TW202229352A - Combination therapy and methods utilizing the same - Google Patents

Combination therapy and methods utilizing the same Download PDF

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TW202229352A
TW202229352A TW110142111A TW110142111A TW202229352A TW 202229352 A TW202229352 A TW 202229352A TW 110142111 A TW110142111 A TW 110142111A TW 110142111 A TW110142111 A TW 110142111A TW 202229352 A TW202229352 A TW 202229352A
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容真 呂
志宏 陳
王驥
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大陸商同潤生物醫藥(上海)有限公司
香港商同潤（香港）有限公司
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Abstract

Provided herein are compositions and methods that comprise anti-OX40 polypeptides and fragment thereof and inhibitors for use in combination therapy. Also provided are methods of using the anti-OX40 polypeptides in combination therapies for the treatment of diseases and conditions.

Description

聯合治療及其使用方法 Combination therapy and how to use it

通過併入的交叉引用By incorporated cross-reference

本申請要求於2020年11月12日向中國國家智慧財產權局提交的題為“COMBINATION THERAPY AND METHODS UTILIZING THE SAME”的國際專利申請No.PCT/CN2020/128453的優先權，其通過引用整體併入本文。 This application claims priority to International Patent Application No. PCT/CN2020/128453, entitled "COMBINATION THERAPY AND METHODS UTILIZING THE SAME", filed with the State Intellectual Property Office of China on November 12, 2020, which is incorporated herein by reference in its entirety .

使用靶向B7免疫球蛋白超家族分子(CTLA-4、PD-1和PD-L1)的拮抗性單源抗體(monoclonal antibody,mAb)對免疫檢查點進行阻斷，產生持久的抗腫瘤免疫應答，這對許多癌症類型具有臨床益處。然而，許多患者對基於免疫檢查點阻斷的單一治療具有原發抗性，並且許多其他患者最終會復發。 Blockade of immune checkpoints with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) to generate durable antitumor immune responses , which has clinical benefit in many cancer types. However, many patients are primary resistant to immune checkpoint blockade-based monotherapy, and many others eventually relapse.

在一些方面，本公開內容提供了用於克服針對在許多癌症類型中的免疫治療的原發性和繼發性抗性的新的組合物及其方法。新的免疫刺激靶標，例如腫瘤壞死因數受體超家族包含許多其他免疫檢查點，可作為下一代免疫調節劑。在一些實施方案中，由活化的免疫細胞表達的共刺激分子OX40(CD134)可用作新的免疫刺激靶標。 In some aspects, the present disclosure provides novel compositions and methods for overcoming primary and secondary resistance to immunotherapy in many cancer types. Novel immunostimulatory targets, such as the tumor necrosis factor receptor superfamily containing many other immune checkpoints, could serve as next-generation immunomodulators. In some embodiments, the co-stimulatory molecule OX40 (CD134) expressed by activated immune cells can be used as a novel immunostimulatory target.

在一個方面，本公開內容提供了用於治療有此需要的對象的方法，其包括：(a)向所述對象施用包含表現出對OX40的結合特異性的抗原結合部分的多肽，其中所述抗原結合部分包含選自(i)至(iii)的至少一個重鏈互補決並區(complementarity-determining region，CDR)(CDRH)和選自(iv)至(vi) 的至少一個輕鏈CDR(CDRL)，其中：(i)CDRH1，其與選自SEQ ID NO：1、7、13、15、21和27的序列具有至少80%的序列同一性；(ii)CDRH2，其與選自SEQ ID NO：3、9、17、23和29的序列具有至少80%的序列同一性；(iii)CDRH3，其與選自SEQ ID NO：5、11、19、25和31的序列具有至少80%的序列同一性；(iv)CDRL1，其與選自SEQ ID NO：2、8、14、16、22和28的序列具有至少80%的序列同一性；(v)CDRL2，其與選自SEQ ID NO：4、10、18、24和30的序列具有至少80%的序列同一性；和(vi)CDRL3，其與選自SEQ ID NO：6、12、20、26和32的序列具有至少80%的序列同一性；以及(b)向所述對象施用針對PI3K的抑制劑。 In one aspect, the present disclosure provides a method for treating a subject in need thereof, comprising: (a) administering to the subject a polypeptide comprising an antigen-binding portion that exhibits binding specificity for OX40, wherein the The antigen-binding portion comprises at least one heavy chain complementarity-determining region (CDR) (CDRH) selected from (i) to (iii) and selected from (iv) to (vi) of at least one light chain CDR (CDRL), wherein: (i) CDRH1 having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) CDRH2 having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29; (iii) CDRH3 with a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31 have at least 80% sequence identity; (iv) CDRL1, which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 16, 22 and 28; (v) ) CDRL2, which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 4, 10, 18, 24, and 30; and (vi) CDRL3, which is identical to a sequence selected from the group consisting of SEQ ID NOs: 6, 12, 20 The sequences of , 26, and 32 have at least 80% sequence identity; and (b) administering to the subject an inhibitor against PI3K.

在一些實施方案中，其中所述抗原結合部分包含：(1)重鏈可變區(VH)，其與選自SEQ ID NO：33、35、37、39、41和43的序列具有至少80%的序列同一性；和(2)輕鏈可變區(VL)，其與選自SEQ ID NO：34、36、38、40、42和44的序列具有至少80%的序列同一性。 In some embodiments, wherein the antigen binding moiety comprises: (1) a heavy chain variable region (VH) having at least 80 V regions with a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43 % sequence identity; and (2) a light chain variable region (VL) having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42, and 44.

在本文中公開的任一種方法的一些實施方案中，所述抗原結合部分包含(1)VH，其與SEQ ID NO：39具有至少80%的序列同一性，和(2)VL，其與SEQ ID NO：40具有至少80%的序列同一性。 In some embodiments of any of the methods disclosed herein, the antigen-binding portion comprises (1) a VH, which has at least 80% sequence identity to SEQ ID NO: 39, and (2) a VL, which is identical to SEQ ID NO: 39 ID NO:40 has at least 80% sequence identity.

在本文中公開的任一種方法的一些實施方案中，所述針對PI3K的抑制劑包括針對PI3Kα、PI3Kβ、PI3Kδ或PI3Kγ的一種或更多種小分子抑制劑。在本文中公開的任一種方法的一些實施方案中，所述針對PI3K的抑制劑包括針對PI3Kδ或PI3Kγ的一種或更多種小分子抑制劑。 In some embodiments of any of the methods disclosed herein, the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3Kα, PI3Kβ, PI3Kδ, or PI3Kγ. In some embodiments of any of the methods disclosed herein, the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3Kδ or PI3Kγ.

在一個方面，本公開內容提供了包括治療有此需要的對象的方法，其包括：(a)向所述對象施用包含表現出對OX40的結合特異性的抗原結合部分的多肽；以及(b)向所述對象施用針對PI3K的抑制劑，其包含選自以下的一種或更多種：渥曼青黴素、LY294002、hibiscone C、Idelalisib、Copanlisib、Duvelisib、Alpelisib、Taselisib、Perifosine、Buparlisib、Umbralisib、PX-866、Dactolisib、CUDC-907、Voxtalisib、CUDC-907、ME-401、IPI-549、SF1126、Tenalisib、INK1117、pictilisib、XL147、Palomid 529、GSK1059615、ZSTK474、PWT33597、IC87114、TG100-115、CAL263、RP6503、PI-103、GNE-477、AEZS-136， 其修飾及其組合。 In one aspect, the present disclosure provides methods comprising treating a subject in need thereof, comprising: (a) administering to the subject a polypeptide comprising an antigen-binding portion that exhibits binding specificity for OX40; and (b) administering to the subject an inhibitor against PI3K comprising one or more selected from the group consisting of wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX- 866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, Tenalisib, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, RP650363 , PI-103, GNE-477, AEZS-136, Modifications and combinations thereof.

在一些實施方案中，所述針對PI3K的抑制劑包含選自以下的一種或更多種：Idelalisib、Copanlisib、Duvelisib、Alpelisib、Taselisib、Perifosine、Buparlisib、Umbralisib、Tenalisib，其修飾及其組合。在一些實施方案中，所述針對PI3K的抑制劑包含Tenalisib。 In some embodiments, the inhibitor against PI3K comprises one or more selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, Tenalisib, modifications and combinations thereof. In some embodiments, the inhibitor against PI3K comprises Tenalisib.

在本文中公開的任一種方法的一些實施方案中，所述多肽包括抗體、其片段或其功能性變體。 In some embodiments of any of the methods disclosed herein, the polypeptide comprises an antibody, a fragment thereof, or a functional variant thereof.

在本文中公開的任一種方法的一些實施方案中，所述多肽的施用發生在所述針對PI3K的抑制劑的施用之前、同時或之後。 In some embodiments of any of the methods disclosed herein, the administration of the polypeptide occurs before, concurrently with, or after the administration of the inhibitor against PI3K.

在本文中公開的任一種方法的一些實施方案中，以相同的單位劑量施用所述多肽和所述針對PI3K的抑制劑。替代地或另外地，在本文中公開的任一種方法的一些實施方案中，以不同的單位劑量施用所述多肽和所述針對PI3K的抑制劑。 In some embodiments of any of the methods disclosed herein, the polypeptide and the inhibitor against PI3K are administered in the same unit dose. Alternatively or additionally, in some embodiments of any of the methods disclosed herein, the polypeptide and the inhibitor against PI3K are administered in different unit doses.

在本文中公開的任一種方法的一些實施方案中，所述多肽和所述針對PI3K的抑制劑的施用協同產生選自以下的一種或更多種特徵：(A)與所述多肽或所述針對PI3K的抑制劑相比，針對患病細胞的毒性程度更大；和(B)與所述多肽或所述針對PI3K的抑制劑相比，腫瘤尺寸降低。 In some embodiments of any of the methods disclosed herein, the administration of the polypeptide and the inhibitor against PI3K synergistically produces one or more characteristics selected from (A) with the polypeptide or the Greater degree of toxicity against diseased cells compared to the inhibitor against PI3K; and (B) reduced tumor size compared to the polypeptide or the inhibitor against PI3K.

在本文中公開的任一種方法的一些實施方案中，所述多肽和所述針對PI3K的抑制劑的施用協同產生選自以下的一種或更多種特徵：(A)與所述多肽或所述針對PI3K的抑制劑相比，針對患病細胞的毒性程度增加至少約20%、至少約40%、至少約60%、至少約80%、至少約100%或至少約200%；和(B)與所述多肽或所述針對PI3K的抑制劑相比，腫瘤尺寸降低至少約10%、至少約20%、至少約30%、至少約40%、至少約50%或至少約60%。 In some embodiments of any of the methods disclosed herein, the administration of the polypeptide and the inhibitor against PI3K synergistically produces one or more characteristics selected from (A) with the polypeptide or the increase the degree of toxicity against diseased cells by at least about 20%, at least about 40%, at least about 60%, at least about 80%, at least about 100%, or at least about 200% compared to an inhibitor against PI3K; and (B) The tumor size is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 60% compared to the polypeptide or the inhibitor against PI3K.

在本文中公開的任一種方法的一些實施方案中，所述患病細胞包括腫瘤細胞或癌細胞。在本文中公開的任一種方法的一些實施方案中，所述患病細胞包括結直腸癌細胞。在本文中公開的任一種方法的一些實施方案中，所述患病細胞包括淋巴瘤細胞。 In some embodiments of any of the methods disclosed herein, the diseased cells comprise tumor cells or cancer cells. In some embodiments of any of the methods disclosed herein, the diseased cells comprise colorectal cancer cells. In some embodiments of any of the methods disclosed herein, the diseased cells comprise lymphoma cells.

在本文中公開的任一種方法的一些實施方案中，所述方法還包括向所述對象施用共治療劑。 In some embodiments of any of the methods disclosed herein, the method further comprises administering to the subject a co-therapeutic agent.

在本文中公開的任一種方法的一些實施方案中，所述對象患有或懷疑患有疾病。 In some embodiments of any of the methods disclosed herein, the subject has or is suspected of having a disease.

在本文中公開的任一種方法的一些實施方案中，所述疾病包括腫瘤或癌症。在本文中公開的任一種方法的一些實施方案中，所述疾病包括結直腸癌。在本文中公開的任一種方法的一些實施方案中，所述疾病包括淋巴瘤。在本文中公開的任一種方法的一些實施方案中，所述疾病包括B細胞淋巴瘤。 In some embodiments of any of the methods disclosed herein, the disease comprises a tumor or cancer. In some embodiments of any of the methods disclosed herein, the disease comprises colorectal cancer. In some embodiments of any of the methods disclosed herein, the disease comprises lymphoma. In some embodiments of any of the methods disclosed herein, the disease comprises B-cell lymphoma.

在一個方面，本公開內容提供了組合物，其包含(a)多肽，其包含表現出對OX40的結合特異性的抗原結合部分，其中所述抗原結合部分包含選自(i)至(iii)的至少一個重鏈CDR(CDRH)和選自(iv)至(vi)的至少一個輕鏈CDR(CDRL)，其中：(i)CDRH1，其與選自SEQ ID NO：1、7、13、15、21和27的序列具有至少80%的序列同一性；(ii)CDRH2，其與選自SEQ ID NO：3、9、17、23和29的序列具有至少80%的序列同一性；(iii)CDRH3，其與選自SEQ ID NO：5、11、19、25和31的序列具有至少80%的序列同一性；(iv)CDRL1，其與選自SEQ ID NO：2、8、14、16、22和28的序列具有至少80%的序列同一性；(v)CDRL2，其與選自SEQ ID NO：4、10、18、24和30的序列具有至少80%的序列同一性；和(vi)CDRL3，其與選自SEQ ID NO：6、12、20、26和32的序列具有至少80%的序列同一性；以及(b)針對PI3K的抑制劑。 In one aspect, the present disclosure provides a composition comprising (a) a polypeptide comprising an antigen-binding moiety that exhibits binding specificity for OX40, wherein the antigen-binding moiety comprises the group consisting of (i) to (iii) at least one heavy chain CDR (CDRH) and at least one light chain CDR (CDRL) selected from (iv) to (vi), wherein: (i) CDRH1, which is selected from SEQ ID NOs: 1, 7, 13, The sequences of 15, 21 and 27 have at least 80% sequence identity; (ii) CDRH2 has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 3, 9, 17, 23 and 29; ( iii) CDRH3 having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31; (iv) CDRL1 with a sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14 , 16, 22 and 28 have at least 80% sequence identity; (v) CDRL2, which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 4, 10, 18, 24 and 30; and (vi) CDRL3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 6, 12, 20, 26 and 32; and (b) an inhibitor against PI3K.

在一些實施方案中，所述抗原結合部分包含：(1)重鏈可變區(VH)，其與選自SEQ ID NO：33、35、37、39、41和43的序列具有至少80%的序列同一性；和(2)輕鏈可變區(VL)，其與選自SEQ ID NO：34、36、38、40、42和44的序列具有至少80%的序列同一性。 In some embodiments, the antigen binding portion comprises: (1) a heavy chain variable region (VH) that is at least 80% identical to a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43 and (2) a light chain variable region (VL) having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 34, 36, 38, 40, 42 and 44.

在本文中公開的任一種方法的一些實施方案中，所述抗原結合部分包含(1)VH，其與SEQ ID NO：39具有至少80%的序列同一性，和(2)VL，其與SEQ ID NO：40具有至少80%的序列同一性。 In some embodiments of any of the methods disclosed herein, the antigen-binding portion comprises (1) a VH, which has at least 80% sequence identity to SEQ ID NO: 39, and (2) a VL, which is identical to SEQ ID NO: 39 ID NO:40 has at least 80% sequence identity.

在本文中公開的任一種方法的一些實施方案中，所述針對PI3K的抑制劑包括針對PI3Kα、PI3Kβ、PI3Kδ或PI3Kγ的一種或更多種小分子抑制劑。在本文中公開的任一種方法的一些實施方案中，所述針對PI3K的抑制劑包括針對PI3Kδ和/或PI3Kγ的一種或更多種小分子抑制劑。 In some embodiments of any of the methods disclosed herein, the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3Kα, PI3Kβ, PI3Kδ, or PI3Kγ. In some embodiments of any of the methods disclosed herein, the inhibitor against PI3K comprises one or more small molecule inhibitors against PI3Kδ and/or PI3Kγ.

在一個方面，本公開內容提供了組合物，其包含(a)多肽，其包含表現出對OX40的結合特異性的抗原結合部分；和(b)針對PI3K的抑制劑，其包含選自以下的一種或更多種：渥曼青黴素、LY294002、hibiscone C、Idelalisib、Copanlisib、Duvelisib、Alpelisib、Taselisib、Perifosine、Buparlisib、Umbralisib、PX-866、Dactolisib、CUDC-907、Voxtalisib、CUDC-907、ME-401、IPI-549、SF1126、Tenalisib、INK1117、pictilisib、XL147、Palomid 529、GSK1059615、ZSTK474、PWT33597、IC87114、TG100-115、CAL263、RP6503、PI-103、GNE-477、AEZS-136，其修飾及其組合。 In one aspect, the present disclosure provides a composition comprising (a) a polypeptide comprising an antigen-binding moiety that exhibits binding specificity for OX40; and (b) an inhibitor against PI3K comprising a One or more of: Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC-907, ME-401 , IPI-549, SF1126, Tenalisib, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, RP6503, PI-103, GNE-477, AEZS-136, their modifications and their combination.

在一些實施方案中，所述針對PI3K的抑制劑包含選自以下的一種或更多種：Idelalisib、Copanlisib、Duvelisib、Alpelisib、Taselisib、Perifosine、Buparlisib、Umbralisib、Tenalisib，其修飾及其組合。在一些實施方案中，所述針對PI3K的抑制劑包含Tenalisib。 In some embodiments, the inhibitor against PI3K comprises one or more selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, Tenalisib, modifications and combinations thereof. In some embodiments, the inhibitor against PI3K comprises Tenalisib.

在本文中公開的任一種方法的一些實施方案中，所述多肽包括抗體、其片段或其功能性變體。 In some embodiments of any of the methods disclosed herein, the polypeptide comprises an antibody, a fragment thereof, or a functional variant thereof.

在本文中公開的任一種方法的一些實施方案中，以相同的單位劑量製備所述多肽和所述針對PI3K的抑制劑。在本文中公開的任一種方法的一些實施方案中，以不同的單位劑量製備所述多肽和所述針對PI3K的抑制劑。 In some embodiments of any of the methods disclosed herein, the polypeptide and the inhibitor against PI3K are prepared in the same unit dose. In some embodiments of any of the methods disclosed herein, the polypeptide and the inhibitor against PI3K are prepared in different unit doses.

在本文中公開的任一種方法的一些實施方案中，所述組合物還包含共治療劑。 In some embodiments of any of the methods disclosed herein, the composition further comprises a co-therapeutic agent.

通過下面的詳細描述，本公開內容的另外的方面和優點對於本領域技術人員將變得明顯，其中僅示出和描述了本公開內容的說明性實施方案。將認識到，本公開內容能夠具有另外的和不同的實施方案，並且其若干細節能夠在多個明顯的方面進行修改，所有這些均不脫離本公開內容。因此，圖式和 描述在本質上應被認為是說明性的，而不是限制性的。 Additional aspects and advantages of the present disclosure will become apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of additional and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the present disclosure. Therefore, the schema and The descriptions are to be considered illustrative in nature, rather than restrictive.

通過引用併入incorporated by reference

本說明書中所提及的所有出版物、專利和專利申請均通過引用以如同每個單獨的出版物、專利或專利申請被具體地和單獨指明通過引用併入本文一樣的相同程度併入本文。 All publications, patents and patent applications mentioned in this specification are incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

本發明的新的特徵在所附的申請專利範圍中具體闡述。通過參考下面的詳細描述，可更好地理解本發明的特徵和優點，所述詳細描述闡述了利用本發明的原理的說明性實施方案以及圖式，其中： The novel features of the present invention are set forth in detail in the appended claims. The features and advantages of the present invention may be better understood by reference to the following detailed description, which sets forth illustrative embodiments and drawings that utilize the principles of the invention, wherein:

圖1A示出了Tenalisib(CN401)聯合α-mOX40 mAb和抗mPD1 mAb在MC38同源模型中的抗腫瘤活性。該圖示出了通過小鼠的平均腫瘤尺寸(n=8)測量的腫瘤生長曲線，紅色箭頭表示給藥天數。將MC38細胞(0.5百萬個細胞/小鼠)注射到c57bl/6小鼠的右脅側中。細胞植入之後6天，當平均腫瘤尺寸達到約70mm3時，向小鼠施用載劑、CN401(15mg/kg、50mg/kg和150mg/kg，經口，每日兩次)、α-OX40 mAb(100μg/小鼠，腹膜內，每週兩次)、α-PD-1 mAb(60μg/小鼠，腹膜內，每週兩次)、或其組合。圖1B示出了每組的體重增長，每週測量三次小鼠體重。 Figure 1A shows the antitumor activity of Tenalisib (CN401) in combination with α-mOX40 mAb and anti-mPD1 mAb in the MC38 syngeneic model. The figure shows tumor growth curves measured by mean tumor size in mice (n=8), red arrows indicate dosing days. MC38 cells (0.5 million cells/mouse) were injected into the right flank of c57bl/6 mice. Six days after cell implantation, when the mean tumor size reached approximately 70 mm, mice were administered vehicle, CN401 (15 mg/kg, 50 mg/kg and 150 mg/kg, orally, twice daily), α-OX40 mAb (100 μg/mouse, ip, twice a week), α-PD-1 mAb (60 μg/mouse, ip, twice a week), or a combination thereof. Figure IB shows body weight gain for each group, with mice body weights measured three times per week.

圖2A示出了Tenalisib(CN401)聯合α-mOX40 mAb和抗mPD1 mAb在MC38同源模型中的抗腫瘤活性。特別地，該圖示出了經載劑處理的小鼠組的每個腫瘤的生長曲線。圖2B示出了經CN401(150mg/kg)處理的小鼠的單個腫瘤生長曲線。圖2C示出了經α-OX40 mAb(100μg/kg)處理的小鼠的單個腫瘤生長曲線。圖2D示出了經α-OX40 mAb(100μg/kg)+CN410(150mg/kg)處理的小鼠的單個腫瘤生長曲線。圖2E示出了經α-OX40 mAb(100μg/kg)+CN401(50mg/kg)處理的小鼠的單個腫瘤生長曲線。圖2F示出了經α-OX40 mAb(100μg/kg)+CN410(15mg/kg)處理的小鼠的單個腫瘤生長曲線。圖2G示出了經α-OX40 mAb(100μg/kg)+CN410(150mg/kg)+PD1 mAb (3mg/kg)處理的小鼠的單個腫瘤生長曲線。 Figure 2A shows the antitumor activity of Tenalisib (CN401) in combination with α-mOX40 mAb and anti-mPD1 mAb in the MC38 syngeneic model. In particular, the figure shows the growth curve for each tumor of the vehicle-treated group of mice. Figure 2B shows individual tumor growth curves of CN401 (150 mg/kg) treated mice. Figure 2C shows individual tumor growth curves of mice treated with [alpha]-OX40 mAb (100 [mu]g/kg). Figure 2D shows individual tumor growth curves of mice treated with α-OX40 mAb (100 μg/kg) + CN410 (150 mg/kg). Figure 2E shows individual tumor growth curves of mice treated with α-OX40 mAb (100 μg/kg) + CN401 (50 mg/kg). Figure 2F shows individual tumor growth curves of mice treated with α-OX40 mAb (100 μg/kg) + CN410 (15 mg/kg). Figure 2G shows individual tumor growth curves of mice treated with α-OX40 mAb (100 μg/kg) + CN410 (150 mg/kg) + PD1 mAb (3 mg/kg).

圖3A示出了Tenalisib(CN401)聯合α-OX40 mAb和抗PD1 mAb在A20同源模型中的抗腫瘤活性。將A20細胞(0.5百萬個/小鼠)注射到balb/c小鼠的右脅側中。細胞植入之後11天，當平均腫瘤尺寸達到約70mm3時，向小鼠施用載劑、CN401(150mg/kg和300mg/kg，經口，每日兩次)、α-OX40 mAb(100μg/小鼠，腹膜內，每週兩次)、α-PD-1 mAb(60μg/小鼠，腹膜內，每週兩次)、或其組合。特別地，該圖示出了通過小鼠的平均腫瘤尺寸(n=6)測量的腫瘤生長曲線，紅色箭頭表示給藥天數。圖3B示出了每組的體重增長，每週測量三次小鼠體重。 Figure 3A shows the antitumor activity of Tenalisib (CN401) in combination with α-OX40 mAb and anti-PD1 mAb in the A20 syngeneic model. A20 cells (0.5 million/mouse) were injected into the right flank of balb/c mice. Eleven days after cell implantation, when the mean tumor size reached approximately 70 mm, mice were administered vehicle, CN401 (150 mg/kg and 300 mg/kg, orally, twice daily), α-OX40 mAb (100 μg/kg/day) mice, ip, twice a week), α-PD-1 mAb (60 μg/mouse, ip, twice a week), or a combination thereof. In particular, the figure shows tumor growth curves measured by mean tumor size in mice (n=6), with red arrows indicating days of dosing. Figure 3B shows body weight gain for each group, and mouse body weights were measured three times per week.

圖4A示出了Tenalisib(CN401)聯合α-OX40 mAb和抗PD1 mAb在A20同源模型中的抗腫瘤活性。特別地，該圖示出了經載劑處理的小鼠組的每個腫瘤的生長曲線。圖4B示出了來自CN401(300mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖4C示出了經CN401(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖4D示出了經α-OX40 mAb(100μg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖4E示出了經α-OX40 mAb處理的小鼠組的每個腫瘤的生長曲線。值得注意的是，3/6小鼠實現了完全應答(無腫瘤)。圖4F示出了經α-OX40 mAb(100μg/kg)+CN410(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。值得注意的是，1/6小鼠實現了完全應答。圖4G示出了經α-OX40 mAb(100μg/kg)+α-PD1 mAb(60μg/小鼠)處理的小鼠組的每個腫瘤的生長曲線。值得注意的是，有3/6只小鼠實現了完全應答。圖4H示出了來自α-OX40 mAb(100μg/kg)+CN410(150mg/kg)+-PD1 mAb(60μg/小鼠)處理的小鼠組的每個腫瘤的生長曲線。值得注意的是，有4/6只小鼠實現了完全應答。 Figure 4A shows the antitumor activity of Tenalisib (CN401) in combination with α-OX40 mAb and anti-PD1 mAb in the A20 syngeneic model. In particular, the figure shows the growth curve for each tumor of the vehicle-treated group of mice. Figure 4B shows the growth curve of each tumor from the CN401 (300 mg/kg) treated group of mice. Figure 4C shows the growth curve of each tumor in the CN401 (150 mg/kg)-treated group of mice. Figure 4D shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/kg). Figure 4E shows the growth curve for each tumor of the α-OX40 mAb-treated group of mice. Notably, 3/6 mice achieved a complete response (no tumor). Figure 4F shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/kg) + CN410 (150 mg/kg). Notably, 1/6 mice achieved a complete response. Figure 4G shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/kg) + α-PD1 mAb (60 μg/mouse). Notably, 3/6 mice achieved a complete response. Figure 4H shows the growth curve of each tumor from the α-OX40 mAb (100 μg/kg)+CN410 (150 mg/kg)+-PD1 mAb (60 μg/mouse) treated group of mice. Notably, 4/6 mice achieved a complete response.

圖5A示出了Tenalisib(CN401)聯合CN1 Ab在A20人源化轉基因小鼠中的抗腫瘤活性。將A20細胞(0.5百萬個/小鼠)注射到balb/c小鼠的右脅側中。細胞植入之後9天，當平均腫瘤尺寸達到約70mm3時，向小鼠施用載劑、CN401(150mg/kg，經口，每日兩次)、CN1(1mg/kg，腹膜內，每週兩次)、或其組合。圖5B示出了示出了每組的體重增長，每週測量三次小 鼠體重。 Figure 5A shows the antitumor activity of Tenalisib (CN401) in combination with CN1 Ab in A20 humanized transgenic mice. A20 cells (0.5 million/mouse) were injected into the right flank of balb/c mice. Nine days after cell implantation, when the mean tumor size reached about 70 mm, mice were administered vehicle, CN401 (150 mg/kg, orally, twice daily), CN1 (1 mg/kg, intraperitoneal, weekly twice), or a combination thereof. Figure 5B shows the body weight gain of each group, and the body weight of the mice was measured three times per week.

圖6A示出了Tenalisib(CN401)聯合CN1在A20人源化Ox40轉基因小鼠同源模型中的抗腫瘤活性。特別地，該圖示出了經載劑處理的小鼠組的每個腫瘤的生長曲線。圖6B示出了經CN401(1mg/kg)處理的小鼠組的每個腫瘤的生長曲線。值得注意的是，有4/8經處理的小鼠實現了完全應答。圖6C示出了經CN401(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。值得注意的是，有1/8經處理的小鼠實現了完全應答。圖6D示出了經CN1(1mg/kg)+CN401(150mg/kg)處理的小鼠的個體生長曲線。值得注意的是，有5/8經處理的小鼠實現了完全應答。 Figure 6A shows the antitumor activity of Tenalisib (CN401) in combination with CN1 in an A20 humanized Ox40 transgenic mouse syngeneic model. In particular, the figure shows the growth curve for each tumor of the vehicle-treated group of mice. Figure 6B shows the growth curve of each tumor in the CN401 (1 mg/kg)-treated group of mice. Notably, 4/8 of the treated mice achieved a complete response. Figure 6C shows the growth curve of each tumor in the CN401 (150 mg/kg)-treated group of mice. Notably, 1/8 of the treated mice achieved a complete response. Figure 6D shows individual growth curves of CN1 (1 mg/kg) + CN401 (150 mg/kg) treated mice. Notably, 5/8 treated mice achieved a complete response.

圖7A示出了用10μM Tenalisib處理72小時的不同腫瘤細胞系的結果，對細胞增殖的影響以相對於對照的百分比來測量。在兩種細胞系(MV-4-11，人白血病細胞；A20，小鼠B細胞淋巴瘤)中顯示出大於50%的抑制。圖7B示出了Tenalisib(RP6530)的化學結構。圖7C示出了用Duvelishib(化合物的濃度範圍為在3倍連續稀釋下從0.002μM至10μM)處理72小時的不同腫瘤細胞系的結果，對細胞增殖的影響以相對於對照的百分比來測量。圖7D示出了Duvelishib的化學結構。 Figure 7A shows the results of different tumor cell lines treated with 10 μM Tenalisib for 72 hours, the effect on cell proliferation was measured as a percentage relative to control. Greater than 50% inhibition was shown in two cell lines (MV-4-11, human leukemia cells; A20, mouse B-cell lymphoma). Figure 7B shows the chemical structure of Tenalisib (RP6530). Figure 7C shows the results of different tumor cell lines treated with Duvelishib (compound concentrations ranging from 0.002 μM to 10 μM at 3-fold serial dilution) for 72 hours, the effect on cell proliferation was measured as a percentage relative to control. Figure 7D shows the chemical structure of Duvelishib.

圖8A示出了Tenalisib(CN401)和Duvelisib聯合α-OX40 mAb和抗PD1 mAb在MC38同源模型中的抗腫瘤活性。將MC38細胞(0.5百萬個細胞/小鼠)注射到c57bl/6小鼠的右脅側中。細胞植入之後6天，當平均腫瘤尺寸達到約70mm3時，向小鼠施用載劑、CN401(15mg/kg、50mg/kg和150mg/kg，經口，每日兩次)、α-OX40 mAb(100μg/小鼠，腹膜內，每週兩次)、α-PD-1 mAb(60μg/小鼠，腹膜內，每週兩次)、Duvelisib(50mg/kg，經口，每日兩次)、或其組合。特別地，該圖示出了通過小鼠的平均腫瘤尺寸(n=8)測量的腫瘤生長曲線，紅色箭頭表示給藥天數。圖8B示出了每組的體重增長，每週測量三次小鼠體重。 Figure 8A shows the antitumor activity of Tenalisib (CN401) and Duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in the MC38 syngeneic model. MC38 cells (0.5 million cells/mouse) were injected into the right flank of c57bl/6 mice. Six days after cell implantation, when the mean tumor size reached approximately 70 mm, mice were administered vehicle, CN401 (15 mg/kg, 50 mg/kg and 150 mg/kg, orally, twice daily), α-OX40 mAb (100 μg/mouse, ip, twice weekly), α-PD-1 mAb (60 μg/mouse, ip, twice weekly), Duvelisib (50 mg/kg, po, twice daily) ), or a combination thereof. In particular, the figure shows tumor growth curves measured by mean tumor size (n=8) in mice, with red arrows indicating days of dosing. Figure 8B shows body weight gain for each group, and mouse body weights were measured three times per week.

