TW201915013A - 用於治療癌症之組合物 - Google Patents
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Abstract
一種在一個體中治療癌症的免疫組合物。該免疫組合物包括一用於治療癌症的免疫治療成份 (immunotherapeutics),以及一具有SEQ ID NOs. 1-3且可選擇性地和細胞趨化因子 (CXC chemokine receptor 4;CXCR4) 結合之多肽 (peptide)。當該免疫組合物的該多肽和細胞趨化因子 (CXCR4) 結合時,同時也調控了該腫瘤的免疫微環境和/或調節免疫細胞相對於該腫瘤的可達性。本揭露也同時提供了一種使用該免疫組合物治療癌症的方法。
Description
本揭露與一免疫組合物有關,該免疫組合物為一可選擇性地和細胞趨化因子 (CXC chemokine receptor 4;CXCR4) 結合之多肽 (peptide) 與一種或多種免疫治療成份 (immunotherapeutics) 之組合。
除了化療、放射線治療和手術以外,免疫療法已被認為是癌症治療的第四大重點。現有的癌症免疫治療成份 (immunotherapeutics) 主要為能夠阻斷T細胞檢查點受體 (T-cell checkpoint receptor) 和他們的同族配位體 (cognate ligand) 之蛋白-蛋白間交互作用 (protein-protein interaction) 的單株抗體 (monoclonal antibodies;mAbs)。臨床上已被核准的單株抗體包括了T細胞檢查點抑制抗體 Ipilimumab (Bristol-Myers-Squibbs公司的Yervoy®)、Pembrolizumab (Merck公司的Keytruda®)、Nivolumab (Bristol-Myers-Squibbs公司的Opdivo®)、Aterzolizumab (Roche和Genetech公司的Tecentriq®)、Avelumab (EMD Serno公司的Bavencio®) 和Duravalumab (AstraZeneca公司的Imfinzi®)。
更進一步地,Ipilmumab為可和細胞毒殺型T淋巴細胞抗原4 (cytotoxic T lymphocyte-associated antigen 4;CTLA4) 受體蛋白質直接結合的一全人類IgG1單株抗體。Pembrolizumab和Nivolumab為人類化 (humanized) 抗細胞程序性死亡蛋白 (Programmed cell death protein 1;PD-1) 之單株抗體,其可以阻斷PD-1和其配位體之結合,進而干擾T細胞的訊息傳遞以及細胞死亡。而Atezolizumab、Avelumab和Durvalumab也為人類化抗細胞程序性死亡蛋白配位體一 (Programmed cell death protein ligand 1;PD-L1) 之單株抗體,其也能夠藉由抑制受體和PD-L1之間的結合。
同時,以基因工程方式執行之自體T細胞療法對能直接地活化T細胞和瞄準癌症細胞,且臨床上在血液性癌症 (haematological cancers) 中展現了顯著效果。在這類療法中,嵌合抗原受體 (chimeric antigen receptors;CARs) 或具癌症特異性的T細胞受體 (T-cell receptors;TCRs) 在體外被轉染且表現於一病患之T細胞上以表現該些細胞的癌症特異性,再將這些經基因工程方式修改的T細胞注入病患體內。
然而,由於引發有效的T細胞抗癌反應或活化相關的免疫抑制機制需要多個步驟,現有的單一免疫療法通常會造成較差的免疫反應或無法克服腫瘤微環境中的免疫抑制機制。因此,在大部分的癌症病患中,現有的單一免疫療法會導致免疫逃脫 (immune escape) 或腫瘤持續成長,造成治療功效不佳。
為使圖式簡明清楚,因此不同圖式中代表相對應元件之符號可能會重複。另外為了使實施例可被完整地理解,本說明書也針對各實施例中的諸多細節進行說明。然而,本技術領域中具有通常技藝之人也可不需上述諸多細節就可實施以下各實施例。本揭露之圖式並不代表部分元件之尺寸和比例,且有可能會將部分元件誇大表示以更佳地說明該元件相關之細節和特徵。本說明書之目的並非限制以下實施例之內容。
本揭露的目的為提供一種經佐劑強化且可促進有效抗腫瘤免疫反應之免疫療法。
本揭露的另一目的為提供一種能夠調節腫瘤微環境中之免疫抑制機制的免疫佐劑。
本揭露的一種實施例提供了一種用於治療癌症的組合物。該組合物包括一種可治療癌症的免疫治療成份 (immunotherapeutics),以及一種多肽,其包括SEQ ID NOs. 1-3的其中一種序列且能選擇性地和細胞趨化因子 (CXC chemokine receptor 4;CXCR4) 結合。
較佳地,該免疫治療成份可選擇性地以CTLA-4、PD-1、PD-L1、TIM-3、LAG-3、B7-1、B7-H3、NKG2A、KIR、BTLA、VISTA/PD-1H、TIGIT、CD96、OX40、CD28、ICOS、HVEM、41BB、CD40L、CD137、GITR、CD27、CD30、DNAM-1、CD28H或上述之輔受體 (co-receptor) 做為標的。
