TW202122114A - Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma - Google Patents

Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma Download PDF

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TW202122114A
TW202122114A TW109119371A TW109119371A TW202122114A TW 202122114 A TW202122114 A TW 202122114A TW 109119371 A TW109119371 A TW 109119371A TW 109119371 A TW109119371 A TW 109119371A TW 202122114 A TW202122114 A TW 202122114A
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oxaliplatin
gemcitabine
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蒙達佛 朱納 伊娃 赫南德茲
納賽爾 奧爾 迪恩 加堯姆
春江 平田
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美商建南德克公司
瑞士商赫孚孟拉羅股份公司
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Abstract

Provided herein are methods of treating B-cell proliferative disorders (such as diffuse large B-cell lymphoma (DLBCL)) using immunoconjugates comprising anti-CD79b antibodies in combination with an anti-CD20 antibody (such as rituximab) and one or more chemotherapeutic agents (such as gemcitabine and oxaliplatin).

Description

使用抗CD79b免疫偶聯物治療彌漫性大B細胞淋巴瘤的方法Method of using anti-CD79b immunoconjugate to treat diffuse large B-cell lymphoma

本發明係關於藉由投與免疫偶聯物來治療B細胞增殖性疾病，例如 彌漫性大B細胞淋巴瘤(DLBCL)的方法，該免疫偶聯物包含抗CD79b抗體與抗CD20抗體(例如 利妥昔單抗(rituximab))及一或多種化學治療劑(例如 吉西他濱(gemcitabine)及奧沙利鉑(oxaliplatin))之組合。The present invention relates to a method for treating B-cell proliferative diseases, such as diffuse large B-cell lymphoma (DLBCL) by administering an immunoconjugate, the immunoconjugate comprising an anti-CD79b antibody and an anti-CD20 antibody ( for example A combination of tuximab (rituximab) and one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin).

非霍奇金淋巴瘤(NHL)係世界上最常見的血液系統惡性疾病且在所有最常見癌症中排名第十三位(Bray等人，(2018) CA Cancer J Clin，68:394-424)。彌漫性大B細胞淋巴瘤(DLBCL)係NHL的一種侵襲性亞型，約佔所有NHL病例的32.5%。DLBCL源自於成熟B細胞，且未治療患者之中值存活期＜ 1年(Rovira等人，(2015) Ann Hematol，378:1396-1407)。大多數的DLBCL細胞表現CD20，它係在細胞週期之起始及分化中起重要作用的一種膜抗原(Anderson等人，(1984) Blood，63:1424-1433)。Non-Hodgkin's Lymphoma (NHL) is the most common hematological malignancy in the world and ranks 13th among all the most common cancers (Bray et al., (2018) CA Cancer J Clin, 68:394-424) . Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of NHL, accounting for about 32.5% of all NHL cases. DLBCL is derived from mature B cells, and the median survival time of untreated patients is <1 year (Rovira et al., (2015) Ann Hematol, 378:1396-1407). Most DLBCL cells express CD20, which is a membrane antigen that plays an important role in the initiation and differentiation of the cell cycle (Anderson et al., (1984) Blood, 63:1424-1433).

DLBCL之一線治療係由抗CD20單株抗體治療結合多藥物化學治療組成(National Comprehensive Cancer Network 2018；Shen等人 ，(2018) Lancet 第5卷，e264)。對於無法藉由一線治療治癒之患者，在大劑量化學療法之後進行自體幹細胞移植可為長期緩解提供第二次機會。對於因年齡、共病或其他因素而無法進行幹細胞移植的復發/難治性(R/R) DLBCL患者，有多種不同的治療選擇，包括各種化學免疫療法。然而，此等化學免疫療法往往以減輕症狀而非長期存活為目的。最近批准的針對R/R DLBCL情形之治療方法包括CAR-T療法及帕妥珠單抗-維多汀(polatuzumab vedotin-piiq)聯合苯達莫司汀(bendamustine)及利妥昔單抗。One line of treatment for DLBCL consists of anti-CD20 monoclonal antibody therapy combined with multi-drug chemotherapy (National Comprehensive Cancer Network 2018; Shen et al . (2018) Lancet Vol. 5, e264). For patients who cannot be cured by first-line treatment, autologous stem cell transplantation after high-dose chemotherapy can provide a second chance for long-term relief. For patients with relapsed/refractory (R/R) DLBCL who cannot undergo stem cell transplantation due to age, comorbidities, or other factors, there are many different treatment options, including various chemotherapy and immunotherapies. However, such chemoimmunotherapy is often aimed at alleviating symptoms rather than long-term survival. Recently approved treatments for R/R DLBCL include CAR-T therapy and Pertuzumab-Vedotine (polatuzumab vedotin-piiq) combined with Bendamustine and Rituximab.

約有一半的復發性DLBCL患者由於難治性疾病而無法對二線療法作出反應(Gisselbrecht等人 ，(2010) J Clin Oncol，28:4184-4190)。在幹細胞移植後復發或因難治性疾病或體弱而不適合幹細胞移植的患者預後較差。此外，很多的復發/難治性患者由於年齡、共病或其他因素而不適合進行侵襲性療法。儘管針對復發性或難治性DLBCL之挽救療法在治療反應率方面顯示出令人鼓舞的結果，但復發性或難治性DLBCL患者的長期存活仍然有限(Lopez等人 ，(2007) European J of Haematology 80:127-32；Gnaoui等人 ，(2007) Ann Oncol 18:1363-68；Mounier等人 ，(2013) Haematologica 98(11)1726-31)。因此，此項技術中需要用於復發性或難治性DLBCL患者之新穎治療方法。About half of patients with relapsed DLBCL are unable to respond to second-line therapy due to refractory disease (Gisselbrecht et al ., (2010) J Clin Oncol, 28:4184-4190). Patients who relapse after stem cell transplantation or who are not suitable for stem cell transplantation due to refractory diseases or frailty have a poor prognosis. In addition, many relapsed/refractory patients are not suitable for aggressive therapy due to age, comorbidities or other factors. Although salvage therapy for relapsed or refractory DLBCL has shown encouraging results in terms of treatment response rate, the long-term survival of patients with relapsed or refractory DLBCL is still limited (Lopez et al ., (2007) European J of Haematology 80 :127-32; Gnaoui et al . (2007) Ann Oncol 18:1363-68; Mounier et al . (2013) Haematologica 98(11) 1726-31). Therefore, there is a need for novel treatment methods for patients with relapsed or refractory DLBCL in this technology.

本文引用的所有參考文獻，包括專利申請案及出版物，均以全文引用之方式併入本文中。All references cited in this article, including patent applications and publications, are incorporated herein by reference in their entirety.

在一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)利妥昔單抗；(c)吉西他濱；以及(d)奧沙利鉑。In one aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following formula Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) Rituximab; (c) Gemcitabine; And (d) Oxaliplatin.

在某些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 19之胺基酸序列的重鏈可變域(VH)及(ii)含SEQ ID NO: 20之胺基酸序列的輕鏈可變域(VL)。在一些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈。在某些實施例中，p在2與5之間。在某些實施例中，p在3與4之間。在某些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In certain embodiments, the anti-CD79b antibody includes (i) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 19 and (ii) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 20 Light chain variable domain (VL). In some embodiments, the anti-CD79b antibody includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在一些實施例中，抗CD79b抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，抗CD79b抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。在一些實施例中，免疫偶聯物係依拉妥珠單抗維多汀(iladatuzumab vedotin)。在某些實施例中，p在2與5之間。在某些實施例中，p係2。In some embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 38. In some embodiments, the immunoconjugate is iladatuzumab vedotin. In some embodiments, p is between 2 and 5. In certain embodiments, p is 2.

在一些實施例中，該免疫偶聯物係以約1 mg/kg至約5 mg/kg之劑量投與。在一些實施例中，該免疫偶聯物係以約1.2 mg/kg、約1.8 mg/kg、約2.4 mg/kg、約3.6 mg/kg或約4.8 mg/kg之劑量投與。在一些實施例中，該免疫偶聯物係以約1.8 mg/kg之劑量投與。In some embodiments, the immunoconjugate is administered at a dose of about 1 mg/kg to about 5 mg/kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.2 mg/kg, about 1.8 mg/kg, about 2.4 mg/kg, about 3.6 mg/kg, or about 4.8 mg/kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg.

