細胞活化劑及擴增劑,諸如細胞介素IL-2、IL-10及IL-15;雙重靶向劑,諸如彼等靶向檢查點(例如PD-1或PDL-1)及免疫抑制(例如TGFβ)者;CAR療法(表現於T細胞或NK細胞中);NK活化療法;或標準照護化學療法。在AML及MDS中,此前所列療法亦可與其他已確立的AML藥劑組合使用,諸如低甲基化劑(例如氮胞苷(azacytidine)、地西他濱(decitabine)))、分化劑(例如靶向IDH1/2)、靶向劑(例如抗FLT3)、靶向抗凋亡蛋白(諸如BCL2(例如維納妥拉(venetoclax))、BCL-XL或MCL1)之藥劑或來那度胺(lenalidomide)。
AMV564可單獨或以組合形式用於治療黑色素瘤(例如,患有不可切除性或轉移性黑色素瘤、完全切除後累及淋巴結之黑色素瘤的患者);非小細胞肺癌(NSCLC) (例如轉移性非鱗狀NSCLC、III NSCLC、表現PD-L1之轉移性NSCLC);頭頸部鱗狀細胞癌(HNSCC);典型霍奇金氏淋巴瘤(Hodgkin lymphoma;cHL);原發性縱隔大B細胞淋巴瘤(PMBCL);尿道上皮癌(例如,表現PD-L1之局部晚期或轉移性尿道上皮癌);高微星體不穩定性癌(例如不可切除性或轉移性、高微星體不穩定性(MSI-H)或錯配修復缺陷;先前治療後進展之實體腫瘤;乳癌;子宮癌;胃癌(例如表現PD-L1之復發性局部晚期或轉移性胃或胃食道交界腺癌);子宮頸癌;肝細胞癌(HCC);梅克爾細胞癌(MCC);及腎細胞癌(RCC)。
相關申請案之交叉參考
本申請案主張2021年4月9日申請之以下美國臨時申請案之權益:第63/173,224號,其全部內容以引用之方式併入本文中。
AMV564 AMV564為SEQ ID NO: 1之均二聚體。AMV564描述於US 9212225 (雙功能抗體16;在胺基末端無6 His標籤之SEQ ID NO: 113)及WO 2016/196230 (SEQ ID NO:139)中。AMV564之醫藥組合物包含具有胺基酸序列SEQ ID NO: 1之多肽之均二聚體及醫藥學上可接受之載劑或賦形劑。
實例 1 : AMV564 離體 耗竭 MDSC 且 活化 T 細胞在此研究中,發現對離體原代細胞(PBMC、MDS骨髓、腫瘤PBMC)進行AMV564治療會耗竭MDSC且活化T細胞。圖1A顯示,用CD33配位體S100A9治療PBMC引起MDSC擴增及CD33表現增加。暴露於AMV564抵消回應於PBMC之S100A9刺激產生之活性氧類(ROS)以擴增MDSC (圖1B),引起MDSC(圖1C)之選擇性耗竭,且增加CD8 T細胞(圖1D)及CD4 T細胞(圖1E)數量及活化狀態(如藉由IFNγ陽性比例評定)。
因此,患者源性周邊血液單核細胞(PBMC)之離體處理導致MDSC之選擇性耗竭(p <0.01)及活性氧類產量的減少。AMV564僅在CD33+靶細胞存在下誘導活化T細胞之顯著增加,其中CD4+及CD8+ T細胞增殖增加>2倍。增殖之增加為劑量依賴性的且伴隨著IFNγ產量之顯著增加。
AMV564在1 pM及10 pM下結合至MDSC (及白血病胚細胞株KG1) (圖1F)。然而,在此等濃度下,基本上不存在證據表明AMV564與單核球、嗜中性球及多形核白血球(PMN)結合。此等濃度在藉由皮下途徑以5-15-50 μg (約0.1-5 pM)劑量給與AMV564時所觀測到的暴露範圍內。如圖1G中所示。