圖9A示出了Tenalisib(CN401)和Duvelisib聯合α-OX40 mAb和抗PD1 mAb在MC38同源模型中的抗腫瘤活性。特別地，該圖示出了經載劑處理的小鼠組的每個腫瘤的生長曲線。圖9B示出了經CN401(150mg/kg) 處理的小鼠組的每個腫瘤的生長曲線。圖9C示出了經α-OX40 mAb(100μg/小鼠)處理的小鼠組的每個腫瘤的生長曲線。圖9D示出了經Duvelisib(50mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖9E示出了經α-OX40 mAb(100μg/小鼠)+CN410(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖9F示出了經α-OX40 mAb(100μg/小鼠)+CN401(50mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖9G示出了經α-OX40 mAb(100μg/小鼠)+CN410(15mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖9H示出了經α-OX40 mAb(100μg/小鼠)+Duvelisib(50mg/kg)處理的小鼠組的每個腫瘤的生長曲線；(i)經α-OX40 mAb(100μg/小鼠)+CN410(150mg/kg)+PD1 mAb(60μg/小鼠)處理的小鼠。 Figure 9A shows the antitumor activity of Tenalisib (CN401) and Duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in the MC38 syngeneic model. In particular, the figure shows the growth curve for each tumor of the vehicle-treated group of mice. Figure 9B shows the growth curve of each tumor in the CN401 (150 mg/kg)-treated group of mice. Figure 9C shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/mouse). Figure 9D shows the growth curve of each tumor in the group of mice treated with Duvelisib (50 mg/kg). Figure 9E shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/mouse) + CN410 (150 mg/kg). Figure 9F shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/mouse) + CN401 (50 mg/kg). Figure 9G shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/mouse) + CN410 (15 mg/kg). Figure 9H shows the growth curve of each tumor in groups of mice treated with α-OX40 mAb (100 μg/mouse) + Duvelisib (50 mg/kg); (i) treated with α-OX40 mAb (100 μg/mouse) +CN410 (150 mg/kg) + PD1 mAb (60 μg/mouse) treated mice.

圖10A示出了Tenalisib(CN401)和Duvelisib聯合α-OX40 mAb和抗PD1 mAb在A20同源模型中的抗腫瘤活性。將A20細胞(0.5百萬個細胞/小鼠)注射到balb/c小鼠的右脅側中。細胞植入之後11天，當平均腫瘤尺寸達到約70mm3時，向小鼠施用載劑、CN401(150mg/kg和300mg/kg，經口，每日兩次)、Duvelisib(50mg/kg，經口，每日兩次)、α-OX40 mAb(100μg/小鼠，腹膜內，每週兩次)、α-PD-1 mAb(60μg/小鼠，腹膜內，每週兩次)、或其組合。特別地，該圖示出了通過小鼠的平均腫瘤尺寸(n=6)測量的腫瘤生長曲線，紅色箭頭表示給藥天數。圖10B示出了每組的體重增長，每週測量三次小鼠體重。 Figure 10A shows the antitumor activity of Tenalisib (CN401) and Duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in the A20 syngeneic model. A20 cells (0.5 million cells/mouse) were injected into the right flank of balb/c mice. Eleven days after cell implantation, when the mean tumor size reached approximately 70 mm, mice were administered vehicle, CN401 (150 mg/kg and 300 mg/kg, orally twice daily), Duvelisib (50 mg/kg, via oral, twice daily), α-OX40 mAb (100 μg/mouse, intraperitoneal, twice weekly), α-PD-1 mAb (60 μg/mouse, intraperitoneal, twice weekly), or its combination. In particular, the figure shows tumor growth curves measured by mean tumor size in mice (n=6), with red arrows indicating days of dosing. Figure 10B shows body weight gain for each group, with mouse body weights measured three times per week.

圖11A示出了CN401和Duvelisib聯合α-OX40 mAb和抗PD1 mAb在A20同源模型中的抗腫瘤活性。特別地，該圖示出了經載劑處理的小鼠組的每個腫瘤的生長曲線。圖11B示出了經CN401(300mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖11C示出了經CN401(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖11D示出了經Duvelisib(50mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖11E示出了經α-OX40 mAb(100μg/小鼠)處理的小鼠組的每個腫瘤的生長曲線。圖11F示出了經α-OX40 mAb(100μg/kg)+CN401(300mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖11G示出了經α-OX40 mAb(100μg/kg)+CN410(150mg/kg)處理的小鼠組的每個腫瘤的 生長曲線。圖11H示出了經α-OX40 mAb(100μg/kg)+Duvelisib(50mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖11I示出了經α-OX40 mAb(100μg/kg)+α-PD1 mAb(60μg/小鼠)處理的小鼠組的每個腫瘤的生長曲線。圖11J示出了經α-OX40 mAb(100μg/小鼠)+CN410(150mg/kg)+α-PD1 mAb(60μg/小鼠)處理的小鼠組的每個腫瘤的生長曲線。 Figure 11A shows the antitumor activity of CN401 and Duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in the A20 syngeneic model. In particular, the figure shows the growth curve for each tumor of the vehicle-treated group of mice. Figure 11B shows the growth curve of each tumor in the CN401 (300 mg/kg)-treated group of mice. Figure 11C shows the growth curve of each tumor in the CN401 (150 mg/kg)-treated group of mice. Figure 1 ID shows the growth curve of each tumor in the group of mice treated with Duvelisib (50 mg/kg). Figure 11E shows the growth curve of each tumor in the group of mice treated with α-OX40 mAb (100 μg/mouse). Figure 11F shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/kg) + CN401 (300 mg/kg). Figure 11G shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/kg) + CN410 (150 mg/kg). Figure 11H shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/kg) + Duvelisib (50 mg/kg). Figure 11I shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/kg) + α-PD1 mAb (60 μg/mouse). Figure 11J shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/mouse) + CN410 (150 mg/kg) + α-PD1 mAb (60 μg/mouse).

圖12A示出了Tenalisib(CN401)聯合CN1和抗PD1 Ab在A20人源化轉基因小鼠中的抗腫瘤活性。將A20細胞(0.5百萬個細胞/小鼠)注射到balb/c小鼠的右脅側中。細胞植入之後9天，當平均腫瘤尺寸達到約70mm3時，向小鼠施用載劑、CN401(150mg/kg，經口，每日兩次)、CN1(1mg/kg，腹膜內，每週兩次)、或其組合。特別地，該圖示出了通過小鼠的平均腫瘤尺寸(n=8)測量的腫瘤生長曲線，黑色箭頭表示給藥天數。圖12B示出了每組的體重增長，每週測量三次小鼠體重。 Figure 12A shows the antitumor activity of Tenalisib (CN401) in combination with CN1 and anti-PD1 Ab in A20 humanized transgenic mice. A20 cells (0.5 million cells/mouse) were injected into the right flank of balb/c mice. Nine days after cell implantation, when the mean tumor size reached about 70 mm, mice were administered vehicle, CN401 (150 mg/kg, orally, twice daily), CN1 (1 mg/kg, intraperitoneal, weekly twice), or a combination thereof. In particular, the figure shows tumor growth curves measured by mean tumor size in mice (n=8), with black arrows indicating days of dosing. Figure 12B shows body weight gain for each group, with mouse body weights measured three times per week.

圖13A示出了Tenalisib(CN401)聯合CN1在A20人源化Ox40轉基因小鼠同源模型中的抗腫瘤活性。特別地，該圖示出了經載劑處理的小鼠組的每個腫瘤的生長曲線。圖13B示出了經CN401(1mg/kg)處理的小鼠組的每個腫瘤的生長曲線。值得注意的是，有4/8的小鼠實現了完全應答。圖13C示出了經CN401(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。值得注意的是，有1/8的小鼠實現了完全應答。圖13D示出了經CN1(1mg/kg)+CN401(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。值得注意的是，5/8的小鼠實現了完全應答。 Figure 13A shows the antitumor activity of Tenalisib (CN401) in combination with CN1 in an A20 humanized Ox40 transgenic mouse syngeneic model. In particular, the figure shows the growth curve for each tumor of the vehicle-treated group of mice. Figure 13B shows the growth curve of each tumor in the CN401 (1 mg/kg)-treated group of mice. Notably, 4/8 mice achieved a complete response. Figure 13C shows the growth curve of each tumor in the CN401 (150 mg/kg)-treated group of mice. Notably, 1/8 of the mice achieved a complete response. Figure 13D shows the growth curve of each tumor for the group of mice treated with CN1 (1 mg/kg) + CN401 (150 mg/kg). Notably, 5/8 mice achieved a complete response.

圖14A示出了Duvelisib聯合α-OX40 mAb在MC38同源模型中的抗腫瘤活性。將MC38細胞(50萬隻/小鼠)注射到C57小鼠的右脅側中。細胞植入之後6天，當平均腫瘤尺寸達到約70mm3時，向小鼠施用載劑、α-OX40 mAb(100μg/小鼠，腹膜內，每週兩次)、Duvelisib(50mg/kg，經口，每日兩次)、或其組合。特別地，該圖示出了通過小鼠的平均腫瘤尺寸(n=8)測量的腫瘤生長曲線，紅色箭頭表示給藥天數。圖14B示出了每組的體重增長，每週測量三次小鼠體重。(C)與載劑組相比，第20天的TGI和p值。 Figure 14A shows the antitumor activity of Duvelisib in combination with α-OX40 mAb in the MC38 syngeneic model. MC38 cells (0.5 million/mouse) were injected into the right flank of C57 mice. Six days after cell implantation, when the mean tumor size reached approximately 70 mm, mice were administered vehicle, α-OX40 mAb (100 μg/mouse, intraperitoneally, twice weekly), Duvelisib (50 mg/kg, via orally twice daily), or a combination thereof. In particular, the figure shows tumor growth curves measured by mean tumor size (n=8) in mice, with red arrows indicating days of dosing. Figure 14B shows body weight gain for each group, with mouse body weights measured three times per week. (C) TGI and p-value at day 20 compared to the vehicle group.

圖15A示出了Duvelisib聯合α-OX40 mAb在MC38同源模型中 的抗腫瘤活性。該圖具體地示出了經載劑處理的小鼠組的每個腫瘤的生長曲線。圖15B示出了經α-OX40 mAb(100μg/小鼠)處理的小鼠組的每個腫瘤的生長曲線。圖15C示出了經Duvelisib(50mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖15D示出了經α-OX40 mAb(100μg/小鼠)+Duvelisib(50mg/kg)處理的小鼠組的每個腫瘤的生長曲線。 Figure 15A shows the antitumor activity of Duvelisib in combination with α-OX40 mAb in the MC38 syngeneic model. The figure specifically shows the growth curve for each tumor of the vehicle-treated group of mice. Figure 15B shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/mouse). Figure 15C shows the growth curve of each tumor in the group of mice treated with Duvelisib (50 mg/kg). Figure 15D shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/mouse) + Duvelisib (50 mg/kg).

圖16A示出了Duvelisib聯合α-OX40 mAb在A20同源模型中的抗腫瘤活性。將A20細胞(0.5百萬個細胞/小鼠)注射到balb/c小鼠的右脅側中。細胞植入之後11天，當平均腫瘤尺寸達到約70mm3時，向小鼠施用載劑、Duvelisib(50mg/kg，經口，每日兩次)、α-OX40 mAb(100μg/小鼠，腹膜內，每週兩次)、或其組合。特別地，該圖示出了通過小鼠的平均腫瘤尺寸(n=6)測量的腫瘤生長曲線，紅色箭頭表示給藥天數。圖16B示出了每組的體重增長，每週測量三次小鼠體重。 Figure 16A shows the antitumor activity of Duvelisib in combination with α-OX40 mAb in the A20 syngeneic model. A20 cells (0.5 million cells/mouse) were injected into the right flank of balb/c mice. Eleven days after cell implantation, when the mean tumor size reached approximately 70 mm, mice were administered vehicle, Duvelisib (50 mg/kg, orally, twice daily), α-OX40 mAb (100 μg/mouse, peritoneal) , twice a week), or a combination thereof. In particular, the figure shows tumor growth curves measured by mean tumor size in mice (n=6), with red arrows indicating days of dosing. Figure 16B shows body weight gain for each group, with mouse body weights measured three times per week.

圖17A示出了Duvelisib聯合α-OX40 mAb在A20同源模型中的抗腫瘤活性。示出了經載劑處理的小鼠組的每個腫瘤的生長曲線。圖17B示出了經Duvelisib(50mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖17C示出了經α-OX40 mAb(100μg/小鼠)處理的小鼠組的每個腫瘤的生長曲線。圖17D示出了經α-OX40 mAb(100μg/小鼠)+Duvelisib(50mg/kg)處理的小鼠組的每個腫瘤的生長曲線。 Figure 17A shows the antitumor activity of Duvelisib in combination with α-OX40 mAb in the A20 syngeneic model. Growth curves for each tumor of the vehicle-treated group of mice are shown. Figure 17B shows the growth curve of each tumor in the group of mice treated with Duvelisib (50 mg/kg). Figure 17C shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/mouse). Figure 17D shows the growth curve of each tumor for the group of mice treated with α-OX40 mAb (100 μg/mouse) + Duvelisib (50 mg/kg).

圖18A示出了CN401聯合CN1在人源化CT26.WT鼠結腸癌模型中的抗腫瘤活性。將CT26.WT細胞(0.1百萬個細胞/小鼠)注射到小鼠的右脅側中。細胞植入之後9天，當平均腫瘤尺寸達到約70mm3時，向小鼠施用載劑CN401(150mg/kg，經口，每日兩次)、CN1(5mg/kg小鼠，腹膜內，每週兩次)、或其組合。特別地，該圖示出了通過小鼠的平均腫瘤尺寸(n=-8)測量的腫瘤生長曲線。圖18B示出了每組的體重增長，每週測量三次小鼠體重。 Figure 18A shows the antitumor activity of CN401 in combination with CN1 in a humanized CT26.WT murine colon cancer model. CT26.WT cells (0.1 million cells/mouse) were injected into the right flank of mice. Nine days after cell implantation, when the average tumor size reached approximately 70 mm, mice were administered the vehicles CN401 (150 mg/kg, orally, twice daily), CN1 (5 mg/kg mice, intraperitoneally, each twice a week), or a combination thereof. In particular, the figure shows tumor growth curves measured by mean tumor size in mice (n=-8). Figure 18B shows body weight gain for each group, with mouse body weights measured three times per week.

圖19A示出了CN401聯合CN1在CT26.WT鼠結腸癌模型中的抗腫瘤活性。示出了經載劑處理的小鼠組的每個腫瘤的生長曲線。圖19B示出了經CN401(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖19C示出了經CN1(5mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖19D示出了經 CN1(5mg/kg)+CN401(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。 Figure 19A shows the antitumor activity of CN401 combined with CN1 in CT26.WT murine colon cancer model. Growth curves for each tumor of the vehicle-treated group of mice are shown. Figure 19B shows the growth curve of each tumor in the CN401 (150 mg/kg)-treated group of mice. Figure 19C shows the growth curve of each tumor in the CN1 (5 mg/kg)-treated group of mice. Figure 19D shows the growth curve of each tumor for the group of mice treated with CN1 (5 mg/kg) + CN401 (150 mg/kg).

圖20A示出了CN401聯合CN1在人源化B16-F10鼠黑素瘤腫瘤模型中的抗腫瘤活性。將B16-F10細胞(0.1百萬個細胞/小鼠)注射到小鼠的右脅側中。細胞植入之後9天，當平均腫瘤尺寸達到約40mm3時，向小鼠施用載劑、CN401(150mg/kg，經口，每日兩次)、CN1(10mg/kg，腹膜內，每週兩次)、或其組合。特別地，該圖示出了通過小鼠的平均腫瘤尺寸(n=8)測量的腫瘤生長曲線。圖20B示出了每組的體重增長，每週測量三次小鼠體重。 Figure 20A shows the antitumor activity of CN401 in combination with CN1 in a humanized B16-F10 murine melanoma tumor model. B16-F10 cells (0.1 million cells/mouse) were injected into the right flank of mice. Nine days after cell implantation, when the mean tumor size reached approximately 40 mm, mice were administered vehicle, CN401 (150 mg/kg, orally, twice daily), CN1 (10 mg/kg, intraperitoneal, weekly twice), or a combination thereof. In particular, the figure shows tumor growth curves measured by mean tumor size in mice (n=8). Figure 20B shows body weight gain for each group, with mouse body weights measured three times per week.

圖21A示出了CN401聯合CN1在B16-F10黑素瘤模型中的抗腫瘤活性。示出了經載劑處理的小鼠組的每個腫瘤的生長曲線。圖20B示出了經CN401(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖20C示出了經CN1(10mg/kg)處理的小鼠組的每個腫瘤的生長曲線。圖20D示出了經CN1(10mg/kg)+CN401(150mg/kg)處理的小鼠組的每個腫瘤的生長曲線。 Figure 21A shows the antitumor activity of CN401 in combination with CN1 in the B16-F10 melanoma model. Growth curves for each tumor of the vehicle-treated group of mice are shown. Figure 20B shows the growth curve of each tumor in the CN401 (150 mg/kg)-treated group of mice. Figure 20C shows the growth curve of each tumor in the CN1 (10 mg/kg)-treated group of mice. Figure 20D shows the growth curve of each tumor for the group of mice treated with CN1 (10 mg/kg) + CN401 (150 mg/kg).

雖然在本文中已經示出和描述了本發明的多個實施方案，但對本領域技術人員來說，這些實施方案顯然僅以示例的方式提供。在不脫離本發明的情況下，本領域技術人員可想到許多變化、改變和替換。應理解，本文中描述的本發明的實施方案可採用多種替代方案。 While various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Numerous variations, changes and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives may be employed to the embodiments of the invention described herein.

如本說明書和申請專利範圍中所使用的，未用數量詞限定的名詞是指一個/種和/或更多個/種，除非上下文另外明確指出。 As used in this specification and in the scope of the claims, nouns not qualified by a quantifier refer to one/species and/or more/species, unless the context clearly dictates otherwise.

術語“約”或“大約”通常意指在如本領域普通技術人員所確定的特定值的可接受的誤差範圍內，其部分地取決於測量或確定該值的方式，即測量系統的局限性。例如，根據本領域的實踐，“約”可意指在1個或多於1個標準差以內。替代地，“約”可意指給定值的高至20%、高至10%、高至5%、或高至1%的範圍。替代地，尤其相對於生物系統或工藝而言，該術語可意指在值的數量級內，優選在5倍以內，並且更優選在2倍以內。在本申請和請求項中描述特定值的情況下，除非另有說明，應假定術語“約”的含義在特定值的可接受誤差範圍內。 The terms "about" or "approximately" generally mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on the manner in which the value is measured or determined, ie, limitations of the measurement system . For example, "about" may mean within 1 or more than 1 standard deviation, according to the practice in the art. Alternatively, "about" may mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, especially with respect to biological systems or processes, the term may mean within an order of magnitude of the value, preferably within 5-fold, and more preferably within 2-fold. Where particular values are described in this application and claims, unless otherwise stated, the meaning of the term "about" is assumed to be within an acceptable error range for the particular value.

替代方案(例如，“或”)的使用應理解為意指替代方案中的任一個、二者或其任何組合。術語“和/或”應被理解為意指替代方案之一或二者。 The use of alternatives (eg, "or") should be understood to mean either, both, or any combination of the alternatives. The term "and/or" should be understood to mean one or both of the alternatives.

術語“細胞”通常是指生物細胞。細胞可以是活的生物體的基本結構、功能和/或生物學單位。細胞可源自具有一個或更多個細胞的任何生物體。一些非限制性實例包括：原核細胞、真核細胞、細菌細胞、古細菌細胞、單細胞真核生物體的細胞、原生動物細胞、來自植物的細胞(例如來自植物作物、水果、蔬菜、穀物、大豆、玉米、小麥、種子、番茄、稻、木薯、甘蔗、南瓜、乾草、馬鈴薯、棉花、***、菸草、開花植物、針葉樹、裸子植物、蕨類、角苔類、石松(clubmoss)、苔類、蘚類)、藻類細胞(例如布朗葡萄藻(Botryococcus braunii)、萊茵衣藻(Chlamydomonas reinhardtii)、微擬球藻(Nannochloropsis gaditana)、蛋白核小球藻(Chlorella pyrenoidosa)、展枝馬尾藻屬(Sargassum patens C.Agardh)等)、海藻(例如海帶)、真菌細胞(例如酵母細胞、來自蘑菇的細胞)、動物細胞、來自無脊椎動物(例如果蠅、刺胞動物、棘皮動物、線蟲等)的細胞、來自脊椎動物(例如魚、兩棲動物、爬行動物、鳥類、哺乳動物)的細胞、來自哺乳動物(例如，豬、牛、山羊、綿羊、齧齒動物、大鼠、小鼠、非人靈長類、人等)的細胞，等等。有時細胞並非源自天然生物體(例如，細胞可以是合成製造的，有時被稱為人工細胞)。 The term "cell" generally refers to biological cells. A cell can be the basic structural, functional and/or biological unit of a living organism. Cells can be derived from any organism having one or more cells. Some non-limiting examples include: prokaryotic cells, eukaryotic cells, bacterial cells, archaeal cells, cells of unicellular eukaryotic organisms, protozoan cells, cells from plants (eg, from plant crops, fruits, vegetables, grains, Soybeans, corn, wheat, seeds, tomatoes, rice, cassava, sugar cane, squash, hay, potatoes, cotton, hemp, tobacco, flowering plants, conifers, gymnosperms, ferns, hornworts, clubmoss, liverworts , moss), algal cells (eg Botryococcus braunii, Chlamydomonas reinhardtii, Nannochloropsis gaditana, Chlorella pyrenoidosa, Sargassum patens C. Agardh, etc.), seaweed (eg kelp), fungal cells (eg yeast cells, cells from mushrooms), animal cells, from invertebrates (eg Drosophila, cnidaria, echinoderms, nematodes, etc.) Cells, cells from vertebrates (eg, fish, amphibians, reptiles, birds, mammals), cells from mammals (eg, pigs, cows, goats, sheep, rodents, rats, mice, non-human primates) class, human, etc.) cells, etc. Sometimes cells are not derived from natural organisms (eg, cells can be manufactured synthetically, sometimes referred to as artificial cells).

如本文中所用，術語“核苷酸”通常是指堿基-糖-磷酸根組合物。核苷酸可包括合成核苷酸。核苷酸也可包括合成的核苷酸類似物。核苷酸可以是核酸序列的單體單元(例如去氧核糖核酸(deoxyribonucleic acid,DNA)和核糖核酸(ribonucleic acid,RNA))。術語核苷酸可包括三磷酸核糖核苷三磷酸腺苷(adenosine triphosphate,ATP)、三磷酸尿苷(uridine triphosphate,UTP)、三磷酸胞苷(Cytidine triphosphate,CTP)、三磷酸鳥苷(Guanosine triphosphate,GTP)，以及去氧核糖核苷三磷酸，例如dATP、dCTP、dITP(肉苷三磷酸(inosine triphosphate,ITP))、dUTP、dGTP、dTTP(胸腺嘧啶三磷酸(Thymidine triphosphate,TTP))、或其衍生物。這樣的衍生物可包括，例如[αS]dATP、7-脫氮-dGTP和7-脫氮-dATP，以及賦予對含有其的核酸分子的核酸酶抗性的核苷酸衍生物。如 本文中所用，術語核苷酸可以是指雙去氧核糖核苷三磷酸(ddNTP)(核糖核苷三磷酸(Nucleoside triphosphate,NTP))及其衍生物。雙去氧核糖核苷三磷酸的說明性實例可包括但不限於ddATP、ddCTP、ddGTP、ddITP和ddTTP。核苷酸可未經標記或通過公知技術標記為可檢測的。也可用量子點進行標記。可檢測標記可包括例如放射性同位素、螢光標記、化學發光標記、生物發光標記和酶標記。核苷酸的螢光標記可包括但不限於螢光素、5-羧基螢光素(FAM)、2’7’-二甲氧基-4’5-二氯-6-羧基螢光素(JOE)、羅丹明、6-羧基羅丹明(R6G)、N,N,N’,N’-四甲基-6-羧基羅丹明(TAMRA)、6-羧基-X-羅丹明(ROX)、4-(4’二甲氨基苯基偶氮)苯甲酸(DABCYL)、Cascade Blue、Oregon Green、Texas Red、花青和5-(2’-氨基乙基)氨基萘-1-磺酸(EDANS)。經螢光標記的核苷酸的具體實例可包括：可獲自Perkin Elmer,Foster City,Calif的[R6G]dUTP、[TAMRA]dUTP、[R110]dCTP、[R6G]dCTP、[TAMRA]dCTP、[JOE]ddATP、[R6G]ddATP、[FAM]ddCTP、[R110]ddCTP、[TAMRA]ddGTP、[ROX]ddTTP、[dR6G]ddATP、[dR110]ddCTP、[dTAMRA]ddGTP和[dROX]ddTTP，可獲自Amersham,Arlington Heights,Ill.的FluoroLink去氧核苷酸，FluoroLink Cy3-dCTP、FluoroLink Cy5-dCTP、FluoroLink Fluor X-dCTP、FluoroLink Cy3-dUTP和FluoroLink Cy5-dUTP；可獲自Boehringer Mannheim,Indianapolis,Ind.的螢光素-15-dATP、螢光素-12-dUTP、四甲基-羅丹明-6-dUTP、IR770-9-dATP、螢光素-12-ddUTP、螢光素-12-UTP和螢光素-15-2’-dATP；以及染色體標記的核苷酸，可獲自Molecular Probes,Eugene,Oreg.Nucleotides的BODIPY-FL-14-UTP、BODIPY-FL-4-UTP、BODIPY-TMR-14-UTP、BODIPY-TMR-14-dUTP、BODIPY-TR-14-UTP、BODIPY-TR-14-dUTP、Cascade Blue-7-UTP、Cascade Blue-7-dUTP、螢光素-12-UTP、螢光素-12-dUTP、Oregon Green 488-5-dUTP、羅丹明綠-5-UTP、羅丹明綠-5-dUTP、四甲基羅丹明-6-UTP、四甲基羅丹明-6-dUTP、Texas Red-5-UTP、Texas Red-5-dUTP和Texas Red-12-dUTP。核苷酸也可通過化學修飾進行標記或標注。經化學修飾的單核苷酸可以是生物素-dNTP。生物素化dNTP的一些非限制性實例可包括生物素-dATP(例如，bio-N6-ddATP、生物素-14-dATP)、生物素-dCTP(例如，生物素-11-dCTP、生物素-14-dCTP)和生物素-dUTP(例如生物素-11-dUTP、生物 素-16-dUTP、生物素-20-dUTP)。 As used herein, the term "nucleotide" generally refers to a phosphonium-sugar-phosphate composition. Nucleotides can include synthetic nucleotides. Nucleotides can also include synthetic nucleotide analogs. Nucleotides can be monomeric units of nucleic acid sequences (eg, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)). The term nucleotide may include ribonucleoside triphosphate (adenosine triphosphate, ATP), uridine triphosphate (UTP), cytidine triphosphate (CTP), guanosine triphosphate (GTP) ), and deoxyribonucleoside triphosphates such as dATP, dCTP, dITP (inosine triphosphate (ITP)), dUTP, dGTP, dTTP (Thymidine triphosphate (TTP)), or their derivative. Such derivatives may include, for example, [αS]dATP, 7-deaza-dGTP, and 7-deaza-dATP, as well as nucleotide derivatives that confer nuclease resistance to nucleic acid molecules containing them. like As used herein, the term nucleotide may refer to dideoxyribonucleoside triphosphates (ddNTPs) (Nucleoside triphosphates (NTPs)) and derivatives thereof. Illustrative examples of dideoxyribonucleoside triphosphates may include, but are not limited to, ddATP, ddCTP, ddGTP, ddITP, and ddTTP. Nucleotides can be unlabeled or labeled detectable by well-known techniques. Quantum dots can also be used for labeling. Detectable labels can include, for example, radioisotopes, fluorescent labels, chemiluminescent labels, bioluminescent labels, and enzymatic labels. Fluorescent labels for nucleotides may include, but are not limited to, luciferin, 5-carboxyluciferin (FAM), 2'7'-dimethoxy-4'5-dichloro-6-carboxyluciferin ( JOE), rhodamine, 6-carboxyrhodamine (R6G), N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX), 4-(4'-Dimethylaminophenylazo)benzoic acid (DABCYL), Cascade Blue, Oregon Green, Texas Red, cyanine, and 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS) ). Specific examples of fluorescently labeled nucleotides may include: [R6G]dUTP, [TAMRA]dUTP, [R110]dCTP, [R6G]dCTP, [TAMRA]dCTP, available from Perkin Elmer, Foster City, Calif. [JOE]ddATP, [R6G]ddATP, [FAM]ddCTP, [R110]ddCTP, [TAMRA]ddGTP, [ROX]ddTTP, [dR6G]ddATP, [dR110]ddCTP, [dTAMRA]ddGTP and [dROX]ddTTP, FluoroLink deoxynucleotides, FluoroLink Cy3-dCTP, FluoroLink Cy5-dCTP, FluoroLink Fluor X-dCTP, FluoroLink Cy3-dUTP, and FluoroLink Cy5-dUTP, available from Amersham, Arlington Heights, Ill.; available from Boehringer Mannheim, Luciferin-15-dATP, Luciferin-12-dUTP, Tetramethyl-rhodamine-6-dUTP, IR770-9-dATP, Luciferin-12-ddUTP, Luciferin- 12-UTP and luciferin-15-2'-dATP; and chromosomally labeled nucleotides, available from Molecular Probes, Eugene, Oreg. BODIPY-FL-14-UTP, BODIPY-FL-4-UTP from Nucleotides , BODIPY-TMR-14-UTP, BODIPY-TMR-14-dUTP, BODIPY-TR-14-UTP, BODIPY-TR-14-dUTP, Cascade Blue-7-UTP, Cascade Blue-7-dUTP, Luciferin -12-UTP, Luciferin-12-dUTP, Oregon Green 488-5-dUTP, Rhodamine Green-5-UTP, Rhodamine Green-5-dUTP, Tetramethylrhodamine-6-UTP, Tetramethyl Rhodamine-6-dUTP, Texas Red-5-UTP, Texas Red-5-dUTP and Texas Red-12-dUTP. Nucleotides can also be labeled or annotated by chemical modification. The chemically modified mononucleotide can be a biotin-dNTP. Some non-limiting examples of biotinylated dNTPs can include biotin-dATP (eg, bio-N6-ddATP, biotin-14-dATP), biotin-dCTP (eg, biotin-11-dCTP, biotin- 14-dCTP) and biotin-dUTP (e.g. biotin-11-dUTP, biotin biotin-16-dUTP, biotin-20-dUTP).

本文中可互換使用的術語“多核苷酸”、“寡核苷酸”或“核酸”通常是指任何長度的核苷酸的聚合形式，呈單鏈、雙鏈或多鏈形式的去氧核糖核苷酸或核糖核苷酸或其類似物。多核苷酸對於細胞可以是外源的或內源的。多核苷酸可存在於無細胞環境中。多核苷酸可以是基因或其片段。多核苷酸可以是DNA。多核苷酸可以是RNA。多核苷酸可具有任何三維結構，並且可執行任何已知或未知的功能。多核苷酸可包括一種或更多種類似物(例如改變的骨架、糖或核堿基)。如果存在修飾，可在聚合物組裝之前或之後進行核苷酸結構的修飾。類似物的一些非限制性實例包括：5-溴尿嘧啶、肽核酸、異種核酸、嗎啉代、鎖核酸、二醇核酸、蘇糖核酸、雙去氧核苷酸、蟲草素、7-脫氮-GTP、螢光團(例如羅丹明或與糖連接的螢光素)、含硫醇的核苷酸、生物素連接的核苷酸、螢光堿基類似物、CpG島、甲基-7-鳥苷、甲基化核苷酸、肌苷、硫尿苷、假尿苷、二氫尿苷、辮苷和懷俄苷。多核苷酸的非限制性實例包括基因或基因片段的編碼或非編碼區、由連鎖分析限定的基因座、外顯子、內含子、訊息RNA(Messenger RNA,mRNA)、轉移RNA(Transfer RNA,tRNA)、核糖體RNA(ribosomal RNA,rRNA)、短干擾RNA(small interfering RNA,siRNA)、小髮夾RNA(short hairpin RNA,shRNA)、小分子RNA(microRNA,miRNA)、核酶、互補去氧核醣核酸(complementary DNA,cDNA)、重組多核苷酸、支鏈多核苷酸、質粒、載體、任何序列的分離DNA、任何序列的分離RNA、無細胞多核苷酸(包括無細胞DNA(cell-free DNA,cfDNA)和無細胞RNA(cell-free RNA,cfRNA))、核酸探針和引物。核苷酸序列可被非核苷酸組分中斷。 The terms "polynucleotide", "oligonucleotide" or "nucleic acid" as used interchangeably herein generally refer to a polymeric form of nucleotides of any length, deoxyribose in single-, double- or multi-stranded form Nucleotides or ribonucleotides or analogs thereof. The polynucleotide can be exogenous or endogenous to the cell. Polynucleotides can exist in a cell-free environment. A polynucleotide can be a gene or a fragment thereof. The polynucleotide can be DNA. The polynucleotide can be RNA. Polynucleotides can have any three-dimensional structure and perform any known or unknown function. A polynucleotide can include one or more analogs (eg, altered backbone, sugar, or nucleoside groups). Modification of the nucleotide structure, if present, can be performed before or after polymer assembly. Some non-limiting examples of analogs include: 5-bromouracil, peptide nucleic acids, heteronucleic acids, morpholinos, locked nucleic acids, diol nucleic acids, threose nucleic acids, dideoxynucleotides, cordycepin, 7-deoxynucleotides Nitrogen-GTP, fluorophores (e.g. rhodamine or sugar-linked luciferin), thiol-containing nucleotides, biotin-linked nucleotides, fluorophores, CpG islands, methyl- 7-guanosine, methylated nucleotides, inosine, thiouridine, pseudouridine, dihydrouridine, braidin, and wyoside. Non-limiting examples of polynucleotides include coding or noncoding regions of genes or gene fragments, loci defined by linkage analysis, exons, introns, messenger RNAs (mRNAs), transfer RNAs (Transfer RNAs). , tRNA), ribosomal RNA (rRNA), short interfering RNA (small interfering RNA, siRNA), small hairpin RNA (shRNA), small molecule RNA (microRNA, miRNA), ribozyme, complementary Complementary DNA (cDNA), recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, cell-free polynucleotides (including cell-free DNA (cell-free DNA) -free DNA, cfDNA) and cell-free RNA (cell-free RNA, cfRNA), nucleic acid probes and primers. Nucleotide sequences can be interrupted by non-nucleotide components.