在可與任何前述實施例組合的一些實施例中，該免疫偶聯物係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與。在某些實施例中，將免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑投與一或多個21天週期。在一些實施例中，該免疫偶聯物在每個週期係以約1.8 mg/kg之劑量投與，利妥昔單抗在每個週期係以約375 mg/m2 之劑量投與，吉西他濱在每個週期係以約1000 mg/m2 之劑量投與，且奧沙利鉑在每個週期係以約100 mg/m2 之劑量投與。在某些實施例中，該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。在某些實施例中，利妥昔單抗係在該免疫偶聯物之前投與。在某些實施例中，吉西他濱係在奧沙利鉑之前投與。在某些實施例中，將免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑投與至多八個21天週期。在某些實施例中，將免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑投與8個21天週期。In some embodiments that can be combined with any of the preceding embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg, rituximab is administered at a dose of about 375 mg/m 2 and gemcitabine It is administered at a dose of about 1000 mg/m 2 , and oxaliplatin is administered at a dose of about 100 mg/m 2 . In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for one or more 21-day cycles. In some embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg per cycle, rituximab is administered at a dose of about 375 mg/m 2 per cycle, gemcitabine It is administered at a dose of approximately 1000 mg/m 2 in each cycle, and oxaliplatin is administered at a dosage of approximately 100 mg/m 2 in each cycle. In certain embodiments, the immunoconjugate and rituximab are administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin are administered on the first day of each 21-day cycle. Administer intravenously in 2 days. In certain embodiments, rituximab is administered before the immunoconjugate. In certain embodiments, gemcitabine is administered before oxaliplatin. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for 8 21-day cycles.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate and rituximab are in each 21-day cycle It was administered intravenously on the first day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate and rituximab are on the 21st day of each cycle. It was administered intravenously on one day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.4 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.4 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate and rituximab are in each 21-day cycle It was administered intravenously on the first day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.4 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.4 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate and rituximab are on the first day of each 21-day cycle It was administered intravenously on one day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約75 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 75 mg/m 2 ; and the immunoconjugate and rituximab are in each 21-day cycle It was administered intravenously on the first day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約75 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 75 mg/m 2 ; and the immunoconjugate and rituximab are on the first of each 21-day cycle It was administered intravenously on one day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.4 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約75 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.4 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 75 mg/m 2 ; and the immunoconjugate and rituximab are in each 21-day cycle It was administered intravenously on the first day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.4 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約75 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.4 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 75 mg/m 2 ; and the immunoconjugate and rituximab are on the first of each 21-day cycle It was administered intravenously on one day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在可與任何前述實施例組合的一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少兩個、至少三個、至少四個、至少五個、至少六個或至少七個21天週期。在一些實施例中，將免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑投與八個21天週期。在一些實施例中，利妥昔單抗係在該免疫偶聯物之前投與。在一些實施例中，吉西他濱係在奧沙利鉑之前投與。在一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In some embodiments that can be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered at least two, at least three, at least four, at least five, At least six or at least seven 21-day cycles. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for eight 21-day cycles. In some embodiments, rituximab is administered before the immunoconjugate. In some embodiments, gemcitabine is administered before oxaliplatin. In some embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在一些實施例中，該人類個體已接受至少一種針對DLBCL之先前療法。在一些實施例中，該人類人類個體已接受至少一種針對DLBCL之先前全身性療法。在一些實施例中，該人類個體已接受至少兩種針對DLBCL之先前療法。在某些實施例中，DLBCL係經組織學確定的非特指型(NOS) DLBCL，或者該人類個體有惰性疾病轉化為DLBCL之病史。在某些實施例中，DLBCL係復發性或難治性DLBCL。在某些實施例中，該人類個體的美國東岸癌症臨床研究合作組織(Eastern Cooperative Oncology Group，ECOG)體能狀態係0、1或2。在某些實施例中，該人類個體沒有計劃進行自體或同種異體幹細胞移植(SCT)。在某些實施例中，該人類個體未曾接受用吉西他濱及鉑基藥劑之組合進行之先前療法。在某些實施例中，根據5.0版國家癌症研究院常見不良事件評價準則(National Cancer Institute Common Terminology Criteria for Adverse Events)，該人類個體之周圍神經病變不大於1級。在某些實施例中，該人類個體未患原發性或繼發性中樞神經系統淋巴瘤。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前，該人類個體並非造血幹細胞移植(HSCT)之候選人。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前，該人類個體並非自體造血幹細胞移植(HSCT)之候選人。在一些實施例中，該人類個體已接受至少兩種針對DLBCL之先前療法。在一些實施例中，該人類個體未接受針對DLBCL之帕妥珠單抗維多汀-piiq先前療法。在一些實施例中，該人類個體係成人。在一些實施例中，若未另外說明，否則該成人患有復發性或難治性彌漫性大B細胞淋巴瘤。In some embodiments, the human individual has received at least one previous therapy for DLBCL. In some embodiments, the human human individual has received at least one previous systemic therapy for DLBCL. In some embodiments, the human individual has received at least two previous therapies for DLBCL. In some embodiments, DLBCL is a histologically determined non-specific (NOS) DLBCL, or the human individual has a history of indolent disease converted to DLBCL. In certain embodiments, DLBCL is relapsed or refractory DLBCL. In certain embodiments, the Eastern Cooperative Oncology Group (ECOG) performance status of the human individual is 0, 1, or 2. In certain embodiments, the human individual has no plans to undergo autologous or allogeneic stem cell transplantation (SCT). In certain embodiments, the human individual has not received prior therapy with a combination of gemcitabine and platinum-based agents. In some embodiments, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, the peripheral neuropathy of the human individual is not greater than grade 1. In certain embodiments, the human individual does not suffer from primary or secondary central nervous system lymphoma. In some embodiments, the human individual is not a candidate for hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human individual is not a candidate for autologous hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human individual has received at least two previous therapies for DLBCL. In some embodiments, the human individual has not received Pertuzumab Vidotin-piiq prior therapy for DLBCL. In some embodiments, the human is an adult. In some embodiments, unless otherwise specified, the adult has relapsed or refractory diffuse large B-cell lymphoma.

在某些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在某些實施例中，在所治療之多名人類個體中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，有33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在某些實施例中，在所治療之多名人類個體中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中有33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級的周圍神經病變。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級的神經毒性。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷4級或更高級的周圍神經病變。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷4級或更高級的神經毒性。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約40%的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約8%的人類個體經歷3級或更高級別的周圍神經病變。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約6%的人類個體經歷周圍神經病變，該疾病導致用該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑進行之治療中止。在某些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。In certain embodiments, after administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin, the human individual does not experience grade 3 or higher peripheral neuropathy, and the disease cannot be in 14 It resolves to grade 1 or lower within days. In certain embodiments, among the multiple human subjects treated, 33% or less of the human subjects experienced 3 treatments after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. Peripheral neuropathy of grade 1 or higher, which cannot resolve to grade 1 or lower within 14 days. In certain embodiments, among the multiple human subjects treated, 33% or more of the multiple human subjects after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin Few human individuals experience grade 3 or higher peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot occur within 14 days. The internal regression is level 1 or lower. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause grade 4 or higher peripheral neuropathy in the human individual. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause neurotoxicity of grade 4 or higher in the human individual. In some embodiments, after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human individual does not experience grade 4 or higher peripheral neuropathy. In some embodiments, after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human individual does not experience grade 4 or higher neurotoxicity. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals causes 33% or less of the human individuals to experience grade 3 or more. High-grade peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals causes less than about 40% of the multiple human individuals to experience Grade 3 or higher. High-grade peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects causes less than about 8% of the human subjects to experience grade 3 or higher. High-grade peripheral neuropathy. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals causes less than about 6% of the multiple human individuals to experience peripheral neuropathy, The disease resulted in the discontinuation of treatment with the immunoconjugate, rituximab, gemcitabine and oxaliplatin. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) Rituximab; (c) Gemcitabine; And (d) Oxaliplatin; wherein after administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin, the human individual has not experienced grade 3 or higher peripheral neuropathy, the The disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能再14天內消退為1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) Rituximab; (c) Gemcitabine; And (d) Oxaliplatin; wherein the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not cause peripheral neuropathy of grade 3 or higher in the human individual, the The disease cannot subside to grade 1 or lower within 14 days.

在某些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 19之胺基酸序列的重鏈可變域(VH)及(ii)含SEQ ID NO: 20之胺基酸序列的輕鏈可變域(VL)。在一些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈。在某些實施例中，p在2與5之間。在某些實施例中，p在3與4之間。在某些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In certain embodiments, the anti-CD79b antibody includes (i) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 19 and (ii) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 20 Light chain variable domain (VL). In some embodiments, the anti-CD79b antibody includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) Rituximab; (c) Gemcitabine; And (d) oxaliplatin; wherein among the multiple human subjects treated, 33 of the multiple human subjects after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin % Or less of human individuals experience grade 3 or higher peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) Rituximab; (c) Gemcitabine; And (d) Oxaliplatin; wherein the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals makes 33% or less of the multiple human individuals Experienced grade 3 or higher peripheral neuropathy, the disease cannot resolve to grade 1 or lower within 14 days.