較佳地,該免疫治療成份可為一抗體、一疫苗、一細胞激素 (cytokine)、一蛋白質、一多肽、一具有該蛋白質或該多肽編碼的表現載體、一小分子、一RNA干擾 (RNAi) 或一適體 (apatmer)。
較佳地,該免疫治療成份為自體免疫細胞 (autologous immune cells)、具腫瘤特異性的自體T細胞 (autologous T cells)、具經修改之T細胞受體 (T-cell receptors;TCR) 的T細胞或具嵌合抗原受體 (chimeric antigen receptors;CARs) 的T細胞。
較佳地,該多肽和該CXCR4結合時會調節該腫瘤的一免疫微環境 (immune microenvironment)。
較佳地,該多肽和該CXCR4結合時會調節該些免疫細胞相對於該腫瘤的可達性。
較佳地,該些免疫細胞包括CD45陽性 (CD45+) 細胞、CD3陽性 (CD3+) T細胞、CD4陽性CD8陰性 (CD4+CD8-) T細胞、CD4陰性CD8陽性 (CD4-CD8+) T細胞、調節T細胞 (regulatory T-cell)、自然殺手細胞 (NK cells)、自然殺手T細胞 (NKT cells)、巨噬細胞 (macrophages)、顆粒球 (granulocytes) 或單核球 (monocytes)。
較佳地,可被該免疫組合物治療的癌症為乳癌、直腸癌、肺癌、胰臟癌、攝護腺癌、腎臟癌、肝癌、淋巴癌或黑色素瘤。
本揭露的另一種實施例提供了一種治療癌症的方法。該方法包括以下一步驟:遞送前述之免疫組合物至一個體中。
較佳地,該多肽是以靜脈注射、皮下注射或腹膜內注射 (intraperitoneal) 的方式遞送至該個體中。
根據本揭露的一種或多種實施例,該多肽包括SEQ ID NOs. 1-3的其中一種序列 (例如:PTX-9908) 並和該免疫治療成份互補且能協同調控腫瘤免疫微環境,和/或調節免疫細胞相對於該腫瘤的可達性。
以下實施例將針對本揭露有更具體的敘述,該實施例之目的在於展示而不在於限制本揭露之內容。
以下的「PTX-9908」(也被稱為CTCE-9908) 為一小型多肽類比物 (analog peptide) 具有SEQ ID NOs: 1-3之中的任一序列且包含基質細胞衍生因子1 (stromal cell derived factor one;SDF-1) 的一部份序列之單體 (monomer) 或雙體 (dimer)。PTX-9908為一CXCR4拮抗物且會阻止SDF-1和CXCR4的結合。CXCR4為一七部穿膜G1偶聯受體蛋白 (seven transmembrane G1-coupled protein) 且廣泛的表現於免疫細胞之中;包括T細胞、B細胞、單核球、多形核細胞 (polymorphonuclear cells;PMNCs)、未成熟樹狀細胞 (dendritic cells) 和固態以及造血組織惡性腫瘤都會表現CXCR4。該SDF-1/CXCR4途徑已被證實和免疫細胞之動員、癌症移轉 (cancer metastasis) 以及人類免疫不全症病毒 (human immunodeficiency virus;HIV) 進入細胞的途徑有關。
本揭露中的PTX-9908可根據美國專利第7,423,011號所描述的方法取得。在本揭露的諸多實施例中,PTX-9908可為一實質上經純化之多肽、一經純化之多肽片段、一經修飾的多肽、一經修飾的多肽片段或一PTX-9908之類似物。
於本揭露中「免疫治療成份」包括但不限於:單株抗體 (monoclonal antibodies)、疫苗、重組細胞激素 (recombinant cytokines)、具親和性之蛋白 (affinity protein) 或經改造的非抗體多肽、有該具親和性之蛋白或非抗體多肽編碼的表現載體 (expression vector)、小分子、RNA干擾和/或以以下分子做為標的的適體:細胞毒殺型T淋巴細胞抗原4 (cytotoxic T lymphocyte-associated antigen 4;CTLA-4)、程序性細胞死亡蛋白 (programmed cell death-1;PD-1)、程序性細胞死亡配體1 (programmed cell death ligand-1;PD-L1)、T細胞免疫球蛋白黏蛋白分子3 (T-cell immunoglobulin and mucin domain 3;TIM-3)、淋巴球啟動基因3 (lymphocyte-activation gene 3;LAG-3)、分化群80 (cluster of differentiation 80;CD80)、分化群276 (CD276,也可稱為B7-H3)、分化群94 (CD94,也可稱為NKG2A)、殺手細胞類免疫球蛋白受體 (killer-cell immunoglobulin-like receptor;KIR)、B和T淋巴球減弱子 (B- and T-lymphocyte