本文中可互換使用的術語“肽”、“多肽”或“蛋白質”通常是指通過肽鍵連接的至少兩個氨基酸殘基的聚合物。該術語並不意味著特定長度的聚合物，也不旨在暗示或區分肽是使用重組技術、化學或酶合成產生的，還是天然存在的。該術語適用於天然存在的氨基酸聚合物以及包含至少一個經修飾氨基酸的氨基酸聚合物。在一些情況下，聚合物可被非氨基酸中斷。該術語包括任何長度的氨基酸鏈，包括全長蛋白質和具有或不具有二級和/或三級結構(例如結構域)的蛋白質。該術語還包括已被修飾，例如通過二硫鍵形成、糖 基化、脂化、乙醯化、磷酸化、氧化和任何其他操作(例如與標記組分綴合)的氨基酸聚合物。如本文中所用，術語“氨基酸”通常是指天然和非天然氨基酸，包括但不限於經修飾的氨基酸和氨基酸類似物。經修飾的氨基酸可包括天然氨基酸和非天然氨基酸，其已經被化學修飾以包括氨基酸上不天然存在的基團或化學部分。氨基酸類似物可以是指氨基酸衍生物。術語“氨基酸”包括D-氨基酸和L-氨基酸。 The terms "peptide", "polypeptide" or "protein" as used interchangeably herein generally refer to a polymer of at least two amino acid residues linked by peptide bonds. The term does not imply a specific length of polymer, nor is it intended to imply or distinguish whether a peptide is produced using recombinant techniques, chemical or enzymatic synthesis, or naturally occurring. The term applies to naturally occurring amino acid polymers as well as amino acid polymers comprising at least one modified amino acid. In some cases, polymers can be interrupted by non-amino acids. The term includes amino acid chains of any length, including full-length proteins and proteins with or without secondary and/or tertiary structure (eg, domains). The term also includes sugars that have been modified, for example by disulfide bond formation, Amino acid polymers for sylation, lipidation, acetylation, phosphorylation, oxidation and any other manipulation (eg conjugation to labelling components). As used herein, the term "amino acid" generally refers to natural and unnatural amino acids, including but not limited to modified amino acids and amino acid analogs. Modified amino acids can include natural amino acids and unnatural amino acids that have been chemically modified to include groups or chemical moieties on the amino acid that do not naturally occur. Amino acid analogs may refer to amino acid derivatives. The term "amino acid" includes D-amino acids and L-amino acids.

如本文中所用，當提及多肽時術語“衍生物”、“變體”或“片段”通常是指與野生型多肽在例如氨基酸序列、結構(例如二級和/或三級)、活性(例如酶活性)和/或功能方面相關的多肽。與野生型多肽相比，多肽的衍生物、變體和片段可包含一種或更多種氨基酸變異(例如，突變、***和缺失)、截短、修飾，及其組合。 As used herein, the terms "derivative," "variant," or "fragment" when referring to a polypeptide generally refer to differences in, e.g., amino acid sequence, structure (eg, secondary and/or tertiary), activity ( such as enzymatic activity) and/or functionally related polypeptides. Derivatives, variants, and fragments of polypeptides can contain one or more amino acid variations (eg, mutations, insertions, and deletions), truncations, modifications, and combinations thereof, compared to wild-type polypeptides.

術語“抗體”通常是指具有免疫球蛋白樣功能的蛋白質結合分子。術語抗體包括抗體(例如，單克隆和多克隆抗體)及其衍生物、變體和片段。抗體包括但不限於，不同類別(即IgA、IgG、IgM、IgD和IgE)和亞類(例如IgG1、IgG2等)的免疫球蛋白(Ig)。其衍生物、變體或片段可以是指保留相應抗體的結合特異性(例如，完全和/或部分)的功能性衍生物或片段。抗原結合片段包括Fab、Fab’、F(ab’)2、可變片段(Fv)、單鏈可變片段(scFv)、微抗體、雙抗體和單域抗體(“sdAb”或“奈米抗體”或“camelids”)。術語抗體包括已經被優化、改造或化學綴合的抗體和抗體的抗原結合片段。已經被優化的抗體的實例包括親和力成熟的抗體。已經被改造的抗體的實例包括Fc優化抗體(例如，在片段可結晶區優化的抗體)和多特異性抗體(例如，雙特異性抗體)。 The term "antibody" generally refers to protein-binding molecules with immunoglobulin-like functions. The term antibody includes antibodies (eg, monoclonal and polyclonal antibodies) and derivatives, variants and fragments thereof. Antibodies include, but are not limited to, immunoglobulins (Ig) of different classes (ie, IgA, IgG, IgM, IgD, and IgE) and subclasses (eg, IgGl, IgG2, etc.). Derivatives, variants or fragments thereof may refer to functional derivatives or fragments that retain the binding specificity (eg, full and/or partial) of the corresponding antibody. Antigen-binding fragments include Fab, Fab', F(ab')2, variable fragments (Fv), single chain variable fragments (scFv), minibodies, diabodies and single domain antibodies ("sdAb" or "nanobodies"). ” or “camelids”). The term antibody includes antibodies and antigen-binding fragments of antibodies that have been optimized, engineered, or chemically conjugated. Examples of antibodies that have been optimized include affinity matured antibodies. Examples of antibodies that have been engineered include Fc-optimized antibodies (eg, antibodies optimized in fragment crystallizable regions) and multispecific antibodies (eg, bispecific antibodies).

本文中可互換使用的術語“抗原結合部分”或“抗原結合結構域”通常是指表現出與特定靶抗原優先結合的構建體。抗原結合結構域可以是多肽構建體，例如抗體、其修飾、其片段，或其組合。抗原結合結構域可以是本文中公開的任何抗體或其功能性變體。抗原結合結構域的非限制性實例可包括鼠抗體、人抗體、人源化抗體、駱駝Ig、鯊魚的僅重鏈抗體(VNAR)、Ig NAR、嵌合抗體、重組抗體、或其抗體片段。抗體片段的非限制性實例包括Fab、Fab’、 F(ab)’2、F(ab)’3、Fv、單鏈抗原結合片段(scFv)、(scFv)2、二硫鍵穩定的Fv(dsFv)、微抗體、雙抗體、三抗體、四抗體、單域抗原結合片段(sdAb、奈米抗體)、重組的僅重鏈抗體(VHH)和其他保持完整抗體結合特異性的抗體片段。 The terms "antigen-binding portion" or "antigen-binding domain" as used interchangeably herein generally refer to constructs that exhibit preferential binding to a particular target antigen. The antigen binding domain can be a polypeptide construct, such as an antibody, a modification thereof, a fragment thereof, or a combination thereof. The antigen binding domain can be any antibody disclosed herein or a functional variant thereof. Non-limiting examples of antigen binding domains may include murine antibodies, human antibodies, humanized antibodies, camelid Ig, shark heavy chain only antibody (VNAR), Ig NAR, chimeric antibodies, recombinant antibodies, or antibody fragments thereof. Non-limiting examples of antibody fragments include Fab, Fab', F(ab)'2, F(ab)'3, Fv, single-chain antigen-binding fragment (scFv), (scFv)2, disulfide stabilized Fv (dsFv), minibody, diabody, tribody, tetrabody Antibodies, single domain antigen binding fragments (sdAbs, nanobodies), recombinant heavy chain only antibodies (VHH) and other antibody fragments that retain intact antibody binding specificity.

術語“增強的活性”、“提高的活性”或“上調的活性”通常是指目的部分(例如，多核苷酸或多肽)的活性被修飾到高於正常水平的宿主株(例如宿主細胞)中目的部分活性的水平。正常活性水平可基本上為零(或無)或高於零。目的部分可包含宿主株的多肽構建體。目的部分可以包含引入至宿主株或引入到宿主株中的異源多肽構建體。例如，可將編碼目的多肽的異源基因敲入(KI)至宿主株的基因組以增強宿主株中目的多肽的活性。 The terms "enhanced activity," "enhanced activity," or "upregulated activity" generally refer to a host strain (eg, a host cell) in which the activity of a moiety of interest (eg, a polynucleotide or polypeptide) is modified to higher than normal levels The level of activity of the part of interest. Normal activity levels may be substantially zero (or none) or above zero. The moiety of interest may comprise the polypeptide construct of the host strain. The moiety of interest may comprise a heterologous polypeptide construct introduced into or into a host strain. For example, a heterologous gene encoding a polypeptide of interest can be knocked into (KI) into the genome of a host strain to enhance the activity of the polypeptide of interest in the host strain.

術語“降低的活性”、“減少的活性”或“下調的活性”通常是指目的部分(例如，多核苷酸或多肽)的活性被修飾到低於正常水平的宿主株(例如宿主細胞)中目的部分活性的水平。目的部分可包含宿主株的內源基因或多肽構建體。在一些情況下，目的部分可在宿主株中被敲除或敲低。在一些實例中，目的部分的活性降低可包括宿主菌株中這樣的活性的完全抑制。 The terms "reduced activity," "reduced activity," or "down-regulated activity" generally refer to a host strain (eg, host cell) in which the activity of a moiety of interest (eg, a polynucleotide or polypeptide) is modified to subnormal levels The level of activity of the part of interest. The portion of interest may comprise an endogenous gene or polypeptide construct of the host strain. In some cases, the moiety of interest can be knocked out or knocked down in the host strain. In some examples, reduced activity of the moiety of interest can include complete inhibition of such activity in the host strain.

本文中可互換使用的術語“對象”、“個體”或“患者”通常是指脊椎動物，優選哺乳動物，例如人。哺乳動物包括但不限於鼠、猿、人、農場動物、運動動物和寵物。體內獲得或體外培養的生物實體的組織、細胞及其後代也包括在內。 The terms "subject", "individual" or "patient" as used interchangeably herein generally refer to a vertebrate, preferably a mammal, such as a human. Mammals include, but are not limited to, mice, apes, humans, farm animals, sport animals, and pets. Tissues, cells and progeny of biological entities obtained in vivo or cultured in vitro are also included.

術語“治療”通常是指獲得有益或期望結果，包括但不限於有益的治療結果和/或有益的預防結果的方法。例如，治療可包括施用本文中公開的系統或細胞群。有益的治療結果意指治療中的一種或更多種疾病、病症或症狀的任何治療相關的改善或效果。對於有益的預防結果，可將組合物施用於處於發生特定疾病、病症或症狀的風險的對象，或報告有一種或更多種疾病生理症狀的對象，即使該疾病、病症或症狀可能還未表現出來。 The term "treatment" generally refers to a method of obtaining beneficial or desired results, including but not limited to beneficial therapeutic results and/or beneficial preventive results. For example, treatment can include administration of the systems or cell populations disclosed herein. Beneficial treatment outcome means any treatment-related improvement or effect of one or more diseases, disorders or symptoms under treatment. For beneficial prophylactic outcomes, the compositions can be administered to subjects who are at risk for developing a particular disease, disorder or symptom, or who report one or more physiological symptoms of a disease, even though the disease, disorder or symptom may not have manifested yet come out.

術語“有效量”或“治療有效量”通常是指在施用於有此需要的對象之後足以產生期望活性的組合物，例如本文中公開的組合物(例如，一個 或更多個單位劑量)的量。在本公開內容的上下文中，術語“治療有效”通常是指足以延遲表現、阻止進展、緩解或減輕通過本公開內容的方法治療的疾病的至少一種症狀的組合物的量。 The term "effective amount" or "therapeutically effective amount" generally refers to a composition, such as a composition disclosed herein (eg, a or more unit doses). In the context of the present disclosure, the term "therapeutically effective" generally refers to an amount of the composition sufficient to delay manifestation, arrest progression, alleviate or alleviate at least one symptom of the disease treated by the methods of the present disclosure.

術語“Tenalisib”、“CN401”和“RP6530”在本文中可互換使用。 The terms "Tenalisib", "CN401" and "RP6530" are used interchangeably herein.

本文中提供了包含抗體(例如抗OX40和/或抗PD-1抗體)和PI3K抑制劑的組合物以及使用其治療或預防癌症的方法。還提供了治療方案，其包括施用抗體和PI3K抑制劑。由於與聯合治療相關的協同作用，與單一治療相比，聯合治療可賦予增強的抗腫瘤作用。 Provided herein are compositions comprising an antibody (eg, an anti-OX40 and/or anti-PD-1 antibody) and a PI3K inhibitor and methods of using the same to treat or prevent cancer. Also provided are treatment regimens that include administration of the antibody and a PI3K inhibitor. Combination therapy may confer enhanced antitumor effects compared to monotherapy due to the synergistic effects associated with combination therapy.

本文中提供了包含抗原結合部分的組合物。本文中還提供了用於治療有此需要的對象的方法，包括(a)向對象施用多肽，所述多肽包含表現出對OX40的結合特異性的抗原結合部分。 Provided herein are compositions comprising antigen binding moieties. Also provided herein are methods for treating a subject in need thereof, comprising (a) administering to the subject a polypeptide comprising an antigen-binding portion that exhibits binding specificity for OX40.

OX40是I型跨膜糖蛋白，主要由T細胞表達(組成性地由調節性T表型表達，以及在啟動之後由效應T細胞表達)。OX40誘導具有抗細胞凋亡(Bcl-2、Bcl-xl和Bfl-1)和細胞週期進程(存活蛋白)特性的蛋白質的表達。OX40在直接刺激效應T細胞的同時，抵消對免疫細胞(包括T淋巴細胞CD4+和CD8+、NK細胞和B淋巴細胞)的抑制。 OX40 is a type I transmembrane glycoprotein expressed primarily by T cells (constitutively by the regulatory T phenotype, and after priming by effector T cells). OX40 induces the expression of proteins with anti-apoptotic (Bcl-2, Bcl-xl and Bfl-1) and cell cycle progression (survivin) properties. OX40 counteracts the suppression of immune cells, including T lymphocytes CD4+ and CD8+, NK cells and B lymphocytes, while directly stimulating effector T cells.

考慮到使用共刺激受體作為用於增強針對腫瘤的免疫應答的靶向治療的生物學原理並且基於體外結果，已經開發了許多刺激OX40信號傳導的藥物。OX40信號傳導可由OX40特異性激動性抗體、OX40L-Fc融合蛋白、用OX40L mRNA轉染DC和經改造得以在表面表達OX40L的腫瘤細胞，及其任何組合觸發。 Considering the biological rationale for the use of costimulatory receptors as targeted therapy for enhancing immune responses against tumors and based on in vitro results, a number of drugs that stimulate OX40 signaling have been developed. OX40 signaling can be triggered by OX40-specific agonistic antibodies, OX40L-Fc fusion proteins, DCs transfected with OX40L mRNA, and tumor cells engineered to express OX40L on their surface, and any combination thereof.

在一個方面，本文中提供了結合OX40或其片段的抗原結合部分。在一個方面，本文中提供的抗原結合部分包括抗體或其中的功能性片段。抗體可包括多克隆抗體、單克隆抗體、嵌合抗體、人源化和靈長類化抗體、CDR移植抗體、人抗體、重組產生的抗體、胞內抗體、多特異性抗體、雙特異性抗體、單價抗體、多價抗體、抗獨特型抗體、合成抗體(包括突變蛋白及其變體)，及 其衍生物(包括Fc融合和其他修飾)，以及任何其他免疫反應性分子，只要其表現出與OX40蛋白的優先締合或結合。此外，除非上下文限制另有規定，否則該術語還包括所有類別的抗體(即IgA、IgD、IgE、IgG和IgM)和所有亞類(即IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)。在一個優選的實施方案中，抗體是單克隆抗體。在一個更優選的實施方案中，抗體是人單克隆抗體。在一個更優選的實施方案中，抗體是人抗OX40單克隆抗體。 In one aspect, provided herein are antigen binding moieties that bind OX40 or a fragment thereof. In one aspect, the antigen-binding portions provided herein include antibodies or functional fragments thereof. Antibodies can include polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized and primatized antibodies, CDR-grafted antibodies, human antibodies, recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies , monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies (including muteins and their variants), and Derivatives thereof (including Fc fusions and other modifications), and any other immunoreactive molecule so long as it exhibits preferential association or binding with the OX40 protein. In addition, unless contextual limitations dictate otherwise, the term also includes all classes of antibodies (i.e., IgA, IgD, IgE, IgG, and IgM) and all subclasses (i.e., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). In a preferred embodiment, the antibody is a monoclonal antibody. In a more preferred embodiment, the antibody is a human monoclonal antibody. In a more preferred embodiment, the antibody is a human anti-OX40 monoclonal antibody.

在一個方面，本文中提供的抗原結合部分包括抗OX40單克隆抗體。在一個實施方案中，示例性多肽、抗原結合部分及其組合可來源於：WO2019214624、US7960515、US9695246、US9475880、US9040048，以及從其改造的序列，所有這些通過引用併入本文。 In one aspect, the antigen binding moieties provided herein comprise anti-OX40 monoclonal antibodies. In one embodiment, exemplary polypeptides, antigen-binding portions, and combinations thereof can be derived from: WO2019214624, US7960515, US9695246, US9475880, US9040048, and sequences engineered therefrom, all of which are incorporated herein by reference.

表1和表2中提供了合適的抗原結合部分及其功能性片段。表3中提供了編碼表1和表2的抗原結合部分及其功能性片段的多核苷酸。在一個實施方案中，抗原結合部分包含與表1的CDR序列或表2的可變多肽序列具有至少約70%、72%、74%、76%、78%、80%、82%、84%、86%、88%、90%、92%、94%、96%、98%或高至約100%的序列同一性。在一個實施方案中，抗原結合部分由包含與表3的序列具有至少約70%、72%、74%、76%、78%、80%、82%、84%、86%、88%、90%、92%、94%、96%、98%或高至約100%的序列同一性的多核苷酸序列編碼。 Suitable antigen binding moieties and functional fragments thereof are provided in Tables 1 and 2 . Polynucleotides encoding the antigen-binding portions of Tables 1 and 2 and functional fragments thereof are provided in Table 3 . In one embodiment, the antigen binding portion comprises at least about 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84% of the CDR sequences of Table 1 or the variable polypeptide sequences of Table 2 , 86%, 88%, 90%, 92%, 94%, 96%, 98% or up to about 100% sequence identity. In one embodiment, the antigen-binding portion consists of a sequence comprising at least about 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90% of the sequences of Table 3 . %, 92%, 94%, 96%, 98%, or up to about 100% sequence identity encodes a polynucleotide sequence.

在一個實施方案中，抗原結合部分包含選自(i)至(iii)的至少一個重鏈CDR(CDRH)和選自(iv)至(vi)的至少一個輕鏈CDR(CDRL)，其中：(i)CDRH1，其與選自SEQ ID NO：1、7、13、15、21和27的序列具有至少80%的序列同一性；(ii)CDRH2，其與選自SEQ ID NO：3、9、17、23和29的序列具有至少80%的序列同一性；(iii)CDRH3，其與選自SEQ ID NO：5、11、19、25和31的序列具有至少80%的序列同一性；(iv)CDRL1，其與選自SEQ ID NO：2、8、14、16、22和28的序列具有至少80%的序列同一性；(v)CDRL2，其與選自SEQ ID NO：4、10、18、24和30的序列具有至少80%的序列同一性；和(vi)CDRL3，其與選自SEQ ID NO：6、12、20、26和32的序列具有至少80%的序列同一性。 In one embodiment, the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from (i) to (iii) and at least one light chain CDR (CDRL) selected from (iv) to (vi), wherein: (i) CDRH1 having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) CDRH2 with a sequence selected from the group consisting of SEQ ID NO: 3, The sequences of 9, 17, 23 and 29 have at least 80% sequence identity; (iii) CDRH3 which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31 (iv) CDRL1 having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NO: 2, 8, 14, 16, 22 and 28; (v) CDRL2 with a sequence selected from the group consisting of SEQ ID NO: 4 , 10, 18, 24 and 30 have at least 80% sequence identity; and (vi) CDRL3, which has at least 80% sequence with a sequence selected from SEQ ID NOs: 6, 12, 20, 26 and 32 identity.

表1：全人抗OX40單克隆抗體的CDR氨基酸序列。分別指定為“1.62.3-u1-IgG1K”、“1.62.3-u1-3-IgG1K”、“1.7.10-u1-IgG1K”、“1.134.9-u1-IgG1L”、“1.186.19-u1-IgG1K”和“1.214.23-u1-IgG1K”。

Figure 110142111-A0202-12-0020-38
Table 1 : CDR amino acid sequences of fully human anti-OX40 monoclonal antibodies. Designated as "1.62.3-u1-IgG1K", "1.62.3-u1-3-IgG1K", "1.7.10-u1-IgG1K", "1.134.9-u1-IgG1L", "1.186.19- u1-IgG1K" and "1.214.23-u1-IgG1K".
Figure 110142111-A0202-12-0020-38

Figure 110142111-A0202-12-0021-2
Figure 110142111-A0202-12-0021-2

在一個方面，本文中提供的抗原結合部分包括抗OX40單克隆抗體，其包含選自表2中的多肽或其任何組合的可變區序列。 In one aspect, the antigen binding moieties provided herein comprise anti-OX40 monoclonal antibodies comprising variable region sequences selected from the polypeptides in Table 2 or any combination thereof.

在一個實施方案中，本文中提供的抗原結合部分包含(1)重鏈可變區(VH)，其與選自SEQ ID NO：33、35、37、39、41和43的序列具有至少70%、72%、74%、76%、78%、80%、82%、84%、86%、88%、90%、92%、94%、96%、98%或高達約100%的序列同一性；和/或(2)輕鏈可變區(VL)，其與選自SEQ ID NO：34、36、38、40、42和44的序列具有至少70%、72%、74%、76%、78%、80%、82%、84%、86%、88%、90%、92%、94%、96%、98%或高達約100%的序列同一性。在一個實施方案中，抗原結合部分包含(1)VH，其與SEQ ID NO：39具有至少70%、72%、74%、76%、78%、80%、82%、84%、86%、88%、90%、92%、94%、96%、98%或高達約100%的序列同一性； 和(2)VL，其與SEQ ID NO：40具有至少70%、72%、74%、76%、78%、80%、82%、84%、86%、88%、90%、92%、94%、96%、98%或高達約100%的序列同一性。 In one embodiment, the antigen binding moieties provided herein comprise (1) a heavy chain variable region (VH) having at least 70 nucleotides with a sequence selected from the group consisting of SEQ ID NOs: 33, 35, 37, 39, 41 and 43 %, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98% or up to about 100% of the sequence identity; and/or (2) a light chain variable region (VL) having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98% or up to about 100% sequence identity. In one embodiment, the antigen binding portion comprises (1) a VH having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86% of SEQ ID NO:39 , 88%, 90%, 92%, 94%, 96%, 98% or up to about 100% sequence identity; and (2) VL having at least 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92% of SEQ ID NO: 40 , 94%, 96%, 98% or up to about 100% sequence identity.

表2：全人抗OX40單克隆抗體的可變區氨基酸序列。分別指定為“1.62.3-u1-IgG1K”、“1.62.3-u1-3-IgG1K”、“1.7.10-u1-IgG1K”、“1.134.9-u1-IgG1L”、“1.186.19-u1-IgG1K”和“1.214.23-u1-IgG1K”。

Figure 110142111-A0202-12-0022-39
Table 2 : Variable region amino acid sequences of fully human anti-OX40 monoclonal antibodies. Designated as "1.62.3-u1-IgG1K", "1.62.3-u1-3-IgG1K", "1.7.10-u1-IgG1K", "1.134.9-u1-IgG1L", "1.186.19- u1-IgG1K" and "1.214.23-u1-IgG1K".
Figure 110142111-A0202-12-0022-39

Figure 110142111-A0202-12-0023-4
Figure 110142111-A0202-12-0023-4

在一些方面，本公開內容涉及分離的核酸分子，其包含編碼如本 文中公開的抗原結合部分的重鏈可變區和/或輕鏈可變區的核酸序列。示例性分離的核酸分子在表3中提供。 In some aspects, the present disclosure relates to isolated nucleic acid molecules comprising nucleic acid sequences encoding heavy chain variable regions and/or light chain variable regions of antigen binding moieties as disclosed herein. Exemplary isolated nucleic acid molecules are provided in Table 3 .

表3：全人抗OX40單克隆抗體的可變區核苷酸序列。分別指定為“1.62.3-u1-IgG1K”、“1.62.3-u1-3-IgG1K”、“1.7.10-u1-IgG1K”、“1.134.9-u1-IgG1L”、“1.186.19-u1-IgG1K”和“1.214.23-u1-IgG1K”。

Figure 110142111-A0202-12-0024-40
Table 3 : Variable region nucleotide sequences of fully human anti-OX40 monoclonal antibodies. Designated as "1.62.3-u1-IgG1K", "1.62.3-u1-3-IgG1K", "1.7.10-u1-IgG1K", "1.134.9-u1-IgG1L", "1.186.19- u1-IgG1K" and "1.214.23-u1-IgG1K".
Figure 110142111-A0202-12-0024-40

Figure 110142111-A0202-12-0025-6
Figure 110142111-A0202-12-0025-6

Figure 110142111-A0202-12-0026-7
Figure 110142111-A0202-12-0026-7

Figure 110142111-A0202-12-0027-8
Figure 110142111-A0202-12-0027-8

Figure 110142111-A0202-12-0028-9
Figure 110142111-A0202-12-0028-9

可使用標準分子生物學技術獲得本公開內容的核酸。對於由雜交瘤(例如，如下文進一步所述的由攜帶人免疫球蛋白基因的轉基因小鼠製備的雜交瘤)表達的抗體，可通過標準(聚合脢連鎖反應polymerase chain reaction,PCR)擴增或cDNA克隆技術獲得編碼由雜交瘤製備的抗體的輕鏈和重鏈的cDNA。對於從免疫球蛋白基因文庫(例如，使用噬菌體展示技術)獲得的抗體，可從基因文庫中回收編碼這樣的抗體的核酸。通過將編碼VH的核酸與編碼重鏈恒定區(CH1、CH2和CH3)的另一個DNA分子可操作地連接，可將編碼VH區的分離核酸轉化為全長重鏈基因。人重鏈恒定區基因的序列是本領域已知的(參見例如Kabat et al.(1991)，同上)，並且可通過標準PCR擴增獲得包含這些區域的DNA片段。重鏈恒定區可以是IgG1、IgG2、IgG3、IgG4、IgA、IgE、IgM或IgD恒定區，但更優選為IgG1或IgG4恒定區。通過將編碼VL的DNA與編碼輕鏈恒定區CL的另一個DNA分子可操作地連接，可將編碼VL區的分離核酸轉化為全長輕鏈基因(以及Fab輕鏈基因)。人輕鏈恒定區基因的序列是本領域已知的(參見例如Kabat et al.，同上)，並且可通過標準PCR擴增獲得包含這些區域的DNA片段。在一些優選的實施方案中，輕鏈恒定區可以是κ或λ恒定區。 Nucleic acids of the present disclosure can be obtained using standard molecular biology techniques. For antibodies expressed by hybridomas (eg, hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below), either by standard (polymerase chain reaction, PCR) amplification or cDNA cloning techniques to obtain cDNAs encoding the light and heavy chains of antibodies produced by hybridomas. For antibodies obtained from immunoglobulin gene libraries (eg, using phage display techniques), nucleic acids encoding such antibodies can be recovered from the gene library. An isolated nucleic acid encoding a VH region can be converted to a full-length heavy chain gene by operably linking the VH-encoding nucleic acid to another DNA molecule encoding the heavy chain constant regions (CH1, CH2, and CH3). The sequences of human heavy chain constant region genes are known in the art (see, eg, Kabat et al. (1991), supra), and DNA fragments containing these regions can be obtained by standard PCR amplification. The heavy chain constant region may be an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but is more preferably an IgGl or IgG4 constant region. An isolated nucleic acid encoding a VL region can be converted into a full-length light chain gene (as well as a Fab light chain gene) by operably linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL. The sequences of human light chain constant region genes are known in the art (see, eg, Kabat et al., supra), and DNA fragments containing these regions can be obtained by standard PCR amplification. In some preferred embodiments, the light chain constant region may be a kappa or lambda constant region.

一旦獲得編碼VH和VL區段的DNA片段，這些DNA片段可以通過標準重組DNA技術進行進一步操作，例如將可變區基因轉化為全長抗體鏈基因、Fab片段基因或scFv基因。在這些操作中，編碼VL或VH的DNA片段與編碼另一蛋白質(例如抗體恒定區或柔性接頭)的另一個DNA片段可操作地連接。在上下文中使用的術語“可操作地連接”旨在意指連接兩個DNA片段使得由兩個DNA片段編碼的氨基酸序列保留在讀框內。 Once DNA fragments encoding the VH and VL segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, such as conversion of variable region genes into full-length antibody chain genes, Fab fragment genes or scFv genes. In these manipulations, a DNA fragment encoding VL or VH is operably linked to another DNA fragment encoding another protein (eg, an antibody constant region or flexible linker). The term "operably linked" as used in this context is intended to mean that two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in frame.

基於以下觀察，認為PI3K是癌症治療的關鍵治療靶標之一：PI3K信號傳導的過度活躍與人腫瘤進展、提高的腫瘤微血管密度和增強的癌細胞的 趨化性和侵襲潛力顯著相關。認為PI3K信號傳導途徑在多種人癌症中失調，使其成為有吸引力的靶標。激酶的突變和/或PTEN的表達降低導致腫瘤轉化，這突出了其在人致癌中的中心作用。PI3K途徑通過多種機制失調，包括腫瘤抑制因數PTEN的喪失或失活、PI3K的突變或擴增，以及酪氨酸激酶生長因數受體或PI3K上游癌基因的啟動。 PI3K is considered one of the key therapeutic targets for cancer therapy based on the observation that hyperactivity of PI3K signaling is associated with human tumor progression, increased tumor microvessel density and enhanced cancer cell proliferation Chemotaxis and invasive potential were significantly correlated. The PI3K signaling pathway is thought to be dysregulated in a variety of human cancers, making it an attractive target. Mutation of the kinase and/or decreased expression of PTEN leads to tumor transformation, highlighting its central role in human carcinogenesis. The PI3K pathway is dysregulated through multiple mechanisms, including loss or inactivation of the tumor suppressor PTEN, mutation or amplification of PI3K, and activation of tyrosine kinase growth factor receptors or oncogenes upstream of PI3K.

本文中提供了包含針對磷酸肌醇3-激酶(PI3K)的抑制劑的組合物。所提供的抑制劑可以是PI3K的直接或間接抑制劑。在一個方面，所提供的抑制劑可直接靶向PI3K途徑中的任何數量的因數。在另一方面，所提供的抑制劑可間接靶向PI3K途徑中的因數。在本公開內容的一些實施方案中，抑制劑可靶向與PI3K信號傳導中涉及的畸變相關的因數，如本文中進一步所述。 Provided herein are compositions comprising inhibitors against phosphoinositide 3-kinase (PI3K). The provided inhibitor can be a direct or indirect inhibitor of PI3K. In one aspect, provided inhibitors can directly target any number of factors in the PI3K pathway. In another aspect, provided inhibitors can indirectly target factors in the PI3K pathway. In some embodiments of the present disclosure, inhibitors may target factors associated with aberrations involved in PI3K signaling, as described further herein.