在某些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 19之胺基酸序列的重鏈可變域(VH)及(ii)含SEQ ID NO: 20之胺基酸序列的輕鏈可變域(VL)。在一些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈。在某些實施例中，p在2與5之間。在某些實施例中，p在3與4之間。在某些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In certain embodiments, the anti-CD79b antibody includes (i) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 19 and (ii) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 20 Light chain variable domain (VL). In some embodiments, the anti-CD79b antibody includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在可與任何前述實施例組合的一些實施例中，該免疫偶聯物係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與。在某些實施例中，將免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑投與一或多個21天週期。在一些實施例中，該免疫偶聯物在每個週期係以約1.8 mg/kg之劑量投與，利妥昔單抗在每個週期係以約375 mg/m2 之劑量投與，吉西他濱在每個週期係以約1000 mg/m2 之劑量投與，且奧沙利鉑在每個週期係以約100 mg/m2 之劑量投與。在某些實施例中，該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。在某些實施例中，利妥昔單抗係在該免疫偶聯物之前投與。在某些實施例中，吉西他濱係在奧沙利鉑之前投與。在某些實施例中，將免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑投與至多八個21天週期。在某些實施例中，將免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑投與8個21天週期。In some embodiments that can be combined with any of the preceding embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg, rituximab is administered at a dose of about 375 mg/m 2 and gemcitabine It is administered at a dose of about 1000 mg/m 2 , and oxaliplatin is administered at a dose of about 100 mg/m 2 . In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for one or more 21-day cycles. In some embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg per cycle, rituximab is administered at a dose of about 375 mg/m 2 per cycle, gemcitabine It is administered at a dose of approximately 1000 mg/m 2 in each cycle, and oxaliplatin is administered at a dosage of approximately 100 mg/m 2 in each cycle. In certain embodiments, the immunoconjugate and rituximab are administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin are administered on the first day of each 21-day cycle. Administer intravenously in 2 days. In certain embodiments, rituximab is administered before the immunoconjugate. In certain embodiments, gemcitabine is administered before oxaliplatin. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for 8 21-day cycles.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the 21st day of each cycle. 1 day intravenous administration, and wherein gemcitabine and oxaliplatin are administered intravenously on the 2nd day of each 21-day cycle; and wherein the immunoconjugate, rituximab, gemcitabine and After oxaliplatin, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the first of each 21-day cycle And oxaliplatin is administered intravenously on the second day of each 21-day cycle; and wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered intravenously. After thaliplatin, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the first 21-day cycle One day intravenous administration, and wherein gemcitabine and oxaliplatin are administered intravenously on the second day of each 21-day cycle; and wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered intravenously. Thaliplatin does not cause peripheral neuropathy of grade 3 or higher in this human individual, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the first of each 21-day cycle It was administered intravenously on the same day, and where gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle; and where the immunoconjugate, rituximab, gemcitabine and oxali were administered Libaplatin does not cause peripheral neuropathy of grade 3 or higher in this human individual, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the 21st day of each cycle. One day of intravenous administration, and wherein gemcitabine and oxaliplatin are administered intravenously on the second day of each 21-day cycle; and wherein among the multiple human subjects being treated, the immunoconjugate is administered After drugs, rituximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced grade 3 or higher peripheral neuropathy, and the disease did not subside within 14 days Level 1 or lower.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the first of each 21-day cycle Administered intravenously every day, and wherein gemcitabine and oxaliplatin are administered intravenously on the 2nd day of each 21-day cycle; and wherein in a plurality of human subjects being treated, the immunoconjugate is administered , Rituximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced grade 3 or higher peripheral neuropathy, and the disease did not subside within 14 days. Level 1 or lower.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the 21st day of each cycle. One day intravenous administration, wherein gemcitabine and oxaliplatin are administered intravenously on the second day of each 21-day cycle; and wherein the immunoconjugate, rituximab are administered to multiple human individuals Anti-, gemcitabine, and oxaliplatin caused 33% or less of the multiple human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 or lower within 14 days .

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the first of each 21-day cycle Administered intravenously every day, and wherein gemcitabine and oxaliplatin are administered intravenously on the 2nd day of each 21-day cycle; and wherein in a plurality of human subjects being treated, the immunoconjugate is administered , Rituximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced grade 3 or higher peripheral neuropathy, and the disease did not subside within 14 days. Level 1 or lower.

在可與任何前述實施例組合的一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。In some embodiments that can be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

在可與任何前述實施例組合的一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少兩個、至少三個、至少四個、至少五個、至少六個或至少七個21天週期。在一些實施例中，將免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑投與八個21天週期。在一些實施例中，利妥昔單抗係在該免疫偶聯物之前投與。在一些實施例中，吉西他濱係在奧沙利鉑之前投與。In some embodiments that can be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered at least two, at least three, at least four, at least five, At least six or at least seven 21-day cycles. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for eight 21-day cycles. In some embodiments, rituximab is administered before the immunoconjugate. In some embodiments, gemcitabine is administered before oxaliplatin.

在可與任何前述實施例組合的一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In some embodiments that can be combined with any of the preceding embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在可與任何前述實施例組合的一些實施例中，抗CD79b抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，抗CD79b抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。在一些實施例中，免疫偶聯物係依拉妥珠單抗維多汀。在某些實施例中，p在2與5之間。在某些實施例中，p係2。In some embodiments that can be combined with any of the foregoing embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 38. In some embodiments, the immunoconjugate is elatuzumab vedotine. In some embodiments, p is between 2 and 5. In certain embodiments, p is 2.