attenuator;BTLA)、抑制T細胞活化的免疫球蛋白V型結構域 (V-domain Ig suppressor of T cell activation;VISTA)、程序性細胞死亡蛋白同源物 (programmed cell death-1 homolog;PD-1H)、T細胞免疫球蛋白和免疫受體酪胺酸基抑制結構域 (T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain;TIGIT)、分化群96 (CD96)、分化群134 (CD134,也可稱為OX40)、分化群28 (CD28)、誘導T細胞共刺激分子 (inducible T-cell costimulatory;ICOS)、皰疹病毒進入調控因子 (herpes virus entry mediator;HVEM)、分化群137 (CD137,也可稱為41BB)、分化群154 (CD154,也可稱為CD40L)、醣皮質素誘導之TNFR相關蛋白 (glucocorticoid-induced TNFR-related protein;GITR)、分化群27 (CD27)、分化群30 (CD30)、DNAX輔助分子1 (DNAX accessory molecule-1;DNAM-1)、分化群28同源物 (CD28 homolog;CD28H) 或其他免疫細胞受體和上述之輔受體。
「免疫治療成份」一詞在本揭露中也可指「免疫治療細胞」,例如細胞激素誘導之殺手細胞 (cytokine-induced killer cells;CIK cells)、自然殺手細胞、樹狀細胞、樹狀-細胞激素誘導之殺手細胞 (DC-CIK cells)、γδ T細胞 (Gamma-delta T cell)、自體免疫細胞 (autologous immune cells)、基因改造之具嵌合抗原受體的T細胞 (genetically engineered chimeric antigen receptor T;CAR-T)、具基因改造之T細胞受體的T細胞 (genetically engineered TCR T cells)、具腫瘤特異性的自體T細胞、自體腫瘤浸潤淋巴球 (autologous tumor infiltrating lymphocyte;autologous TIL) 和/或免疫細胞療法中用來注射入一個體的基因改造之週邊血單核細胞。
「免疫細胞」一詞在本揭露中也可包括CD45陽性細胞、CD3陽性T細胞、CD4陽性CD8陰性T細胞、CD4陰性CD8陽性T細胞、調節T細胞、自然殺手細胞、自然殺手T細胞、巨噬細胞、顆粒球、單核球、細胞激素誘導之殺手細胞、樹狀細胞、樹狀-細胞激素誘導之殺手細胞、γδ T細胞、基因改造之具嵌合抗原受體的T細胞、具基因改造之T細胞受體的T細胞、具腫瘤特異性的自體T細胞、自體腫瘤浸潤淋巴球和/或免疫細胞療法中用來注射入一個體的基因改造之週邊血單核細胞。
「治療」一詞在本揭露中涵蓋了能改善病程進展的治療 (disease modifying treatment) 和對症狀的治療 (symptomatic treatment),即分別為在症狀發作之能降低病程嚴重度的治療和/或緩解症狀的治療。本揭露提供的治療方法大致包括:給予一個體有效治療劑量的一種或多種小分子、多肽、抗體、RNA干擾或適體。適合的個體包括被識別出已罹患或易罹患一種或多種疾病的病患。適合接受治療的典型病患包括哺乳動物,更精確地來說為靈長類,特別是人類。其他適合的病患包括伴侶動物,例如狗、貓或馬等;或為一家畜,例如牛、豬或羊等。
根據本揭露的一種面向,PTX-9908是用於與一種或多種免疫治療成份結合以治療或產生一醫藥成分以治療多種癌症。該多種癌症包括但不限於:無法切除性 (unresectable) 或轉移性 (metastatic) 黑色素瘤 (melanoma)、轉移性非小細胞肺癌 (metastatic non-small cell lung cancer;NSCLS)、復發 (recurrent) 或轉移性頭頸鱗狀細胞癌 (squamous cell carcinoma of the head and neck;SCCHN)、典型何杰金氏淋巴瘤 (classical Hodgkin lymphoma;cHL)、晚期原位 (locally advanced) 或轉移性尿道癌 (urothelial carcinoma)、帶有高度微衛星體不穩定性 (microsatellite instability-high;MSI-H) 生物標記或誤配修補缺陷 (mismatch repair deficiency;dMMR) 的固態瘤、轉移性腎細胞癌 (renal cell carcinoma)、肝細胞癌 (hepatocellular carcinoma;HCC)、轉移性Merkel氏細胞癌 (Merkel cell carcinoma;MCC) 或皮膚、肺、腎、膀胱、頭頸、肝、乳房和其他身體器官的其他類上皮細胞癌 (carcinoma),以及白血病 (leukemia)、多發性骨髓瘤 (multiple myeloma) 和消化系統的其他種腫瘤。