實例 2 : AMV564 使患者 耗竭 MDSC 且 活化 T 細胞在此臨床研究中,發現用AMV564治療引起周邊血液MDSC及骨髓MDSC及AML胚細胞之耗竭,而嗜中性球未減少(圖2A至圖2F)。單核球及顆粒球MDSC之快速耗竭均為顯而易見的,對循環嗜中性球或單核球群影響很小或無影響。早期T細胞活化之證據在T細胞之快速再分佈/著邊中顯而易見(此明顯的短暫淋巴球減少症係T細胞活化及向淋巴結及組織遷移之結果)。在圖2A至圖2F中,引入AMV564給藥之時段(15 μg;3天)由淺色條表示且目標AMV564給藥(100 μg)由深色條表示。在MDSC中,在周邊血液(圖2A及圖2B)及骨髓(圖2C)中觀測到耗竭。圖2D至圖2E分別顯示AMV564治療對周邊血液T細胞、周邊血液嗜中性球及周邊血液胚細胞之影響。
實例 3 : AMV564 耗竭實體腫瘤患者中之 MDSC在引入給藥時(在一些患者中為第1天至第3天)觀測到回應於T細胞活化之周邊血液MDSC的初始增加(圖3A至圖3C)。隨著T細胞遷移至淋巴結及組織,亦觀測到與T細胞活化一致之周邊血液T細胞之快速再分佈/著邊(圖3C)。然而,在目標劑量下,周邊MDSC得到控制。相對於基線,在第15天評估時,骨髓MDSC亦實質上減少。然而,一旦AMV564治療停止,骨髓及周邊血液MDSC均反彈。
實例 4 : AMV564 係選擇性且有效的條件性促效劑原代人類T細胞及KG-1細胞暴露於AMV564。量測靶標依賴性細胞毒性(圖4A)、靶標依賴性T細胞增殖(圖4B)、分化單核球及嗜中性球之活力(圖4C)、分化單核球及嗜中性球之活力(圖4D),全部使用CD3/CD28作為參考T細胞刺激。由於KG1表現CD33且AMV564與KG1之結合類似於其與MDSC之結合,因此KG1在此等檢定中被用作MDSC之替代物。AMV564在類似於CD3-CD28刺激之最大含量下誘導KG1之有效劑量依賴性細胞死亡(圖4A)。此伴隨著子細胞之增加,反映了T細胞增殖水準等於或超過CD3-CD28參考刺激(圖4B)。然而,不同於使用CD3-CD28之一般T細胞刺激,不存在證據表明AMV564促進自體單核球或嗜中性球之顯著細胞死亡(圖4C),且類似地,不存在證據表明此等細胞群誘導T細胞增殖(圖4D)。
實例 5 : AMV564 在 實體腫瘤患者中之 1 期臨床研究此研究募集了患有不可切除之晚期轉移性實體腫瘤之成年患者,該等腫瘤自最後一次抗腫瘤治療以來復發且惡化且不存在公認之標準療法。患者之ECOG體能狀態為≤2且具有適當器官功能。患者僅用AMV564 (15、50或75 μg/天)治療或用AMV564 (5、15或50 μg/天)與以每3週(Q3W) 200 mg經靜脈內投與之派立珠單抗組合治療。在兩種情況下,均在21天週期內之第1至第5天及第8至第12天藉由皮下注射一天一次地投與AMV564。AMV564具有良好耐受性,且藥效學分析展示在先前用其他療法治療之異質癌症患者的1期人群中緩解免疫抑制(減少MDSC及Treg)且促進效應CD8及Th1 CD4反應的證據。
一般而言,用AMV564治療之患者表現出與包括CD4 Th1輔助細胞、抗原呈遞細胞之T細胞之活化一致的細胞介素型態,且改善T細胞趨向組織,諸如腫瘤組織的遷移(IFNγ、IL-15、IL-18、可溶性顆粒酶B及CXCL10之增加)。雖然觀測到強烈的T細胞活化,但無細胞介素釋放症候群發作。
實例 6 : 實體腫瘤患者中之 MDSC 控制與 Treg 控制相關M-MDSC及G-MDSC在患有實體腫瘤且用AMV564 (圖5A:卵巢-15 μg AMV564;圖5B:皮膚-50 μg AMV564;圖5C:小腸-15 μg AMV564;圖5D:胃食道交界處-15 μg AMV564)治療之患者中得到控制,該等患者用AMV564治療(在21天週期之第1至第5天及第8至第12天每天一次皮下注射)。圖5E描繪Treg自基線(B)經過兩個療法週期(C1及C2)之變化。