在一些實施例中，該人類個體已接受至少一種針對DLBCL之先前療法。在一些實施例中，該人類人類個體已接受至少一種針對DLBCL之先前全身性療法。在一些實施例中，該人類個體已接受至少兩種針對DLBCL之先前療法。在某些實施例中，DLBCL係經組織學確定的非特指型(NOS) DLBCL，或者該人類個體有惰性疾病轉化為DLBCL之病史。在某些實施例中，DLBCL係復發性或難治性DLBCL。在某些實施例中，該人類個體的美國東岸癌症臨床研究合作組織(Eastern Cooperative Oncology Group，ECOG)體能狀態係0、1或2。在某些實施例中，該人類個體沒有計劃進行自體或同種異體幹細胞移植(SCT)。在某些實施例中，該人類個體未曾接受用吉西他濱及鉑基藥劑之組合進行之先前療法。在某些實施例中，根據5.0版國家癌症研究院常見不良事件評價準則(National Cancer Institute Common Terminology Criteria for Adverse Events)，該人類個體之周圍神經病變不大於1級。在某些實施例中，該人類個體未患原發性或繼發性中樞神經系統淋巴瘤。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前，該人類個體並非造血幹細胞移植(HSCT)之候選人。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前，該人類個體並非自體造血幹細胞移植(HSCT)之候選人。在一些實施例中，該人類個體已接受至少兩種針對DLBCL之先前療法。在一些實施例中，該人類個體未接受針對DLBCL之帕妥珠單抗維多汀-piiq先前療法。在一些實施例中，該人類個體係成人。在一些實施例中，若未另外說明，否則該成人患有復發性或難治性彌漫性大B細胞淋巴瘤。In some embodiments, the human individual has received at least one previous therapy for DLBCL. In some embodiments, the human human individual has received at least one previous systemic therapy for DLBCL. In some embodiments, the human individual has received at least two previous therapies for DLBCL. In some embodiments, DLBCL is a histologically determined non-specific (NOS) DLBCL, or the human individual has a history of indolent disease converted to DLBCL. In certain embodiments, DLBCL is relapsed or refractory DLBCL. In certain embodiments, the Eastern Cooperative Oncology Group (ECOG) performance status of the human individual is 0, 1, or 2. In certain embodiments, the human individual has no plans to undergo autologous or allogeneic stem cell transplantation (SCT). In certain embodiments, the human individual has not received prior therapy with a combination of gemcitabine and platinum-based agents. In some embodiments, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, the peripheral neuropathy of the human individual is not greater than grade 1. In certain embodiments, the human individual does not suffer from primary or secondary central nervous system lymphoma. In some embodiments, the human individual is not a candidate for hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human individual is not a candidate for autologous hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human individual has received at least two previous therapies for DLBCL. In some embodiments, the human individual has not received Pertuzumab Vidotin-piiq prior therapy for DLBCL. In some embodiments, the human is an adult. In some embodiments, unless otherwise specified, the adult has relapsed or refractory diffuse large B-cell lymphoma.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級的周圍神經病變。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級的神經毒性。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷4級或更高級的周圍神經病變。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷4級或更高級的神經毒性。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約40%的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約8%的人類個體經歷3級或更高級別的周圍神經病變。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約6%的人類個體經歷周圍神經病變，該疾病導致用該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑進行之治療中止。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該人類個體中引起完全反應。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該人類個體中引起部分反應。In some embodiments that can be combined with any of the preceding embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause peripheral nerves of grade 3 or higher in the human individual Lesions, the disease cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause grade 4 or higher peripheral neuropathy in the human individual. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause neurotoxicity of grade 4 or higher in the human individual. In some embodiments, after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human individual does not experience grade 4 or higher peripheral neuropathy. In some embodiments, after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human individual does not experience grade 4 or higher neurotoxicity. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals causes 33% or less of the human individuals to experience grade 3 or more. High-grade peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals causes less than about 40% of the multiple human individuals to experience Grade 3 or higher. High-grade peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects causes less than about 8% of the human subjects to experience grade 3 or higher. High-grade peripheral neuropathy. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals causes less than about 6% of the multiple human individuals to experience peripheral neuropathy, The disease resulted in the discontinuation of treatment with the immunoconjugate, rituximab, gemcitabine and oxaliplatin. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin elicits a complete response in the human individual. In some embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin elicits a partial response in the human individual.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑引起該人類個體之無進展存活。在一些實施例中、投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約13個月、至少約14個月、至少約15個月、至少約16個月、至少約17個月、至少約18個月、至少約19個月、至少約20個月、至少約21個月、至少約22個月、至少約23個月、至少約24個月或至少約25個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約5個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約6個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約9.5個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約11個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約14個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該人類個體之無進展存活期相較於向相應人類個體投與利妥昔單抗、吉西他濱及奧沙利鉑的無進展存活期增加。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中人類個體之無進展存活期相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體之無進展存活期增加。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes progression-free survival of the human individual. In some embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin allows the human individual to start treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin Have lasting at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, At least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about A progression-free survival period of 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 4 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period that lasts at least about 5 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period that lasts at least about 6 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 9.5 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 11 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 14 months. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin makes the progression-free survival of the human individual compared to the administration of rituximab, gemcitabine to the corresponding human individual And the progression-free survival of oxaliplatin increased. In some embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals makes the progression-free survival of the human individuals in the multiple human individuals compared to the administration benefit. The progression-free survival of multiple human individuals corresponding to tuximab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑引起該人類個體之無事件存活。在一些實施例中、投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約13個月、至少約14個月、至少約15個月、至少約16個月、至少約17個月、至少約18個月、至少約19個月、至少約20個月、至少約21個月、至少約22個月、至少約23個月、至少約24個月或至少約25個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約5個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約6個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約9.5個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約11個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約14個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該人類個體之無事件存活期相較於向相應人類個體投與利妥昔單抗、吉西他濱及奧沙利鉑的無事件存活期增加。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中人類個體之無事件存活期相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體之無事件存活期增加。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin caused event-free survival of the human individual. In some embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin allows the human individual to start treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin Have lasting at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, At least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about An event-free survival period of 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival that lasts at least about 4 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival period that lasts at least about 5 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 6 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 9.5 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 11 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 14 months. In some embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin makes the event-free survival of the human individual compared to the administration of rituximab, gemcitabine to the corresponding human individual And the event-free survival of oxaliplatin increased. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals makes the event-free survival of the human individuals in the multiple human individuals compared to the benefits of administration. The event-free survival of multiple human individuals corresponding to tuximab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後存活至少約10個月或更長時間、至少約11個月或更長時間、至少約12個月或更長時間、至少約13個月或更長時間、至少約14個月或更長時間、或至少約15個月或更長時間。在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑引起該多名人類個體中之人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後至少約10個月或更長時間、至少約11個月或更長時間、至少約12個月或更長時間、至少約13個月或更長時間、至少約14個月或更長時間、或至少約15個月或更長時間的中值總體存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該人類個體之存活期相較於向相應人類個體投與利妥昔單抗、吉西他濱及奧沙利鉑的存活期增加。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中人類個體之中值總體存活期相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體之中值總體存活期增加。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin allows the human individual to start the immunoconjugate, rituximab, Survival after treatment with gemcitabine and oxaliplatin for at least about 10 months or longer, at least about 11 months or longer, at least about 12 months or longer, at least about 13 months or longer, at least About 14 months or more, or at least about 15 months or more. In some embodiments that can be combined with any of the foregoing embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals causes the human individuals of the multiple human individuals to start Immunoconjugates, rituximab, gemcitabine and oxaliplatin treatment at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least A median overall survival of about 13 months or more, at least about 14 months or more, or at least about 15 months or more. In some embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin makes the survival of the human individual compared to the administration of rituximab, gemcitabine, and oxaliplatin to the corresponding human individual. The survival time of thaliplatin is increased. In some embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals makes the median overall survival of the human individuals in the multiple human individuals compared to the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. The median overall survival of multiple human individuals corresponding to rituximab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起腫瘤溶解症候群。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與針對腫瘤溶解症候群之預防性治療。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not cause tumor lysis syndrome in the human individual. In some embodiments, the method provided herein further comprises administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human individual before, during and/or after the human individual Preventive treatment for tumor lysis syndrome.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起感染。在一些實施例中，感染係肺孢子蟲感染或皰疹病毒感染。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與針對感染之預防性治療。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin will not cause infection in the human individual. In some embodiments, the infection is a Pneumocystis infection or a herpes virus infection. In some embodiments, the method provided herein further comprises administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human individual before, during and/or after the human individual Preventive treatment for infection.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會使該人類個體之嗜中性白血球減少症。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與針對嗜中性白血球減少症之預防性治療。在一些實施例中，針對嗜中性白血球減少症之預防性治療包含向該人類個體投與G-CSF。在一些實施例中，本文所提供之方法進一步包括當該人類個體在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後出現3級或4級嗜中性白血球減少症時，停止用免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑進行之治療。在一些實施例中，該等方法進一步包括當該人類個體體內之絕對嗜中性白血球計數(ANC)增加至 ＞1000/µL時，重新開始用免疫偶聯物，利妥昔單抗，吉西他濱及奧沙利鉑進行之治療。在一些實施例中，該等方法進一步包括投與一或多種生長因子來治療嗜中性白血球減少症。在一些實施例中，該一或多種生長因子包含G-CSF。在一些實施例中，該等方法進一步包括當在21天週期之第7天或之前，該人類個體體內之ANC恢復至＞ 1000/µL時，重新開始用免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑進行之治療，且不降低免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之劑量。在一些實施例中，該等方法進一步包括當在21天週期之第7天之後，該人類個體體內之ANC恢復至＞ 1000個/μl時，重新開始用免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑進行之治療，其中該免疫偶聯物之劑量降低至1.4 mg/kg。在一些實施例中，該等方法進一步包括當減少免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之先前劑量時，中止用免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑進行之治療。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not cause neutropenia in the human individual. In some embodiments, the method provided herein further comprises administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human individual before, during and/or after the human individual Preventive treatment for neutropenia. In some embodiments, the preventive treatment for neutropenia comprises administering G-CSF to the human individual. In some embodiments, the methods provided herein further include when the human individual develops grade 3 or 4 neutropenia after administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin At that time, treatment with immunoconjugates, rituximab, gemcitabine and oxaliplatin was stopped. In some embodiments, the methods further include when the absolute neutrophil count (ANC) in the human individual increases to >1000/µL, restarting the immunoconjugate, rituximab, gemcitabine and Treatment with oxaliplatin. In some embodiments, the methods further include administering one or more growth factors to treat neutropenia. In some embodiments, the one or more growth factors comprise G-CSF. In some embodiments, the methods further include when the ANC in the human individual returns to> 1000/μL on or before the 7th day of the 21-day cycle, restarting the immunoconjugate, rituximab , Gemcitabine and oxaliplatin without reducing the dose of immunoconjugates, rituximab, gemcitabine and oxaliplatin. In some embodiments, the methods further include when the ANC in the human individual returns to> 1000/μl after the 7th day of the 21-day cycle, restarting the immunoconjugate, rituximab , Gemcitabine and oxaliplatin, in which the dose of the immunoconjugate is reduced to 1.4 mg/kg. In some embodiments, the methods further include discontinuing the use of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin when the previous dose of immunoconjugate, rituximab, gemcitabine, and oxaliplatin is reduced. Treatment with oxaliplatin.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會引起該人類個體之B型肝炎再活化。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與B型肝炎再活化之預防性治療。在一些實施例中，本文所提供之方法進一步包括當在人類個體中偵測到乙型肝炎再活化時，向該人類個體投與抗病毒藥物。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not cause hepatitis B reactivation in the human individual. In some embodiments, the method provided herein further comprises administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human individual before, during and/or after the human individual Preventive treatment for hepatitis B reactivation. In some embodiments, the methods provided herein further include administering an antiviral drug to the human individual when hepatitis B reactivation is detected in the human individual.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會引起選自由以下組成之群的一或多例不良事件：藥物誘發之肝損傷、進行性多灶性腦白質病、全身性超敏反應、過敏性反應、類過敏性反應及第二惡性疾病。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not cause one or more adverse events selected from the group consisting of: Drug-induced liver injury, progressive multifocal leukoencephalopathy, systemic hypersensitivity, allergic reactions, allergic reactions and second malignant diseases.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得完全反應率(CRR)相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體之CRR增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in a complete response rate (CRR) compared to administration Correspondingly, the CRR of multiple human individuals for rituximab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得客觀反應率(ORR)相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體之ORR增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects makes the objective response rate (ORR) compared to administration Rituximab, gemcitabine, and oxaliplatin have correspondingly increased ORRs in multiple human individuals.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得最佳總體反應率(BOR)相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體之BOR增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in the best overall response rate (BOR) compared to Correspondingly, BOR increased in multiple human subjects administered rituximab, gemcitabine, and oxaliplatin.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得反應持續時間(DOR)相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體之DOR增加。In some embodiments that can be combined with any of the preceding embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects makes the duration of response (DOR) compared to administration Corresponding human subjects with rituximab, gemcitabine, and oxaliplatin have increased DOR.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的1年無進展存活率係至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的2年無進展存活率係至少約63%或更高、至少約65%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的5年無進展存活率係至少約14%或更高、至少約15%或更高、至少約20%或更高、至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得1年、2年、3.5年或5年無進展存活率相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects caused no symptoms for 1 year in the multiple human subjects. The survival rate of progression is at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher High, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a 2-year progression-free survival rate of at least about 63% in the multiple human individuals. Or higher, at least about 65% or higher, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a 5-year progression-free survival rate of at least about 14% in the multiple human individuals. Or higher, at least about 15% or higher, at least about 20% or higher, at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher High, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in a 1-year, 2-year, 3.5-year, or 5-year progression-free survival rate compared to administration. Correspondingly with rituximab, gemcitabine and oxaliplatin, the number of human individuals increased.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的1年總體存活率係至少約42%或更高、至少約45%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的2年總體存活率係至少約67%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的3.5年總體存活率係至少約38%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的5年總體存活率係至少約15%或更高、至少約20%或更高、至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得1年、2年、3.5年或5年總體存活率相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects caused a total of 1 year in the multiple human subjects. The survival rate is at least about 42% or higher, at least about 45% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher , At least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a 2-year overall survival rate of at least about 67% or Higher, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a 3.5-year overall survival rate of at least about 38% or Higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher , At least about 95% or higher, or about 100%. In some embodiments, administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a 5-year overall survival rate of at least about 15% or Higher, at least about 20% or higher, at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher , At least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in a 1 year, 2 year, 3.5 year, or 5 year overall survival rate compared to administration Rituximab, gemcitabine, and oxaliplatin were correspondingly increased in multiple human individuals.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的2年無事件存活率係至少約44%或更高、至少約45%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得1年、2年、3.5年或5年無事件存活率相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects caused 2 years of non-existence in the multiple human subjects. Event survival rate is at least about 44% or higher, at least about 45% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher High, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in a 1-year, 2-year, 3.5-year, or 5-year event-free survival rate compared to the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. Correspondingly with rituximab, gemcitabine and oxaliplatin, the number of human individuals increased.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的客觀反應率係至少約44%或更高、至少約45%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。In some embodiments that can be combined with any of the foregoing embodiments, the objective response rate of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin caused by the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals At least about 44% or higher, at least about 45% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher, at least About 90% or higher, at least about 95% or higher, or about 100%.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的完全反應率係至少約35%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。In some embodiments that can be combined with any of the foregoing embodiments, the complete response rate of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin caused by the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals At least about 35% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher, at least About 90% or higher, at least about 95% or higher, or about 100%.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的部分反應率係至少約10%或更高、至少約20%或更高、至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得部分反應率相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體之部分反應增加。In some embodiments that can be combined with any of the foregoing embodiments, the partial response rate caused by the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals At least about 10% or higher, at least about 20% or higher, at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least About 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects makes the partial response rate compared to administration of rituximab Corresponding partial responses of multiple human individuals with monoclonal antibodies, gemcitabine and oxaliplatin increased.