在某些實施例中,腫瘤免疫微環境可因PTX-9908和CXCR4之結合而被調節。例如,如圖1所示,PTX-9908和CXCR4之結合關係可能使腫瘤微環境中的免疫抑制機制被弱化,進而使和PTX-9908一同使用之免疫治療成份 (如:抗體10) 進入腫瘤微環境中,發揮其完整的治療能力。
在其他實施例中,PTX-9908和CXCR4結合時也可調節免疫細胞相對於腫瘤位置之可達性。如圖1所示,PTX-9908和CXCR4之結合關係可能導致免疫細胞之浸潤或動員能力於腫瘤中被調節,使與癌症有關之纖維母細胞70 (cancer associated fibroblast)構成之屏蔽較鬆散,因此使細胞毒殺免疫細胞 (又稱為免疫作用細胞 (immune effector cells),可為細胞毒殺T細胞30 (Cytotoxic T cell,即為CD8陽性T細胞) 和自然殺手T細胞40,或未顯示於圖1中的CD3陽性T細胞或自然殺手細胞) 或免疫治療細胞到達該腫瘤處並殲滅該腫瘤,和/或降低位於腫瘤微環境之免疫抑制細胞50和60 (可為單核球、顆粒球或調節T細胞) 的量。
在本揭露的另一面向,PTX-9908是用於與一種或多種免疫治療成份結合以治療或產生一醫藥成分以治療多種病毒感染。上述病毒感染包括但不限於以下病毒所造成的感染:人類免疫不全症病毒、人類乳突狀瘤病毒 (human papilomavirus;HPV)、Epstein-Barr二氏病毒 (Epstein-Barr virus;EBV)、巨細胞病毒 (Cytomegalovirus;CMV)、人類疱疹病毒 (human herpesvirus;HHV)、水痘帶狀病毒 (Varicella zoster virus;VZV)、肝炎病毒 (hepatitis virus)、麻疹病毒 (measles virus)、腺病毒 (adenovirus) 或其他可能會在宿主體內造成持續性感染的病毒。
在某些實施例中,PTX-9908和CXCR4結合時可調節病毒感染處的免疫微環境。例如,PTX-9908和CXCR4之結合可能導致病毒感染處之免疫抑制機制被弱化,進而使免疫治療成份之組合 (如:抗體) 發揮其完整的治療能力。
在其他實施例中,免疫細胞相對於病毒感染處之可達性也可於PTX-9908和CXCR4結合時被調節。例如:PTX-9908和CXCR4之結合可能導致在病毒感染處的免疫細胞之浸潤或動員能力提高,進而使被活化的免疫細胞或免疫治療細胞到達感染處並殲滅該病毒。
本揭露的再一面向和一種治療已罹患或易罹患一種或多種癌症的一個體之方法有關。上述癌症可包括無法切除性或轉移性黑色素瘤、轉移性非小細胞肺癌、復發或轉移性頭頸鱗狀細胞癌、典型何杰金氏淋巴瘤、晚期原位或轉移性尿道癌、帶有高度微衛星體不穩定性生物標記或誤配修補缺陷的固態瘤、轉移性腎細胞癌、肝細胞癌、轉移性Merkel氏細胞癌或皮膚、肺、腎、膀胱、頭頸、肝、乳房和其他身體器官的其他種上皮細胞癌,以及白血病、多發性骨髓瘤和消化系統的其他種腫瘤。
在一實施例中,該方法包括給予該個體PTX-9908和一種或多種免疫治療成份的組合。較佳地,以靜脈注射、皮下注射或腹膜內注射方式給予該個體PTX-9908。該被給予的PTX-9908較佳地為能夠調節腫瘤微環境中的免疫抑制機制和/或能夠調節免疫細胞相對於該腫瘤之可達性的一有效治療劑量。換言之,PTX-9908以能夠和免疫治療成份之組合產生協同效應的一劑量被遞送至該個體中。
本揭露的再一面向和一種治療已罹患或易罹患一種或多種病毒感染的一個體之方法有關。上述病毒感染可包括以下病毒所造成的感染:人類免疫不全症病毒、人類乳突瘤病毒、Epstein-Barr二氏病毒、巨細胞病毒、人類疱疹病毒、水痘帶狀病毒、肝炎病毒、麻疹病毒、腺病毒或其他可能會在宿主體內造成持續性感染的病毒。
在一實施例中,該方法包括給予該個體PTX-9908和一種或多種免疫治療成份的組合。較佳地,以靜脈注射皮下注射或腹膜內注射方式給予該個體PTX-9908。該被給予的PTX-9908較佳地為能夠調節病毒感染處微環境中的免疫抑制機制和/或能夠調節免疫細胞相對於該感染處之可達性的一有效治療劑量。換言之,PTX-9908以能夠和免疫治療成份產生協同效應的一劑量被地送至該個體中。
一「有效治療劑量」指的是為了達成所需治療成效 (如阻止或抑制腫瘤成長,或使感染處或循環系統中的病毒量下降) 於所需之治療時間中有效之劑量。一PTX-9908的有效治療劑量可能會因各種因素而改變,如:該個體的病程、年齡、性別和體重,以及PTX-9908在該個體中引發所需反應之能力。有效治療劑量也可為之PTX-9908其所帶來的治療之益遠大於其毒性或有害反應的一劑量。
需特別注意的是,PTX-9908之劑量可能會因病況嚴重的程度而有不同,可調整給藥方案以提供最佳化治療。對任何個體而言,應根據專業人士或監控給藥過程者之判斷,隨著時間依該個體需求,特別調整給藥方案。