PI3K是一組質膜相關脂質激酶，包含三個亞基：p85調節亞基、p55調節亞基和p110催化亞基。根據其結構和特定底物的不同，PI3K分為3類：I類、II類和III類。I類PI3K由IA類和IB類PI3K組成。IA類PI3K是p58調節亞基和p110催化亞基的異二聚體，是與人癌症最明顯相關的類型。IA類PI3K包含由不同基因(分別為PIK3CA、PIK3CB和PIK3CD)產生的p110α、p110β和p110δ催化亞基，而由PIK3CG產生的p110γ代表IB類PI3K中唯一的催化亞基。p85調節亞基由p85a(p85a、p55a和p50a剪接變體)、p85b和p55g組成，分別由基因PIK3R1、PIK3R2和PIK3R3編碼。作為p110啟動和下游分子的整合點，p85調節亞基結合並整合來自多種跨膜和胞內蛋白，包括酪氨酸激酶相關受體、蛋白激酶C(Protein kinase C,PKC)、含Src同源2結構域的蛋白酪氨酸磷酸酶1(SH2-containing protein tyrosine phos-phatase 1,SHP1)、Rac、Rho、激素受體、Src以及突變Ras的信號。 PI3Ks are a group of plasma membrane-associated lipid kinases that contain three subunits: the p85 regulatory subunit, the p55 regulatory subunit, and the p110 catalytic subunit. Depending on their structure and specific substrates, PI3Ks are divided into three classes: class I, class II, and class III. Class I PI3Ks consist of class IA and class IB PI3Ks. Class IA PI3Ks are heterodimers of the p58 regulatory subunit and the p110 catalytic subunit and are the type most clearly associated with human cancer. Class IA PI3Ks contain p110α, p110β and p110δ catalytic subunits produced by different genes (PIK3CA, PIK3CB and PIK3CD, respectively), while p110γ produced by PIK3CG represents the only catalytic subunit in class IB PI3Ks. The p85 regulatory subunit consists of p85a (p85a, p55a and p50a splice variants), p85b and p55g, encoded by the genes PIK3R1, PIK3R2 and PIK3R3, respectively. As an integration point for the initiation and downstream molecules of p110, the p85 regulatory subunit binds and integrates proteins from a variety of transmembrane and intracellular proteins, including tyrosine kinase-related receptors, protein kinase C (PKC), Src-containing homology Signals of 2-domain protein tyrosine phosphatase 1 (SH2-containing protein tyrosine phos-phatase 1, SHP1), Rac, Rho, hormone receptors, Src, and mutant Ras.

在一個方面，所提供的PI3K抑制劑是：PI3K/mTOR抑制劑、泛PI3K抑制劑、同種型特異性抑制劑，或其任何組合。 In one aspect, the provided PI3K inhibitor is: a PI3K/mTOR inhibitor, a pan-PI3K inhibitor, an isoform-specific inhibitor, or any combination thereof.

在一個方面，PI3K抑制劑是雙重PI3K/mTOR抑制劑。示例性雙重PI3K/mTOR抑制劑選自：BGT-226、DS-7423、PF-04691502、PKI-179、GSK458/Omipalisib、P7170、SB2343/VS-5584、BEZ235/Dactolisib、GDC-0084、GDC-0980/Apitolisib、LY3023414、PQR309/Bimiralisib、XL765/Voxtalisib、 SF-1126、PF-05212384/gedatolisib/PKI-587，或其組合。 In one aspect, the PI3K inhibitor is a dual PI3K/mTOR inhibitor. Exemplary dual PI3K/mTOR inhibitors are selected from: BGT-226, DS-7423, PF-04691502, PKI-179, GSK458/Omipalisib, P7170, SB2343/VS-5584, BEZ235/Dactolisib, GDC-0084, GDC-0980 /Apitolisib, LY3023414, PQR309/Bimiralisib, XL765/Voxtalisib, SF-1126, PF-05212384/gedatolisib/PKI-587, or a combination thereof.

在一個方面，PI3K抑制劑是泛-PI3K抑制劑。示例性泛PI3K抑制劑選自：GDC-0941/Pictilisib、PX-866、TG100-115、CH5132799、XL147/Pilaralisib、ZSTK474、BKM-120/Buparlisib、BAY80-6946/Copanlisib、WX-037、AZD8186、KA2237、CAL-120、ME401、AMG319、GSK2636771、INCB050465、INK-1117、TGR-1202、RP6530、GDC-0032、BYL719、IPI-145、CAL-101，或其組合。 In one aspect, the PI3K inhibitor is a pan-PI3K inhibitor. Exemplary pan-PI3K inhibitors are selected from: GDC-0941/Pictilisib, PX-866, TG100-115, CH5132799, XL147/Pilaralisib, ZSTK474, BKM-120/Buparlisib, BAY80-6946/Copanlisib, WX-037, AZD8186, KA2237 , CAL-120, ME401, AMG319, GSK2636771, INCB050465, INK-1117, TGR-1202, RP6530, GDC-0032, BYL719, IPI-145, CAL-101, or a combination thereof.

在一個方面，PI3K抑制劑是同種型特異性抑制劑。示例性同種型特異性抑制劑選自：AZD8835 δ/α、WX-037 α、AZD8186 β/δ、KA2237 β/δ、GS-9820/CAL-120 β/δ、ME401/PWT-143 δ、AMG 319 δ、GSK2636771 β、INCB050465/Parsaclisib δ、Serabelisib/INK-1117 α、Umbralisib/TGR-1202 δ、RP6530/Tenalisib δ/γ、GDC-0032/Taselisib α/δ/γ(Taselisib)、BYL719/Alpelisib α、Duvelisib/IPI-145 δ/γ、CAL-101/idelalisib δ，或其組合。在一個實施方案中，PI3K抑制劑是同種型特異性抑制劑。在一個實施方案中，PI3K抑制劑是同種型特異性抑制劑並且是Taselisib。 In one aspect, the PI3K inhibitor is an isoform-specific inhibitor. Exemplary isoform-specific inhibitors are selected from the group consisting of: AZD8835 delta/alpha, WX-037 alpha, AZD8186 beta/delta, KA2237 beta/delta, GS-9820/CAL-120 beta/delta, ME401/PWT-143 delta, AMG 319 delta, GSK2636771 beta, INCB050465/Parsaclisib delta, Serabelisib/INK-1117 alpha, Umbralisib/TGR-1202 delta, RP6530/Tenalisib delta/gamma, GDC-0032/Taselisib alpha/delta/gamma(Taselisib), BYL719/Alpelisib alpha , Duvelisib/IPI-145 delta/gamma, CAL-101/idelalisib delta, or a combination thereof. In one embodiment, the PI3K inhibitor is an isoform-specific inhibitor. In one embodiment, the PI3K inhibitor is an isoform-specific inhibitor and is Taselisib.

其他合適的PI3K抑制劑包括但不限於：CUDC-907/Fimepinostat和Rigosertib/ON-01910。 Other suitable PI3K inhibitors include, but are not limited to: CUDC-907/Fimepinostat and Rigosertib/ON-01910.

在一個實施方案中，PI3K抑制劑是針對選自以下的一個或更多個成員：I類催化性PI3K(例如，PI3Kα、PI3Kβ、PI3Kδ、PI3Kγ)、I類調節性PI3K(例如，PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、PIK3R6)、II類PI3K(例如，PIK3C2A、PIK3C2B、PIK3C2G)和III類PI3K(例如，PIK3C3)。在一些情況下，PI3K抑制劑可針對選自以下的一個或更多個成員：PI3Kα、PI3Kβ、PI3Kδ和PI3Kγ。在一些情況下，PI3K抑制劑可針對選自以下的一個或更多個成員：PI3Kδ和PI3Kγ。在一些實例中，PI3K抑制劑可同時針對PI3Kδ和PI3Kγ。 In one embodiment, the PI3K inhibitor is against one or more members selected from class I catalytic PI3Ks (eg, PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ), class I regulatory PI3Ks (eg, PIK3R1, PIK3R2 , PIK3R3, PIK3R4, PIK3R5, PIK3R6), class II PI3Ks (eg, PIK3C2A, PIK3C2B, PIK3C2G), and class III PI3Ks (eg, PIK3C3). In some cases, the PI3K inhibitor can be directed against one or more members selected from the group consisting of PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. In some cases, the PI3K inhibitor can be directed against one or more members selected from the group consisting of PI3Kδ and PI3Kγ. In some examples, a PI3K inhibitor can target both PI3Kδ and PI3Kγ.

在一個實施方案中，PI3K抑制劑選自：渥曼青黴素、LY294002、hibiscone C、Idelalisib、Copanlisib、Duvelisib、Alpelisib、Taselisib、Perifosine、Buparlisib、Umbralisib、PX-866、Dactolisib、CUDC-907、Voxtalisib、CUDC-907、 ME-401、IPI-549、SF1126、Tenalisib(RP6530)、INK1117、pictilisib、XL147、Palomid 529、GSK1059615、ZSTK474、PWT33597、IC87114、TG100-115、CAL263、RP6503、PI-103、GNE-477和AEZS-136。在一個實施方案中，PI3K抑制劑選自：Idelalisib、Copanlisib、Duvelisib、Alpelisib、Taselisib、Perifosine、Buparlisib、Umbralisib和Tenalisib。在一個實施方案中，PI3K抑制劑包含Tenalisib。 In one embodiment, the PI3K inhibitor is selected from the group consisting of: Wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, CUDC -907, ME-401, IPI-549, SF1126, Tenalisib(RP6530), INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, RP6503, PI-103, GNE-477 and AEZS- 136. In one embodiment, the PI3K inhibitor is selected from the group consisting of: Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib and Tenalisib. In one embodiment, the PI3K inhibitor comprises Tenalisib.

在另一個方面，提供了通過PI3K途徑間接靶向病理信號傳導的抑制劑。除PI3K途徑成員的自身異常外，通過該途徑的病理信號傳導還可以以其他方式發生，包括酪氨酸激酶生長因數受體(例如人表皮生長因數受體2和胰島素樣生長因數-1受體)、細胞黏附分子(例如整合素、G蛋白偶聯受體G Protein-Coupled Receptors,GPCR)和癌基因(例如RAS)，所有這些都可被靶向，以解決異常的PI3K信號傳導。 In another aspect, inhibitors are provided that indirectly target pathological signaling through the PI3K pathway. In addition to the intrinsic abnormalities of PI3K pathway members, pathological signaling through this pathway can occur in other ways, including tyrosine kinase growth factor receptors such as human epidermal growth factor receptor 2 and insulin-like growth factor-1 receptors ), cell adhesion molecules (eg, integrins, G Protein-Coupled Receptors, GPCRs), and oncogenes (eg, RAS), all of which can be targeted to address aberrant PI3K signaling.

在一個方面，本文中提供的包含抗原結合部分和抑制劑的組合物可用於治療和預防疾病。所提供的組合物可用於聯合治療以對抗癌症並降低和/或消除對免疫治療的原發性和/或繼發性抗性。 In one aspect, the compositions provided herein comprising an antigen binding moiety and an inhibitor can be used to treat and prevent disease. The provided compositions can be used in combination therapy to combat cancer and reduce and/or eliminate primary and/or secondary resistance to immunotherapy.

在一個方面，用於治療有此需要的對象的方法包括：(a)向對象施用包含表現出對OX40的結合特異性的抗原結合部分的多肽。在一個實施方案中，抗原結合部分包含選自(i)至(iii)的至少一個重鏈CDR(CDRH)和選自(iv)至(vi)的至少一個輕鏈CDR(CDRL)，其中：(i)CDRH1，其與選自SEQ ID NO：1、7、13、15、21和27的序列具有至少80%的序列同一性；(ii)CDRH2，其與選自SEQ ID NO：3、9、17、23和29的序列具有至少80%的序列同一性；(iii)CDRH3，其與選自SEQ ID NO：5、11、19、25和31的序列具有至少80%的序列同一性；(iv)CDRL1，其與選自SEQ ID NO：2、8、14、16、22和28的序列具有至少80%的序列同一性；(v)CDRL2，其與選自SEQ ID NO：4、10、18、24和30的序列具有至少80%的序列同一性；和(vi)CDRL3，其與選自SEQ ID NO：6、12、20、26和32的序列具有至少80%的序列同一性；以及(b)向對象施用針對PI3K的抑制劑。 In one aspect, a method for treating a subject in need thereof comprises: (a) administering to the subject a polypeptide comprising an antigen-binding portion that exhibits binding specificity for OX40. In one embodiment, the antigen binding moiety comprises at least one heavy chain CDR (CDRH) selected from (i) to (iii) and at least one light chain CDR (CDRL) selected from (iv) to (vi), wherein: (i) CDRH1 having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 1, 7, 13, 15, 21 and 27; (ii) CDRH2 with a sequence selected from the group consisting of SEQ ID NO: 3, The sequences of 9, 17, 23 and 29 have at least 80% sequence identity; (iii) CDRH3 which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 5, 11, 19, 25 and 31 (iv) CDRL1 having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NO: 2, 8, 14, 16, 22 and 28; (v) CDRL2 with a sequence selected from the group consisting of SEQ ID NO: 4 , 10, 18, 24 and 30 have at least 80% sequence identity; and (vi) CDRL3, which has at least 80% sequence with a sequence selected from SEQ ID NOs: 6, 12, 20, 26 and 32 identity; and (b) administering to the subject an inhibitor against PI3K.

在一個方面，所述方法包括治療有此需要的對象，其包括：(a) 向對象施用包含表現出對OX40的結合特異性的抗原結合部分的多肽；(b)向對象施用針對PI3K的抑制劑。在一個實施方案中，抑制劑是PI3K/mTOR抑制劑、泛PI3K抑制劑、同種型特異性抑制劑，或其任何組合。在一個實施方案中，抑制劑是同種型特異性抑制劑。在一個實施方案中，抑制劑包含選自以下的一個或更多個成員：渥曼青黴素、LY294002、hibiscone C、Idelalisib、Copanlisib、Duvelisib、Alpelisib、Taselisib、Perifosine、Buparlisib、Umbralisib、PX-866、Dactolisib、CUDC-907、Voxtalisib、CUDC-907、ME-401、IPI-549、SF1126、RP6530、INK1117、pictilisib、XL147、Palomid 529、GSK1059615、ZSTK474、PWT33597、IC87114、TG100-115、CAL263、RP6503、PI-103、GNE-477和AEZS-136。在一個實施方案中，抑制劑包含選自以下的一個或更多個成員：Idelalisib、Copanlisib、Duvelisib、Alpelisib、Taselisib、Perifosine、Buparlisib和Umbralisib。在一個方面，抑制劑包含Tenalisib。 In one aspect, the method comprises treating a subject in need thereof, comprising: (a) administering to the subject a polypeptide comprising an antigen-binding portion that exhibits binding specificity for OX40; (b) administering to the subject an inhibitor against PI3K. In one embodiment, the inhibitor is a PI3K/mTOR inhibitor, a pan-PI3K inhibitor, an isoform-specific inhibitor, or any combination thereof. In one embodiment, the inhibitor is an isoform-specific inhibitor. In one embodiment, the inhibitor comprises one or more members selected from wortmannin, LY294002, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib , CUDC-907, Voxtalisib, CUDC-907, ME-401, IPI-549, SF1126, RP6530, INK1117, pictilisib, XL147, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, RP6503, PI- 103, GNE-477 and AEZS-136. In one embodiment, the inhibitor comprises one or more members selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib and Umbralisib. In one aspect, the inhibitor comprises Tenalisib.

在一個方面，多肽和針對PI3K的抑制劑的施用協同產生選自以下的一種或更多種特徵：(A)與多肽或針對PI3K的抑制劑相比，針對患病細胞的毒性程度更大；(B)與多肽或針對PI3K的抑制劑相比，腫瘤尺寸降低。在一個實施方案中，多肽和針對PI3K的抑制劑的施用協同產生選自以下的一種或更多種特徵：(A)與多肽或針對PI3K的抑制劑相比，針對患病細胞的毒性程度增加至少約20%、至少約40%、至少約60%、至少約80%、至少約100%或至少約200%；和/或(B)與多肽或針對PI3K的抑制劑相比，腫瘤尺寸降低至少約10%、至少約20%、至少約30%、至少約40%、至少約50%或至少約60%。在一個實施方案中，腫瘤尺寸的降低可以是至少約或至多約：1倍、5倍、10倍、15倍、20倍、40倍、60倍、80倍、100倍、或高至約200倍。在一個實施方案中，腫瘤尺寸的降低是腫瘤的消除。 In one aspect, the administration of the polypeptide and the inhibitor against PI3K synergistically produces one or more characteristics selected from: (A) a greater degree of toxicity against diseased cells than the polypeptide or inhibitor against PI3K; (B) Reduced tumor size compared to polypeptides or inhibitors against PI3K. In one embodiment, the administration of the polypeptide and the inhibitor against PI3K synergistically produces one or more characteristics selected from the group consisting of: (A) an increased degree of toxicity against diseased cells compared to the polypeptide or the inhibitor against PI3K at least about 20%, at least about 40%, at least about 60%, at least about 80%, at least about 100%, or at least about 200%; and/or (B) reduced tumor size compared to the polypeptide or inhibitor to PI3K At least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 60%. In one embodiment, the reduction in tumor size can be at least about or at most about: 1-fold, 5-fold, 10-fold, 15-fold, 20-fold, 40-fold, 60-fold, 80-fold, 100-fold, or as high as about 200 times. In one embodiment, the reduction in tumor size is tumor elimination.

在一些方面，本公開內容還提供了在對象中增強(例如，刺激)免疫應答的方法，其包括向對象施用所述多肽和/或向對象施用所述抑制劑，使得對象的免疫應答被增強。在一個方面，所述增強是比缺乏組合物或多肽或抑制劑的相應方法更強。例如，對象是哺乳動物。在一個具體實施方案中，對象是人。在一個方面，所述增強是比缺乏組合物或多肽或抑制劑的相應方法強至 少約或至多約1倍、2倍、3倍、4倍、10倍、20倍、30倍、40倍、60倍、100倍、200倍、300倍或500倍。例如，對象是哺乳動物。在一個具體實施方案中，對象是人。 In some aspects, the present disclosure also provides methods of enhancing (eg, stimulating) an immune response in a subject, comprising administering the polypeptide to the subject and/or administering the inhibitor to the subject, such that the immune response of the subject is enhanced . In one aspect, the enhancement is greater than the corresponding method in the absence of the composition or polypeptide or inhibitor. For example, the subject is a mammal. In a specific embodiment, the subject is a human. In one aspect, the enhancement is greater than the corresponding method lacking the composition or polypeptide or inhibitor by up to About 1, 2, 3, 4, 10, 20, 30, 40, 60, 100, 200, 300, or 500 times less or at most about 1, 2, 3, 4, 10, 20, 30, 40, 60, 100, 200, 300 or 500 times less. For example, the subject is a mammal. In a specific embodiment, the subject is a human.

在一個方面，增強免疫應答或其類似表達意指刺激、引起、提高、改善或增強哺乳動物免疫系統的任何應答。免疫應答可以是細胞應答(即細胞介導的，例如細胞毒性T淋巴細胞介導的)或體液應答(即抗體介導的應答)，並且可以是初級或次級免疫應答。增強免疫應答的實例包括提高CD4+輔助性T細胞活性和細胞溶解性T細胞的產生。可使用本領域技術人員已知的多種體外或體內測量來評估免疫應答的增強，包括但不限於細胞毒性T淋巴細胞測定、細胞因數的釋放(例如IL-2產生或IFN-γ產生)、腫瘤消退、荷瘤動物的存活、抗體產生、免疫細胞增殖、細胞表面標誌物的表達和細胞毒性。通常來說，與未經治療的哺乳動物或未使用本文中公開的方法治療的哺乳動物的免疫應答相比，本公開內容的方法增強哺乳動物的免疫應答。在一個實施方案中，多肽和/或抑制劑用於增強人對對象靶標的免疫應答。在一個實施方案中，所述方法增強細胞免疫應答，特別是細胞毒性T細胞應答。在另一個實施方案中，細胞免疫應答是T輔助細胞應答。在另一個實施方案中，免疫應答是細胞因數產生，特別是IFN-γ產生或IL-2產生。 In one aspect, enhancing an immune response or the like means stimulating, eliciting, enhancing, ameliorating or enhancing any response of the immune system of a mammal. An immune response can be a cellular response (ie, cell-mediated, eg, mediated by cytotoxic T lymphocytes) or a humoral response (ie, an antibody-mediated response), and can be a primary or secondary immune response. Examples of enhancing immune responses include increasing CD4+ helper T cell activity and cytolytic T cell production. Enhancement of immune responses can be assessed using a variety of in vitro or in vivo measures known to those of skill in the art, including but not limited to cytotoxic T lymphocyte assays, cytokine release (eg, IL-2 production or IFN-γ production), tumor Regression, survival of tumor-bearing animals, antibody production, immune cell proliferation, expression of cell surface markers, and cytotoxicity. In general, the methods of the present disclosure enhance the immune response of a mammal compared to the immune response of an untreated mammal or a mammal not treated using the methods disclosed herein. In one embodiment, the polypeptides and/or inhibitors are used to enhance a human immune response to a target in a subject. In one embodiment, the method enhances cellular immune responses, particularly cytotoxic T cell responses. In another embodiment, the cellular immune response is a T helper cell response. In another embodiment, the immune response is cytokine production, particularly IFN-γ production or IL-2 production.

本文中公開的任何一種組合物和方法可用於治療對象的靶細胞、靶組織、靶狀況或靶疾病。 Any of the compositions and methods disclosed herein can be used to treat a target cell, target tissue, target condition, or target disease in a subject.

靶疾病可以是病毒、細菌和/或寄生物感染；炎症和/或自身免疫性疾病；或者贅生物，例如癌症和/或腫瘤。 The target disease may be a viral, bacterial, and/or parasitic infection; an inflammatory and/or autoimmune disease; or a neoplasm, such as cancer and/or tumor.

靶細胞可以是患病細胞。患病細胞可具有改變的代謝、基因表達和/或形態特徵。患病細胞可以是癌細胞、糖尿病細胞和凋亡細胞。患病細胞可以是來自患病對象的細胞。示例性疾病可包括血液病、癌症、代謝病、眼病、器官病、肌肉骨骼病、心臟病等。 The target cells can be diseased cells. Diseased cells can have altered metabolism, gene expression and/or morphological characteristics. Diseased cells can be cancer cells, diabetic cells, and apoptotic cells. A diseased cell can be a cell from a diseased subject. Exemplary diseases may include hematological diseases, cancers, metabolic diseases, eye diseases, organ diseases, musculoskeletal diseases, heart diseases, and the like.

可使用本文中公開的任一種方法或組合物殺傷多種靶細胞。靶細胞可包括多種細胞類型。靶細胞可在體外或體內。靶細胞可以是離體的。靶細 胞可以是分離的細胞。靶細胞可以是生物體內的細胞。靶細胞可以是生物體。靶細胞可以是細胞培養物中的細胞。靶細胞可以是細胞集合中的一個。靶細胞可以是哺乳動物細胞或來源於哺乳動物細胞。靶細胞可以是齧齒動物細胞或來源於齧齒動物細胞。靶細胞可以是人細胞或來源於人細胞。靶細胞可以是原核細胞或來源於原核細胞。靶細胞可以是細菌細胞或來源於細菌細胞。靶細胞可以是古細菌細胞或來源於古細菌細胞。靶細胞可以是真核細胞或來源於真核細胞。靶細胞可以是多能幹細胞。靶細胞可以是植物細胞或來源於植物細胞。靶細胞可以是動物細胞或來源於動物細胞。靶細胞可以是無脊椎動物細胞或來源於無脊椎動物細胞。靶細胞可以是脊椎動物細胞或來源於脊椎動物細胞。靶細胞可以是微生物細胞或來源於微生物細胞。靶細胞可以是真菌細胞或來源於真菌細胞。靶細胞可來自特定器官或組織。 A variety of target cells can be killed using any of the methods or compositions disclosed herein. Target cells can include a variety of cell types. Target cells can be in vitro or in vivo. Target cells can be ex vivo. target The cells can be isolated cells. The target cells can be cells in an organism. The target cell can be an organism. The target cells can be cells in cell culture. The target cell can be one of a collection of cells. The target cells can be mammalian cells or derived from mammalian cells. The target cells can be rodent cells or derived from rodent cells. Target cells can be human cells or derived from human cells. Target cells can be prokaryotic cells or derived from prokaryotic cells. The target cells can be bacterial cells or derived from bacterial cells. The target cells may be archaeal cells or derived from archaeal cells. Target cells can be eukaryotic cells or derived from eukaryotic cells. The target cells can be pluripotent stem cells. The target cells can be plant cells or derived from plant cells. The target cells can be animal cells or derived from animal cells. Target cells can be invertebrate cells or derived from invertebrate cells. The target cells can be vertebrate cells or derived from vertebrate cells. The target cells can be microbial cells or derived from microbial cells. The target cells may be fungal cells or derived from fungal cells. Target cells can be derived from a specific organ or tissue.

靶細胞可以是幹細胞或母細胞。靶細胞可包括幹細胞(例如，成體幹細胞、胚胎幹細胞、誘導多能性幹(induced pluripotent stem,iPS)細胞)和母細胞(例如，心臟母細胞、神經母細胞等)。靶細胞可包括哺乳動物幹細胞和母細胞，包括齧齒動物幹細胞、齧齒動物母細胞、人幹細胞、人母細胞等。克隆細胞可包含細胞的後代。靶細胞可包含靶核酸。靶細胞可在活的生物體中。靶細胞可以是經遺傳修飾的細胞。靶細胞可以是宿主細胞。 Target cells can be stem cells or blast cells. Target cells can include stem cells (eg, adult stem cells, embryonic stem cells, induced pluripotent stem (iPS) cells) and blast cells (eg, cardioblasts, neuroblasts, etc.). Target cells can include mammalian stem cells and blast cells, including rodent stem cells, rodent blast cells, human stem cells, human blast cells, and the like. Clonal cells may contain progeny of the cells. The target cell can contain the target nucleic acid. The target cell can be in a living organism. Target cells can be genetically modified cells. The target cell can be a host cell.

靶細胞可以是全能幹細胞，然而，在本公開內容的一些實施方案中，可使用術語“細胞”但可不指全能幹細胞。靶細胞可以是植物細胞，但在本公開內容的一些實施方案中，可使用術語“細胞”但可不指植物細胞。靶細胞可以是多能細胞。例如，靶細胞可以是多能造血細胞，其可分化為造血細胞譜系中的其他細胞，但可能不能分化為任何其他非造血細胞。靶細胞可能夠發育成整個生物體。靶細胞可能會或可能不會發育成整個生物體。靶細胞可以是整個生物體。 The target cells may be totipotent stem cells, however, in some embodiments of the present disclosure, the term "cell" may be used but may not refer to totipotent stem cells. The target cell may be a plant cell, although in some embodiments of the present disclosure, the term "cell" may be used but may not refer to a plant cell. The target cells can be pluripotent cells. For example, a target cell can be a pluripotent hematopoietic cell that can differentiate into other cells in the hematopoietic cell lineage, but may not be able to differentiate into any other non-hematopoietic cell. Target cells may be able to develop into entire organisms. Target cells may or may not develop into whole organisms. The target cell can be the entire organism.

靶細胞可以是原代細胞。例如，原代細胞的培養物可傳代0次、1次、2次、4次、5次、10次、15次或更多。細胞可以是單細胞生物。細胞可在培養物中生長。 The target cells can be primary cells. For example, cultures of primary cells can be passaged 0, 1, 2, 4, 5, 10, 15, or more. A cell can be a unicellular organism. Cells can be grown in culture.

靶細胞可以是患病細胞。患病細胞可具有改變的代謝、基因表達 和/或形態特徵。患病細胞可以是癌細胞、糖尿病細胞和凋亡細胞。患病細胞可以是來自患病對象的細胞。示例性疾病可包括血液病、癌症、代謝病、眼病、器官病、肌肉骨骼病、心臟病等。 The target cells can be diseased cells. Diseased cells can have altered metabolism, gene expression and/or morphological features. Diseased cells can be cancer cells, diabetic cells, and apoptotic cells. A diseased cell can be a cell from a diseased subject. Exemplary diseases may include hematological diseases, cancers, metabolic diseases, eye diseases, organ diseases, musculoskeletal diseases, heart diseases, and the like.

如果靶細胞是原代細胞，則其可通過任何方法從個體收穫。例如，可通過單采、白細胞分離、密度梯度分離等收穫白細胞。可通過活體組織檢查收穫來自例如皮膚、肌肉、骨髓、脾、肝、胰腺、肺、腸、胃等組織的細胞。可使用合適的溶液來分散或懸浮收穫的細胞。這樣的溶液通常可以是結合低濃度的可接受緩衝液的方便地補充有胎牛血清或其他天然存在的因數的平衡鹽溶液(例如生理鹽水、磷酸鹽緩衝液(phosphate buffered saline,PBS)、Hank’s平衡鹽溶液等)。緩衝液可包括羥乙基哌嗪乙硫磺酸(HEPES)、磷酸鹽緩衝液、乳酸緩衝液等。細胞可立即使用，也可儲存(例如，通過冷凍)。冷凍細胞可解凍並且可以能夠重複使用。細胞可在二甲基亞碸(Dimethyl sulfoxide,DMSO)、血清、培養基緩衝液(例如，10%DMSO、50%血清、40%緩衝培養基)和/或一些其他用於在冷凍溫度下保存細胞的這樣的常用溶液中冷凍。 If the target cells are primary cells, they can be harvested from the individual by any method. For example, leukocytes can be harvested by apheresis, leukocyte separation, density gradient separation, and the like. Cells from tissues such as skin, muscle, bone marrow, spleen, liver, pancreas, lung, intestine, stomach, etc. can be harvested by biopsy. Appropriate solutions can be used to disperse or suspend the harvested cells. Such solutions may typically be balanced salt solutions (eg, physiological saline, phosphate buffered saline (PBS), Hank's, etc.) conveniently supplemented with fetal bovine serum or other naturally occurring factors in combination with low concentrations of acceptable buffers. balanced salt solution, etc.). Buffers may include hydroxyethylpiperazine ethanethiosulfonic acid (HEPES), phosphate buffer, lactate buffer, and the like. Cells can be used immediately or stored (eg, by freezing). Frozen cells can be thawed and can be reused. Cells can be prepared in dimethyl sulfoxide (DMSO), serum, media buffers (eg, 10% DMSO, 50% serum, 40% buffered media), and/or some other means for preserving cells at freezing temperatures. Freeze in such common solutions.