在另一個態樣中，本文提供一種套組，該套組包括含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合使用以治療患有彌漫性大B細胞淋巴瘤(DLBCL)的有需要之人類個體。In another aspect, this document provides a kit that includes an immunoconjugate containing the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and Tuximab, gemcitabine, and oxaliplatin are used in combination to treat human individuals in need with diffuse large B-cell lymphoma (DLBCL).

在另一個態樣中，本文提供一種套組，該套組包含帕妥珠單抗維多汀-piiq，其係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合使用以治療患有彌漫性大B細胞淋巴瘤(DLBCL)的有需要之人類個體。In another aspect, provided herein is a kit comprising Pertuzumab Vidotin-piiq, which is combined with rituximab, gemcitabine, and oxaliplatin according to any of the foregoing embodiments Used to treat human individuals in need with diffuse large B-cell lymphoma (DLBCL).

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and The combination of tuximab, gemcitabine and oxaliplatin is used in the treatment of diffuse large B-cell lymphoma (DLBCL).

在另一個態樣中，本文提供利妥昔單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間。In another aspect, provided herein is rituximab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、利妥昔單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, rituximab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及利妥昔單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間。In another aspect, provided herein is oxaliplatin, which is used in the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with immunoconjugates, gemcitabine, and rituximab according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and A combination of tuximab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered After platinum, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and A combination of tuximab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered It does not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and The combination of tuximab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein in a number of human individuals to be treated, the immunoconjugate, oxaliplatin is administered After tuximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 within 14 days Or lower.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and The combination of tuximab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, rituximab, gemcitabine are administered to multiple human individuals And oxaliplatin caused 33% or less of the multiple human individuals to experience peripheral neuropathy of grade 3 or higher, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供利妥昔單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is rituximab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered After anti-, gemcitabine, and oxaliplatin, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供利妥昔單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is rituximab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered , Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in this human individual, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供利妥昔單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is rituximab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein among the multiple human subjects to be treated, the HVR-L3 is administered After the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease could not be It resolves to grade 1 or lower within 14 days.

在另一個態樣中，本文提供利妥昔單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is rituximab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Rituximab, gemcitabine, and oxaliplatin caused 33% or less of the human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、利妥昔單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, rituximab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered After anti-, gemcitabine, and oxaliplatin, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、利妥昔單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, rituximab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered , Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in this human individual, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、利妥昔單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, rituximab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein among the multiple human subjects to be treated, the HVR-L3 is administered After the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease could not be It resolves to grade 1 or lower within 14 days.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、利妥昔單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, rituximab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Rituximab, gemcitabine, and oxaliplatin caused 33% or less of the human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及利妥昔單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is oxaliplatin, which is used in the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with immunoconjugates, gemcitabine, and rituximab according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered After anti-, gemcitabine, and oxaliplatin, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及利妥昔單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is oxaliplatin, which is used in the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with immunoconjugates, gemcitabine, and rituximab according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered , Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in this human individual, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及利妥昔單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is oxaliplatin, which is used in the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with immunoconjugates, gemcitabine, and rituximab according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein among the multiple human subjects to be treated, the HVR-L3 is administered After the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease could not be It resolves to grade 1 or lower within 14 days.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及利妥昔單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is oxaliplatin, which is used in the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with immunoconjugates, gemcitabine, and rituximab according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Rituximab, gemcitabine, and oxaliplatin caused 33% or less of the human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower.

在一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)奧妥珠單抗(obinutuzumab)；(c)吉西他濱；以及(d)奧沙利鉑。In one aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following formula Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) obinutuzumab; (c ) Gemcitabine; and (d) Oxaliplatin.

在某些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 19之胺基酸序列的重鏈可變域(VH)及(ii)含SEQ ID NO: 20之胺基酸序列的輕鏈可變域(VL)。在一些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈。在某些實施例中，p在2與5之間。在某些實施例中，p在3與4之間。在某些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In certain embodiments, the anti-CD79b antibody includes (i) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 19 and (ii) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 20 Light chain variable domain (VL). In some embodiments, the anti-CD79b antibody includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在一些實施例中，抗CD79b抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，抗CD79b抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。在一些實施例中，免疫偶聯物係依拉妥珠單抗維多汀。在某些實施例中，p在2與5之間。在某些實施例中，p係2。In some embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 38. In some embodiments, the immunoconjugate is elatuzumab vedotine. In some embodiments, p is between 2 and 5. In certain embodiments, p is 2.

在可與任何前述實施例組合的一些實施例中，該免疫偶聯物係以約1.8 mg/kg之劑量投與，奧妥珠單抗係以約1000 mg之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與。在某些實施例中，將免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑投與一或多個21天週期。在某些實施例中，該免疫偶聯物在每個週期係以約1.8 mg/kg之劑量投與，奧妥珠單抗在每個週期係以約1000 mg之劑量投與，吉西他濱在每個週期係以約1000 mg/m2 之劑量投與，且奧沙利鉑在每個週期係以約100 mg/m2 之劑量投與。在某些實施例中，奧妥珠單抗係在該免疫偶聯物之前投與。在某些實施例中，吉西他濱係在奧沙利鉑之前投與。在某些實施例中，將免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑投與至多八個21天週期。在某些實施例中，將免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑投與八個21天週期。In some embodiments that can be combined with any of the foregoing embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg, otuzumab is administered at a dose of about 1000 mg, and gemcitabine is administered at a dose of about The dose of 1000 mg/m 2 is administered, and the oxaliplatin is administered at a dose of about 100 mg/m 2 . In certain embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin are administered for one or more 21-day cycles. In certain embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg per cycle, otuzumab is administered at a dose of about 1000 mg per cycle, and gemcitabine is administered at a dose of about 1000 mg per cycle. Each cycle is administered at a dose of about 1000 mg/m 2 , and oxaliplatin is administered at a dosage of about 100 mg/m 2 in each cycle. In certain embodiments, otuzumab is administered before the immunoconjugate. In certain embodiments, gemcitabine is administered before oxaliplatin. In certain embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles. In certain embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin are administered for eight 21-day cycles.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, the administration dose of otuzumab is about 1000 mg, and the administration of gemcitabine The dose is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, and the dosage of gemcitabine is about 1000 mg. It is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.4 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, where in each cycle, the administration dose of the immunoconjugate is about 1.4 mg/kg, the administration dose of otuzumab is about 1000 mg, and the administration of gemcitabine The dose is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.4 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dose of the immunoconjugate is about 1.4 mg/kg, the dose of otuzumab is about 1000 mg, and the dose of gemcitabine It is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約75 mg/m2 。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, the administration dose of otuzumab is about 1000 mg, and the administration of gemcitabine The dose is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 75 mg/m 2 .

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約75 mg/m2 。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, and the dosage of gemcitabine is about 1000 mg. It is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 75 mg/m 2 .

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.4 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約75 mg/m2 。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, where in each cycle, the administration dose of the immunoconjugate is about 1.4 mg/kg, the administration dose of otuzumab is about 1000 mg, and the administration of gemcitabine The dose is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 75 mg/m 2 .

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a) 包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.4 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約75 mg/m2 。In another aspect, this document provides a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising: Immunoconjugate
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dose of the immunoconjugate is about 1.4 mg/kg, the dose of otuzumab is about 1000 mg, and the dose of gemcitabine It is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 75 mg/m 2 .