為了最佳化PTX-9908遞送至該個體之過程,PTX-9908較佳地可和一藥學上可被接受的載體 (carrier) 或賦形劑 (excipient) 結合,上述之該載體或該賦形劑可包括各種溶劑、分散液、塗層、抗菌 (antibacterial) 或抗真菌 (antifungal) 劑、等張 (isotonic) 劑或延緩吸收劑 (absorption delay agents) 等可和人體生理上相容的各種介質。在一實施例中,該載體適合以注射 (parenteral) 方式遞送。另外,該載體也可適合以靜脈注射、皮下注射、腹膜內注射、肌肉注射 (intramuscular)、舌下給藥或口服方式遞送。藥學上可被接受的載體包括無菌液態溶液或分散液,和用來即時調配無菌注射液或介質之無菌粉末。
PTX-9908之劑型也可為溶液、微乳夜 (microemulsion)、微脂體 (liposome) 或其他具規律之結構,使有效成分達高濃度。該載體也可為一溶液或分散液,該溶液或該分散液可包括:水、乙醇、多元醇 (polyol,例如:甘油 (glycerol)、丙二醇 (propylene glycol)、液態聚乙二醇 (polyethylene glycol)) 或上述物質之混合物。如需維持適當的流動性,則需使用如卵磷脂 (lecithin) 類的介質;如在分散液或在介面活性劑 (surfactant) 之中則須維持所需的粒子大小。在許多情況下,該劑型成分之中最好包括等張劑,例如:糖、多元醇如甘露醇 (mannitol) 或山梨醇 (sorbitol),或氯化鈉 (sodium chloride)。如需使該可注射劑型有較長的吸收時間,則可以於該劑型成分之中包括一延緩吸收劑,例如:單硬脂酸酯 (monostearate) 和明膠 (gelatin)。該可注射劑型也可和一種或多種化合物共同配置以增加PTX-9908之可溶性。
更進一步地,PTX-9908也可以一延時釋放劑型 (time release formulation) 給藥,例如在包括一緩釋聚合物的成份之中被遞送;或也可和能夠使PTX-9908不被快速釋放之載體一同被製備,如一控制釋放劑型,其包括植入式和微膠囊 (microencapsulated) 藥物遞送系統。也可使用可生物分解和可生物相容之聚合物,例如乙酸乙烯酯共聚物 (ethylene vinyl acetate)、聚酸酐 (polyanhydride)、聚羥酸 (polyglycolic acid)、膠原蛋白 (collagen)、聚原酸酯 (polyorthoester)、聚乳酸 (polylactic acid) 和聚乳酸-聚羥酸共聚物 (polylactic-polyglycolic copolymers;PLG)。許多上述劑型的製備方法已被其他專利保護或大致上為本領域中具有通常技藝者所知。
也可將PTX-9908加入一適量之適合溶劑,或前述成分中所需物質之組合物,以製備無菌注射溶液。該無菌注射溶液可再經無菌過濾程序 (filtered sterilization)。一般來說,可將PTX-9908加入一無菌載體 (sterilized vehicle) 以製備一分散液,且該載體包括一基本散布媒介和前述成分中所需物質。若為了制備無菌粉末供調配無菌注射溶液之所需,較佳的製備方法係以真空乾燥 (vacuum drying) 和凍乾 (freeze-drying)製程,取上述經無菌過濾之該無菌注射溶液完成乾燥後,得到PTX-9908粉末和其他附加成分。
本揭露之實施例中的PTX-9908可被修改以調整該些多肽之特性但又同時保留其調節免疫微環境或調節免疫細胞可達性的特質。例如:PTX-9908可被修改以調整其藥物動力學特性,如其體內 (in vivo) 穩定性或半衰期。PTX-9908也可被修改使一種或多種可被偵測之物質標記在該多肽上,如各種酵素、輔基 (prosthetic group)、螢光 (fluorescent) 物質、發光 (luminescent) 物質和放射性物質。更進一步地,PTX-9908也可被改為和一個或多個官能基結合,以獲得額外或更佳的治療效果。
本揭露中的多種實施例提供了一種PTX-9908之修改方案,即PTX-9908以一「前驅藥」(prodrug)之型態被製備,此時該多肽本身並不調節免疫微環境或調節免疫細胞可達性,但其可於體內的新陳代謝之中被轉換為具免疫活性的PTX-9908。
療效評估I
30隻7至9周齡的C57BL/6雌性小鼠分別被接種MC38人類直腸癌細胞,並於小鼠中腫瘤平均體積達80至120 mm3
(或為100 mm3
左右) 時開始進行治療。將該些小鼠隨機分配為3組 (即每一組10隻小鼠)。第一組以腹膜內注射 (intraperitoneal) 方式每二周給予1劑磷酸鹽緩衝液 (phosphate buffered saline;PBS),共給予5劑。第二組以腹膜內注射方式每二周給予1劑抗PD-1抗體 (anti-PD-1 antibody),且劑量為10 mg/kg,共給予5劑。第三組以腹膜內注射方式每二周給予1劑劑量為10 mg/kg之抗PD-1抗體,共給予5劑;以及以一週內5天給藥2天不給藥的給藥日程給予每1劑劑量為25 mg/kg之PTX-9908,共給予13劑。當第一組之平均腫瘤體積到達2000 mm3
時本研究即行終止。
於本研究中,腫瘤體積以mm3