可作為靶細胞的細胞的非限制性實例包括但不限於淋巴細胞，例如B細胞、T細胞(細胞毒性T細胞、自然殺傷T細胞、調節性T細胞、T輔助細胞)、自然殺傷細胞、細胞因數誘導的殺傷(Cytokine-induced killer cells,CIK)細胞(參見例如US20080241194)；髓樣細胞，例如粒細胞(嗜鹼性粒細胞、嗜酸性粒細胞、中性粒細胞/超節段性中性粒細胞)、單核細胞/巨噬細胞、紅細胞(網織紅細胞)、肥大細胞、凝血細胞/巨核細胞、樹突細胞；來自內分泌系統的細胞，包括甲狀腺(甲狀腺上皮細胞、濾泡旁細胞)、甲狀旁腺(甲狀旁腺主細胞、嗜氧細胞)、腎上腺(嗜鉻細胞)、松果體(松果體細胞)細胞；神經系統細胞，包括神經膠質細胞(星形膠質細胞、小膠質細胞)、巨細胞神經分泌細胞、星狀細胞、伯特歇爾細胞和垂體(***、促腎上腺皮質激素、促甲狀腺激素、生長激素、促乳激素)；呼吸系統的細胞，包括肺細胞(I型肺細胞、II型肺細胞)、克拉拉細胞、杯狀細胞、塵細胞；循環系統的細胞，包括心肌細胞、周細胞；消化系統細胞，包括胃(胃主細胞、周緣細胞)、杯狀細胞、帕內特細胞、G細胞、D細胞、ECL細胞、I細胞、K細胞、S細胞；腸內分泌細胞， 包括腸嗜鉻細胞、胺前體攝取脫羧化細胞(Amine Precursor Uptake Decarboxylation cell,APUD細胞)、肝(肝細胞、庫普弗細胞)、軟骨/骨/肌肉；骨細胞，包括成骨細胞、骨細胞、破骨細胞、牙(成牙骨質細胞、成釉細胞)；軟骨細胞，包括成軟骨細胞、軟骨細胞；皮膚細胞，包括毛細胞、角質細胞、黑素細胞(色素痣細胞)；肌肉細胞，包括肌細胞；泌尿系統細胞，包括足細胞、腎小球旁細胞、腎小球內系膜細胞/腎小球外系膜細胞、腎近端小管刷狀緣細胞、緻密斑細胞；生殖系統細胞，包括***、支援細胞、間質細胞、卵子；和其他細胞，包括脂肪細胞、成纖維細胞、肌腱細胞、表皮角質形成細胞(分化表皮細胞)、表皮基底細胞(幹細胞)、指甲和腳趾甲的角質形成細胞、甲床基底細胞(幹細胞)、髓質毛幹細胞、皮質毛幹細胞、角質毛幹細胞、角質毛根鞘細胞、赫胥黎層毛根鞘細胞、亨勒層毛根鞘細胞、外毛根鞘細胞、毛基質細胞(幹細胞)，濕複層屏障上皮細胞、角膜、舌、口腔、食管、肛管、遠端尿道和***的複層鱗狀上皮表面上皮細胞，角膜、舌、口腔、食管、肛管、遠端尿道和***上皮的基底細胞(幹細胞)，泌尿上皮細胞(襯裡膀胱和尿管)，外分泌分泌上皮細胞，唾液腺黏液細胞(富含多糖的分泌)，唾液腺漿液細胞(富含糖蛋白酶的分泌)、舌中的馮．埃布納腺細胞(清洗味蕾)、乳腺細胞(乳汁分泌)、淚腺細胞(淚分泌)、耳中的蠟狀腺細胞(蠟分泌)、小汗腺暗細胞(糖蛋白分泌)、小汗腺透明細胞(小分子分泌)。大汗腺細胞(氣味分泌，對性激素敏感)、眼瞼內的莫爾腺細胞(特殊汗腺)、皮脂腺細胞(富含脂質的皮脂分泌)、鼻內的鮑曼腺細胞(洗嗅覺上皮)、布倫納腺十二指腸細胞(酶和鹼性黏液)、精囊細胞(分泌***成分，包括用於***遊動的果糖)、***細胞(分泌***成分)、尿道球腺細胞(黏液分泌)、***細胞(***潤滑劑分泌)、利特雷腺細胞(黏液分泌)、子宮內膜細胞(碳水化合物分泌)、呼吸道和消化道分離的杯狀細胞(黏液分泌)、胃內壁黏液細胞(黏液分泌)、胃腺酶原細胞(胃蛋白酶原分泌)、胃泌酸腺細胞(鹽酸分泌)、胰腺泡狀腺細胞(碳酸氫鹽和消化酶分泌)、小腸帕內特細胞(溶菌酶分泌)、肺II型肺細胞(表面活性物質分泌)、肺克拉拉細胞、激素分泌細胞、垂體前葉細胞、生長激素、促乳素、促甲狀腺素、***、促腎上腺皮質激素、中間垂體細胞、大細胞神經分泌細胞、腸道和呼吸道細胞、甲狀腺細胞、甲狀腺上皮細胞、濾泡旁細胞、甲狀旁腺細胞、甲 狀旁腺主細胞、嗜氧細胞、腎上腺細胞、嗜鉻細胞、睾丸間質細胞、卵泡內膜細胞、破裂卵泡的黃體細胞、顆粒黃體細胞、膜黃體細胞、腎小球旁細胞(腎素分泌)、腎緻密斑細胞、代謝和儲存細胞、屏障功能細胞(肺、腸道、外分泌腺和泌尿生殖道)、腎、I型肺細胞(肺的襯裡空氣空間)、胰管細胞(泡心細胞)、(汗腺、唾液腺、乳腺等)的非紋狀管細胞、(精囊、***等)的管細胞、封閉體腔內襯的上皮細胞、具有推進功能的纖毛細胞、胞外基質分泌細胞、收縮細胞；骨骼肌細胞、幹細胞、心肌細胞、血液和免疫系統細胞、紅細胞(紅細胞)、巨核細胞(血小板前體)、單核細胞、結締組織巨噬細胞(多種類型)、表皮朗格漢斯細胞、破骨細胞(骨中)、樹突細胞(淋巴組織中)、小膠質細胞(中樞神經系統中)、中性粒細胞、嗜酸性粒細胞、嗜鹼性粒細胞、肥大細胞、輔助性T細胞、抑制性T細胞、細胞毒性T細胞、自然殺傷性T細胞、B細胞、自然殺傷細胞、網織紅細胞、血液和免疫系統的幹細胞和定向母細胞(多種類型)、多能幹細胞、全能幹細胞、誘導多能幹細胞、成體幹細胞、感覺感測器細胞、自主神經元細胞、感覺器官和外周神經元支援細胞、中樞神經系統神經元和神經膠質細胞、晶狀體細胞、色素細胞、黑素細胞、視網膜色素上皮細胞、生殖細胞、卵母細胞/卵母細胞、***細胞、***細胞、精原細胞(***細胞的幹細胞)、***、哺育細胞、卵巢卵泡細胞、支援細胞(睾丸中)、胸腺上皮細胞、間質細胞和間質腎細胞。 Non-limiting examples of cells that can be target cells include, but are not limited to, lymphocytes, such as B cells, T cells (cytotoxic T cells, natural killer T cells, regulatory T cells, T helper cells), natural killer cells, cells Cytokine-induced killer (CIK) cells (see e.g. US20080241194); myeloid cells e.g. granulocytes (basophils, eosinophils, neutrophils/ultra-segmental neutrophils) ), monocytes/macrophages, red blood cells (reticulocytes), mast cells, thrombocytes/megakaryocytes, dendritic cells; cells from the endocrine system, including thyroid (thyroid epithelial cells, parafollicular cells), Parathyroid (parathyroid chief cells, aerobic cells), adrenal glands (chromaffin cells), pineal gland (pineal cells) cells; cells of the nervous system, including glial cells (astrocytes, microglia) cells), giant cell neurosecretory cells, stellate cells, Bertcher cells and pituitary gland (gonadotropins, adrenocorticotropic hormones, thyrotropin, growth hormone, prolactin); cells of the respiratory system, including lung cells (type I pneumocytes, type II pneumocytes), Clara cells, goblet cells, dust cells; circulatory system cells, including cardiomyocytes, pericytes; digestive system cells, including stomach (stomach chief cells, peripheral cells), Goblet cells, Paneth cells, G cells, D cells, ECL cells, I cells, K cells, S cells; enteroendocrine cells, Including enterochromaffin cells, Amine Precursor Uptake Decarboxylation cells (APUD cells), liver (hepatocytes, Kupffer cells), cartilage/bone/muscle; osteocytes, including osteoblasts, bone cells, osteoclasts, teeth (cementoblasts, ameloblasts); chondrocytes, including chondroblasts, chondrocytes; skin cells, including hair cells, keratinocytes, melanocytes (pigmented nevus cells); muscle cells , including muscle cells; cells of the urinary system, including podocytes, paraglomerular cells, inner/outer glomerular mesangial cells, renal proximal tubule brush border cells, and parenchyma cells; reproductive system Cells, including sperm, support cells, stromal cells, eggs; and other cells, including adipocytes, fibroblasts, tenocytes, epidermal keratinocytes (differentiating epidermal cells), epidermal basal cells (stem cells), fingernails and toenails keratinocytes, nail bed basal cells (stem cells), medullary hair stem cells, cortical hair stem cells, keratinous hair stem cells, horny hair root sheath cells, Huxley's layer hair root sheath cells, Henle layer hair root sheath cells, outer hair root sheath cells , hair stromal cells (stem cells), wet stratified barrier epithelial cells, stratified squamous surface epithelial cells of cornea, tongue, oral cavity, esophagus, anal canal, distal urethra and vagina, cornea, tongue, oral cavity, esophagus, anus Basal cells (stem cells) of the epithelium of the tube, distal urethra and vagina, urothelial cells (lining the bladder and urinary tract), exocrine secretory epithelial cells, salivary gland mucus cells (rich in polysaccharide secretion), salivary gland serous cells (rich in glycoproteinases) secretion), Feng in the tongue. Ebner gland cells (cleansing taste buds), mammary gland cells (milk secretion), lacrimal gland cells (tear secretion), wax gland cells in the ear (wax secretion), eccrine dark cells (glycoprotein secretion), eccrine clear cells (small molecular secretion). Apocrine cells (smell secreting, sensitive to sex hormones), Moiré gland cells in the eyelids (special sweat glands), sebocytes (lipid-rich sebum secretion), Bowman's gland cells in the nose (washes the olfactory epithelium), Brenner glands Duodenal cells (enzymes and alkaline mucus), seminal vesicle cells (secreting semen components, including fructose for sperm motility), prostate cells (secreting semen components), bulbourethral gland cells (mucus secretion), Bartholin gland cells (vaginal lubricant secretion) ), Litre gland cells (mucus secretion), endometrial cells (carbohydrate secretion), goblet cells isolated from the respiratory and alimentary tract (mucus secretion), gastric lining mucous cells (mucus secretion), gastric adenoenzyme ( Pepsinogen secretion), oxyntic gland cells (hydrochloric acid secretion), pancreatic alveolar gland cells (bicarbonate and digestive enzymes secretion), small intestinal Paneth cells (lysozyme secretion), lung type II pneumocytes (surfactant secretion) ), lung Clara cells, hormone secreting cells, anterior pituitary cells, growth hormone, prolactin, thyrotropin, gonadotropin, adrenocorticotropic hormone, intermediate pituitary cells, large cell neurosecretory cells, intestinal and respiratory cells , thyroid cells, thyroid epithelial cells, parafollicular cells, parathyroid cells, nails Parathyroid chief cells, aerobic cells, adrenal cells, chromaffin cells, Leydig cells, endometrial cells, luteal cells of ruptured follicles, granulosa luteal cells, membranous luteal cells, paraglomerular cells (renin secreting cells) ), renal plaque compact cells, metabolic and storage cells, barrier function cells (lung, gut, exocrine glands and genitourinary tract), kidney, type I pneumocytes (air spaces lining the lungs), pancreatic duct cells (vesicular heart cells) ), non-striatal cells of (sweat glands, salivary glands, mammary glands, etc.), duct cells (seminal vesicles, prostate, etc.), epithelial cells lining the closed body cavity, ciliated cells with propulsive function, extracellular matrix secreting cells, contractile cells ; Skeletal muscle cells, stem cells, cardiomyocytes, blood and immune system cells, erythrocytes (red blood cells), megakaryocytes (platelet precursors), monocytes, connective tissue macrophages (various types), epidermal Langerhans cells, Osteoclasts (in bone), dendritic cells (in lymphoid tissue), microglia (in central nervous system), neutrophils, eosinophils, basophils, mast cells, helper T cells , suppressor T cells, cytotoxic T cells, natural killer T cells, B cells, natural killer cells, reticulocytes, stem cells and committed blasts of the blood and immune system (various types), pluripotent stem cells, totipotent stem cells, Induced pluripotent stem cells, adult stem cells, sensory sensor cells, autonomic neuron cells, sensory organs and peripheral neuron support cells, central nervous system neurons and glial cells, lens cells, pigment cells, melanocytes, retina Pigment epithelium, germ cells, oocytes/oocytes, sperm cells, spermatocytes, spermatogonia (stem cells of spermatocytes), sperm, nurse cells, ovarian follicle cells, support cells (in testes), thymus Epithelial cells, mesenchymal cells and interstitial kidney cells.

特別應注意的是癌細胞。在一些實施方案中，靶細胞是癌細胞。癌細胞的非限制性實例包括下述癌症的細胞，包括：棘皮瘤、腺泡細胞癌、聽神經瘤、肢端雀斑樣痣黑素瘤、肢端螺旋體瘤、急性嗜酸性粒細胞白血病、急性淋巴細胞白血病、急性原巨核細胞性白血病、急性單核細胞白血病、成熟的急性粒細胞白血病、急性髓樣樹突狀細胞白血病、急性粒細胞白血病、急性早幼粒細胞白血病、釉質瘤、腺癌、腺樣囊性癌、腺瘤、牙源性腺瘤樣瘤、腎上腺皮質癌、成人T細胞白血病、侵襲性NK細胞白血病、後天免疫缺乏症候群(Acquired Immunodeficiency Syndrome,AIDS)相關癌症、AIDS相關淋巴瘤、腺泡狀軟組織肉瘤、成釉細胞纖維瘤、肛門癌、間變性大細胞淋巴瘤、甲狀腺未分化癌、血管免疫母細胞性T細胞淋巴瘤、血管平滑肌脂肪瘤、血管肉瘤、闌 尾癌、星形細胞瘤、非典型畸胎樣橫紋肌樣瘤、基底細胞癌、基底樣癌、B細胞白血病、B細胞淋巴瘤、貝利尼導管癌、膽道癌、膀胱癌、母細胞瘤、骨癌、骨腫瘤、腦幹膠質瘤、腦腫瘤、乳腺癌、布倫納腫瘤、支氣管腫瘤、細支氣管肺泡癌、棕色瘤、伯基特淋巴瘤、未知原發部位的癌症、類癌瘤、上皮癌、原位癌、陰莖癌、未知原發部位癌、癌肉瘤、卡斯爾曼病、中樞神經系統胚胎性腫瘤、小腦星形細胞瘤、腦星形細胞瘤、宮頸癌、膽管癌、軟骨瘤、軟骨肉瘤、脊索瘤、絨毛膜癌、脈絡叢乳頭狀瘤、慢性淋巴細胞白血病、慢性單核細胞白血病、慢性髓細胞性白血病、慢性骨髓增生性疾病、慢性中性粒細胞白血病、透明細胞瘤、結腸癌、結直腸癌、顱咽管瘤、皮膚T細胞淋巴瘤、惡性萎縮性丘疹病、隆突性纖維皮膚肉瘤、皮樣囊腫、結締組織增生性小圓細胞瘤、彌漫大B細胞淋巴瘤、胚胎發育不良性神經上皮腫瘤、胚胎癌、內胚竇瘤、子宮內膜癌、子宮內膜癌、子宮內膜樣腫瘤、腸病相關T細胞淋巴瘤、室管膜母細胞瘤、室管膜瘤、上皮樣肉瘤、紅白血病、食管癌、上皮神經母細胞瘤、尤因家族腫瘤、尤因家族肉瘤、尤因氏肉瘤、顱外生殖細胞腫瘤、性腺外生殖細胞腫瘤、肝外膽管癌、***外佩吉特病、輸卵管癌、胎中胎、纖維瘤、纖維肉瘤、濾泡性淋巴瘤、濾泡性甲狀腺癌、膽囊癌、膽囊癌、神經節細胞膠質瘤、節細胞神經瘤、胃癌、胃淋巴瘤、胃腸道癌、胃腸道類癌瘤、胃腸道間質瘤、胃腸道間質瘤、生殖細胞腫瘤、生殖細胞瘤、妊娠母細胞瘤、滋養細胞腫瘤、骨巨細胞瘤、多形性膠質母細胞瘤、膠質瘤、大腦膠質瘤病、血管球瘤、胰升糖素瘤、成性腺細胞瘤、顆粒細胞瘤、毛細胞白血病、毛細胞白血病、頭頸癌、頭頸癌、心臟癌、血管母細胞瘤、血管外皮細胞瘤、血管肉瘤、血液系統惡性腫瘤、肝細胞癌、肝脾T細胞淋巴瘤、遺傳性乳腺癌-卵巢癌綜合征、霍奇金淋巴瘤、霍奇金淋巴瘤、下嚥癌、下丘腦膠質瘤、炎性乳腺癌、眼內黑素瘤、胰島細胞癌、胰島細胞腫瘤、幼年型髓細胞單核細胞白血病、卡波西肉瘤、卡波西肉瘤、腎癌、克拉茨金瘤、克魯肯貝格腫瘤、喉癌、喉癌、惡性雀斑樣痣黑素瘤、白血病、白血病、唇和口腔癌、脂肪肉瘤、肺癌、黃體瘤、***瘤、***肉瘤、淋巴上皮瘤、淋巴球白血病、淋巴瘤、巨球蛋白血症、惡性纖維組織細胞瘤、惡性纖維組織細胞瘤、骨惡性纖維組織細胞瘤、惡性膠質瘤、惡性間皮瘤、惡性周圍神經鞘瘤、惡性橫紋肌瘤、惡性氚瘤、MALT淋巴瘤、套細 胞淋巴瘤肥大細胞淋巴瘤、縱膈生殖細胞腫瘤、縱隔腫瘤、甲狀腺髓樣癌、髓母細胞瘤、髓母細胞瘤、髓上皮瘤、黑素瘤、黑素瘤、腦膜瘤、梅克爾細胞癌、間皮瘤、間皮瘤、具有隱匿性原發部位的轉移性鱗狀頸癌、轉移性尿路上皮癌、苗勒管混合瘤、單核細胞白血病、口腔癌、多發性黏液性腺細胞瘤骨髓瘤、多發性內分泌瘤病、多發性骨髓瘤、多發性骨髓瘤、蕈樣肉芽腫病、蕈樣肉芽腫病、骨髓增生異常疾病、骨髓增生異常綜合征、髓性白血病、髓樣肉瘤、骨髓增生性疾病、黏液瘤、鼻腔癌、鼻咽癌、贅生物、神經鞘瘤、神經母細胞瘤、神經母細胞瘤、神經纖維瘤、神經瘤、結節性黑素瘤、非霍奇金淋巴瘤、非霍奇金淋巴瘤、非黑素瘤皮膚癌、非小細胞肺癌、眼部腫瘤學、少突星形細胞瘤、少突神經膠質瘤、嗜酸細胞瘤、視神經鞘腦膜瘤、口腔癌、口腔癌、口咽癌、骨肉瘤、骨肉瘤、卵巢癌、卵巢癌、卵巢上皮癌症、卵巢生殖細胞腫瘤、卵巢惡性程度低的潛在腫瘤、乳腺佩吉特病、肺上溝瘤、胰腺癌、胰腺癌、乳頭狀甲狀腺癌、乳頭狀瘤、副神經節瘤、鼻竇癌、甲狀旁腺癌、陰莖癌、血管周圍上皮樣細胞腫瘤、咽癌、嗜鉻細胞瘤、中等分化松果體實質腫瘤、松果體母細胞瘤、垂體細胞瘤、垂體腺瘤、垂體瘤、漿細胞腫瘤、胸膜肺母細胞瘤、多胚瘤、前體T淋巴細胞淋巴瘤、原發性中樞神經系統淋巴瘤、原發性滲出性淋巴瘤、原發性肝細胞癌、原發性肝癌、原發性腹膜癌、原始神經外胚葉腫瘤、***癌、腹膜假黏液瘤、直腸癌、腎細胞癌、涉及NUT15號染色體基因的呼吸道癌、視網膜母細胞瘤、橫紋肌瘤、橫紋肌肉瘤、裡氏轉化、骶尾部畸胎瘤、唾液腺癌、肉瘤、神經鞘瘤病、皮脂腺癌、繼發性腫瘤、精原細胞瘤、漿液性腫瘤、支援-間質細胞瘤、性索間質瘤、塞紮裡綜合征、印戒細胞癌、皮膚癌、小藍圓細胞瘤、小細胞癌、小細胞肺癌、小細胞淋巴瘤、小腸癌、軟組織肉瘤、生長抑素瘤、煙灰疣、脊髓腫瘤、脊髓腫瘤、脾邊緣區淋巴瘤、鱗狀細胞癌、胃癌、淺表擴散性黑素瘤、幕上原始神經外胚葉腫瘤、表面上皮間質瘤、滑膜肉瘤、T細胞急性淋巴細胞白血病、T細胞大顆粒淋巴細胞白血病、T細胞白血病、T細胞淋巴瘤、T細胞幼淋巴細胞白血病、畸胎瘤、終末淋巴癌、睾丸癌症、卵泡膜細胞瘤、喉癌、胸腺癌、胸腺瘤、甲狀腺癌、腎盂和輸尿管移行細胞癌、移行細胞癌、臍尿管癌、尿道癌、泌尿生殖系統腫瘤、子宮肉瘤、葡萄膜黑素瘤、***癌、弗納-莫里森綜合征、疣狀癌、視覺途徑膠質瘤、外陰癌、 華氏巨球蛋白血症、沃辛瘤、腎母細胞瘤及其組合。在一些實施方案中，靶向癌細胞代表癌細胞群中的亞群，例如癌症幹細胞。在一些實施方案中，癌症屬於造血譜系，例如淋巴瘤。抗原可以是腫瘤相關抗原。 Of particular note are cancer cells. In some embodiments, the target cells are cancer cells. Non-limiting examples of cancer cells include cells of cancers including: acanthoma, acinar cell carcinoma, acoustic neuroma, acroleptoma melanoma, acrospiral tumor, acute eosinophilic leukemia, acute lymphoid Cellular leukemia, acute promegakaryocytic leukemia, acute monocytic leukemia, mature acute myeloid leukemia, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute promyelocytic leukemia, amelioma, adenocarcinoma, Adenoid cystic carcinoma, adenoma, odontogenic adenomatous tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, Acquired Immunodeficiency Syndrome (AIDS)-related cancer, AIDS-related lymphoma, Acinar soft tissue sarcoma, ameloblastoma fibroma, anal carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix Tail cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, basaloid carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, biliary tract carcinoma, bladder cancer, blastoma , Bone Cancer, Bone Tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner Tumor, Bronchial Tumor, Bronchioloalveolar Carcinoma, Brown Tumor, Burkitt Lymphoma, Cancer of Unknown Primary Site, Carcinoid Tumor , Epithelial carcinoma, carcinoma in situ, penile carcinoma, carcinoma of unknown primary site, carcinosarcoma, Castleman's disease, embryonal tumor of the central nervous system, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, bile duct cancer , chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disease, chronic neutrophilic leukemia, Clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, malignant atrophic papulosis, fibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, endometrial carcinoma, endometrial carcinoma, endometrioid tumor, enteropathy-associated T-cell lymphoma, ependymoblastoma tumor, ependymoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, epithelial neuroblastoma, Ewing family tumor, Ewing family sarcoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, Extrahepatic cholangiocarcinoma, extramammary Paget's disease, fallopian tube cancer, fetus in utero, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, gallbladder cancer, ganglion cell glioma, ganglion Cell neuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, germ cell tumor, germ cell tumor, gestational blastoma, trophoblastic tumor, bone Giant cell tumor, glioblastoma multiforme, glioma, cerebral gliomatosis, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, hairy cell leukemia, head and neck cancer, Head and neck cancer, cardiac cancer, hemangioblastoma, hemangiopericytoma, angiosarcoma, hematological malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, hereditary breast-ovarian cancer syndrome, Hodgkin lymphoma , Hodgkin's lymphoma, hypopharyngeal carcinoma, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, pancreatic islet cell carcinoma, pancreatic islet cell tumor, juvenile myelomonocytic leukemia, Kaposi's sarcoma, Posey's Sarcoma, Kidney Cancer, Kratzkin's Tumor, Krukenberg's Tumor, Laryngeal Cancer, Laryngeal Cancer, Laryngeal Malignant Melanoma, Leukemia, Leukemia, Lip and Mouth Cancer, Liposarcoma, Lung Cancer, Lumpy Tumor, Lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphocytic leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant fibrous histiocytoma, malignant fibrous histiocytoma of bone, malignant glioma, malignant interstitial Skin tumor, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant tritium tumor, MALT lymphoma, mantle Mast cell lymphoma, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid carcinoma, medulloblastoma, medulloblastoma, medulloepithelial tumor, melanoma, melanoma, meningioma, Merkel cell Carcinoma, mesothelioma, mesothelioma, metastatic squamous neck carcinoma with occult primary site, metastatic urothelial carcinoma, mixed Mullerian tumor, monocytic leukemia, oral cancer, multiple mucinous gland cells myeloma, multiple endocrine neoplasia, multiple myeloma, multiple myeloma, mycosis fungoides, myeloid granulomatosis, myelodysplastic disease, myelodysplastic syndrome, myeloid leukemia, myeloid sarcoma , myeloproliferative disease, myxoma, nasal cavity cancer, nasopharyngeal carcinoma, neoplasm, schwannoma, neuroblastoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin Lymphoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ocular oncology, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, Oral Cancer, Oral Cancer, Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer, Ovarian Cancer, Epithelial Ovarian Cancer, Ovarian Germ Cell Tumor, Potential Tumor of Low Malignancy of Ovarian, Paget's Disease of Breast, Superior Sulcus Tumor, Pancreas carcinoma, pancreatic cancer, papillary thyroid cancer, papilloma, paraganglioma, sinus cancer, parathyroid cancer, penile cancer, perivascular epithelioid cell tumor, pharyngeal cancer, pheochromocytoma, moderately differentiated pineal Somatic parenchymal tumor, pineoblastoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasma cell tumor, pleuropulmonary blastoma, polyembryoma, precursor T lymphocyte lymphoma, primary central nervous system Lymphoma, primary effusion lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal cancer, primitive neuroectodermal tumor, prostate cancer, peritoneal pseudomyxoma, rectal cancer, renal cell carcinoma, Respiratory cancer, retinoblastoma, rhabdomyomas, rhabdomyosarcoma, Richter's transformation, sacrococcygeal teratoma, salivary gland cancer, sarcoma, schwannomatosis, sebaceous gland cancer, secondary tumors, spermatogonia involving the NUT15 chromosome gene Cell tumor, serous tumor, supporting-stromal cell tumor, sex cord stromal tumor, Sezari syndrome, signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell Lymphoma, small bowel cancer, soft tissue sarcoma, somatostatinoma, soot wart, spinal cord tumor, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, gastric cancer, superficial diffuse melanoma, supratentorial primitive neuroectodermal lobe Tumor, surface epithelial stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, terminal lymphoma , testicular cancer, theca cell tumor, laryngeal cancer, thymic cancer, thymoma, thyroid cancer, transitional cell carcinoma of renal pelvis and ureter, transitional cell carcinoma, urachal carcinoma, urethral carcinoma, genitourinary tumor, uterine sarcoma, uveal Melanoma, vaginal cancer, Verner-Morrison syndrome, verrucous carcinoma, visual pathway glioma, vulvar cancer, Waldenström's macroglobulinemia, Worth's tumor, Wilms tumor, and combinations thereof. In some embodiments, targeted cancer cells represent a subset of a cancer cell population, such as cancer stem cells. In some embodiments, the cancer is of the hematopoietic lineage, eg, lymphoma. The antigen can be a tumor-associated antigen.

在一些情況下，對象可患有或疑似患有自身免疫病。自身免疫病的非限制性實例可包括急性瀰漫性腦脊髓炎(acute disseminated encephalomyelitis,ADEM)、急性壞死性出血性白質腦炎、艾迪生病、無丙種球蛋白血症、過敏性哮喘、鼻鼽、斑禿、澱粉樣變、強直性脊柱炎、抗體介導的移植排斥、抗GBM/抗TBM腎炎、抗磷脂綜合征(antiphospholipid syndrome,APS)、自身免疫性血管性水腫、自身免疫性再生障礙性貧血、自身免疫性自主神經功能障礙、自身免疫性肝炎、自身免疫性高脂血症、自身免疫性免疫缺陷、自身免疫性內耳病(Autoimmune Inner Ear Disease,AIED)、自身免疫性心肌炎、自身免疫性胰腺炎、自身免疫性視網膜病變、自身免疫性血小板增多症紫癜(Autoimmune thrombocytopenia,ATP)、自身免疫性甲狀腺疾病、自身免疫性蕁麻疹、軸突和神經元神經病、巴羅病、***、大皰性類天皰瘡、心肌病、卡斯爾曼病、乳糜瀉、美洲錐蟲病、慢性疲勞綜合征、慢性炎症性脫髓鞘性多發性神經病(chronic inflammatory demyelinating polyneuropathy,CIDP)、慢性復發米多灶性造口肌炎(Chronic Recurrent Multifocal Osteomyelitis,CRMO)、許爾許斯特勞斯綜合征、瘢痕性類天皰瘡/良性黏膜類天皰瘡、克羅恩病、柯根綜合征、冷凝集素病、先天性心臟傳導阻滯、柯薩奇心肌炎、CREST病、原發性混合性冷球蛋白血症、脫髓鞘性神經病、皰疹樣皮炎、肌痹、德維克病(視神經脊髓炎)、盤狀狼瘡、心肌梗死後綜合征、子宮內膜異位症、嗜酸性筋膜炎、結節性紅斑、實驗性變態反應性腦脊髓炎、伊文思綜合征、纖維肌痛、纖維化性肺泡炎、巨細胞動脈炎(顳動脈炎)、腎小球腎炎、肺出血-腎炎綜合征、肉芽腫性多血管炎(Granulomatosis with polyangiitis,GPA)、格雷夫斯病、格林-巴厘綜合征、橋本腦炎、橋本甲狀腺炎、溶血性貧血、過敏性紫癜、妊娠皰疹、低丙種球蛋白血症、高丙種球蛋白血症、特發性血小板減少性紫癜(idiopathic thrombocytopenia purpura,ITP)、IgA腎病、IgG4相關硬化病、免疫調節脂蛋白、包涵體肌炎、炎症性腸病、胰島素依賴型糖尿病(1型)、間質性膀胱炎、幼年 關節炎、幼年糖尿病、川崎綜合征、蘭伯特-伊頓綜合征、白細胞碎裂性血管炎、扁平苔蘚、硬化性苔蘚、木樣結膜炎、線狀IgA病(LAD)、狼瘡(Systemic Lupus Erythematosus,SLE)、萊姆病、美尼爾病、顯微鏡下多血管炎、混合型結締組織病(mixed connective tissue disease,MCTD)、意義不明單株免疫球蛋白增高症(monoclonal gammopathy of undetermined significance,MGUS)、蠶蝕性角膜潰瘍、Mucha-Habermann病、多發性硬化症、重症肌無力、肌炎、發作性睡病、視神經脊髓炎(德維克氏病)、中性粒細胞減少症、眼瘢痕性天皰瘡、視神經炎、復發性風濕病、PANDAS(與鏈球菌相關的小兒自身免疫性神經精神疾病(Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection,PANDAS)、副腫瘤性小腦變性、陣發性夜間血紅素尿(paroxysmal nocturnal hemoglobinuria,PNH)、帕裡-龍貝格綜合征、Parsonnage-Turner綜合征、扁桃體炎(中間葡萄膜炎)、天皰瘡、周圍神經病、靜脈周圍腦脊髓炎、惡性貧血、POEMS綜合征、結節性多動脈炎、I、II、&III型自身免疫性多內分泌腺綜合征、風濕性多肌痛、多肌炎、心肌梗死後綜合征、心包切開術後綜合征、孕酮皮炎、原發性膽汁性肝硬變、原發性硬化性膽管炎、銀屑病、銀屑病關節炎、特發性肺纖維化、壞疽性膿皮病、純紅細胞再生障礙、雷諾現象、反射***感神經營養不良、萊特爾綜合征、復發性多軟骨炎、下肢不寧綜合征、腹膜後纖維化、風濕熱、類風濕性關節炎、結節病、施密特綜合征、鞏膜炎、硬皮病、舍葛籣綜合征、***和睾丸自身免疫、僵人綜合征、亞急性細菌性心內膜炎(Subacute Bacterial Endocarditis,SBE)、Susac綜合征、交感性眼炎、大動脈炎、顳動脈炎/巨細胞動脈炎、血小板減少性紫癜(thrombotic thrombocytopenic purpura,TTP)、托洛薩-亨特綜合征、橫貫性脊髓炎、潰瘍性結腸炎、未分化結締組織疾病(undifferentiated connective tissue disease,UCTD)、葡萄膜炎、血管炎、白癜風、華氏巨球蛋白血症(Waldenstrom's macroglobulinemia,WM)和韋氏肉芽腫病(肉芽腫伴多血管炎(GPA)。 In some instances, the subject may have or be suspected of having an autoimmune disease. Non-limiting examples of autoimmune diseases may include acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, allergic asthma, rhizoma , alopecia areata, amyloidosis, ankylosing spondylitis, antibody-mediated transplant rejection, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic Anemia, autoimmune autonomic dysfunction, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmunity pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenia (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal and neuronal neuropathy, Barrow's disease, Behcet's disease disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP) , Chronic Recurrent Multifocal Osteomyelitis (CRMO), Hulsh-Strauss Syndrome, Cicatricial Pemphigoid/Benign Mucosal Pemphigoid, Crohn's Disease, Coleus Root syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST disease, primary mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, muscle paralysis, German Wake's disease (neuromyelitis optica), discoid lupus, post-myocardial infarction syndrome, endometriosis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), glomerulonephritis, pulmonary hemorrhage-nephritic syndrome, granulomatosis with polyangiitis (GPA), Graves disease , Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, anaphylactoid purpura, herpes gestationis, hypogammaglobulinemia, hypergammaglobulinemia, idiopathic thrombocytopenic purpura thrombocytopenia purpura (ITP), IgA nephropathy, IgG4-related sclerosis, immunomodulatory lipoproteins, inclusion body myositis, inflammatory bowel disease, insulin-dependent diabetes mellitus (type 1), interstitial bladder inflammation, childhood Arthritis, juvenile diabetes, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), lupus (Systemic Lupus Erythematosus, SLE), Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), monoclonal gammopathy of undetermined significance (MGUS) , eroding corneal ulcers, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Dweck's disease), neutropenia, ocular scarring Pemphigus, optic neuritis, recurrent rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection, PANDAS), paraneoplastic cerebellar degeneration, paroxysmal nocturnal blood redness paroxysmal nocturnal hemoglobinuria (PNH), Parry-Lomborg syndrome, Parsonnage-Turner syndrome, tonsillitis (intermediate uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune polyendocrine syndrome types I, II, & III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone Dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynaud's phenomenon, Reflex sympathetic dystrophy, Reiter syndrome, relapsing polychondritis, restless lower extremity syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, Scleroderma, Shegard syndrome, sperm and testicular autoimmunity, stiff man syndrome, Subacute Bacterial Endocarditis (SBE), Susac syndrome, sympathetic ophthalmia, Takayasu arteritis, temporalis Arteritis/giant cell arteritis, thrombotic thrombocytopenic purpura (TTP), Tolosa-Hunter syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease (undifferentiated connective tissue disease) ive tissue disease (UCTD), uveitis, vasculitis, vitiligo, Waldenstrom's macroglobulinemia (WM), and Wechsler's granulomatosis (granulomatosis with polyangiitis (GPA).