在可與任何前述實施例組合的一些實施例中，免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑係投與至少兩個、至少三個、至少四個、至少五個、至少六個或至少七個21天週期。在一些實施例中，將免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑投與八個21天週期。在一些實施例中，奧妥珠單抗係在該免疫偶聯物之前投與。在一些實施例中，吉西他濱係在奧沙利鉑之前投與。在一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In some embodiments that can be combined with any of the foregoing embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin are administered at least two, at least three, at least four, at least five, At least six or at least seven 21-day cycles. In some embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin are administered for eight 21-day cycles. In some embodiments, otuzumab is administered before the immunoconjugate. In some embodiments, gemcitabine is administered before oxaliplatin. In some embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在一些實施例中，該人類個體已接受至少一種針對DLBCL之先前療法。在一些實施例中，該人類人類個體已接受至少一種針對DLBCL之先前全身性療法。在一些實施例中，該人類個體已接受至少兩種針對DLBCL之先前療法。在某些實施例中，DLBCL係經組織學確定的非特指型(NOS) DLBCL，或者該人類個體有惰性疾病轉化為DLBCL之病史。在某些實施例中，DLBCL係復發性或難治性DLBCL。在某些實施例中，該人類個體的美國東岸癌症臨床研究合作組織(Eastern Cooperative Oncology Group，ECOG)體能狀態係0、1或2。在某些實施例中，該人類個體沒有計劃進行自體或同種異體幹細胞移植(SCT)。在某些實施例中，該人類個體未曾接受用吉西他濱及鉑基藥劑之組合進行之先前療法。在某些實施例中，根據5.0版國家癌症研究院常見不良事件評價準則(National Cancer Institute Common Terminology Criteria for Adverse Events)，該人類個體之周圍神經病變不大於1級。在某些實施例中，該人類個體未患原發性或繼發性中樞神經系統淋巴瘤。在一些實施例中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之前，該人類個體並非造血幹細胞移植(HSCT)之候選人。在一些實施例中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之前，該人類個體並非自體造血幹細胞移植(HSCT)之候選人。在一些實施例中，該人類個體已接受至少兩種針對DLBCL之先前療法。在一些實施例中，該人類個體未接受針對DLBCL之帕妥珠單抗維多汀-piiq先前療法。在一些實施例中，該人類個體係成人。在一些實施例中，若未另外說明，否則該成人患有復發性或難治性彌漫性大B細胞淋巴瘤。In some embodiments, the human individual has received at least one previous therapy for DLBCL. In some embodiments, the human human individual has received at least one previous systemic therapy for DLBCL. In some embodiments, the human individual has received at least two previous therapies for DLBCL. In some embodiments, DLBCL is a histologically determined non-specific (NOS) DLBCL, or the human individual has a history of indolent disease converted to DLBCL. In certain embodiments, DLBCL is relapsed or refractory DLBCL. In certain embodiments, the Eastern Cooperative Oncology Group (ECOG) performance status of the human individual is 0, 1, or 2. In certain embodiments, the human individual has no plans to undergo autologous or allogeneic stem cell transplantation (SCT). In certain embodiments, the human individual has not received prior therapy with a combination of gemcitabine and platinum-based agents. In some embodiments, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, the peripheral neuropathy of the human individual is not greater than grade 1. In certain embodiments, the human individual does not suffer from primary or secondary central nervous system lymphoma. In some embodiments, the human individual is not a candidate for hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin. In some embodiments, the human individual is not a candidate for autologous hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin. In some embodiments, the human individual has received at least two previous therapies for DLBCL. In some embodiments, the human individual has not received Pertuzumab Vidotin-piiq prior therapy for DLBCL. In some embodiments, the human is an adult. In some embodiments, unless otherwise specified, the adult has relapsed or refractory diffuse large B-cell lymphoma.

在某些實施例中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在某些實施例中，在所治療之多名人類個體中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之後，有33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在某些實施例中，在所治療之多名人類個體中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中有33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級的周圍神經病變。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級的神經毒性。在一些實施例中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷4級或更高級的周圍神經病變。在一些實施例中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷4級或更高級的神經毒性。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約40%的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約8%的人類個體經歷3級或更高級別的周圍神經病變。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約6%的人類個體經歷周圍神經病變，該疾病導致用該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑進行之治療中止。在某些實施例中，免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。In certain embodiments, after the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin, the human individual does not experience grade 3 or higher peripheral neuropathy, and the disease cannot be in 14 It resolves to grade 1 or lower within days. In certain embodiments, among the multiple human subjects treated, 33% or less of the human subjects experienced 3% or less after the administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin. Peripheral neuropathy of grade 1 or higher, which cannot resolve to grade 1 or lower within 14 days. In certain embodiments, among the multiple human subjects treated, 33% or more of the multiple human subjects after administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin Few human individuals experience grade 3 or higher peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin does not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot occur within 14 days. The internal regression is level 1 or lower. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin does not cause grade 4 or higher peripheral neuropathy in the human individual. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin does not cause grade 4 or higher neurotoxicity in the human individual. In some embodiments, the human individual does not experience grade 4 or higher peripheral neuropathy after administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin. In some embodiments, after administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin, the human individual does not experience neurotoxicity of grade 4 or higher. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects causes 33% or less of the human subjects to experience grade 3 or more. High-grade peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals causes less than about 40% of the multiple human individuals to experience Grade 3 or higher. High-grade peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals causes less than about 8% of the multiple human individuals to experience Grade 3 or higher. High-grade peripheral neuropathy. In some embodiments, administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals causes less than about 6% of the multiple human individuals to experience peripheral neuropathy, The disease resulted in the discontinuation of treatment with the immunoconjugate, otuzumab, gemcitabine and oxaliplatin. In certain embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) otuzumab; (c) gemcitabine; And (d) Oxaliplatin; wherein after administration of the immunoconjugate, otuzumab, gemcitabine and oxaliplatin, the human individual has not experienced grade 3 or higher peripheral neuropathy, the The disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) otuzumab; (c) gemcitabine; And (d) Oxaliplatin; wherein the administration of the immunoconjugate, otuzumab, gemcitabine and oxaliplatin does not cause peripheral neuropathy of grade 3 or higher in the human individual, the The disease cannot resolve to grade 1 or lower within 14 days.

在某些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 19之胺基酸序列的重鏈可變域(VH)及(ii)含SEQ ID NO: 20之胺基酸序列的輕鏈可變域(VL)。在一些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈。在某些實施例中，p在2與5之間。在某些實施例中，p在3與4之間。在某些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In certain embodiments, the anti-CD79b antibody includes (i) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 19 and (ii) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 20 Light chain variable domain (VL). In some embodiments, the anti-CD79b antibody includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) otuzumab; (c) gemcitabine; And (d) oxaliplatin; wherein among the multiple human subjects treated, after administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin, 33 of the multiple human subjects % Or less of human individuals experience grade 3 or higher peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中向多名个体投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) otuzumab; (c) gemcitabine; And (d) Oxaliplatin; wherein administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin to multiple individuals allows 33% or less of the human individuals to experience Peripheral neuropathy of grade 3 or higher, which cannot resolve to grade 1 or lower within 14 days.

在某些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 19之胺基酸序列的重鏈可變域(VH)及(ii)含SEQ ID NO: 20之胺基酸序列的輕鏈可變域(VL)。在一些實施例中，抗CD79b抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈。在某些實施例中，p在2與5之間。在某些實施例中，p在3與4之間。在某些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In certain embodiments, the anti-CD79b antibody includes (i) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 19 and (ii) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 20 Light chain variable domain (VL). In some embodiments, the anti-CD79b antibody includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在可與任何前述實施例組合的一些實施例中，該免疫偶聯物係以約1.8 mg/kg之劑量投與，奧妥珠單抗係以約1000 mg之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與。在某些實施例中，將免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑投與一或多個21天週期。在某些實施例中，該免疫偶聯物在每個週期係以約1.8 mg/kg之劑量投與，奧妥珠單抗在每個週期係以約1000 mg之劑量投與，吉西他濱在每個週期係以約1000 mg/m2 之劑量投與，且奧沙利鉑在每個週期係以約100 mg/m2 之劑量投與。在某些實施例中，奧妥珠單抗係在該免疫偶聯物之前投與。在某些實施例中，吉西他濱係在奧沙利鉑之前投與。在某些實施例中，將免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑投與至多八個21天週期。在某些實施例中，將免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑投與八個21天週期。In some embodiments that can be combined with any of the foregoing embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg, otuzumab is administered at a dose of about 1000 mg, and gemcitabine is administered at a dose of about The dose of 1000 mg/m 2 is administered, and the oxaliplatin is administered at a dose of about 100 mg/m 2 . In certain embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin are administered for one or more 21-day cycles. In certain embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg per cycle, otuzumab is administered at a dose of about 1000 mg per cycle, and gemcitabine is administered at a dose of about 1000 mg per cycle. Each cycle is administered at a dose of about 1000 mg/m 2 , and oxaliplatin is administered at a dosage of about 100 mg/m 2 in each cycle. In certain embodiments, otuzumab is administered before the immunoconjugate. In certain embodiments, gemcitabine is administered before oxaliplatin. In certain embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles. In certain embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin are administered for eight 21-day cycles.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, the administration dose of otuzumab is about 1000 mg, and the administration of gemcitabine The dose is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 100 mg/m 2 ; and wherein after administration of the immunoconjugate, otuzumab, gemcitabine and oxaliplatin , The human individual has not experienced grade 3 or higher peripheral neuropathy, and the disease cannot subside to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, and the dosage of gemcitabine is about 1000 mg. It is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and after the administration of the immunoconjugate, otuzumab, gemcitabine and oxaliplatin, The human individual has not experienced grade 3 or higher peripheral neuropathy, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, the administration dose of otuzumab is about 1000 mg, and the administration of gemcitabine The dose is about 1000 mg/m 2 , and the dose of oxaliplatin is about 100 mg/m 2 ; and the administration of the immunoconjugate, otuzumab, gemcitabine and oxaliplatin will not In this human individual, it caused peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一个21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, and the dosage of gemcitabine is about 1000 mg. It is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the administration of the immunoconjugate, otuzumab, gemcitabine and oxaliplatin will not cause This human individual caused peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, the administration dose of otuzumab is about 1000 mg, and the administration of gemcitabine The dose is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 100 mg/m 2 ; and among the multiple human subjects to be treated, the immunoconjugate, octopyr After monoclonal antibodies, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 or higher within 14 days Low level.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, and the dosage of gemcitabine is about 1000 mg. The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; After anti-, gemcitabine and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 or lower within 14 days level.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中向多名人類個體投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, the administration dose of otuzumab is about 1000 mg, and the administration of gemcitabine The dosage is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered to multiple human subjects. Thaliplatin caused 33% or less of the multiple human individuals to experience peripheral neuropathy of grade 3 or higher, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)奧妥珠單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中向多名人類個體投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human individual in need, the method comprising administering to the human individual an effective amount of: (a) comprising the following The immunoconjugate of formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) otuzumab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, and the dosage of gemcitabine is about 1000 mg. It is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate, otuzumab, gemcitabine and oxa are administered to multiple human individuals Libaplatin caused 33% or less of the multiple human individuals to experience peripheral neuropathy of grade 3 or higher, and the disease cannot resolve to grade 1 or lower within 14 days.