表示且使用以下公式計算得到體積:V = (L* W* W)/2;其中V代表腫瘤體積,L代表腫瘤長度 (即腫瘤最長處) 而W代表腫瘤寬度 (即腫瘤中和L互相垂直之最長距離)。採用於上述三組中所獲得之腫瘤體積資料,以獨立樣本t檢定 (Independent-Samples T Test) 對每一組之間的平均腫瘤體積執行統計分析。上述分析結果中原始P值 (P-value) 取至小數第三位,但若P值小於0.001則不調整該P值。所有檢定皆為雙邊檢定 (two-sided)。
如圖2A中所示,在三組小鼠的腫瘤成長曲線 (平均腫瘤體積隨著時間的變化) 中可見第三組的平均腫瘤體積有下降趨勢。平均腫瘤體積抑制率是使用以下述公式計算所量測到的腫瘤體積而得:平均腫瘤體積抑制率 (%) = (控制組之平均腫瘤體積 (C) – 該實驗組之平均腫瘤體積 (T)) / 控制組之平均腫瘤體積 (C)*100%。如圖2B所示,第三組之腫瘤體積抑制率顯著地高於第二組。
於本研究終止時量測腫瘤重量。如圖3A中所示,第三組之腫瘤重量相較於第二組之腫瘤重量少了24.6%。使用以下公式計算所量測到的腫瘤重量而得腫瘤成長抑制率 (TGI):腫瘤成長抑制率 (%) = (控制組之平均腫瘤重量 (C) – 該實驗組的平均腫瘤重量 (T)) / 控制組之平均腫瘤重量 (C)* 100%。如圖3B所示,第三組之腫瘤成長抑制率顯著地高於第二組。
在本研究進行的過程中也全程監控小鼠體重。如圖4中所示,沒有在第三組小鼠身上發現會影響其體重的副作用。
更進一步地,如圖5所示,以流式細胞儀 (flow cytometry) 分析腫瘤中之活細胞,發現第三組和其他組相比,在CD45陽性 (CD45+) 細胞族群之中有較高比率的CD3陽性 (CD3+) T 細胞、CD4陰性CD8陽性 (CD4-CD8+) T細胞和自然殺手T細胞 (NKT cells);因此該實驗結果代表了正調控 (upregulate) 細胞毒殺性免疫細胞相對於該腫瘤微環境之可達性。
圖2至圖5中的實驗結果清楚地展現了PTX-9908和抗PD-1療法於治療大腸癌時之協同效應。
療效評估II
30隻7至9周齡的BALB/C雌性小鼠分別被接種EMT-6人類乳癌細胞,並於小鼠中腫瘤平均體積達80至120 mm3
(或為100 mm3
左右) 時開始進行治療。將該些小鼠隨機分配為3組。第一組以腹膜內注射方式每二周給予1劑磷酸鹽緩衝液,共給予6劑。第二組以腹膜內注射方式每二周給予1劑抗PD-1抗體,且劑量為10 mg/kg,共給予6劑。第三組以腹膜內注射方式每二周給予1劑劑量為10 mg/kg之抗PD-1抗體,共給予6劑;以及以一週內5天給藥2天不給藥的給藥日程給予每1劑劑量為25 mg/kg之PTX-9908,共給予15劑。當第一組之平均腫瘤體積到達2000 mm3
時本研究即行終止。
於本研究中,腫瘤體積以mm3
表示且使用以下公式計算得到體積:V = (L* W* W)/2;其中V代表腫瘤體積,L代表腫瘤長度 (即腫瘤最長處) 而W代表腫瘤寬度 (即腫瘤中和L互相垂直之最長距離)。採用於上述三組中所獲得之腫瘤體積資料,以獨立樣本t檢定對每一組之間的平均腫瘤體積執行統計分析。上述分析結果中原始P值取至小數第三位,但若P值小於0.001則不調整該P值。所有檢定皆為雙邊檢定。
如圖6A中所示,在三組小鼠的腫瘤成長曲線 (平均腫瘤體積隨著時間的變化) 中可見第三組的平均腫瘤體積有下降趨勢。使用以下公式計算所量測到的腫瘤體積而得平均腫瘤體積抑制率:平均腫瘤體積抑制率 (%) = (控制組之平均腫瘤體積 (C) – 該實驗組之平均腫瘤體積 (T)) / 控制組之平均腫瘤體積 (C)*100%。如圖6B所示,第三組之腫瘤體積抑制率顯著地高於第二組。
於本研究終止時量測腫瘤重量。如圖7A所示,第三組之腫瘤重量相較於第二組之腫瘤重量少了53.7%。使用以下公式計算所量測到的腫瘤重量而得腫瘤成長抑制率 (TGI):腫瘤成長抑制率 (%) = (控制組之平均腫瘤重量 (C) – 該實驗組的平均腫瘤重量 (T)) / 控制組之平均腫瘤重量 (C)* 100%。如圖7B所示,第三組之腫瘤成長抑制率顯著地高於第二組。
在本研究進行的過程中也全程監控小鼠體重。如圖8中所示,沒有在第三組小鼠身上發現會影響其體重的副作用。
更進一步地,如圖9所示,以流式細胞儀分析腫瘤中之活細胞,發現第三組和其他組相比,在CD45陽性細胞族群之中有著較高比率的CD3陽性T細胞、CD4陰性CD8陽性T細胞,和較低比率的顆粒球 (granulocyte) 與單核球 (monocyte)。在免疫微環境中,已知顆粒球和單核球之存在會負調節抗PD-1抗體所引起的抗腫瘤反應,因此該實驗結果代表正調控細胞毒殺性免疫細胞相對於該腫瘤微環境之可達性,和負調控 (downregulate) 抑制性免疫細胞相對於該腫瘤微環境之可達性。
圖6至圖9中的實驗結果清楚地展現了PTX-9908和抗PD-1療法於治療乳癌時之協同效應。
療效評估III
30隻7至9周齡的C57BL/6雌性小鼠分別被接種LL/2人類肺癌細胞,並於小鼠中腫瘤平均體積達80至120 mm3
(或為100 mm3