在一些情況下，自身免疫病包括選自以下的一個或更多個疾病：類風濕性關節炎、I型糖尿病、系統性紅斑狼瘡(狼瘡或SLE)、重症肌無力、多發性硬化、硬皮病、阿狄森氏病、大皰性類天皰瘡、尋常型天皰瘡、格林- 巴厘綜合征、舍葛籣綜合征、肌痹、血栓性血小板減少性紫癜、高丙種球蛋白血症、意義未明的單克隆丙種球蛋白病(MGUS)、華氏巨球蛋白血症(WM)、慢性炎性脫髓鞘性多發性神經根神經病(CIDP)、甲狀腺炎性神經根神經病(H)、格雷夫斯病、韋格納肉芽腫和抗體介導的移植排斥(例如，對於組織移植，如腎移植)。在實例中，自身免疫病可以是I型糖尿病、狼瘡或類風濕性關節炎。 In some cases, the autoimmune disease includes one or more diseases selected from the group consisting of rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus (lupus or SLE), myasthenia gravis, multiple sclerosis, scleroderma disease, Addison's disease, bullous pemphigoid, pemphigoid vulgaris, Guillain- Bali syndrome, Shegart syndrome, muscle paralysis, thrombotic thrombocytopenic purpura, hypergammaglobulinemia, monoclonal gammopathy of undetermined significance (MGUS), Waldenstrom's macroglobulinemia (WM), Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), thyroid inflammatory radiculoneuropathy (H), Graves' disease, Wegener's granulomatosis, and antibody-mediated transplant rejection (eg, for tissue transplants, such as Kidney transplant). In an example, the autoimmune disease can be type I diabetes, lupus, or rheumatoid arthritis.

在一些情況下，靶細胞形成腫瘤(即實體瘤)。用本文中的方法治療的腫瘤可穩定腫瘤生長(例如，一個或更多個腫瘤的尺寸增加不超過1%、5%、10%、15%或20%，和/或不轉移)。在一些情況下，腫瘤穩定至少約1、2、3、4、5、6、7、8、9、10、11、12或更多周。在一些情況下，腫瘤穩定至少約1、2、3、4、5、6、7、8、9、10、11、12或更多個月。在一些情況下，腫瘤穩定至少約1、2、3、4、5、6、7、8、9、10或更多年。在一些情況下，腫瘤的尺寸或腫瘤細胞的數量降低至少約5%、10%、15%、20%、25、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或更多。在某些情況下，腫瘤被完全消除，或降低至檢測水平以下。在一些情況下，對象在治療之後至少約1、2、3、4、5、6、7、8、9、10、11、12或更多周內保持無腫瘤(例如緩解)。在一些情況下，對象在治療之後至少約1、2、3、4、5、6、7、8、9、10、11、12或更多個月內保持無腫瘤。在一些情況下，對象在治療之後至少約1、2、3、4、5、6、7、8、9、10或更多年保持沒有腫瘤。 In some instances, the target cells form tumors (ie, solid tumors). Tumors treated with the methods herein can stabilize tumor growth (eg, one or more tumors do not increase in size by more than 1%, 5%, 10%, 15%, or 20%, and/or do not metastasize). In some instances, the tumor is stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks. In some instances, the tumor is stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months. In some cases, the tumor is stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years. In some instances, the size of the tumor or the number of tumor cells is reduced by at least about 5%, 10%, 15%, 20%, 25, 30%, 35%, 40%, 45%, 50%, 55%, 60% , 65%, 70%, 75%, 80%, 85%, 90%, 95% or more. In some cases, tumors were completely eliminated, or reduced to below detection levels. In some instances, the subject remains tumor free (eg, in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks following treatment. In some instances, the subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months after treatment. In some instances, the subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years following treatment.

在另一個具體方面，本公開內容提供了在哺乳動物中治療癌症的方法，包括向哺乳動物施用治療有效量的本公開內容提供的多肽和/或抗原結合部分。在一個方面，施用可通過降低或抑制癌細胞的進一步生長或擴散、癌細胞死亡、抑制癌症復發、降低與癌症相關的疼痛或改善動物存活來治療對象。癌症復發的抑制考慮了先前已經通過放射、化學治療、手術或其他技術治療的癌症部位和周圍組織。效果可以是主觀的或客觀的。例如，如果動物是人，則人可注意到作為改善或對治療的應答的主觀症狀的活力或生活力的改善或疼痛的減輕。或者，基於體檢、實驗室參數、腫瘤標誌物或放射學發現，臨床醫師可注意到腫瘤尺寸或腫瘤負擔的降低。臨床醫師可觀察到的對治療應答的一些實驗室跡象包括測試的正常化，例如白細胞計數、紅細胞計數、血小板計數、 紅細胞沉降率和多種酶水平的正常化。此外，臨床醫師可觀察到可檢測的腫瘤標誌物的降低。或者，可使用其他測試來評價客觀改善，例如聲圖、核磁共振測試和正電子發射測試。在一些實施方案中，多肽包含本公開內容提供的OX40抗體或其結合部分片段。在另外的實施方案中，多肽和/或抗原結合部分是表1或表2中提供的。在另外的實施方案中，哺乳動物是人。 In another specific aspect, the present disclosure provides a method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a polypeptide and/or antigen-binding portion provided by the present disclosure. In one aspect, administration can treat a subject by reducing or inhibiting further growth or spread of cancer cells, cancer cell death, inhibiting cancer recurrence, reducing cancer-related pain, or improving animal survival. Inhibition of cancer recurrence takes into account cancer sites and surrounding tissue that have previously been treated with radiation, chemotherapy, surgery, or other techniques. Effects can be subjective or objective. For example, if the animal is a human, the human may notice an improvement in vitality or vitality or a reduction in pain as a subjective symptom of improvement or response to treatment. Alternatively, a clinician may notice a reduction in tumor size or tumor burden based on physical examination, laboratory parameters, tumor markers, or radiological findings. Some laboratory signs of response to therapy that are observable by clinicians include normalization of tests such as white blood cell count, red blood cell count, platelet count, erythrocyte sedimentation rate, and normalization of various enzyme levels. In addition, clinicians can observe a decrease in detectable tumor markers. Alternatively, other tests can be used to assess objective improvement, such as sonograms, nuclear magnetic resonance tests, and positron emission tests. In some embodiments, the polypeptide comprises an OX40 antibody or binding portion fragment thereof provided by the present disclosure. In additional embodiments, the polypeptides and/or antigen binding moieties are provided in Table 1 or Table 2 . In additional embodiments, the mammal is a human.

在一些實施方案中，本文中公開了藥物組合物，其包含至少：(a)本文中公開的抗OX40抗體；和(b)藥學上可接受的賦形劑。在實施治療方法時，主題多肽或抗原結合部分可作為單一治療單獨施用，或與一種或更多種另外的治療劑或治療組合施用。因此，在另一個方面，本公開內容提供了聯合治療，其包含本公開內容提供的結合部分或多肽聯合一種或更多種另外的治療或治療劑。 In some embodiments, disclosed herein are pharmaceutical compositions comprising at least: (a) an anti-OX40 antibody disclosed herein; and (b) a pharmaceutically acceptable excipient. In practicing the method of treatment, the subject polypeptide or antigen-binding portion can be administered alone as a monotherapy, or in combination with one or more additional therapeutic agents or treatments. Accordingly, in another aspect, the present disclosure provides a combination therapy comprising a binding moiety or polypeptide provided by the present disclosure in combination with one or more additional treatments or therapeutic agents.

還提供了聯合治療和/或治療方案，其包括施用包含抗OX40抗體和PI3K抑制劑的藥物組合物。在一個實施方案中，抗OX40抗體靶向人OX40並且PI3K抑制劑是Tenalisib。 Combination therapy and/or treatment regimens are also provided which include administration of a pharmaceutical composition comprising an anti-OX40 antibody and a PI3K inhibitor. In one embodiment, the anti-OX40 antibody targets human OX40 and the PI3K inhibitor is Tenalisib.

本文中還提供了包含任何上述包含抗原結合部分和/或抗PI3K抑制劑的多肽的藥物組合物。 Also provided herein are pharmaceutical compositions comprising any of the above-described polypeptides comprising an antigen binding moiety and/or an anti-PI3K inhibitor.

藥物組合物可任選地包含一種或更多種另外的藥物活性成分，例如另一種抗體或藥物。本發明的藥物組合物還可以以與例如另一種免疫刺激劑、抗癌劑、抗病毒劑或疫苗的聯合治療來施用，使得抗OX40抗體增強針對疫苗的免疫應答。藥學上可接受的載體可包括例如藥學上可接受的液體、凝膠或固體載體、水性介質、非水性介質、抗微生物劑、等張劑、緩衝劑、抗氧化劑、麻醉劑、混懸劑/分散劑、螯合劑、稀釋劑、佐劑、賦形劑或非毒性輔助物質，其他本領域已知的組分或更多的多種組合 The pharmaceutical composition may optionally contain one or more additional pharmaceutically active ingredients, such as another antibody or drug. The pharmaceutical compositions of the present invention can also be administered in combination therapy with, for example, another immunostimulatory, anticancer, antiviral, or vaccine, such that anti-OX40 antibodies enhance the immune response to the vaccine. Pharmaceutically acceptable carriers can include, for example, pharmaceutically acceptable liquid, gel or solid carriers, aqueous media, non-aqueous media, antimicrobial agents, isotonic agents, buffers, antioxidants, anesthetics, suspensions/dispersions Agents, chelating agents, diluents, adjuvants, excipients or non-toxic auxiliary substances, other components known in the art or various combinations of more

對於向對象施用，本文中公開的多肽可與一種或更多種藥學上可接受的載體或賦形劑一起以藥物組合物來提供。術語“藥學上可接受的載體”包括但不限於不干擾成分生物活性的有效性並且對其施用的患者是非毒性的任何載體。合適的藥物載體的實例是本領域公知的，並且包括磷酸鹽緩衝液、水、 乳劑(例如油/水乳劑)、多種類型的潤濕劑、無菌溶液等。這樣的載體可通過常規方法配製並且可以以合適的劑量施用於對象。優選地，組合物是無菌的。這些組合物還可包含輔料，例如防腐劑、乳化劑和分散劑。可通過包含多種抗細菌劑和抗真菌劑來確保防止微生物的作用。 For administration to a subject, the polypeptides disclosed herein can be provided in a pharmaceutical composition together with one or more pharmaceutically acceptable carriers or excipients. The term "pharmaceutically acceptable carrier" includes, but is not limited to, any carrier that does not interfere with the effectiveness of the biological activity of the ingredient and that is non-toxic to the patient to which it is administered. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline, water, Emulsions (eg, oil/water emulsions), various types of wetting agents, sterile solutions, and the like. Such carriers can be formulated by conventional methods and administered to a subject at a suitable dosage. Preferably, the composition is sterile. These compositions may also contain adjuvants such as preservatives, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents.

藥物組合物可以是任何合適的形式，取決於期望的施用方法。其可以以單位劑型提供，可在密封容器中提供並且可作為藥盒的一部分提供。這樣的藥盒可包括使用說明。其可包括多個所述單位劑型。 The pharmaceutical composition can be in any suitable form, depending on the desired method of administration. It can be presented in unit dosage form, in a sealed container and as part of a kit. Such kits may include instructions for use. It may comprise a plurality of such unit dosage forms.

本發明的藥物組合物可通過多種途徑在體內施用於有此需要的對象，包括但不限於經口、靜脈內、動脈內、皮下、腸胃外、鼻內、肌內、顱內、心內、腦室內、氣管內、經頰、經直腸、腹膜內、皮內、經表面、經皮和鞘內，或通過植入或吸入的其他方式。所述組合物可被配製成固體、半固體、液體或氣體形式的製劑；包括但不限於片劑、膠囊劑、粉劑、顆粒劑、軟膏劑、溶液劑、栓劑、灌腸劑、注射劑、吸入劑和氣霧劑。適當的製劑和施用途徑可根據預期應用和治療方案來選擇。 The pharmaceutical compositions of the present invention can be administered in vivo to a subject in need thereof by a variety of routes, including but not limited to oral, intravenous, intraarterial, subcutaneous, parenteral, intranasal, intramuscular, intracranial, intracardiac, Intracerebroventricular, intratracheal, buccal, rectal, intraperitoneal, intradermal, topical, transdermal and intrathecal, or by other means by implantation or inhalation. The compositions may be formulated into solid, semi-solid, liquid or gaseous forms; including but not limited to tablets, capsules, powders, granules, ointments, solutions, suppositories, enemas, injections, inhalation and aerosols. Appropriate formulations and routes of administration can be selected depending on the intended application and treatment regimen.

本公開內容的物質的劑量可在寬範的範圍內變化，這取決於待治療的疾病或病症、待治療個體的年齡和狀況等，並且醫師將最終確定使用的適當劑量。 Dosages of the agents of the present disclosure can vary widely depending on the disease or disorder being treated, the age and condition of the individual being treated, etc., and the physician will ultimately determine the appropriate dose to use.

施用頻率可在治療進程中確定和調整，並且基於降低靶細胞例如增殖性或致瘤性細胞的數量、保持贅生性細胞的降低、降低贅生性細胞的增殖、或延緩轉移的發展。在一些實施方案中，可調整或減弱施用的劑量以控制潛在的副作用和/或毒性。或者，所述治療組合物的持續連續釋放製劑是可行的。 The frequency of administration can be determined and adjusted over the course of treatment and is based on reducing the number of target cells, eg, proliferative or tumorigenic cells, maintaining a reduction in neoplastic cells, reducing proliferation of neoplastic cells, or delaying the development of metastases. In some embodiments, the dose administered may be adjusted or reduced to manage potential side effects and/or toxicity. Alternatively, sustained continuous release formulations of the therapeutic composition are feasible.

本領域技術人員將理解，合適的劑量可因患者而異。確定最佳劑量將通常涉及治療有益結果與任何風險或有害副作用的平衡。選擇的劑量水平將取決於多種因素，包括但不限於特定化合物的活性，施用途徑，施用時間，化合物的***速率，治療持續時間，組合物中使用的其他藥物、化合物和/或材料，病症的嚴重程度，以及患者的物種、性別、年齡、重量、狀況、一般健康和既往病史。化合物的量和施用途徑最終將由醫師、獸醫或臨床醫師自行決定， 儘管通常來說會選擇劑量以在作用部位達到實現期望效果而不造成實質性的傷害或有害副作用的局部濃度。 Those skilled in the art will understand that appropriate dosages may vary from patient to patient. Determining the optimal dose will generally involve balancing the beneficial outcome of the treatment with any risk or detrimental side effects. The dose level selected will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds and/or materials used in the composition, the Severity, as well as the patient's species, sex, age, weight, condition, general health, and past medical history. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian or clinician, Although generally the dosage will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial harm or deleterious side effects.

一般而言，可以以多種範圍施用包含所述抗原結合部分的多肽。包括每劑約5μg/kg體重至約100mg/kg體重；每劑約50μg/kg體重至約5mg/kg體重；每劑約100μg/kg體重至約10mg/kg體重。其他範圍包括每劑約100μg/kg體重至約20mg/kg體重和每劑約0.5mg/kg體重至約20mg/kg體重。在某些實施方案中，劑量為至少約100μg/kg體重、至少約250μg/kg體重、至少約750μg/kg體重、至少約3mg/kg體重、至少約5mg/kg體重，至少約10mg/kg體重。 In general, polypeptides comprising the antigen binding portion can be administered in a variety of ranges. These include about 5 μg/kg body weight to about 100 mg/kg body weight per dose; about 50 μg/kg body weight to about 5 mg/kg body weight per dose; about 100 μg/kg body weight to about 10 mg/kg body weight per dose. Other ranges include about 100 μg/kg body weight to about 20 mg/kg body weight per dose and about 0.5 mg/kg body weight to about 20 mg/kg body weight per dose. In certain embodiments, the dose is at least about 100 μg/kg body weight, at least about 250 μg/kg body weight, at least about 750 μg/kg body weight, at least about 3 mg/kg body weight, at least about 5 mg/kg body weight, at least about 10 mg/kg body weight .

在一些實施方案中，多肽還包含可檢測標記、治療劑或藥代動力學修飾部分。在一些實施方案中，可檢測標記包括螢光標記、放射性標記、酶、核酸探針或造影劑。 In some embodiments, the polypeptide further comprises a detectable label, a therapeutic agent, or a pharmacokinetic modifying moiety. In some embodiments, detectable labels include fluorescent labels, radiolabels, enzymes, nucleic acid probes, or contrast agents.

腸胃外施用(例如，靜脈內注射)的相容製劑將包含多肽，其包含濃度為約10μg/ml至約100mg/ml的本文中公開的抗原結合部分。在某些選定的實施方案中，多肽或抗原結合部分的濃度將包括20μg/ml、40μg/ml、60μg/ml、80μg/ml、100μg/ml、200μg/ml、300μg/ml、400μg/ml、500μg/ml、600μg/ml、700μg/ml、800μg/ml、900μg/ml或1mg/ml。在另一些優選實施方案中，ADC濃度將包括2mg/ml、3mg/ml、4mg/ml、5mg/ml、6mg/ml、8mg/ml、10mg/ml、12mg/ml、14mg/ml、16mg/ml、18mg/ml、20mg/ml、25mg/ml、30mg/ml、35mg/ml、40mg/ml、45mg/ml、50mg/ml、60mg/ml、70mg/ml、80mg/ml、90mg/ml或100mg/ml。 Compatible formulations for parenteral administration (eg, intravenous injection) will comprise a polypeptide comprising an antigen-binding moiety disclosed herein at a concentration of from about 10 μg/ml to about 100 mg/ml. In certain selected embodiments, the concentration of the polypeptide or antigen binding moiety will include 20 μg/ml, 40 μg/ml, 60 μg/ml, 80 μg/ml, 100 μg/ml, 200 μg/ml, 300 μg/ml, 400 μg/ml, 500 μg/ml, 600 μg/ml, 700 μg/ml, 800 μg/ml, 900 μg/ml or 1 mg/ml. In other preferred embodiments, ADC concentrations will include 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 8 mg/ml, 10 mg/ml, 12 mg/ml, 14 mg/ml, 16 mg/ml ml, 18mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 35mg/ml, 40mg/ml, 45mg/ml, 50mg/ml, 60mg/ml, 70mg/ml, 80mg/ml, 90mg/ml or 100mg/ml.

在一個實施方案中，抑制劑的濃度為1mg、4mg、7mg、10mg、13mg、16mg、19mg、22mg、25mg、28mg、31mg、34mg、37mg、40mg、43mg、46mg、49mg、52mg、55mg、58mg、61mg、64mg、67mg、70mg、73mg、76mg、79mg、82mg、85mg、88mg、91mg、94mg、97mg或100mg。在一個實施方案中，抑制物是Tenalisib並且其以4mg的劑量施用。在一個實施方案中，Tenalisib以兩片2mg的片劑施用。 In one embodiment, the concentration of inhibitor is 1 mg, 4 mg, 7 mg, 10 mg, 13 mg, 16 mg, 19 mg, 22 mg, 25 mg, 28 mg, 31 mg, 34 mg, 37 mg, 40 mg, 43 mg, 46 mg, 49 mg, 52 mg, 55 mg, 58 mg , 61 mg, 64 mg, 67 mg, 70 mg, 73 mg, 76 mg, 79 mg, 82 mg, 85 mg, 88 mg, 91 mg, 94 mg, 97 mg, or 100 mg. In one embodiment, the inhibitor is Tenalisib and it is administered at a dose of 4 mg. In one embodiment, Tenalisib is administered in two 2 mg tablets.

在一個方面，所述多肽和針對PI3K的抑制劑以相同的單位劑量 製備。一方面，多肽和針對PI3K的抑制劑以不同的單位劑量製備。在一個方面，多肽和抑制劑同時、順序或同時和順序施用。 In one aspect, the polypeptide and the inhibitor against PI3K are in the same unit dose preparation. In one aspect, the polypeptide and the inhibitor against PI3K are prepared in different unit doses. In one aspect, the polypeptide and inhibitor are administered simultaneously, sequentially, or both.

在一個方面，可進一步向對象施用共治療劑。 In one aspect, a co-therapeutic agent can be further administered to the subject.

共治療劑的非限制性實例可包括細胞毒劑、化學治療劑、生長抑制劑、用於放射治療的藥劑、抗血管生成劑、凋亡劑、抗微管蛋白劑和其他治療癌症的藥劑，例如，抗CD20抗體、抗PD1抗體(例如派姆單抗)血小板衍生生長因數抑制劑(例如GLEEVECTM(甲磺酸伊馬替尼))、COX-2抑制劑(例如塞來昔布)、干擾素、細胞因數、與以下靶標的一種或更多種結合的拮抗劑(例如中和抗體)：PDGFR-β、BlyS、APRIL、BCMA受體、TRAIL/Apo2、其他生物活性和有機化學試劑等。 Non-limiting examples of co-therapeutic agents can include cytotoxic agents, chemotherapeutic agents, growth inhibitors, agents for radiation therapy, anti-angiogenic agents, apoptotic agents, anti-tubulin agents, and other agents for the treatment of cancer, such as , anti-CD20 antibodies, anti-PD1 antibodies (eg, pembrolizumab) platelet-derived growth factor inhibitors (eg, GLEEVEC ™ (imatinib mesylate)), COX-2 inhibitors (eg, celecoxib), interferon , cytokines, antagonists (eg neutralizing antibodies) that bind to one or more of the following targets: PDGFR-β, BlyS, APRIL, BCMA receptors, TRAIL/Apo2, other biologically active and organic chemical agents, etc.

共治療劑，例如化學治療劑的非限制性實例可包括烷化劑，例如噻替呱和CYTOXAN®環磷醯胺；烷基磺酸酯類，例如白消安、英丙舒凡和呱泊舒凡；氮雜環丙烷類，例如苯佐替呱(benzodopa)、卡波醌、美妥替呱(meturedopa)和烏瑞替派(uredopa)；乙撐亞胺類(ethylenimines)和甲基蜜胺類，包括六甲蜜胺、三乙撐蜜胺(triethylenemelamine)、三乙撐磷醯胺(trietylenephosphoramide)、三乙撐硫代磷醯胺(triethiylenethiophosphoramide)和三甲蜜胺；番荔枝內酯類(acetogenins)(尤其是布拉他辛和布拉他辛酮)；δ-9-四氫***酚(屈***酚，MARINOL®)；β-拉帕醌；拉帕醇；秋水仙堿；樺木酸；喜樹堿類(包括合成的類似物拓撲替康(HYCAMTIN®)、CPT-11(伊立替康、CAMPTOSAR®)、乙醯喜樹堿、scopolectin和9-氨基喜樹堿)；苔蘚蟲素；卡利他汀(callystatin)；CC-1065(包括其阿多來新、卡折來新和比折來新合成類似物)；鬼臼毒素；鬼臼酸；替尼泊苷；念珠藻素(特別是念珠藻素1和念珠藻素8)；尾海兔素；倍癌黴素(包括合成類似物KW-2189和CB1-TM1)；五加素；水鬼蕉堿；匍枝珊瑚醇類；海綿抑制素；氮芥類，例如苯丁酸氮芥、萘氮芥、氯磷醯胺、雌莫司汀、異環磷醯胺、氮芥、鹽酸甲氧氮芥、美法侖、新恩比興、苯芥膽甾醇、潑尼莫司汀、曲磷胺和尿嘧啶氮芥；亞硝基脲類，例如卡莫司汀、氯脲黴素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀；抗生素，例如烯二炔類抗生素；達因黴素，包括達因黴素A；埃斯培拉黴素類；以及新制癌菌素發 色團和相關色蛋白烯二炔抗生素發色團、阿克拉黴素、放線菌素、安麯黴素、重氮絲氨酸、博來黴素、放線菌素C(cactinomycin)、卡柔比星、洋紅黴素、嗜癌菌素、色黴素、更生黴素、柔紅黴素、地托比星、6-重氮-5-氧代-L-正亮氨酸、ADRIAMYCIN®多柔比星(包括嗎啉代-多柔比星、氰基嗎啉代-多柔比星、2-吡咯啉基-多柔比星和去氧多柔比星)、表柔比星、依索比星、伊達比星、麻西羅黴素、絲裂黴素類(例如絲裂黴素C)、黴酚酸、諾加黴素、橄欖黴素類、培洛黴素、潑非黴素、嘌呤黴素、三鐵阿黴素、羅多比星、鏈黑菌素、鏈脲黴素、殺結核菌素、烏苯美司、淨司他丁、佐柔比星；抗代謝物類，例如甲氨蝶呤和5-氟脲嘧啶(5-FU)；葉酸類似物，例如二甲葉酸、甲氨蝶呤、蝶羅呤、三甲曲沙；嘌呤類似物，例如氟達拉濱、6-巰基嘌呤、硫咪嘌呤、硫鳥嘌呤；嘧啶類似物，例如安西他濱、阿紮胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、二去氧尿苷、去氧氟尿苷、依諾他濱、氟尿苷；雄激素，例如卡魯睾酮、丙酸屈他雄酮、環硫雄醇、美雄烷、睾內酯；抗腎上腺類，例如氨魯米特、米托坦、曲洛司坦；葉酸補充劑，例如亞葉酸；醋葡醛內酯；醛磷醯胺糖苷；氨基乙醯丙酸；恩尿嘧啶；安吖啶；貝斯布西；比生群；依達曲沙；地磷醯胺(defofamine)；秋水仙胺；地吖醌；依洛尼塞；依利醋銨；埃博黴素類；依託格魯；硝酸鎵；羥基脲；香菇多糖；氯尼達明；美登木素生物鹼類，例如美登素和安絲菌素；米托胍腙；米托蒽醌；莫呱達醇；尼曲吖啶；噴司他丁；蛋氨氮芥(phenamet)；吡柔比星；洛索蒽醌；2-乙醯肼；丙卡巴肼；PSK®多糖複合物(JHS Natural Products,Eugene,Oreg.)；雷佐生；根黴素；西佐喃；鍺螺胺(spirogermanium)；細交鏈孢菌酮酸(tenuazonic acid)；三亞胺醌；2,2’,2”-三氯三乙胺；單端孢黴烯類(尤其是T-2毒素、疣孢菌素A、漆斑菌素A和蛇形菌素)；烏拉坦；長春地辛(ELDISINE®，FILDESIN®)；達卡巴嗪；甘露莫司汀；二溴甘露醇；二溴衛矛醇；呱泊溴烷；加西托星；***糖苷(“Ara-C”)；噻替呱；紫杉烷類，例如紫杉烷，包括TAXOL®紫杉醇(Bristol-Myers Squibb Oncology, Princeton,N.J.)、ABRAXANETM不含克列莫佛的白蛋白工程化的紫杉醇納米粒製劑(American Pharmaceutical Partners,Schaumberg,Ill.)和TAXOTERE®多西他賽(Rhône-Poulenc Rorer,Antony,France)；苯丁酸氮芥；吉西他濱(GEMZAR®)；6-硫鳥嘌呤；巰基嘌呤；甲氨蝶呤；鉑類似物，例如順鉑和卡鉑；長春堿 (ONCOVIN®)；鉑；依託泊苷(VP-16)；異環磷醯胺；米托蒽醌；長春新堿(ONCOVIN®)；奧沙利鉑；甲醯四氫葉酸；長春瑞濱(NAVELBINE®)；諾消靈(novantrone)；依達曲沙；道諾黴素；氨基喋呤；伊班膦酸鹽；拓撲異構酶抑制劑RFS 2000；二氟甲基鳥氨酸(Difluoromethylornithine,DMFO)；類視黃醇，例如視黃酸；卡培他濱(XELODA®)；上述任意一種的藥學上可接受的鹽、酸或衍生物；以及上述兩種或更多種的組合，例如CHOP，是環磷醯胺、多柔比星、長春新堿和潑尼松龍聯合治療的縮寫，以及FOLFOX，是奧沙利鉑(ELOXATINTM)聯合5-FU和甲醯四氫葉酸的治療方案的縮寫。另外的化學治療劑包括用作抗體藥物綴合物的細胞毒劑，例如美登木素生物鹼(例如DM1)以及瑞奧西汀例如MMAE和MMAF。 Non-limiting examples of co-therapeutic agents, such as chemotherapeutic agents, may include alkylating agents, such as thietidine and CYTOXAN® ; Shufan; aziridines such as benzodopa, carboquinone, meturedopa and uredopa; ethylenimines and methyl honey Amines, including hexamethylmelamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins ) (especially bratacin and bratacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL® ); beta-lapachone; lapasol; colchicine; betulinic acid; Trees (including the synthetic analogs topotecan (HYCAMTIN ® ), CPT-11 (irinotecan, CAMPTOSAR ® ), acetyl camptothecin, scopolectin and 9-aminocamptothecin); bryostatins; Callystatin; CC-1065 (including its synthetic analogs of adolecin, kazelestine and biszelest); podophyllotoxin; podophyllotoxin; teniposide; candida (particularly Candidin 1 and Candidin 8); Aplysin; Duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); Penicillin; Statins; nitrogen mustards, such as chlorambucil, chlorambucil, chlorphosphamide, estramustine, ifosfamide, nitrogen mustard, methoxamidine hydrochloride, melphalan, sinenbi Cholesterol, Benzodiazepine, Cholesterol, Prednimustine, Trifosamide, and Uracil Mustard; mustine and ramustine; antibiotics, such as enediyne antibiotics; dynemycins, including dynemycin A; esperamycins; and neocarboxin chromophores and related chromoproteins Nedyne antibiotic chromophore, aclarithromycin, actinomycin, anthromycin, azaserine, bleomycin, actinomycin C (cactinomycin), carrubicin, carrubicin, carcinophilus tetracycline, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIMYCIN® doxorubicin (including morpholino-doxorubicin) rubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, ethorubicin, idarubicin, maxi Roxithromycin, mitomycins (e.g. mitomycin C), mycophenolic acid, nogamycin, oleomycin, peclomycin, prednisolone, puromycin, adriamycin Sulphur, rhodorubicin, streptozotocin, streptozotocin, tuberculin, black Benmesex, netstatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as folic acid, methotrexate, Pteroxate, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thioazapine, thioguanine; pyrimidine analogs such as amcitabine, azacitidine, 6-azauridine , carmofur, cytarabine, dideoxyuridine, deoxyfluridine, enoctabine, floxuridine; androgens such as calurotestosterone, drostanolone propionate, cyclothiosterol , Meandrostane, Testosterone; Antiadrenal such as Aminoglutide, Mitotane, Trilostane; Folic Acid Supplements such as Leucovorin; Acetoglucuronolactone; Propionic acid; Eniluracil; Amacridine; Bethbush; Bisantrine; Edatrexate; defofamine; Colchicamide; bleomycins; etoglu; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansothrin; Modatrol; Nitroacridine ; Pentostatin; Phenamet; Pirarubicin; Loxoxantrone; Products, Eugene, Oreg.); Razoxan; Rhizomycin; Sizoran; Spirogermanium; Tenuazonic acid; Triimine quinone; Trichlorotriethylamine; Trichothecenes (especially T-2 toxins, Verrucosporin A, Myricin A, and Serpentin); Urethane; Vindesine (ELDISINE ® , FILDESIN ® ); Dacarbazine; Mannomustine; Dibromomannitol; Dibromodulitol; For example taxanes including TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE ™ cremophor-free albumin engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, Ill.) and TAXOTERE® docetaxel (Rhône-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine (GEMZAR ® ); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine (ONCOVIN ® ); platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vinblastine (ONCOVIN ® ); oxaliplatin; Folic Acid; Vinorelbine (NAVELBINE ® ); Novant rone); Edatrexate; Daunomycin; Aminopterin; Ibandronate; Topoisomerase Inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoids, For example, retinoic acid; capecitabine ( XELODA® ); a pharmaceutically acceptable salt, acid or derivative of any of the foregoing; and combinations of two or more of the foregoing, for example CHOP, is cyclophosphamide, Abbreviation for doxorubicin, vinblastine, and prednisolone combination therapy, and FOLFOX, abbreviation for oxaliplatin (ELOXATIN ™ ) in combination with 5-FU and methyltetrahydrofolate. Additional chemotherapeutic agents include cytotoxic agents used as antibody drug conjugates, such as maytansinoids (eg, DM1) and reoxetines such as MMAE and MMAF.