在可與任何前述實施例組合的一些實施例中，免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。In some embodiments that can be combined with any of the preceding embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

在可與任何前述實施例組合的一些實施例中，免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑係投與至少兩個、至少三個、至少四個、至少五個、至少六個或至少七個21天週期。在一些實施例中，將免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑投與八個21天週期。在一些實施例中，奧妥珠單抗係在該免疫偶聯物之前投與。在一些實施例中，吉西他濱係在奧沙利鉑之前投與。In some embodiments that can be combined with any of the foregoing embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin are administered at least two, at least three, at least four, at least five, At least six or at least seven 21-day cycles. In some embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin are administered for eight 21-day cycles. In some embodiments, otuzumab is administered before the immunoconjugate. In some embodiments, gemcitabine is administered before oxaliplatin.

在可與任何前述實施例組合的一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In some embodiments that can be combined with any of the preceding embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在可與任何前述實施例組合的一些實施例中，抗CD79b抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，抗CD79b抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。在一些實施例中，免疫偶聯物係依拉妥珠單抗維多汀。在某些實施例中，p在2與5之間。在某些實施例中，p係2。In some embodiments that can be combined with any of the foregoing embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 38. In some embodiments, the immunoconjugate is elatuzumab vedotine. In some embodiments, p is between 2 and 5. In certain embodiments, p is 2.