實例 7 :接受 AMV564 療法之 實體腫瘤患者的 CD8 與 Treg 比率增加圖6A至圖6G顯示,對於接受AMV564療法之大部分實體腫瘤患者,觀測到CD8/Treg比率增加(在21天週期之第1至第5天及第8至第12天一天一次皮下注射(圖6A:小腸-病情穩定(15 μg劑量);圖6B:卵巢-完全反應(15 μg劑量);圖6C:GE交界處-病情進展(15 μg劑量);圖6D:子宮內膜-病情穩定(50μ g劑量);圖6E:結腸直腸-病情進展(50 μg劑量);圖6F:皮膚-病情穩定(50 μg劑量);圖6G:闌尾-病情穩定(50 μg劑量))。
實例 8 : AMV564 促進卵巢癌患者中有利的 CD4 及 CD8 T 細胞極化先前接受過多個基於鉑之化學療法、手術、輻射、派立珠單抗(最佳反應穩定疾病,在研究開始前6個月完成)以及尼拉帕尼(niraparib)及來曲唑(letrozole)療法方案的卵巢癌患者接受15 µg AMV564治療(在21天週期之第1至第5天及第8至第12天藉由皮下注射一天一次)。此患者表現出CD8/Treg持續增加、% CD8增加、效應CD8 (TBX21及/或顆粒酶B陽性)及記憶CD8細胞保持不變或增加、TBX21陽性CD4 T輔助細胞動態增加、及PD1陽性CD8比例動態調變,但總體上無實質性增加,如圖7A至圖7E中所示。如藉由以6至8週間隔進行之CT掃描所評定,此患者自病情穩定進展為部分反應,再進展為完全反應。
實例 9 : 用 AMV564 治療之患者表現出無 CRS 之 T 細胞活化的跡象圖8A至圖8F(分別為患者1、2、3、11、9及14)顯示用AMV564 (在21天週期之第1至第5天及第8至第12天藉由皮下注射一天一次)治療之六名實體腫瘤患者中之IFNγ及IL-6量測結果。如可見,存在明顯證據表明全身性IFNγ產生而無過量IL-6產生(對於大部分患者,IFNγ:IL-6之比率為約1:1或更好)。
在5個治療週期中,實體腫瘤患者(資料未示出)在稍後時間點(例如第2週期結束時及第3、4週期)表現出IFNγ、TNFα及IL18及其他因子之增加,與I類MHC上調、樹突狀細胞活化及T細胞遷移(MDSC誘發因子G-CSF降低)一致。此同一患者在基線時以不佳CD8/Treg進入研究。在整個治療過程中,尤其在約第3週期觀測到改善,其中觀測到CD8 T細胞增殖及活化(Ki67及CD38比例)之增加,與CD8效應功能(T-bet及顆粒酶B陽性比例) 之改善一致。此反映觀測到細胞介素及因子增加之時間與改善之樹突狀細胞活化及Th1反應一致,表明隨時間推移,即使在此晚期患者中,AMV564亦驅動更有利的免疫極化。
實例 10 : 用 AMV564 及派立珠單抗治療圖9A至圖9D顯示用AMV564與派立珠單抗組合治療之四名實體腫瘤患者中之M-MDSC及G-MDSC量測結果,AMV564在21天週期之第1至第5天及第8至第12天一天一次地皮下注射(5 µg/天(圖9A及圖9B)或15 µg/天(圖9C及圖9D),派立珠單抗每3週(Q3W) 200 mg經靜脈內投與。AMV564投與天數由沿x軸之條表示,且派立珠單抗治療天數用星號表示。如可見,觀測到極好的MDSC控制。
圖10A至圖10D顯示用AMV 564 (在21天週期之第1至第5天及第8至第12天一天一次地皮下注射15 µg)與派立珠單抗(以200 mg Q3W經靜脈內投與)組合治療之兩名患者之資料(圖10A及圖10C:患者15;圖10B及圖10D:患者16)。此資料顯示在第1-2週期中CD8效應細胞比例實質上增加及CD8/Treg比率實質上增加的證據。資料亦顯示T-Bet及顆粒酶B陽性CD8細胞之擴增。在此研究中,此等效果在5 μg AMV564組合群組中不明顯。