左右) 時開始進行治療。將該些小鼠隨機分配為3組。第一組以腹膜內注射方式每二周給予1劑磷酸鹽緩衝液,共給予5劑。第二組以腹膜內注射方式每二周給予1劑抗PD-1抗體,且劑量為10 mg/kg,共給予5劑。第三組以腹膜內注射方式每二周給予1劑劑量為10 mg/kg之抗PD-1抗體,共給予5劑;以及以一週內5天給藥2天不給藥的給藥日程給予每1劑劑量為25 mg/kg之PTX-9908,共給予13劑。當第一組之平均腫瘤體積到達2000 mm3
時本研究即行終止。
於本研究中,腫瘤體積以mm3
表示且使用以下公式計算得到體積:V = (L* W* W)/2;其中V代表腫瘤體積,L代表腫瘤長度 (即腫瘤最長處) 而W代表腫瘤寬度 (即腫瘤中和L互相垂直之最長距離)。採用於上述三組中所獲得之腫瘤體積資料,以獨立樣本t檢定對每一組之間的平均腫瘤體積執行統計分析。上述分析結果中原始P值取至小數第三位,但若P值小於0.001則不調整該P值。所有檢定皆為雙邊檢定。
如圖10A中所示,在三組小鼠的腫瘤成長曲線 (平均腫瘤體積隨著時間的變化) 中可見第三組的平均腫瘤體積有下降趨勢。使用以下公式計算所量測到的腫瘤體積而得平均腫瘤體積抑制率:平均腫瘤體積抑制率 (%) = (控制組之平均腫瘤體積 (C) – 該實驗組之平均腫瘤體積 (T)) / 控制組之平均腫瘤體積 (C)*100%。如圖10B所示,第三組之腫瘤體積抑制率顯著地高於第二組。
在本研究進行的過程中也全程監控小鼠體重。如圖11中所示,沒有在第三組小鼠身上發現會影響其體重的副作用。
更進一步地,如圖12所示,以流式細胞儀分析腫瘤中之活細胞,發現第三組和其他組相比,在CD45陽性細胞族群之中有著較高比率的CD3陽性T細胞、CD4陰性CD8陽性T細胞,和較低比率的單核球。在免疫微環境中,已知單核球之存在會負調節抗PD-1抗體所引起的抗腫瘤反應,因此該實驗結果代表可正調控細胞毒殺性免疫細胞相對於該腫瘤微環境之可達性,和負調控抑制性免疫細胞相對於該腫瘤微環境之可達性。
圖10至圖12中的實驗結果清楚地展現了PTX-9908和抗PD-1療法於治療肺癌時之協同效應。
總之,根據本揭露的多種實施例,具有SEQ ID NOs. 1-3的其中一種序列且能選擇性地和細胞趨化因子結合之多肽 (如PTX-9908),能夠和免疫治療成份互補且產生協同效應調節腫瘤免疫微環境和/或調節免疫細胞相對於該腫瘤的可達性,因此而增進了免疫療法之效力。
綜上所述,本創作符合發明專利要件,爰依法提出專利申請。惟,以上所述者僅為本創作之較佳實施例,本創作之範圍並不以上述實施例為限,舉凡熟習本案技藝之人士爰依本創作之精神所作之等效修飾或變化,皆應涵蓋於以下申請專利範圍內。
10‧‧‧抗體
20‧‧‧PTX-9908
30‧‧‧細胞毒殺T細胞
40‧‧‧自然殺手T細胞
50‧‧‧免疫抑制細胞1
60‧‧‧免疫抑制細胞2
70‧‧‧與癌症有關之纖維母細胞
80‧‧‧血管
本說明將可由以下之敘述配合附圖以更佳地理解,其中: 圖1為符合本揭露的一種實施例之PTX-9908調控腫瘤微環境(microenvironment) 中免疫抑制機制以增進免疫組合物之療效的示意圖。 圖2A為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示MC38異種移植小鼠模型 (xenograft mouse model) 在以該治療組合物治療或未以該治療組合物治療時,其平均腫瘤體積之不同。 圖2B為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示MC38異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其腫瘤體積抑制率之不同。 圖3A為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示MC38異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其腫瘤重量之不同。 圖3B為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示MC38異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其腫瘤成長抑制率 (tumor growth inhibition;TGI) 之不同。 圖4為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示MC38異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其體重的一致性。 圖5為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示MC38異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其腫瘤組織內免疫細胞之種類。 圖6A為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示EMT-6異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其平均腫瘤體積之不同。 