在一個方面，共治療劑可以是抗激素劑或內分泌治療劑，其作用是調節、降低、阻斷或抑制可促進癌症生長的激素的作用，並且通常是以系統性或全身治療的形式施用。其本身可能是激素。實例包括抗***和選擇性***受體調節劑(selective estrogen-receptor modulator,SERM)，包括例如他莫昔芬(包括NOLVADEX®他莫昔芬)、EVISTA®雷洛昔芬、屈洛昔芬、4-羥基他莫昔芬、三昔芬、酮替芬、LY117018、奧那司酮和FARESTON®托瑞米芬；抗孕酮；***受體下調劑(estrogen receptor downregulator,ERD)；具有抑制或關閉卵巢功能的藥劑，例如，促黃體激素釋放激素(Luteinizing hormone-releasing hormone,LHRH)激動劑，例如LUPRON®和ELIGARD)、醋酸亮丙瑞林、醋酸戈舍瑞林、醋酸布舍瑞林和曲普瑞林；其他抗雄激素藥，例如氟他胺、尼魯他胺和比卡魯胺；以及抑制酶芳香酶(其調節腎上腺中***的產生)的芳香酶抑制劑，例如，如4(5)-咪唑、氨魯米特、MEGASE®醋酸甲地孕酮、AROMASIN®依西美坦、福美司坦、法倔唑、RIVISOR®伏氯唑、FEMARA®來曲唑和ARIMIDEX®阿那曲唑。另外，化學治療劑的這樣的定義包括雙膦酸鹽，例如氯膦酸鹽(例如BONEFOS®或OSTAC®)、DIDROCAL®依替膦酸鹽、NE-58095、ZOMETA®唑來膦酸/唑來膦酸鹽、FOSAMAX®阿侖膦酸鹽、AREDIA®帕米膦酸鹽、SKELID®替魯膦酸鹽、或ACTONEL®利塞膦酸鹽；以及曲沙他濱(1,3-二氧戊環核苷胞嘧啶類似物)；反義寡核苷酸，特別是抑制與 異常細胞增殖有關的信號傳導途徑中的基因表達的反義寡核苷酸，所述基因為例如PKC-α、Raf、H-Ras和表皮生長因數受體(EGFR)；疫苗，例如THERATOPE®疫苗和基因治療疫苗，例如ALLOVECTIN®疫苗、LEUVECTIN®疫苗和VAXID®疫苗；LURTOTECAN®拓撲異構酶1抑制劑；ABARELIX®rmRH；二甲苯磺酸拉帕替尼(ErbB-2和EGFR雙酪氨酸激酶小分子抑制劑，也被稱為GW572016)；以及任何上述的藥學上可接受的鹽、酸或衍生物。 In one aspect, the co-therapeutic agent may be an antihormone or endocrine therapeutic agent that acts to modulate, reduce, block or inhibit the action of hormones that promote cancer growth, and is usually administered in the form of systemic or systemic therapy. It may itself be a hormone. Examples include anti-estrogens and selective estrogen-receptor modulators (SERMs) including, for example, tamoxifen (including NOLVADEX® tamoxifen), EVISTA® raloxifene , droloxifene fen, 4-hydroxytamoxifen, trioxifen, ketotifen, LY117018, onapristone, and FARESTON® toremifene; antiprogestin; estrogen receptor downregulator (ERD); Agents that suppress or shut down ovarian function, eg, luteinizing hormone-releasing hormone (LHRH) agonists such as LUPRON® and ELIGARD), leuprolide acetate, goserelin acetate, buser acetate Relin and triptorelin; other antiandrogens, such as flutamide, nilutamide, and bicalutamide; and aromatase inhibitors that inhibit the enzyme aromatase, which regulates the production of estrogen in the adrenal glands, For example, such as 4(5)-imidazole, aminoglutamine, MEGASE® megestrol acetate, AROMASIN® exemestane, formestane, fadrozole, RIVISOR® vorozole , FEMARA® letrozole and ARIMIDEX ® anastrozole. Additionally, such definition of chemotherapeutic agents includes bisphosphonates such as clodronate (eg BONEFOS® or OSTAC® ), DIDROCAL® etidronate, NE-58095, ZOMETA® zoledronic acid/zoledronic acid phosphonates, FOSAMAX ® alendronate, AREDIA ® pamidronate, SKELID ® tiludronate, or ACTONEL ® risedronate; and trosacitabine (1,3-dioxolane) cyclic nucleoside cytosine analogs); antisense oligonucleotides, especially antisense oligonucleotides that inhibit the expression of genes in signaling pathways associated with abnormal cell proliferation, such as PKC-alpha, Raf , H-Ras and epidermal growth factor receptor (EGFR); vaccines such as THERATOPE® vaccine and gene therapy vaccines such as ALLOVECTIN® vaccine, LEUVECTIN® vaccine and VAXID® vaccine; LURTOTECAN® topoisomerase 1 inhibitor; ABARELIX® rmRH; lapatinib xylene sulfonate (a small molecule inhibitor of ErbB-2 and EGFR dual tyrosine kinase, also known as GW572016); and any of the foregoing pharmaceutically acceptable salts, acids or derivatives.

在一個實施方案中，共治療劑還可包括抗體，例如阿侖單抗(Campath)、貝伐單抗(AVASTIN®,Genentech)；西妥昔單抗(ERBITUX®,Imclone)；帕尼單抗(VECTIBIX®,Amgen)、利妥昔單抗(RITUXAN®,Genentech/Biogen Idec)、帕妥珠單抗(OMNITARG®,2C4,Genentech)、曲妥珠單抗(HERCEPTIN®,Genentech)、托西莫單抗(Bexxar,Corixia)以及抗體藥物綴合物，吉妥珠單抗奧佐米星(MYLOTARG®,Wyeth)。具有作為與本發明化合物組合的藥劑的治療潛力的其他人源化單克隆抗體包括：阿泊珠單抗、阿塞珠單抗、阿利珠單抗、巴匹珠單抗、莫比伐單抗、莫坎妥珠單抗、西利珠單抗、賽妥珠單抗、cidfusituzumab、cidtuzumab、達克珠單抗、依庫珠單抗、依法珠單抗、依帕珠單抗、厄利珠單抗、feMzumab、芳妥珠單抗、奧吉妥珠單抗、奧英妥珠單抗、伊匹單抗、拉貝珠單抗、林妥珠單抗、馬妥珠單抗、美泊利單抗、莫維珠單抗、莫妥珠單抗、那他珠單抗、尼妥珠單抗、諾洛珠單抗、努馬珠單抗、奧瑞珠單抗、奧馬珠單抗、帕利珠單抗、帕考珠單抗、培非他珠單抗、派克土珠單抗、培克利珠單抗、雷利珠單抗、雷尼珠單抗、瑞絲利維珠單抗、瑞絲利珠單抗、瑞昔維珠單抗、羅維利珠單抗、魯普利珠單抗、西羅妥珠單抗、西普利珠單抗、松妥珠單抗、四曲妥他克珠單抗、他克多珠單抗、他利珠單抗、替非巴珠單抗、托西珠單抗、托拉珠單抗、西莫白介素圖考珠單抗、圖克斯妥珠單抗、烏馬珠單抗、烏頭克珠單抗、烏斯他珠單抗、維西珠單抗和抗白細胞介素12(ABT-874/J695,Wyeth Research and Abbott Laboratories)，其是經遺傳修飾以識別白細胞介素12 p40蛋白的重組僅人序列全長IgG1λ抗體。 In one embodiment, the co-therapeutic agent may also include antibodies, eg, alemtuzumab (Campath), bevacizumab ( AVASTIN® , Genentech); cetuximab ( ERBITUX® , Imclone); panitumumab (VECTIBIX®, Amgen), Rituximab ( RITUXAN® , Genentech/Biogen Idec ) , Pertuzumab ( OMNITARG® , 2C4, Genentech), Trastuzumab ( HERCEPTIN® , Genentech), Tosi Momomab (Bexxar, Corixia) and antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG ® , Wyeth). Other humanized monoclonal antibodies that have therapeutic potential as agents in combination with the compounds of the present invention include: apolizumab, atezolizumab, atezolizumab, bapizumab, mobivacizumab , mocantuzumab, cilizumab, certolizumab, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epalizumab, erizumab anti, feMzumab, fentuzumab, ogiltuzumab, intuzumab, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab Anti-, motezizumab, motuzumab, natalizumab, nimotuzumab, novolizumab, numalizumab, ocrelizumab, omalizumab, paclitaxel Lelibizumab, Pacolizumab, Pefiltezumab, Paxolizumab, Pexelizumab, Lelizumab, Ranibizumab, Rislivizumab, Resilizumab, Rexivizumab, Rovilizumab, Ruprilizumab, Cirostuzumab, Sipilizumab, Sostuzumab, Tetrastuzumab Clinizumab, Talcdolizumab, Talcizumab, Tefibacuzumab, Tocilizumab, Tocilizumab, Simoleukin Tocolizumab, Tuxto cilizumab, umalizumab, aconitizumab, ustalizumab, vecilizumab, and anti-interleukin 12 (ABT-874/J695, Wyeth Research and Abbott Laboratories), which are Recombinant human sequence-only full-length IgGlλ antibody genetically modified to recognize the interleukin 12 p40 protein.

在一個實施方案中，共治療劑可以是酪氨酸激酶抑制劑，例如EGFR靶向劑(例如，小分子、抗體等)；小分子HER2酪氨酸激酶抑制劑，例 如可獲自Takeda的TAK165；CP-724,714，ErbB2受體酪氨酸激酶的經口選擇性抑制劑(Pfizer和OSI)；雙重HER抑制劑，例如EKB-569(可獲自Wyeth)，其優先結合EGFR但抑制HER2和EGFR過表達細胞二者；拉帕替尼(GSK572016；可獲自Glaxo-SmithKline)，經口HER2和EGFR酪氨酸激酶抑制劑；PKI-166(可獲自Novartis)；泛HER抑制劑，例如卡奈替尼(CI-1033；Pharmacia)；Raf-1抑制劑，例如可獲自ISIS Pharmaceuticals的抑制Raf-1信號傳導的反義劑ISIS-5132；非HER靶向TK抑制劑，例如甲磺酸伊馬替尼(GLEEVEC®，可獲自Glaxo SmithKline)；多靶向酪氨酸激酶抑制劑，例如舒尼替尼(SUTENT®，可獲自Pfizer)；VEGF受體酪氨酸激酶抑制劑，例如瓦他拉尼(PTK787/ZK222584，可獲自Novartis/ScheringAG)；MAPK胞外調節激酶I抑制劑CI-1040(可獲自Pharmacia)；喹唑啉類，例如PD 153035,4-(3-氯苯胺基)喹唑啉；吡啶並嘧啶類；嘧啶並嘧啶；吡咯並嘧啶類，例如CGP 59326、CGP 60261和CGP 62706；吡唑並嘧啶類，4-(苯基氨基)-7H-吡咯並[2,3-d]嘧啶；薑黃素(二阿魏醯甲烷，4,5-雙(4-氟苯胺基)鄰苯二甲醯亞胺)；含有硝基噻吩部分的酪氨酸磷酸化抑制劑；PD-0183805(Warner-Lamber)；反義分子(例如，與編碼HER的核酸結合的那些)；喹喔啉(美國專利No.5,804,396)；色氨酸磷酸化抑制劑(tryphostin)(美國專利No.5,804,396)；ZD6474(Astra Zeneca)；PTK-787(Novartis/Schering AG)；泛HER抑制劑，例如CI-1033(Pfizer)；Affinitac(ISIS 3521；Isis/Lilly)；甲磺酸伊馬替尼(GLEEVEC®)；PKI 166(Novartis)；GW2016(Glaxo SmithKline)；CI-1033(Pfizer)；EKB-569(Wyeth)；司馬沙尼(Pfizer)；ZD6474(AstraZeneca)；PTK-787(Novartis/Schering AG)；INC-1C11(Imclone)；和雷帕黴素(sirolimus，RAPAMUNE®)。 In one embodiment, the co-therapeutic agent may be a tyrosine kinase inhibitor, such as an EGFR targeting agent (eg, small molecule, antibody, etc.); a small molecule HER2 tyrosine kinase inhibitor, such as TAK165 available from Takeda CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds EGFR but inhibits HER2 and EGFR Overexpressing cells both; lapatinib (GSK572016; available from Glaxo-SmithKline), oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as card Nettinib (CI-1033; Pharmacia); Raf-1 inhibitors such as ISIS-5132, an antisense inhibitor of Raf-1 signaling available from ISIS Pharmaceuticals; non-HER targeting TK inhibitors such as methanesulfonic acid Imatinib (GLEEVEC ® , available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (SUTENT ® , available from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as Vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK ecto-regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines such as PD 153035, 4-(3-chloro anilino)quinazolines; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[ 2,3-d]pyrimidine; curcumin (diferulomethane, 4,5-bis(4-fluoroanilino)phthalimide); inhibition of tyrosine phosphorylation containing a nitrothiophene moiety PD-0183805 (Warner-Lamber); antisense molecules (eg, those that bind to nucleic acids encoding HER); quinoxaline (US Pat. No. 5,804,396); tryphostin (US Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); Ni (GLEEVEC ® ); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); C I-1033 (Pfizer); EKB-569 (Wyeth); Semazanide (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone); and rapamycin (sirolimus) , RAPAMUNE ® ).

在一個實施方案中，共治療劑還可包括生長抑制劑，例如在體外或體內抑制細胞(例如，其生長依賴於PD-L1表達的細胞)生長和/或增殖的化合物或組合物。生長抑制劑可以是顯著降低S期細胞百分比的生長抑制劑。生長抑制劑的非限制性實例包括阻斷細胞週期進程(在S期以外的地方)的藥劑，例如誘導G1阻滯和M期阻滯的藥劑。經典的M期阻斷劑包括長春花(長春新堿和長春堿)，紫杉烷，和拓撲異構酶II抑制劑，例如蒽環類抗生素多柔比星 ((8S-順式)-10-[(3-氨基-2,3,6-三去氧-α-L-來蘇六吡喃糖基)氧基]-7,8,9,10-四氫-6,8,11-三羥基-8-(羥基乙醯基)-1-甲氧基-5,12-萘二酮)、表柔比星、柔紅黴素、依託泊苷和博來黴素。那些阻滯G1的藥劑也會溢出到S期阻滯，例如DNA烷化劑，例如他莫西芬、潑尼松、達卡巴嗪、雙氯乙基甲胺、順鉑、甲氨蝶呤、5-氟尿嘧啶和ara-C。紫杉烷類(紫杉醇和多西他賽)是來源於紫杉樹的抗癌藥物。多西他賽(TAXOTERE®,Rhone-Poulenc Rorer)來源於歐洲紫杉，是紫杉醇(TAXOL®,Bristol-Myers Squibb)的半合成類似物。紫杉醇和多西他賽促進微管蛋白二聚體組裝成微管，並通過防止解聚穩定微管，從而抑制細胞有絲***。在一個實施方案中，共治療劑還可包括***、干擾素、秋水仙堿、氯苯氨啶、環孢素、兩性黴素、甲硝噠唑、阿侖單抗、阿利維A酸、別嘌呤醇、氨磷汀、三氧化二砷、天冬醯胺酶、活BCG、貝伐唑嗪、貝伐單抗、阿法達貝汀、地尼白介素、右雷佐生、法依泊汀、埃羅替尼、非格司亭、醋酸組氨瑞林、替伊莫單抗、干擾素α-2a、干擾素α-2b、來那度胺、左旋咪唑、美司鈉、甲氧沙林、諾龍、奈拉濱、巰諾莫單抗、奧普瑞白介素、帕利夫明、帕米膦酸鹽、培加酶、培門冬酶、聚乙二醇非格司亭、培美曲塞二鈉、普卡黴素、卟吩姆鈉、奎納克林、拉布立酶、沙格司亭、替莫唑胺、VM-26、6-TG、托瑞米芬、維甲酸、ATRA、戊柔比星、唑來膦酸鹽和唑來膦酸、以及其藥學上可接受的鹽。共治療劑還可包括氫化可的松、醋酸氫化可的松、醋酸可的松、新戊酸替可的松、曲安奈德、曲安奈德醇、莫米松、安西奈德、布***、***、氟輕松、氟輕松醋酸酯、倍他米松、倍他米松磷酸鈉、***、***磷酸鈉、氟考龍、氫化可的松-17-丁酸酯、氫化可的松-17-戊酸酯、氟考龍己酸酯、氟考龍戊酸酯和氟考龍甲酸酯：免疫選擇性抗炎肽(ImSAID)，例如苯丙氨酸-穀氨醯胺-甘氨酸(FEG)及其D異構形式(feG)(IMULAN BioTherapeutics,LLC)；抗風濕藥，例如硫唑嘌呤、環孢素(環孢素A)、D-青黴胺、金鹽、羥基氯喹、來氟米特米諾環素、柳氮磺胺吡啶、腫瘤壞死因數α(TNFα)阻斷劑，例如依那西普(ENBREL®)、英夫利昔單抗(REMICADE®)、阿達木單抗(HUMIRA®)、賽妥珠單抗(CIMZIA®)、戈利木單抗(SIMPONI®)，白細胞介素1(IL-1)阻斷劑，例如阿那白滯素(KINERET®)，T細胞共刺激阻斷劑，例如阿巴西普(ORENCIA®)，白細胞介素6(IL-6)阻斷劑例如托珠單抗(ACTEMERA®)； 白細胞介素13(IL-13)阻斷劑，例如來瑞組單抗；干擾素α(IFN)阻斷劑，例如隆利組單抗；β7整合素阻斷劑，例如rhuMAb Beta7；IgE途徑阻斷劑，例如抗M1 prime；分泌型同源三聚體LTa3和膜結合異源三聚體LTa/β2阻斷劑，例如抗淋巴毒素α(LTa)；其他研究性藥劑，例如硫鉑、PS-341、苯基丁酸鹽、ET-18-OCH3或法尼基轉移酶抑制劑(L-739749、L-744832)；多酚類，例如槲皮苷、白藜蘆醇、白皮杉醇、表沒食子兒茶鹼沒食子酸酯、茶黃素、黃烷醇、原花青素、樺木酸及其衍生物等；自噬抑制劑，例如氯喹；δ-9-四氫***酚(屈***酚，MARINOL®)；β-拉帕醌；拉帕醇；秋水仙堿；樺木酸；乙醯喜樹堿、scopolectin和9-氨基喜樹堿)；鬼臼毒素；替加氟(UFTORAL®)；貝沙羅汀(TARGRETIN®)；雙膦酸鹽，例如氯膦酸鹽(例如BONEFOS®或OSTAC®)、依替膦酸鹽(DIDROCAL®)、NE-58095、唑來膦酸/唑來膦酸鹽(ZOMETA®)、阿侖膦酸鹽(FOSAMAX®)、帕米膦酸鹽(AREDIA®)、替魯膦酸鹽(SKELID®)或利塞膦酸鹽(ACTONEL®)；以及表皮生長因數受體(EGF-R)；疫苗，例如THERATOPE®疫苗；呱立福辛、COX-2抑制劑(例如，塞來昔布或依託考昔)、蛋白酶體抑制劑(例如，PS341)；CCI-779；Tipifamib(R11577)；奧拉非尼，ABT510；Bcl-2抑制劑，例如奧利默森鈉(GENAENSE®)；匹克生瓊；法尼基轉移酶抑制劑，例如lonafamib(SCH6636，SARASARTM)；以及任何上述物質的藥學上可接受的鹽、酸或衍生物；以及上述兩種或多種的組合。 In one embodiment, a co-therapeutic agent may also include growth inhibitors, such as compounds or compositions that inhibit the growth and/or proliferation of cells (eg, cells whose growth is dependent on PD-L1 expression) in vitro or in vivo. The growth inhibitory agent can be one that significantly reduces the percentage of cells in S phase. Non-limiting examples of growth inhibitors include agents that block cell cycle progression (outside S phase), such as agents that induce G1 arrest and M phase arrest. Classic M-phase blockers include periwinkle (vinca and vinca), taxanes, and topoisomerase II inhibitors such as the anthracycline doxorubicin ((8S-cis)-10 -[(3-Amino-2,3,6-trideoxy-α-L-lythohexapyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11- trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthalenedione), epirubicin, daunorubicin, etoposide, and bleomycin. Agents that block G1 also spill over into S-phase block, such as DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, diclofenac, cisplatin, methotrexate, 5-Fluorouracil and ara-C. Taxanes (paclitaxel and docetaxel) are anticancer drugs derived from the yew tree. Docetaxel (TAXOTERE ® , Rhone-Poulenc Rorer) is derived from European yew and is a semisynthetic analog of paclitaxel (TAXOL ® , Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of tubulin dimers into microtubules and stabilize microtubules by preventing depolymerization, thereby inhibiting cell mitosis. In one embodiment, the co-therapeutic agent may also include dexamethasone, interferon, colchicine, chlorpheniramine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alicitidine , Allopurinol, Amifostine, Arsenic trioxide, Asparaginase, Live BCG, Bevacazosin, Bevacizumab, Dalbetine alfa, Denileukin, Dexrazoxane, Epoetin, Epstein-Barr Rotinib, filgrastim, histrelin acetate, tiimumab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, Nandrolone, Nelarabine, Capronomab, Oprelleukin, Palifumin, Pamidronate, Pegase, Pegaspargase, Pegylated Filgrastim, Pemetrexed Disodium, Pukamycin, Porfim Sodium, Quinacrine, Rasburicase, Sagarrastim, Temozolomide, VM-26, 6-TG, Toremifene, Retinoic Acid, ATRA, Valorox Ricin, zoledronate and zoledronic acid, and pharmaceutically acceptable salts thereof. Co-therapeutic agents may also include hydrocortisone, hydrocortisone acetate, cortisone acetate, ticcortisone pivalate, triamcinolone acetonide, triamcinolone acetonide, mometasone, amcinonide, budesonide, Desonide, Fluocinolone, Fluocinolone Acetate, Betamethasone, Betamethasone Sodium Phosphate, Dexamethasone, Dexamethasone Sodium Phosphate, Fluocinolone, Hydrocortisone-17-Butyrate, Hydrocortisone Pine-17-valerate, flucolone caproate, flucolone valerate, and flucolone formate: immunoselective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine- Glycine (FEG) and its D isoform (feG) (IMULAN BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, Leflunomide minocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etanercept (ENBREL ® ), infliximab (REMICADE ® ), adalimumab ( HUMIRA ® ), certolizumab (CIMZIA ® ), golimumab (SIMPONI ® ), interleukin 1 (IL-1) blockers such as anakinra (KINERET ® ), T cells costimulatory blockers such as abatacept (ORENCIA ® ), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA ® ); interleukin 13 (IL-13) blockers, e.g. lelimumab; interferon alpha (IFN) blockers, e.g. lolitimab; β7 integrin blockers, e.g. rhuMAb Beta7; IgE pathway blockers, e.g. anti-M1 prime; Blockers of polymeric LTa3 and membrane-bound heterotrimeric LTa/β2, such as antilymphotoxin alpha (LTa); other investigational agents, such as thioplatinum, PS-341, phenylbutyrate, ET-18- OCH3 or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatephylline gallate , theaflavins, flavanols, proanthocyanidins, betulinic acid and its derivatives, etc.; autophagy inhibitors, such as chloroquine; δ-9-tetrahydrocannabinol (dronabinol, MARINOL ® ); β-Lapachone; Lappaol; Colchicine; Betulinic Acid; Acetyl Camptothecin, Scopolectin, and 9-Aminocamptothecin); Podophyllotoxin; Tegafur (UFTORAL ® ); Bexarotene (TARGRETIN ® ); Bisphosphonic Acid Salts such as clodronate (eg BONEFOS ® or OSTAC ® ), etidronate (DIDROCAL ® ), NE-58095, zoledronic acid/zoledronate (ZOMETA ® ), alendronate (FOSAMAX ® ), pamidronate (AREDIA ® ), tiludronate (S KELID ® ) or risedronate (ACTONEL ® ); and epidermal growth factor receptor (EGF-R); vaccines, such as THERATOPE ® vaccine; or etoricoxib), proteasome inhibitors (eg, PS341); CCI-779; Tipifamib ( R11577 ); olafenib, ABT510; Agarose; farnesyltransferase inhibitors such as lonafamib (SCH6636, SARASAR ™ ); and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing; and combinations of two or more of the foregoing.

用於治療癌症的聯合治療還包括本公開內容提供的多肽與手術的組合以去除腫瘤。可在手術之前、期間或之後向哺乳動物施用多肽和/或包含多肽的聯合治療。 Combination therapy for the treatment of cancer also includes the polypeptides provided by the present disclosure in combination with surgery to remove tumors. The polypeptide and/or combination therapy comprising the polypeptide can be administered to the mammal before, during, or after surgery.

用於治療癌症的聯合治療還包括本公開內容提供的結合分子與放射治療的組合，例如電離(電磁)放射治療(例如，X射線或γ射線)和粒子束放射治療(例如，高線性能量輻射)。輻射源可在哺乳動物的外部或內部。可在放射治療之前、期間或之後向哺乳動物施用結合分子。 Combination therapy for the treatment of cancer also includes the combination of the binding molecules provided by the present disclosure with radiation therapy, such as ionizing (electromagnetic) radiation therapy (eg, X-rays or gamma rays) and particle beam radiation therapy (eg, high linear energy radiation) ). The radiation source can be external or internal to the mammal. The binding molecule can be administered to the mammal before, during, or after radiation therapy.

在本發明的另一方面，提供了包含可用於治療、預防和/或診斷上述疾病的材料的製品。製品包括容器以及在容器上或與容器相聯接的標記或包裝***物。合適的容器包括例如瓶、小瓶、注射器、IV溶液袋等。容器可由多 種材料，例如玻璃或塑膠形成。容器容納單獨地或與另一組合物組合有效治療、預防和/或診斷病症的組合物，並且可具有無菌進入口(例如，容器可以是靜脈內溶液袋或具有可通過皮下注射針刺穿的塞的小瓶)。組合物中的至少一種活性劑是之前如本文中所限定的抗OX40抗體。 In another aspect of the present invention, articles of manufacture comprising materials useful in the treatment, prevention and/or diagnosis of the aforementioned diseases are provided. Articles of manufacture include containers and indicia or packaging inserts on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. Containers can be multiple materials such as glass or plastic. The container contains a composition effective for treating, preventing and/or diagnosing a disorder, alone or in combination with another composition, and may have a sterile access port (for example, the container may be an intravenous solution bag or have a hypodermic needle pierceable stoppered vials). At least one active agent in the composition is an anti-OX40 antibody as previously defined herein.

標記或包裝***物指示所述組合物用於治療所選擇的病症。此外，該製品可包含：(a)第一容器，其中包含組合物，其中所述組合物包含本公開內容的抗體；以及(b)第二容器，其中包含組合物，其中所述組合物包含PI3K抑制劑。在本發明的該實施方案中的製品可還包含指示所述組合物可用於治療特定病症的包裝***物。 The label or package insert indicates that the composition is used to treat the condition of choice. Furthermore, the article of manufacture can comprise: (a) a first container comprising a composition, wherein the composition comprises an antibody of the present disclosure; and (b) a second container comprising a composition, wherein the composition comprises PI3K inhibitors. The article of manufacture in this embodiment of the invention may further comprise a packaging insert indicating that the composition can be used to treat a particular condition.

作為替代或補充，該製品可還包含第二(或第三)容器，所述第二(或第三)容器包含可藥用緩衝劑，例如抑菌注射用水(bacteriostatic water for injection,BWFI)、磷酸緩衝鹽水、林格溶液和右旋糖溶液。其還可包含從商業和使用者的角度來看所期望的其他材料，包括其他緩衝劑、稀釋劑、濾器、針和注射器。 Alternatively or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), Phosphate-buffered saline, Ringer's solution, and dextrose solution. It may also contain other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.

實施例Example

實施例1：CN401與OX86(α-mOX40 mAb)和α-mPD1 mAb在MC38同源模型中的聯用Example 1: Combination of CN401 with OX86 (α-mOX40 mAb) and α-mPD1 mAb in MC38 homology model

研究設計：腫瘤挑戰、藥物治療和腫瘤生長監測Study Design: Tumor Challenge, Drug Therapy, and Tumor Growth Monitoring

進行示例性研究以評價本文中提供的聯合治療在小鼠模型中的安全性和耐受性。研究測試了Tenalisib(CN401)、CN1(抗huOX40，克隆1.134.9-u1-IgGlL)或OX86(抗小鼠OX40，來自BioXcell)抗體和抗PD-1抗體(RMP1-14，來自BioXcell)在小鼠腫瘤模型中施用的協同作用。還評價了CN401在體外多種腫瘤細胞系中的抗腫瘤活性。 Exemplary studies were performed to evaluate the safety and tolerability of the combination treatments provided herein in mouse models. Studies tested Tenalisib (CN401), CN1 (anti-huOX40, clone 1.134.9-u1-IgGlL) or OX86 (anti-mouse OX40, from BioXcell) antibodies and anti-PD-1 antibodies (RMP1-14, from BioXcell) in small Synergy of administration in a murine tumor model. The antitumor activity of CN401 in various tumor cell lines in vitro was also evaluated.

六至八周齡的C57bl/6小鼠(20至25g)購自Shanghai Super-B&K laboratory animal Corp.Ltd.，並將MC38細胞(每只小鼠50萬個細胞)通過皮下接種到小鼠的右脅側中。當腫瘤可觸及(約70mm3)時開始處理。抗OX40 mAb以100μg/小鼠通過腹膜內施用，每週兩次，共3周。CN401以15mg/kg或50mg/kg或150mg/kg經口管飼，每天兩次，共3周。抗PD-1 mAb以60μg/小鼠通過腹膜內施用，每週兩次，共3周。對照組接受不含活性產品的載劑(0.5% MC和PBS)。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six- to eight-week-old C57bl/6 mice (20 to 25 g) were purchased from Shanghai Super-B&K laboratory animal Corp. Ltd., and MC38 cells (500,000 cells per mouse) were subcutaneously inoculated into mice. Right flank. Treatment was initiated when the tumor was palpable (approximately 70 mm 3 ). Anti-OX40 mAb was administered intraperitoneally at 100 μg/mouse twice a week for 3 weeks. CN401 was given by oral gavage at 15 mg/kg or 50 mg/kg or 150 mg/kg twice a day for 3 weeks. Anti-PD-1 mAb was administered intraperitoneally at 60 μg/mouse twice a week for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

表4：實驗設計

Figure 110142111-A0202-12-0054-37
Table 4 : Experimental Design
Figure 110142111-A0202-12-0054-37

圖1A至圖1B和圖2A至圖2G提供了CN401聯合α-mOX40 mAb和抗mPD1 mAb在MC38同源模型中的抗腫瘤活性。 Figures 1A-1B and 2A-2G provide the antitumor activity of CN401 in combination with α-mOX40 mAb and anti-mPD1 mAb in the MC38 syngeneic model.

表5：CN401聯合α-mOX40 mAb和抗mPD1 mAb在MC38同源模型中的抗腫瘤活性：與載劑組相比，第20天的TGI和p值。

Figure 110142111-A0202-12-0055-12
Table 5 : Antitumor activity of CN401 combined with α-mOX40 mAb and anti-mPD1 mAb in MC38 syngeneic model: TGI and p-value at day 20 compared to vehicle group.
Figure 110142111-A0202-12-0055-12

統計分析Statistical Analysis

當數據擬合正態分佈時，進行單因素方差分析或學生t檢驗以比較組之間的腫瘤體積和腫瘤重量，否則使用曼-惠特尼檢驗。所有生長曲線均通過GraphPad Prism 8.0完成。 One-way ANOVA or Student's t-test was performed to compare tumor volume and tumor weight between groups when the data fit a normal distribution, otherwise the Mann-Whitney test was used. All growth curves were done with GraphPad Prism 8.0.

實施例2：Tenalisib(CN401)與OX86(α-mOX40mAb)和α-mPD1 mAb在A20同源模型中的聯用Example 2: Combination of Tenalisib (CN401) with OX86 (α-mOX40mAb) and α-mPD1 mAb in A20 homology model

研究設計：腫瘤挑戰、藥物處理和腫瘤生長監測Study Design: Tumor Challenge, Drug Management, and Tumor Growth Monitoring

六至八周齡的Balb/c小鼠(20至25g)購自Shanghai Super-B&K laboratory animal Corp.Ltd.，並通過皮下接種的方式將A20細胞(每只小鼠50萬個細胞)接種到小鼠的右脅側中。當腫瘤可觸及(約70mm3)時開始處理。抗OX40 mAb以100μg/小鼠通過腹膜內施用，每週兩次，共3周。CN401以150mg/kg或300mg/kg進行經口管飼，每天兩次，共3周。對照組接受不含活性產品的載劑(0.5% MC和PBS)。抗PD-1 mAb以60μg/小鼠通過腹膜內施用，每週兩次，共3周。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six- to eight-week-old Balb/c mice (20 to 25 g) were purchased from Shanghai Super-B&K laboratory animal Corp. Ltd., and A20 cells (500,000 cells per mouse) were inoculated subcutaneously. right flank of the mouse. Treatment was initiated when the tumor was palpable (approximately 70 mm 3 ). Anti-OX40 mAb was administered intraperitoneally at 100 μg/mouse twice a week for 3 weeks. CN401 was administered by oral gavage at 150 mg/kg or 300 mg/kg twice daily for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Anti-PD-1 mAb was administered intraperitoneally at 60 μg/mouse twice a week for 3 weeks. Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

表6：實驗設計

Figure 110142111-A0202-12-0056-13
Table 6 : Experimental Design
Figure 110142111-A0202-12-0056-13

如表7中提供的，在A20同源模型中，CN401和α-OX40 mAb存在協同作用，參見圖3A至圖3B。 As provided in Table 7 , there is synergy between CN401 and α-OX40 mAbs in the A20 homology model, see Figures 3A-3B .

表7：CN401聯合α-OX40 mAb和抗PD1 mAb在A20同源模型中的抗腫瘤活性：與載劑組相比，第17天的TGI和p值。未示出載劑組的數據。

Figure 110142111-A0202-12-0056-35
Table 7 : Antitumor activity of CN401 combined with α-OX40 mAb and anti-PD1 mAb in A20 syngeneic model: TGI and p-value at day 17 compared to vehicle group. Data for vehicle groups are not shown.
Figure 110142111-A0202-12-0056-35

Figure 110142111-A0202-12-0057-16
Figure 110142111-A0202-12-0057-16

圖4A至圖4H中提供了在A20同基因小鼠模型中施用CN401聯合α-OX40 mAb和抗PD1 mAb的抗腫瘤活性。值得注意的是，4至7組中的小鼠實現了完全應答(無腫瘤)。 The antitumor activity of administering CN401 in combination with α-OX40 mAb and anti-PD1 mAb in the A20 isogenic mouse model is provided in Figures 4A-4H . Notably, mice in groups 4 to 7 achieved complete responses (tumor-free).