圖11A及圖11B顯示用AMV 564 (在21天週期之第1至第5天及第8至第12天每天一次地皮下注射15 µg)與派立珠單抗(以200 mg Q3W經靜脈內投與)組合治療之兩名患者之CD8 T細胞增殖資料(圖11A:患者15;圖11B:患者16)。此資料顯示CD8增殖顯著增加(藉由CD8 Ki67評定)及活化顯著增加(藉由CD 8 CD38評定)的證據。3名組合給藥患者中之2名自不佳基線水準顯著且快速增加,表明AMV564及派立珠單抗組合之潛在益處。
實例 11 : AMV564 選擇性靶向 M - MDSC 及 G - MDSC 以耗竭且活化實體腫瘤患者中之 T 細胞對用15 µg或50 μg皮下投與之AMV564治療之實體腫瘤患者量測M-MDSC及G-MDSC。如圖12A至圖12B中可見,治療與該兩種MDSC亞型之下降相關。此係重要的,因為M-MDSC升高常與較低水準之周邊T細胞相關。
用AMV564 (單獨或與派立珠單抗組合)治療實體腫瘤患者使得顆粒酶B及TBX21 (T-bet)在CD8+ T細胞上之共表現增加(圖13A)。此外,在接受治療之患者的第一與第二週期之間,顆粒酶B+ CD8+ T細胞之頻率顯著增加(圖13B)
實例 12 : AMV564 誘導 調節免疫反應單獨或其與派立珠單抗組合用15 μg或50 μg AMV564治療之實體腫瘤患者(n=11單藥療法,n=4組合)表現出有利的、大致為1:1之IFNγ:IL-6比率(圖14A及圖14B)。在許多情況下,用其他T細胞銜接體治療產生在0.1與0.01之間的比率。
在用AMV564治療之實體腫瘤患者中,IL-6、IL-1β、IL-10及TNFα (其均為髓源性細胞介素)之水準保持較低(圖15A、圖15B及資料未示出)。相比之下,在此等患者中,促進Th1極化、巨噬細胞活化及T細胞遷移至腫瘤之促炎性細胞介素之水準升高(圖15A、圖15B及資料未示出)。
使用KG-1細胞作為靶細胞之活體外細胞毒性檢定表明,在大範圍之AMV564比率內,AMV564與有利的IFNγ:IL-6比率相關(圖15C)。
實例 13 : AMV564 擴增周邊 T 細胞庫經由TCRβ CDR3深度定序在不同治療週期(第1週期,第1天相比於第2週期,第1天)對三名患者(小腸癌、鱗狀細胞癌及胰臟癌)之T細胞庫進行評定。評定治療期間之擴增、受限或從頭產生之純系以使治療對TCR庫及疾病演變之影響相關聯。如圖16A至圖16C中可見,僅在一個治療週期後,T細胞庫之顯著擴增係明顯的(p=0.008)。觀測到每名患者具有約30至超過300個差異偵測到的T細胞純系,包括一些在基線時不可偵測或極罕見的T細胞純系。
實例 14 : 卵巢癌患者中之 T 細胞庫擴增與增加之 CD8 記憶細胞相關。一名用15 µg AMV564治療且已確認為RECIST CR之卵巢癌患者在治療過程中表現出CD8細胞(圖17A)及CD8記憶細胞(圖17B)之增加。
跨治療時間點之特異性T細胞重排的追蹤表明若干純系經擴增且最終主導了此患者之細胞庫(圖17C)。八個擴增最多的T細胞純系中之兩者匹配與靶向SLC3A2新抗原(在某些癌症中上調且常與不良預後相關)之T細胞一致的CDR3序列(圖17C)。
以引用方式併入本文中所提及之所有公開案、專利及專利申請案特此以全文引用之方式併入,如同每一個別公開案、專利或專利申請案具體且個別地指示為以引用之方式併入。在有衝突之情況下,以本申請案(包括本文中之任何定義)為凖。
等效物熟習此項技術者將認識到或能夠僅使用常規實驗即可確定本文所描述之本發明特定實施例的許多等效物。此類等效物意欲由以下申請專利範圍涵蓋。