圖6B為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示EMT-6異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其腫瘤體積抑制率之不同。 圖7A為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示EMT-6異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其腫瘤重量之不同。 圖7B為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示EMT-6異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其腫瘤成長抑制率之不同。 圖8為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示EMT-6異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其體重的一致性。 圖9為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示EMT-6異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其腫瘤組織內免疫細胞之種類。 圖10A為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示LL/2異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其平均腫瘤體積之不同。 圖10B為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示LL/2異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其腫瘤體積抑制率之不同。 圖11為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示LL/2異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其體重的一致性。 圖12為符合本揭露的一種實施例之一實驗結果,該實驗結果顯示LL/2異種移植小鼠模型在以該治療組合物治療或未以該治療組合物治療時,其腫瘤組織內免疫細胞之種類。
Claims (8)
- 一種用於治療癌症的組合物,包括: 一種多肽,其包括SEQ ID NOs. 1-3的其中一種序列且其能選擇性地和細胞趨化因子 (CXC chemokine receptor 4;CXCR4) 結合;以及 一種可治療癌症的免疫治療成份。
- 如申請專利範圍第1項所述的組合物,其中該免疫治療成份可選擇性地以CTLA-4、PD-1、PD-L1、TIM-3、LAG-3、B7-1、B7-H3、NKG2A、KIR、BTLA、VISTA/PD-1H、TIGIT、CD96、OX40、CD28、ICOS、HVEM、41BB、CD40L、CD137、GITR、CD27、CD30、DNAM-1、CD28H或上述之輔受體 (co-receptor) 做為標的。
- 如申請專利範圍第2項所述的組合物,其中該免疫治療成份為一抗體、一疫苗、一細胞激素 (cytokine)、一蛋白質、一多肽、一具有該蛋白質或該多肽編碼的表現載體、一小分子、一RNA干擾 (RNAi) 或一適體 (aptamer)。
- 如申請專利範圍第1項所述的組合物,該免疫治療成份為自體免疫細胞 (autologous immune cells)、具腫瘤特異性的自體T細胞 (autologous T cells)、具經修改之T細胞受體 (T-cell receptors) 的T細胞或具嵌合抗原受體 (chimeric antigen receptors;CARs) 的T細胞。
- 如申請專利範圍第1項所述的組合物,其中當該多肽和該CXCR4結合時會調節該腫瘤的一免疫微環境 (immune microenvironment)。
- 如申請專利範圍第1項所述的組合物,其中當該多肽和該CXCR4結合時會調節該些免疫細胞相對於該腫瘤的可達性。
- 如申請專利範圍第6項所述的組合物,其中該些免疫細胞為CD45陽性 (CD45+) 細胞、CD3陽性 (CD3+) T細胞、CD4陽性CD8陰性 (CD4+CD8-) T細胞、CD4陰性CD8陽性 (CD4-CD8+) T細胞、調節T細胞 (regulatory T-cell)、自然殺手細胞 (NK cells)、自然殺手T細胞 (NKT cells)、巨噬細胞 (macrophages)、顆粒球 (granulocytes) 或單核球 (monocytes)。
- 如申請專利範圍第1項所述的組合物,其中該癌症為乳癌、直腸癌、肺癌、胰臟癌、攝護腺癌、腎臟癌、肝癌、淋巴癌或黑色素瘤。
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