統計分析Statistical Analysis

當數據擬合正態分佈時，進行單因素方差分析或學生t檢驗以比較組之間的腫瘤體積和腫瘤重量，否則使用曼-惠特尼檢驗。所有生長曲線均通過GraphPad Prism 8.0完成。 One-way ANOVA or Student's t-test was performed to compare tumor volume and tumor weight between groups when the data fit a normal distribution, otherwise the Mann-Whitney test was used. All growth curves were done with GraphPad Prism 8.0.

實施例3：CN401和CN1(抗huOX40)在A20人源化轉基因小鼠中的聯用Example 3: Combination of CN401 and CN1 (anti-huOX40) in A20 humanized transgenic mice

研究設計：腫瘤挑戰、藥物處理和腫瘤生長監測Study Design: Tumor Challenge, Drug Management, and Tumor Growth Monitoring

六至八周齡的Balb/c-hPD1/hOX40轉基因小鼠(20至25g)購自GemPharmatech，並通過皮下接種的方式將A20細胞(每只小鼠50萬個細胞)接種到小鼠的右脅側中。當腫瘤可觸及(約70mm3)時開始處理。CN1以1mg/kg通過腹膜內施用，每週兩次，共3周。CN401以150mg/kg經口管飼，每天兩次，共3周。對照組施用不含活性產品的載劑(0.5% MC和PBS)。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six- to eight-week-old Balb/c-hPD1/hOX40 transgenic mice (20 to 25 g) were purchased from GemPharmatech, and A20 cells (500,000 cells per mouse) were subcutaneously inoculated into the right flank of the mice. flank. Treatment was initiated when the tumor was palpable (approximately 70 mm 3 ). CN1 was administered intraperitoneally at 1 mg/kg twice a week for 3 weeks. CN401 was given by oral gavage at 150 mg/kg twice a day for 3 weeks. The control group was administered vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

表8：示例性研究設計

Figure 110142111-A0202-12-0057-34
Table 8 : Exemplary Study Design
Figure 110142111-A0202-12-0057-34

Figure 110142111-A0202-12-0058-20
Figure 110142111-A0202-12-0058-20

如表9中提供的，在A20人源化轉基因小鼠中，CN401和α-OX40 mAb存在協同作用，參見圖5A至圖5B。 As provided in Table 9 , there is synergy between CN401 and α-OX40 mAbs in A20 humanized transgenic mice, see Figures 5A-5B .

表9：CN401聯合CN1 Ab在A20人源化轉基因小鼠中的抗腫瘤活性：與載劑組相比，第19天的TGI和p值。

Figure 110142111-A0202-12-0058-33
Table 9 : Antitumor activity of CN401 in combination with CN1 Ab in A20 humanized transgenic mice: TGI and p-value at day 19 compared to vehicle group.
Figure 110142111-A0202-12-0058-33

統計分析Statistical Analysis

當數據擬合正態分佈時，進行單因素方差分析或學生t檢驗以比較組之間的腫瘤體積和腫瘤重量，否則使用曼-惠特尼檢驗。所有生長曲線均通過GraphPad Prism 8.0完成。 One-way ANOVA or Student's t-test was performed to compare tumor volume and tumor weight between groups when the data fit a normal distribution, otherwise the Mann-Whitney test was used. All growth curves were done with GraphPad Prism 8.0.

實施例4：CN401和CN1在A20人源化Ox40轉基因小鼠同源模型中的聯用Example 4: Combination of CN401 and CN1 in A20 humanized Ox40 transgenic mouse homology model

研究設計Research design

六至八周齡的Balb/c-hPD1/hOX40轉基因小鼠(20至25g)購自 GemPharmatech，並通過皮下接種將A20(每只小鼠50萬個細胞)接種到小鼠的右脅側中。當腫瘤可觸及(約70mm3)時開始處理。CN1以1mg/kg通過腹膜內施用，每週兩次，共3周。CN401以150mg/kg進行經口管飼，每天兩次，共3周。對照組接受不含活性產品的載劑(0.5% MC和PBS)。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six to eight week old Balb/c-hPD1/hOX40 transgenic mice (20 to 25 g) were purchased from GemPharmatech and A20 (500,000 cells per mouse) was inoculated into the right flank of mice by subcutaneous inoculation . Treatment was initiated when the tumor was palpable (approximately 70 mm 3 ). CN1 was administered intraperitoneally at 1 mg/kg twice a week for 3 weeks. CN401 was administered by oral gavage at 150 mg/kg twice daily for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

圖6A至圖6D示出了CN401聯合CN1在A20人源化Ox40轉基因小鼠同源模型中的抗腫瘤活性。值得注意的是，14至16組中的經處理小鼠實現了完全應答(無腫瘤)。 Figures 6A to 6D show the antitumor activity of CN401 in combination with CN1 in an A20 humanized Ox40 transgenic mouse syngeneic model. Notably, treated mice in groups 14 to 16 achieved complete responses (no tumor).

實施例5：Tenalisb(CN401)或Duvelishib對多種腫瘤細胞系的體外抗腫瘤活性Example 5: In vitro antitumor activity of Tenalisb (CN401) or Duvelishib on various tumor cell lines

細胞增殖測定Cell Proliferation Assay

在72小時的處理之後，通過用CellTiter-Glo®發光細胞活力測定試劑盒(Promega，#G7572)定量ATP來評價Tenalisib對11種腫瘤細胞系的細胞生長抑制活性。除MC38細胞系從Wuxi Biology company獲得之外，其餘10種細胞系均從美國典型培養物保藏中心(American Type Culture Collection,ATCC)獲得。根據ATCC培養方法將所有細胞系保持在補充有10%熱滅活胎牛血清(Fetal Bovine Serum,FBS)和100單位/ml青黴素和100μg/ml鏈黴素的特定培養基中。所有細胞培養物都保持在37℃和5% CO2的濕潤環境中。 The cytostatic activity of Tenalisib on 11 tumor cell lines was assessed by quantification of ATP with the CellTiter- Glo® Luminescent Cell Viability Assay Kit (Promega, #G7572) after 72 hours of treatment. Except MC38 cell line obtained from Wuxi Biology company, the other 10 cell lines were obtained from American Type Culture Collection (American Type Culture Collection, ATCC). All cell lines were maintained in specific medium supplemented with 10% heat-inactivated fetal bovine serum (Fetal Bovine Serum, FBS) and 100 units/ml penicillin and 100 μg/ml streptomycin according to the ATCC culture method. All cell cultures were maintained at 37 °C and 5% CO in a humidified environment.

將所有11種腫瘤細胞系以每孔100μl培養基中5000個細胞的密度接種在96孔白色不透明板(Corning，costar#3917)中。在第二天，將所有細胞系都用不同濃度的Tenalisib或Duvelisib(範圍為0.002μM至10μM)處理。在處理之後72小時，將100μl CTG測定試劑添加至每孔，並通過Envision 2105(PerkinElmar)多模式讀板儀讀取相對發光單位(relative light unit,RLU)。通過Graphpad Prism 8.0軟體用經DMSO處理的孔的RLU(相對發光單位)歸一化來分析報告增殖抑制參數IC50。 All 11 tumor cell lines were seeded in 96-well white opaque plates (Corning, costar #3917) at a density of 5000 cells per well in 100 μl of medium. On the second day, all cell lines were treated with varying concentrations of Tenalisib or Duvelisib (ranging from 0.002 μM to 10 μM). 72 hours after treatment, 100 μl of CTG assay reagent was added to each well and relative light units (RLU) were read by an Envision 2105 (PerkinElmar) multimode plate reader. The reported proliferation inhibition parameter IC50 was analyzed by Graphpad Prism 8.0 software normalized with the RLU (relative luminescence units) of DMSO-treated wells.

Tenalisib在11個細胞系中的2個中具有活性，顯示出最大增殖抑制大於50%。Tenalisib在MV-4-11細胞系中的IC50為1.652μM，在A20細胞系中為5.49μM。 Tenalisib was active in 2 of 11 cell lines, showing maximal inhibition of proliferation greater than 50%. The IC50 of Tenalisib was 1.652 μM in MV-4-11 cell line and 5.49 μM in A20 cell line.

Tenalisib和Duvelishib選擇性抑制MV-4-11和A20細胞增殖。將11種腫瘤細胞系用Tenalisib(A)或Duvelisib(B)處理72小時。在3倍連續稀釋下化合物濃度範圍為0.002μM至10μM。用CellTiter-Glo®發光細胞活力測定試劑盒(Promega，#G7572)評價細胞活力，參見圖7A至圖7D。 Tenalisib and Duvelishib selectively inhibit MV-4-11 and A20 cell proliferation. Eleven tumor cell lines were treated with Tenalisib (A) or Duvelisib (B) for 72 hours. Compound concentrations ranged from 0.002 μM to 10 μM at 3-fold serial dilutions. Cell viability was assessed with the CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega, #G7572), see Figures 7A-7D .

實施例6：Tenalisib(CN401)和Duvelisib與OX86(α-mOX40 mAb)和α-mPD1 mAb在MC38同源模型中的聯用Example 6: Combination of Tenalisib (CN401) and Duvelisib with OX86 (α-mOX40 mAb) and α-mPD1 mAb in MC38 homology model

研究設計Research design

六至八周齡的C57bl/6小鼠(20至25g)購自Shanghai Super-B&K laboratory animal Corp.Ltd.，並通過皮下接種將MC38細胞(每只小鼠50萬個細胞)接種到小鼠的右脅側中。當腫瘤可觸及(約70mm3)時開始處理。抗OX40 mAb以100μg/小鼠通過腹膜內施用，每週兩次，共3周。CN401以15mg/kg或50mg/kg或150mg/kg經口管飼，每天兩次，共3周。抗PD-1 mAb以60μg/小鼠通過腹膜內施用，每週兩次，共3周。Duvelisib以50mg/kg經口管飼，每天兩次，共3周。對照組接受不含活性產品的載劑(0.5% MC和PBS)。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six to eight week old C57bl/6 mice (20 to 25 g) were purchased from Shanghai Super-B&K laboratory animal Corp. Ltd. and MC38 cells (500,000 cells per mouse) were inoculated into mice by subcutaneous inoculation right flank. Treatment was initiated when the tumor was palpable (approximately 70 mm 3 ). Anti-OX40 mAb was administered intraperitoneally at 100 μg/mouse twice a week for 3 weeks. CN401 was given by oral gavage at 15 mg/kg or 50 mg/kg or 150 mg/kg twice a day for 3 weeks. Anti-PD-1 mAb was administered intraperitoneally at 60 μg/mouse twice a week for 3 weeks. Duvelisib was given by oral gavage at 50 mg/kg twice daily for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

表10：示例性研究設計

Figure 110142111-A0202-12-0060-31
Table 10 : Exemplary Study Design
Figure 110142111-A0202-12-0060-31

Figure 110142111-A0202-12-0061-23
Figure 110142111-A0202-12-0061-23

Tenalisib(CN401)和duvelisib聯合α-OX40 mAb和抗PD1 mAb在MC38同源模型中的抗腫瘤活性，參見圖8A和圖8B。在MC38同源模型中，在CN401/duvelisib和α-OX40 mAb之間沒有協同作用，參見表11。 Antitumor activity of Tenalisib (CN401) and duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in the MC38 syngeneic model, see Figures 8A and 8B . In the MC38 homology model, there was no synergy between CN401/duvelisib and α-OX40 mAb, see Table 11 .

表11：Tenalisib(CN401)和duvelisib聯合α-OX40 mAb和抗PD1 mAb在MC38同源模型中的抗腫瘤活性：與載劑組相比，第20天的TGI和p值。

Figure 110142111-A0202-12-0061-30
Table 11 : Antitumor activity of Tenalisib (CN401) and duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in MC38 syngeneic model: TGI and p-values at day 20 compared to vehicle group.
Figure 110142111-A0202-12-0061-30

Figure 110142111-A0202-12-0062-25
Figure 110142111-A0202-12-0062-25

圖9A至圖9H示出了來自表11的組的每個腫瘤的生長曲線。 Figures 9A-9H show growth curves for each tumor from the groups in Table 11 .

實施例7：Tenalisib(CN401)和duvelisib與OX86(α-mOX40mAb)和α-mPD1 mAb在A20同源模型中的聯用Example 7: Combination of Tenalisib (CN401) and duvelisib with OX86 (α-mOX40mAb) and α-mPD1 mAb in A20 homology model

研究設計Research design

六至八周齡的Balb/c小鼠(20至25g)購自Shanghai Super-B&K laboratory animal Corp.Ltd.，並通過皮下接種將A20細胞(每只小鼠50萬個細胞)接種到小鼠的右脅側中。當腫瘤可觸及(約70mm3)時開始處理。抗OX40 mAb以100μg/小鼠通過腹膜內施用，每週兩次，共3周。CN401以150mg/kg或300mg/kg經口管飼，每天兩次，共3周。抗PD-1 mAb以60μg/小鼠通過腹膜內施用，每週兩次，共3周。Duvelisib以50mg/kg經口管飼，每天兩次，共3周。對照組接受不含活性產品的載劑(0.5% MC和PBS)。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six to eight week old Balb/c mice (20 to 25 g) were purchased from Shanghai Super-B&K laboratory animal Corp. Ltd. and A20 cells (500,000 cells per mouse) were inoculated into mice by subcutaneous inoculation right flank. Treatment was initiated when the tumor was palpable (approximately 70 mm 3 ). Anti-OX40 mAb was administered intraperitoneally at 100 μg/mouse twice a week for 3 weeks. CN401 was given by oral gavage at 150 mg/kg or 300 mg/kg twice a day for 3 weeks. Anti-PD-1 mAb was administered intraperitoneally at 60 μg/mouse twice a week for 3 weeks. Duvelisib was given by oral gavage at 50 mg/kg twice daily for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

表12：示例性研究設計

Figure 110142111-A0202-12-0062-29
Table 12 : Exemplary Study Design
Figure 110142111-A0202-12-0062-29

Figure 110142111-A0202-12-0063-27
Figure 110142111-A0202-12-0063-27

表13示出了Tenalisib(CN401)和duvelisib聯合α-OX40 mAb和抗PD1 mAb在A20同源模型中的抗腫瘤活性：與載劑組相比，第17天的TGI和p值。在A20同源模型中，在CN401/duvelisib和α-OX40 mAb之間存在協同作用。

Figure 110142111-A0202-12-0063-28
Table 13 shows the antitumor activity of Tenalisib (CN401) and duvelisib in combination with α-OX40 mAb and anti-PD1 mAb in the A20 syngeneic model: TGI and p-values at day 17 compared to the vehicle group. In the A20 homology model, there is synergy between CN401/duvelisib and α-OX40 mAb.
Figure 110142111-A0202-12-0063-28

Figure 110142111-A0202-12-0064-41
Figure 110142111-A0202-12-0064-41

圖10A和圖10B示出了Tenalisib(CN401)和duvelisib聯合α-OX40 mAb和抗PD1 mAb處理的小鼠的平均腫瘤體積和平均體重。圖11A至圖11J示出了與載劑對照相比，來自表13的組的小鼠的單個腫瘤生長曲線。 Figures 10A and 10B show the mean tumor volume and mean body weight of mice treated with Tenalisib (CN401) and duvelisib in combination with α-OX40 mAb and anti-PD1 mAb. Figures 11A-11J show individual tumor growth curves for mice from the groups of Table 13 compared to vehicle controls.

實施例8：Tenalisib(CN401)和CN1在A20人源化轉基因小鼠中的聯用Example 8: Combination of Tenalisib (CN401) and CN1 in A20 humanized transgenic mice

研究設計Research design

六至八周齡的Balb/c-hPD1/hOX40轉基因小鼠(20至25g)購自GemPharmatech，並通過皮下接種將A20(每只小鼠50萬個細胞)接種到小鼠的右脅側中。當腫瘤可觸及(約70mm3)時開始處理。CN1以1mg/kg通過腹膜內施用，每週兩次，共3周。CN401以150mg/kg經口管飼，每天兩次，共3周。對照組接受不含活性產品的載劑(0.5% MC和PBS)。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six to eight week old Balb/c-hPD1/hOX40 transgenic mice (20 to 25 g) were purchased from GemPharmatech and A20 (500,000 cells per mouse) was inoculated into the right flank of mice by subcutaneous inoculation . Treatment was initiated when the tumor was palpable (approximately 70 mm 3 ). CN1 was administered intraperitoneally at 1 mg/kg twice a week for 3 weeks. CN401 was given by oral gavage at 150 mg/kg twice a day for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

表14：示例性研究設計

Figure 110142111-A0202-12-0064-42
Table 14 : Exemplary Study Design
Figure 110142111-A0202-12-0064-42

Figure 110142111-A0202-12-0065-43
Figure 110142111-A0202-12-0065-43

表15示出了Tenalisib(CN401)聯合CN1在A20人源化轉基因小鼠中的抗腫瘤活性：與載劑組相比，第19天的TGI和p值。

Figure 110142111-A0202-12-0065-44
Table 15 shows the antitumor activity of Tenalisib (CN401) in combination with CN1 in A20 humanized transgenic mice: TGI and p-value at day 19 compared to vehicle group.
Figure 110142111-A0202-12-0065-44

如表X以及圖12A和圖12B所示，在A20人源化轉基因小鼠中，CN401和α-OX40 mAb之間存在協同作用。圖13A至圖13D提供了通過測量單個腫瘤生長曲線所顯示的抗腫瘤活性，值得注意的是在3個處理組中，相應地在4/8、1/8和5/8的小鼠中實現了完全應答。 As shown in Table X and Figures 12A and 12B , there is synergy between CN401 and α-OX40 mAbs in A20 humanized transgenic mice. Figures 13A - 13D provide the anti-tumor activity shown by measuring individual tumor growth curves, notably in 4/8, 1/8 and 5/8 mice across the 3 treatment groups, respectively fully responded.

結果示出了CN-1/α-huOX40抗體與PI3K抑制劑的組合在A20腫瘤模型中表現出協同抗腫瘤活性，並且CN-1/α-huOX40抗體與PI3K抑制劑的組合可在A20同源模型中誘導腫瘤消退。 The results show that the combination of CN-1/α-huOX40 antibody and PI3K inhibitor exhibits synergistic antitumor activity in the A20 tumor model, and the combination of CN-1/α-huOX40 antibody and PI3K inhibitor can be homologous in A20 Induce tumor regression in the model.

實施例9：Duvelisib和OX86(α-mOX40 mAb)在MC38同源模型中的聯用Example 9: Combination of Duvelisib and OX86 (α-mOX40 mAb) in the MC38 homology model

研究設計Research design

六至八周齡的C57bl/6小鼠(20至25g)購自Shanghai Super-B&K laboratory animal Corp.Ltd.，並通過皮下接種將MC38細胞(每只小鼠50萬個細胞)接種到小鼠的右脅側中。當腫瘤可觸及(約70mm3)時開始處理。抗OX40 mAb以100μg/小鼠通過腹膜內施用，每週兩次，共3周。Duvelisib以50mg/kg經口管飼，每天兩次，共3周。對照組接受不含活性產品的載劑(0.5% MC和PBS)。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six to eight week old C57bl/6 mice (20 to 25 g) were purchased from Shanghai Super-B&K laboratory animal Corp. Ltd. and MC38 cells (500,000 cells per mouse) were inoculated into mice by subcutaneous inoculation right flank. Treatment was initiated when the tumor was palpable (approximately 70 mm 3 ). Anti-OX40 mAb was administered intraperitoneally at 100 μg/mouse twice a week for 3 weeks. Duvelisib was given by oral gavage at 50 mg/kg twice daily for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

表16：示例性研究設計

Figure 110142111-A0202-12-0066-45
Table 16 : Exemplary Study Design
Figure 110142111-A0202-12-0066-45

圖14A和圖14B示出了duvelisib聯合α-OX40 mAb在MC38同源模型中的抗腫瘤活性。表16中提供了與載劑組相比，第20天的TGI和p值。 Figures 14A and 14B show the antitumor activity of duvelisib in combination with alpha-OX40 mAb in the MC38 syngeneic model. The TGI and p-values at day 20 compared to the vehicle group are provided in Table 16 .

表17：duvelisib聯合α-OX40 mAb在MC38同源模型中的抗腫瘤活性。示出了與載劑劑組相比，第20天的TGI和p值。

Figure 110142111-A0202-12-0066-46
Table 17 : Antitumor activity of duvelisib in combination with α-OX40 mAb in the MC38 syngeneic model. TGI and p-values at day 20 are shown compared to the vehicle group.
Figure 110142111-A0202-12-0066-46

圖15A至圖15D示出了在MC38同源模型中，與對照相比，duvelisib聯合α-OX40 mAb在如表17所述的處理同源模型中顯示抗腫瘤活性。 Figures 15A-15D show that in the MC38 syngeneic model, duvelisib in combination with a-OX40 mAb showed antitumor activity in the treatment syngeneic model as described in Table 17 compared to controls.

實施例10：Duvelisib和OX86(α-OX40 mAb)在A20同源模型中的聯用Example 10: Combination of Duvelisib and OX86 (α-OX40 mAb) in the A20 homology model

研究設計Research design

六至八周齡的Balb/c小鼠(20至25g)購自Shanghai Super-B&K laboratory animal Corp.Ltd.，並通過皮下接種將A20細胞(每只小鼠50萬個細胞)接種到小鼠的右脅側中。當腫瘤可觸及(約70mm3)時開始處理。抗OX40 mAb以100μg/小鼠通過腹膜內施用，每週兩次，共3周。Duvelisib以50mg/kg經口管飼，每天兩次，共3周。對照組接受不含活性產品的載劑(0.5% MC和PBS)。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six to eight week old Balb/c mice (20 to 25 g) were purchased from Shanghai Super-B&K laboratory animal Corp. Ltd. and A20 cells (500,000 cells per mouse) were inoculated into mice by subcutaneous inoculation right flank. Treatment was initiated when the tumor was palpable (approximately 70 mm 3 ). Anti-OX40 mAb was administered intraperitoneally at 100 μg/mouse twice a week for 3 weeks. Duvelisib was given by oral gavage at 50 mg/kg twice daily for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

表18：示例性研究設計

Figure 110142111-A0202-12-0067-47
Table 18 : Exemplary Study Design
Figure 110142111-A0202-12-0067-47

圖16A和圖16B示出了duvelisib聯合α-OX40 mAb在A20同源模型中的抗腫瘤活性。表19示出了與載劑組相比，第17天的TGI和p值。在A20同源模型中，duvelisib和α-OX40 mAb存在協同作用。 Figures 16A and 16B show the antitumor activity of duvelisib in combination with alpha-OX40 mAb in the A20 syngeneic model. Table 19 shows the TGI and p-values at day 17 compared to the vehicle group. In the A20 homology model, there is synergy between duvelisib and α-OX40 mAb.

表19：duvelisib聯合α-OX40 mAb在A20同源模型中的抗腫瘤活性：與載劑組 相比，第17天的TGI和p值。

Figure 110142111-A0202-12-0068-48
Table 19 : Antitumor activity of duvelisib in combination with α-OX40 mAb in A20 syngeneic model: TGI and p-value at day 17 compared to vehicle group.
Figure 110142111-A0202-12-0068-48

圖17A至圖17D示出了與對照相比，來自表19所示處理的小鼠組的每個腫瘤的生長曲線。 Figures 17A-17D show growth curves for each tumor from the groups of mice treated as shown in Table 19 compared to controls.

實施例11：CN401和CN1在人源化CT26.WT鼠結腸癌模型中的聯用Example 11: Combination of CN401 and CN1 in humanized CT26.WT murine colon cancer model

研究設計Research design

進行示例性研究以評價本文中提供的聯合治療在小鼠模型中的安全性和耐受性。研究測試了Tenalisib(CN401)和抗huOX40(CN1)抗體在人OX40轉基因小鼠模型中施用的協同作用。 Exemplary studies were performed to evaluate the safety and tolerability of the combination treatments provided herein in mouse models. The study tested the synergy of Tenalisib (CN401) and anti-huOX40 (CN1) antibody administration in a human OX40 transgenic mouse model.

六至八周齡的人OX40轉基因balb/c小鼠(20至25g)購自Jiangsu GemPharmatech Co.,Ltd.，並通過皮下接種將CT26.WT鼠結腸癌細胞(每只小鼠10萬個細胞)接種到小鼠的右脅側中。當腫瘤可觸及(約70mm3)時開始處理。CN1以5mg/kg通過腹膜內施用，每週兩次，共3周。CN401以150mg/kg經口管飼，每天兩次，共3周。對照組接受不含活性產品的載劑(0.5% MC和PBS)。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six to eight week old human OX40 transgenic balb/c mice (20 to 25 g) were purchased from Jiangsu GemPharmatech Co., Ltd., and CT26.WT murine colon cancer cells (100,000 cells per mouse) were subcutaneously inoculated. ) into the right flank of mice. Treatment was initiated when the tumor was palpable (approximately 70 mm 3 ). CN1 was administered intraperitoneally at 5 mg/kg twice a week for 3 weeks. CN401 was given by oral gavage at 150 mg/kg twice a day for 3 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

表20：實驗設計

Figure 110142111-A0202-12-0068-49
Table 20 : Experimental Design
Figure 110142111-A0202-12-0068-49

Figure 110142111-A0202-12-0069-50
Figure 110142111-A0202-12-0069-50

圖18A至圖18B以及圖19A至圖19D中提供了CN401聯合CN1在人源化CT26.WT腫瘤模型中的抗腫瘤活性。 The antitumor activity of CN401 in combination with CN1 in a humanized CT26.WT tumor model is provided in Figures 18A-18B and 19A-19D .

表21：CN401聯合CN1在人源化CT26.WT腫瘤模型中的抗腫瘤活性：與載劑組相比，第17天的TGI和p值。

Figure 110142111-A0202-12-0069-51
Table 21 : Antitumor activity of CN401 in combination with CN1 in humanized CT26.WT tumor model: TGI and p-value at day 17 compared to vehicle group.
Figure 110142111-A0202-12-0069-51

實施例12：CN401和CN1在人源化B16-F10鼠黑色素瘤腫瘤模型中的聯用Example 12: Combination of CN401 and CN1 in a humanized B16-F10 mouse melanoma tumor model

研究設計Research design

進行示例性研究以評價本文中提供的聯合治療在小鼠模型中的安全性和耐受性。研究測試了Tenalisib(CN401)和抗huOX40(CN1)抗體在人OX40轉基因小鼠模型中施用的協同作用。 Exemplary studies were performed to evaluate the safety and tolerability of the combination treatments provided herein in mouse models. The study tested the synergy of Tenalisib (CN401) and anti-huOX40 (CN1) antibody administration in a human OX40 transgenic mouse model.

六至八周齡的人OX40轉基因C57bl/6小鼠(20至25g)購自Biocytogen Pharmaceuticals(Beijing)Co.,Ltd.，並通過皮下接種將B16-F10鼠黑素瘤細胞(每只小鼠10萬個細胞)接種到小鼠的右脅側中。當腫瘤可觸及(約 40mm3)時開始處理。CN1以10mg/kg通過腹膜內施用，每週兩次，共2周。CN401以150mg/kg經口管飼，每天兩次，共2周。對照組接受不含活性產品的載劑(0.5% MC和PBS)。每週測量三次腫瘤尺寸和體重。動物實驗根據AAALAC標準進行，並獲得Super-B&K實驗動物中心IACUC批准。 Six- to eight-week-old human OX40 transgenic C57bl/6 mice (20 to 25 g) were purchased from Biocytogen Pharmaceuticals (Beijing) Co., Ltd. and subcutaneously inoculated with B16-F10 murine melanoma cells (per mouse). 100,000 cells) were inoculated into the right flank of mice. Treatment was initiated when the tumor was palpable (approximately 40 mm3 ). CN1 was administered intraperitoneally at 10 mg/kg twice a week for 2 weeks. CN401 was given by oral gavage at 150 mg/kg twice a day for 2 weeks. The control group received vehicle without active product (0.5% MC and PBS). Tumor size and body weight were measured three times a week. Animal experiments were performed according to AAALAC standards and approved by the Super-B&K Laboratory Animal Center IACUC.

表22：實驗設計

Figure 110142111-A0202-12-0070-52
Table 22 : Experimental Design
Figure 110142111-A0202-12-0070-52

圖20A至圖20B和圖21A和圖21D中提供了CN401聯合CN1在人源化B16-F10腫瘤模型中的抗腫瘤活性。 The antitumor activity of CN401 in combination with CN1 in a humanized B16-F10 tumor model is provided in Figures 20A-20B and Figures 21A and 21D .

表23：CN401聯合CN1(抗huOX40 Ab)在人源化B16-F10腫瘤模型中的抗腫瘤活性：與載劑組相比，第14天的TGI和p值。

Figure 110142111-A0202-12-0070-53
Table 23 : Antitumor activity of CN401 in combination with CN1 (anti-huOX40 Ab) in humanized B16-F10 tumor model: TGI and p-value at day 14 compared to vehicle group.
Figure 110142111-A0202-12-0070-53

儘管已經在本文中示出和描述了本發明的優選實施方案，但是對 於本領域技術人員明顯的是，這些實施方案僅作為示例提供。在不背離本發明的情況下，本領域技術人員將想到許多變化、改變和替代。應當理解，本文所述的本發明的一些實施方案的各種替代方案可用於實施本發明。旨在所附請求項限定本發明的範圍並且由此涵蓋了這些請求項及其等同方案的範圍內的方法和結構。 While the preferred embodiments of the invention have been shown and described herein, the It will be apparent to those skilled in the art that these embodiments are provided by way of example only. Numerous variations, changes and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to some of the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the appended claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims (5)

一種組合物，其包含： A composition comprising: (a)多肽，其包含表現出對OX40的結合特異性的抗原結合部分，其中所述抗原結合部分包含選自(i)至(iii)的至少一個重鏈CDR(CDRH)和/或選自(iv)至(vi)的至少一個輕鏈CDR(CDRL)，其中： (a) a polypeptide comprising an antigen-binding portion that exhibits binding specificity for OX40, wherein the antigen-binding portion comprises at least one heavy chain CDR (CDRH) selected from (i) to (iii) and/or selected from At least one light chain CDR (CDRL) of (iv) to (vi), wherein: (i)CDRH1，其與選自SEQ ID NO：15的序列具有至少80%的序列同一性； (i) CDRH1 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 15; (ii)CDRH2，其與選自SEQ ID NO：17的序列具有至少80%的序列同一性； (ii) CDRH2 having at least 80% sequence identity to a sequence selected from SEQ ID NO: 17; (iii)CDRH3，其與選自SEQ ID NO：19的序列具有至少80%的序列同一性； (iii) CDRH3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 19; (iv)CDRL1，其與選自SEQ ID NO：16的序列具有至少80%的序列同一性； (iv) CDRL1 having at least 80% sequence identity to a sequence selected from SEQ ID NO: 16; (v)CDRL2，其與選自SEQ ID NO：18的序列具有至少80%的序列同一性；和 (v) CDRL2 having at least 80% sequence identity to a sequence selected from SEQ ID NO: 18; and (vi)CDRL3，其與選自SEQ ID NO：20的序列具有至少80%的序列同一性；以及 (vi) CDRL3 having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 20; and (b)針對PI3K的抑制劑。 (b) Inhibitors against PI3K. 請求項1所述的組合物，其中所述抗原結合部分包含： The composition of claim 1, wherein the antigen binding moiety comprises: (1)重鏈可變區(VH)，其與選自SEQ ID NO：39的序列具有至少80%的序列同一性；和/或 (1) a heavy chain variable region (VH) having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NO: 39; and/or (2)輕鏈可變區(VL)，其與選自SEQ ID NO：40的序列具有至少80%的序列同一性。 (2) A light chain variable region (VL) having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NO:40. 請求項1或2所述的組合物，其中所述針對PI3K的抑制劑包含選自以下的一種或更多種：Idelalisib、Copanlisib、Duvelisib、Alpelisib、Taselisib、Perifosine、Buparlisib、Umbralisib和Tenalisib。 The composition of claim 1 or 2, wherein the inhibitor against PI3K comprises one or more selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib and Tenalisib. 請求項1或2所述的組合物，其中所述針對PI3K的抑制劑選自Tenalisib。 The composition of claim 1 or 2, wherein the inhibitor against PI3K is selected from Tenalisib. 請求項1或2所述的組合物，其還包含針對PD-1與PD-L1結合的抑制劑，特別是包含表現出對PD-1或PD-L1的結合特異性的抗原結合部分的多肽，並且更特別是針對PD-1或PD-L1的抗體、其片段或其功能性變體。 The composition of claim 1 or 2, further comprising an inhibitor against the binding of PD-1 to PD-L1, particularly a polypeptide comprising an antigen-binding moiety that exhibits binding specificity to PD-1 or PD-L1 , and more particularly antibodies against PD-1 or PD-L1, fragments or functional variants thereof.
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