圖 1A 至圖 1G呈現之資料顯示AMV264離體耗竭MDSC且活化T細胞,且AMD564在1 pm及10 pm下結合MSC及KG-1細胞,但在此等濃度下不結合單核球。圖1A顯示,用CD33配位體S100A9處理PBMC引起MDSC擴增及CD33表現增加。圖1B至圖1E顯示,暴露於AMV564抵消回應於PBMC之S100A9刺激而產生之活性氧類(ROS)以擴增MDSC(圖1B),引起MDSC之選擇性耗竭(圖1C),且增加CD8 T細胞(圖1D)及CD4 T細胞(圖1E)數量及活化狀態(如藉由IFNγ陽性比例評定)。
圖 2A 至圖 2F顯示,AMV564治療導致周邊血液及骨髓MDSC及AML胚細胞之耗竭,而嗜中性球未減少。圖2A及圖2B顯示周邊血液中MDSC之耗竭。圖2C顯示骨髓中之MDSC耗竭。圖2E至圖2G顯示AMV564治療對周邊血液T細胞(圖2E)、周邊血液嗜中性球圖2F及周邊血液胚細胞(圖2G)之影響。淺色條表示引入劑量之天數,且深色條表示目標劑量之天數。
圖 3A 至圖 3C呈現之資料顯示AMV564對周邊血液MDSC、骨髓MDSC、周邊血液T細胞之影響。圖3A顯示AM564對周邊血液MDSC中之CD45+細胞百分比之影響。圖3B顯示AM564對骨髓MDSC中之CD45+細胞百分比之影響。圖3C顯示AM564對周邊血液T細胞中之CD45+細胞百分比之影響。淺色條表示引入劑量之天數,且深色條表示目標劑量之天數。
圖 4A 至圖 4D呈現之資料顯示AMV564係選擇性且有效的條件性促效劑。單個空心圓及三角形顯示在不存在AMV564之情況下CD3/CD28刺激之結果。圖4A顯示AMV564在類似於CD3-CD28刺激之最大水準下誘導KG1之有效劑量依賴性細胞死亡(圖4A)。圖4B顯示子細胞之增加,反映了T細胞增殖水準等於或超過CD3-CD28參考刺激。圖4C顯示,不存在證據表明AMV564促進自體單核球或嗜中性球之顯著細胞死亡。圖4D顯示,與使用CD3-CD28之一般T細胞刺激不同,不存在證據表明此等細胞群誘導T細胞增殖。
圖 5A 至圖 5E呈現之資料顯示實體腫瘤患者中之MDSC控制與Treg控制相關。圖5A至圖5D顯示,M-MDSC及G-MDSC在患有實體腫瘤且用AMV564 (圖5A:卵巢-15 μg AMV564;圖5B:皮膚-50 μg AMV564;圖5C:小腸-15 μg AMV564;圖5D:胃食道交界處-15 μg AMV564)治療之患者中得到控制,該等患者用AMV564治療(在21天週期之第1至第5天及第8至第12天一天一次皮下注射)。實心方形為G-MDSC且實心圓為M-MDSC。圖5E描繪Treg自基線(B)經過兩個療法週期(C1及C2)之變化。軸之條表示AMV564之給藥天數。
圖 6A 至圖 6G呈現之資料顯示CD8:Treg之比值在實體瘤患者中AMV564療法上有所改善。具體而言,圖6A至圖6G顯示,對於接受AMV564療法之大部分實體腫瘤患者觀測到CD8/Treg比率增加(在21天週期之第1至第5天及第8至第12天一天一次地皮下注射(圖6A:小腸-病情穩定(15 μg劑量);圖6B:卵巢-完全反應(15 μg劑量);圖6C:GE交界處-病情進展(15 μg劑量);圖6D:子宮內膜-病情穩定(50μ g劑量);圖6E:結腸直腸-病情進展(50 μg劑量);圖6F:皮膚-病情進展(50 μg劑量);圖6G:闌尾-病情穩定(50 μg劑量))。虛線表示基線比率;沿x軸之條表示給藥天數且較寬條表示健康對照之比率,健康對照之周邊血液樣品在同一基於流量的檢定中處理。
圖 7A 至圖 7E呈現之資料顯示AMV564在投與15 μg AMV564 (在21天週期之第1至第5天及第8至第12天一天一次地皮下注射)之卵巢癌患者中促進有利的CD4及CD8 T細胞極化。圖7A顯示150天內之CD8/Treg比率。圖7B顯示維持或增加之效應物CD8 (TBX21及/或顆粒酶B陽性)及PD1陽性CD8比例之動態調變。圖7C顯示TBX21陽性CD4 T輔助細胞之動態增加。圖7D顯示T細胞之持續增加。圖7E顯示CD8 T細胞之百分比的增加。虛線表示基線比率;沿x軸之條表示給藥天數且寬條表示健康對照之比率。
圖 8A 至圖 8F顯示在六名用AMV564治療之實體腫瘤患者中之IFNγ第1週期、IFNγ第2週期、IL-6第1週期及IL-6第2週期水準(患者1 (圖8A);患者2 (圖8B);患者3 (圖8C);患者11 (圖8D);患者9 (8E);患者14 (圖8F-僅第1週期))。
圖 9A 至圖 9D顯示在四名用AMV564與派立珠單抗(pembrolizumab)組合治療之實體腫瘤患者中之M-MDSC及G-MDSC量測結果。圖9A及圖9B顯示對用AMV564與派立珠單抗組合治療之實體腫瘤患者所觀測到的結果,AMV564分別在21天週期之第1至第5天及第8至第12天以5 μg/天一天一次地皮下注射,派立珠單抗以每3週(Q3W) 200 mg經靜脈內投與。圖9C及圖9D顯示對用AMV564與派立珠單抗組合治療之實體腫瘤患者所觀測到的結果,AMV564分別在21天週期之第1至第5天及第8至第12天以15 μg/天一天一次地皮下注射,派立珠單抗以每3週(Q3W) 200 mg經靜脈內投與。實心方形為G-MDSC,且實心圓為M-MDSC。軸之條表示AMV564給藥天數。
圖 10A 至圖 10D顯示AMV564與派立珠單抗之組合對兩名實體腫瘤患者中之T-Bet及顆粒酶B陽性CD8細胞及CD8/Treg比率之影響。圖10A及圖10C顯示對用AMV 564 (分別在21天週期之第1至第5天及第8至第12天一天一次地皮下注射15 µg)與派立珠單抗(以200 mg Q3W經靜脈內投與)組合治療之患者15所觀測到的結果。圖10B及圖10D顯示對用AMV 564 (在21天週期之第1至第5天及第8至第12天一天一次地皮下注射15 µg)與派立珠單抗(以200 mg Q3W經靜脈內投與)組合治療之患者16所觀測到的結果。虛線表示基線比率;沿x軸之條表示AMV564之給藥天數且寬條表示健康對照之比率。
圖 11A 至圖 11B顯示AMV564與派立珠單抗之組合治療對兩名實體腫瘤患者中之CD8細胞增生及活化之影響。圖11A及圖11B顯示對用AMV 564 (在21天週期之第1至第5天及第8至第12天一天一次皮下注射15 µg)與派立珠單抗(以200 mg Q3W經靜脈內投與)組合治療之患者15 (圖11A)及患者16 (圖11B)所觀測到的結果。
圖 12A 至圖 12B顯示AMV564在5個治療週期過程中對M-MDSC細胞及G-MDSC細胞含量之影響(* p < 0.05,**p <0.01)。圖12A顯示用15 µg或50 μg皮下投與之AMV564治療實體腫瘤患者對M-MDSC含量之影響。圖12B顯示用15 µg或50 μg皮下投與之AMV564治療實體腫瘤患者對G-MDSC含量之影響。
圖 13A 至圖 13B顯示單獨或與派立珠單抗組合之AMV564對CD8+ T細胞上之顆粒酶B及TBX21共表現(圖13A)及顆粒酶B+ CD8+細胞頻率(圖13B)的影響。
圖 14A 至圖 14B顯示單獨或與派立珠單抗組合之AMV564對IFNγ及IL-6含量之影響。圖14A顯示在用單獨或與派立珠單抗組合之15 μg或50 μg AMV564治療之實體腫瘤患者中所觀測到的IFNγ及IL-6含量(n=11單藥療法,n=4組合)。圖14B顯示AMV564相對於其他T細胞銜接體表現出有利的、大約為1:1之IFNγ:IL-6比率。
圖 15A 至圖 15C顯示單獨或與派立珠單抗組合之AMV564對患者中及活體外細胞毒性檢定中之各種細胞介素之含量的影響。圖15A顯示單獨或與派立珠單抗組合之AMV564對患者中之TNFα、IL-1β及IL-10含量之影響。圖15B顯示單獨或與派立珠單抗組合之AMV564對IP-10 (CXCL10)之含量的影響。圖15C顯示使用KG-1細胞作為靶細胞執行之AMV564細胞毒性檢定之結果。
圖 16A 至圖 16C顯示單獨或與派立珠單抗組合之AMV564對三名不同患者之T細胞庫之影響。圖16A顯示小腸癌症患者中之T細胞庫的擴增。圖16B顯示陰莖鱗狀細胞癌患者中之T細胞庫的擴增。圖16C顯示胰臟癌患者中之T細胞庫的擴增。橙色圓表示顯著擴增或在基線不可偵測之純系。
圖 17A 至圖 17C顯示AMV564對被確認為RECIST CR之卵巢癌患者之CD8及CD8記憶細胞及T細胞重排之影響。圖17A顯示用15 μg AMV564治療之卵巢癌患者之CD8細胞在治療過程中的增加。圖17B顯示用15 μg AMV564治療之卵巢癌患者之CD8記憶細胞在治療過程中的增加。圖17C顯示在卵巢癌患者中跨治療時間點之特異性T細胞重排的追蹤。
Claims (41)
- 一種治療罹患實體腫瘤之患者的方法,該方法包含向該患者投與免疫療法及AMV564,其中AMV564係在該免疫療法之前、之後或與其一起投與。
- 如請求項1之方法,其中AMV564係藉由皮下注射投與。
- 如請求項1之方法,其中該AMV564係在投與該免疫療法之後4至6週內投與。
- 如請求項3之方法,其中該AMV564係在14天時間內投與至少7天。
- 如請求項4之方法,其中該AMV564係在14天時間內投與10天。
- 如請求項5之方法,其中該AMV564係在14天時間內分兩個時段連續投與5天。
- 如請求項5之方法,其中該AMV564係連續投與5天,隨後兩天不投與且隨後連續投與5天。
- 如請求項4至7中任一項之方法,其中該AMV564係在21天週期內投與,其中AMV564係在14天時間內投與至少7天且在隨後的7天時間內不投與。
- 如請求項8之方法,其中該21天週期重複至少兩次。
- 如請求項9之方法,其中AMV564係在14天時間內投與至少10天,其中連續投與5天,隨後2天不投與,隨後連續投與5天。
- 如請求項1至10中任一項之方法,其中投與時,每天投與之AMV564劑量為5、10、15、20、25、30、35、40、45或50 μg。
- 如請求項1之方法,其中AMV564係在療法之第一週內的5天以15 µg/天投與,且接著在此後每週一次投與50 µg。
- 如請求項1之方法,其中AMV564係每週一次投與5 µg至50 µg。
- 如請求項1之方法,其中AMV564係在療法之第一週內的5天以15 µg/天投與,且接著在此後每週一次投與15 µg。
- 如請求項1之方法,其中AMV564係在療法之第一週內的5天以15 µg/天投與,且接著在此後每週一次投與15 µg至50 µg。
- 如請求項1至15中任一項之方法,其中該免疫療法為CR T細胞療法、CTL療法及抗體療法。
- 如請求項1之方法,其中該實體腫瘤係選自乳癌、胰臟癌、卵巢癌、大腸癌、直腸癌、非小細胞肺癌、尿道上皮癌、鱗狀細胞癌、直腸癌、陰莖癌、子宮內膜癌、小腸癌、闌尾癌。
- 如請求項1之方法,其中該AMV564之投與達成0.1 pM至5 pM AMV564之穩態暴露。
- 如請求項1之方法,其中該AMV564之投與達成0.5 pM至3 pM AMV564之穩態暴露。
- 如請求項1之方法,其中該AMV564之投與達成1 pM至5 pM AMV564之穩態暴露。
- 如請求項1之方法,其中該免疫療法為抗PD-L1抗體或抗PD-1抗體。
- 如請求項21之方法,其中該抗PD-1抗體為納武單抗(nivolumab)、派立珠單抗(pembrolizumab)及西米普利單抗(cemiplimab)。
- 如請求項21之方法,其中該抗PD-L1抗體為阿特珠單抗(atezolizumab)、阿維魯單抗(avelumab)或德瓦魯單抗(durvalumab)。
- 如請求項1之方法,其中該免疫療法為CAR T細胞療法且AMV564係在投與該CAR T細胞療法之後1至5天、5至10天或5至14天投與。
- 一種治療患者之癌症之方法,該方法包含向該患者投與AMV564,其中該癌症不表現CD33。
- 如請求項25之方法,其中AMV564係藉由皮下注射投與。
- 如請求項25或26之方法,其中AMV564係在療法之第一週內的5天以15 µg/天投與,且接著在此後每週一次投與50 µg。
- 如請求項25之方法,其中AMV564係每週一次投與50 µg。
- 如請求項25之方法,其中AMV564係在療法之第一週內的5天以15 µg/天投與,且接著在此後每週一次投與15 µg。
- 如請求項25之方法,其中AMV564係在療法之第一週內的5天以15 µg/天投與,且接著在此後每週一次投與15 µg至50 µg。
- 如請求項25之方法,其中注射之AMV564之劑量為5 μg至50 μg。
- 如請求項25至31中任一項之方法,其中該實體腫瘤係選自胰臟癌、卵巢癌、大腸癌、直腸癌、非小細胞肺癌、尿道上皮癌、鱗狀細胞癌、直腸癌、陰莖癌、子宮內膜癌、小腸癌及闌尾癌。
- 如請求項25至31中任一項之方法,其中該實體腫瘤係選自小細胞肺癌(NSCLC) (例如轉移性非鱗狀NSCLC、III NSCLC、表現PD-L1之轉移性NSCLC)、黑色素瘤、梅克爾(Merkel)細胞癌、高微星體不穩定性癌(例如不可切除性或轉移性、高微星體不穩定性(MSI-H)或錯配修復缺陷);接受檢查點阻斷後病情進展的患者。
- 如請求項1至31中任一項之方法,其中該患者患有選自以下之癌症:黑色素瘤(例如患有不可切除性或轉移性黑色素瘤、完全切除後累及淋巴結之黑色素瘤的患者);非小細胞肺癌(NSCLC) (例如轉移性非鱗狀NSCLC、III NSCLC、表現PD-L1之轉移性NSCLC);頭頸部鱗狀細胞癌(HNSCC);典型霍奇金氏淋巴瘤(Classical Hodgkin Lymphoma) (cHL);原發性縱隔大B細胞淋巴瘤(PMBCL);尿道上皮癌(例如表現PD-L1之局部晚期或轉移性尿道上皮癌);高微星體不穩定性癌(例如不可切除性或轉移性、高微星體不穩定性(MSI-H)或錯配修復缺陷;先前治療後進展之實體腫瘤;胃癌(例如表現PD-L1之復發性局部晚期或轉移性胃或胃食道交界腺癌);子宮頸癌;肝細胞癌(HCC);梅克爾細胞癌(MCC);及腎細胞癌(RCC)。
- 一種擴增T細胞之方法,該方法包含在AMV564存在下培養該T細胞。
- 如請求項35之方法,其中該T細胞表現嵌合抗原受體。
- 如請求項35或36之方法,其中該培養持續至少5天。
- 一種擴增NK細胞之方法,該方法包含在AMV564存在下培養該NK細胞。
- 如請求項38之方法,其中該NK細胞表現嵌合抗原受體。
- 如請求項38或39之方法,其中該培養持續至少5天。
- 一種擴增細胞毒性淋巴球(CTL)之方法,該方法包含在AMV 564存在下培養該CTL。
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