在一些實施例中，該人類個體已接受至少一種針對DLBCL之先前療法。在一些實施例中，該人類人類個體已接受至少一種針對DLBCL之先前全身性療法。在一些實施例中，該人類個體已接受至少兩種針對DLBCL之先前療法。在某些實施例中，DLBCL係經組織學確定的非特指型(NOS) DLBCL，或者該人類個體有惰性疾病轉化為DLBCL之病史。在某些實施例中，DLBCL係復發性或難治性DLBCL。在某些實施例中，該人類個體的美國東岸癌症臨床研究合作組織(Eastern Cooperative Oncology Group，ECOG)體能狀態係0、1或2。在某些實施例中，該人類個體沒有計劃進行自體或同種異體幹細胞移植(SCT)。在某些實施例中，該人類個體未曾接受用吉西他濱及鉑基藥劑之組合進行之先前療法。在某些實施例中，根據5.0版國家癌症研究院常見不良事件評價準則(National Cancer Institute Common Terminology Criteria for Adverse Events)，該人類個體之周圍神經病變不大於1級。在某些實施例中，該人類個體未患原發性或繼發性中樞神經系統淋巴瘤。在一些實施例中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之前，該人類個體並非造血幹細胞移植(HSCT)之候選人。在一些實施例中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之前，該人類個體並非自體造血幹細胞移植(HSCT)之候選人。在一些實施例中，該人類個體已接受至少兩種針對DLBCL之先前療法。在一些實施例中，該人類個體未接受針對DLBCL之帕妥珠單抗維多汀-piiq先前療法。在一些實施例中，該人類個體係成人。在一些實施例中，若未另外說明，否則該成人患有復發性或難治性彌漫性大B細胞淋巴瘤。In some embodiments, the human individual has received at least one previous therapy for DLBCL. In some embodiments, the human human individual has received at least one previous systemic therapy for DLBCL. In some embodiments, the human individual has received at least two previous therapies for DLBCL. In some embodiments, DLBCL is a histologically determined non-specific (NOS) DLBCL, or the human individual has a history of indolent disease converted to DLBCL. In certain embodiments, DLBCL is relapsed or refractory DLBCL. In certain embodiments, the Eastern Cooperative Oncology Group (ECOG) performance status of the human individual is 0, 1, or 2. In certain embodiments, the human individual has no plans to undergo autologous or allogeneic stem cell transplantation (SCT). In certain embodiments, the human individual has not received prior therapy with a combination of gemcitabine and platinum-based agents. In some embodiments, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, the peripheral neuropathy of the human individual is not greater than grade 1. In certain embodiments, the human individual does not suffer from primary or secondary central nervous system lymphoma. In some embodiments, the human individual is not a candidate for hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin. In some embodiments, the human individual is not a candidate for autologous hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin. In some embodiments, the human individual has received at least two previous therapies for DLBCL. In some embodiments, the human individual has not received Pertuzumab Vidotin-piiq prior therapy for DLBCL. In some embodiments, the human is an adult. In some embodiments, unless otherwise specified, the adult has relapsed or refractory diffuse large B-cell lymphoma.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級的周圍神經病變。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級的神經毒性。在一些實施例中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷4級或更高級的周圍神經病變。在一些實施例中，在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷4級或更高級的神經毒性。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約40%的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約8%的人類個體經歷3級或更高級別的周圍神經病變。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約6%的人類個體經歷周圍神經病變，該疾病導致用該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑進行之治療中止。在一些實施例中，免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該人類個體中引起完全反應。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該人類個體中引起部分反應。In some embodiments that can be combined with any of the preceding embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin does not cause peripheral nerves of grade 3 or higher in the human individual Lesions, the disease cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin does not cause grade 4 or higher peripheral neuropathy in the human individual. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin does not cause grade 4 or higher neurotoxicity in the human individual. In some embodiments, the human individual does not experience grade 4 or higher peripheral neuropathy after administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin. In some embodiments, after administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin, the human individual does not experience neurotoxicity of grade 4 or higher. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects causes 33% or less of the human subjects to experience grade 3 or more. High-grade peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals causes less than about 40% of the multiple human individuals to experience Grade 3 or higher. High-grade peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals causes less than about 8% of the multiple human individuals to experience Grade 3 or higher. High-grade peripheral neuropathy. In some embodiments, administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals causes less than about 6% of the multiple human individuals to experience peripheral neuropathy, The disease resulted in the discontinuation of treatment with the immunoconjugate, otuzumab, gemcitabine and oxaliplatin. In some embodiments, the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles. In some embodiments, the administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin elicits a complete response in the human individual. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin caused a partial response in the human individual.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑引起該人類個體之無進展存活。在一些實施例中、投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約13個月、至少約14個月、至少約15個月、至少約16個月、至少約17個月、至少約18個月、至少約19個月、至少約20個月、至少約21個月、至少約22個月、至少約23個月、至少約24個月或至少約25個月的無進展存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月的無進展存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約5個月的無進展存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約6個月的無進展存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約9.5個月的無進展存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約11個月的無進展存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約14個月的無進展存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該人類個體之無進展存活期相較於向相應人類個體投與奧妥珠單抗、吉西他濱及奧沙利鉑的無進展存活期增加。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中人類個體之無進展存活期相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體之無進展存活期增加。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes progression-free survival of the human individual. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin allows the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin Have lasting at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, At least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about A progression-free survival period of 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 4 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is a progression-free survival period that lasts at least about 5 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is a progression-free survival period that lasts at least about 6 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 9.5 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 11 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 14 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin makes the progression-free survival of the human individual compared to the administration of otuzumab, gemcitabine to the corresponding human individual And the progression-free survival of oxaliplatin increased. In some embodiments, the administration of immunoconjugates, oltuzumab, gemcitabine, and oxaliplatin to multiple human individuals makes the progression-free survival of the human individuals in the multiple human individuals compared to that of the oxaliplatin administration. The progression-free survival of multiple human individuals corresponding to tocilizumab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑引起該人類個體之無事件存活。在一些實施例中、投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約13個月、至少約14個月、至少約15個月、至少約16個月、至少約17個月、至少約18個月、至少約19個月、至少約20個月、至少約21個月、至少約22個月、至少約23個月、至少約24個月或至少約25個月的無事件存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月的無事件存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約5個月的無事件存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約6個月的無事件存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約9.5個月的無事件存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約11個月的無事件存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後有持續至少約14個月的無事件存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該人類個體之無事件存活期相較於向相應人類個體投與奧妥珠單抗、吉西他濱及奧沙利鉑的無事件存活期增加。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中人類個體之無事件存活期相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體之無事件存活期增加。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin caused event-free survival of the human individual. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin allows the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin Have lasting at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, At least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about An event-free survival period of 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is an event-free survival that lasts at least about 4 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is an event-free survival period that lasts at least about 5 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 6 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 9.5 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 11 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, otuzumab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 14 months. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin makes the event-free survival of the human individual compared to the administration of otuzumab, gemcitabine to the corresponding human individual And the event-free survival of oxaliplatin increased. In some embodiments, the administration of immunoconjugates, oltuzumab, gemcitabine, and oxaliplatin to multiple human individuals makes the event-free survival of the human individuals in the multiple human individuals compared to that of the oxaliplatin administration. The event-free survival of multiple human individuals corresponding to tocilizumab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後存活至少約10個月或更長時間、至少約11個月或更長時間、至少約12個月或更長時間、至少約13個月或更長時間、至少約14個月或更長時間、或至少約15個月或更長時間。在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑引起該多名人類個體中之人類個體在開始免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑治療後至少約10個月或更長時間、至少約11個月或更長時間、至少約12個月或更長時間、至少約13個月或更長時間、至少約14個月或更長時間、或至少約15個月或更長時間的中值總體存活期。在一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該人類個體之存活期相較於向相應人類個體投與奧妥珠單抗、吉西他濱及奧沙利鉑的存活期增加。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得該多名人類個體中人類個體之中值總體存活期相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體之中值總體存活期增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of the immunoconjugate, otuzumab, gemcitabine and oxaliplatin allows the human individual to start the immunoconjugate, otuzumab, Survival after treatment with gemcitabine and oxaliplatin for at least about 10 months or longer, at least about 11 months or longer, at least about 12 months or longer, at least about 13 months or longer, at least About 14 months or more, or at least about 15 months or more. In some embodiments that can be combined with any of the foregoing embodiments, the administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals causes the human individuals of the multiple human individuals to start At least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 12 months or more after treatment with immunoconjugates, otuzumab, gemcitabine, and oxaliplatin A median overall survival of about 13 months or more, at least about 14 months or more, or at least about 15 months or more. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin makes the survival of the human individual compared to the administration of otuzumab, gemcitabine, and oxaliplatin to the corresponding human individual. The survival time of thaliplatin is increased. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals makes the median overall survival of the human individuals in the multiple human individuals compared to the administration The median overall survival of multiple human individuals corresponding to otuzumab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起腫瘤溶解症候群。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與針對腫瘤溶解症候群之預防性治療。In some embodiments that can be combined with any of the preceding embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin does not cause tumor lysis syndrome in the human individual. In some embodiments, the method provided herein further comprises administering to the human subject before, during, and/or after administering the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin to the human subject Preventive treatment for tumor lysis syndrome.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起感染。在一些實施例中，感染係肺孢子蟲感染或皰疹病毒感染。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與針對感染之預防性治療。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin will not cause infection in the human individual. In some embodiments, the infection is a Pneumocystis infection or a herpes virus infection. In some embodiments, the method provided herein further comprises administering to the human subject before, during, and/or after administering the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin to the human subject Preventive treatment for infection.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起嗜中性白血球減少症。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與針對嗜中性白血球減少症之預防性治療。在一些實施例中，針對嗜中性白血球減少症之預防性治療包含向該人類個體投與G-CSF。在一些實施例中，本文所提供之方法進一步包括當該人類個體在投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之後出現3級或4級嗜中性白血球減少症時，停止用免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑進行之治療。在一些實施例中，該等方法進一步包括當該人類個體體內之絕對嗜中性白血球計數(ANC)增加至 ＞1000個/μl時，重新開始用免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑進行之治療。在一些實施例中，該等方法進一步包括投與一或多種生長因子來治療嗜中性白血球減少症。在一些實施例中，該一或多種生長因子包含G-CSF。在一些實施例中，該等方法進一步包括當在21天週期之第7天或之前，該人類個體體內之ANC恢復至＞ 1000個/μl時，重新開始用免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑進行之治療，且不降低免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之劑量。在一些實施例中，該等方法進一步包括當在21天週期之第7天之後，該人類個體體內之ANC恢復至＞ 1000個/μl時，重新開始用免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑進行之治療，其中該免疫偶聯物之劑量降低至1.4 mg/kg。在一些實施例中，該等方法進一步包括當出現免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之先前劑量減少時，中止用免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑進行之治療。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin does not cause neutropenia in the human individual. In some embodiments, the method provided herein further comprises administering to the human subject before, during, and/or after administering the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin to the human subject Preventive treatment for neutropenia. In some embodiments, the preventive treatment for neutropenia comprises administering G-CSF to the human individual. In some embodiments, the methods provided herein further include when the human individual develops grade 3 or 4 neutropenia after administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin At that time, the treatment with immunoconjugates, otuzumab, gemcitabine and oxaliplatin was stopped. In some embodiments, the methods further include when the absolute neutrophil count (ANC) in the human individual increases to >1000/μl, restarting the immunoconjugate, otuzumab, gemcitabine And oxaliplatin. In some embodiments, the methods further include administering one or more growth factors to treat neutropenia. In some embodiments, the one or more growth factors comprise G-CSF. In some embodiments, the methods further include when the ANC in the human individual recovers to> 1000 ANCs/μl on or before the 7th day of the 21-day cycle, restarting the use of immunoconjugates, otuzumab Anti-, gemcitabine and oxaliplatin treatment without reducing the dose of immunoconjugates, otuzumab, gemcitabine and oxaliplatin. In some embodiments, the methods further include when the ANC in the human individual recovers to> 1000/μl after the 7th day of the 21-day cycle, restarting the immunoconjugate, otuzumab , Gemcitabine and oxaliplatin, in which the dose of the immunoconjugate is reduced to 1.4 mg/kg. In some embodiments, the methods further include discontinuing the use of the immunoconjugate, otuzumab, gemcitabine when the previous dose of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin is reduced. And oxaliplatin.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起B型肝炎再活化。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與針對B型肝炎再活化之預防性治療。在一些實施例中，本文所提供之方法進一步包括當在人類個體中偵測到B型肝炎再活化時，向該人類個體投與抗病毒藥物。In some embodiments that can be combined with any of the preceding embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin will not cause hepatitis B reactivation in the human individual. In some embodiments, the method provided herein further comprises administering to the human subject before, during, and/or after administering the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin to the human subject Preventive treatment for reactivation of hepatitis B. In some embodiments, the methods provided herein further include administering an antiviral drug to the human individual when hepatitis B reactivation is detected in the human individual.

在可與任何前述實施例組合的一些實施例中，投與免疫偶聯物，奧妥珠單抗，吉西他濱及奧沙利鉑不會引起選自由以下組成之群的一或多例不良事件：藥物誘發之肝損傷、進行性多灶性腦白質病、全身性超敏反應、過敏性反應、類過敏性反應及第二惡性疾病。In some embodiments that can be combined with any of the preceding embodiments, the administration of the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin does not cause one or more adverse events selected from the group consisting of: Drug-induced liver injury, progressive multifocal leukoencephalopathy, systemic hypersensitivity, allergic reactions, allergic reactions and second malignant diseases.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得完全反應率(CRR)相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體之CRR增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects results in a complete response rate (CRR) compared to administration Correspondingly, the CRR of multiple human individuals of otuzumab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得客觀反應率(ORR)相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體之ORR增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects makes the objective response rate (ORR) compared to administration Correspondingly, the ORR of multiple human individuals with otuzumab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得最佳總體反應率(BOR)相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體之BOR增加。In some embodiments that can be combined with any of the preceding embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects results in the best overall response rate (BOR) compared to Correspondingly, the BOR of multiple human subjects who were administered otuzumab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得反應持續時間(DOR)相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體之DOR增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects makes the duration of response (DOR) compared to administration The DOR of multiple human individuals corresponding to otuzumab, gemcitabine, and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的1年無進展存活率係至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的2年無進展存活率係至少約63%或更高、至少約65%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的5年無進展存活率係至少約14%或更高、至少約15%或更高、至少約20%或更高、至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得1年、2年、3.5年或5年無進展存活率相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects caused no symptoms for 1 year in the multiple human subjects. The survival rate of progression is at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher High, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals causes a 2-year progression-free survival rate of at least about 63% in the multiple human individuals. Or higher, at least about 65% or higher, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugate, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals causes a 5-year progression-free survival rate of at least about 14% in the multiple human individuals. Or higher, at least about 15% or higher, at least about 20% or higher, at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher High, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects results in a 1-year, 2-year, 3.5-year, or 5-year progression-free survival rate compared to administration. Correspondingly, the number of human individuals with otuzumab, gemcitabine and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的1年總體存活率係至少約42%或更高、至少約45%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的2年總體存活率係至少約67%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的3.5年總體存活率係至少約38%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的5年總體存活率係至少約15%或更高、至少約20%或更高、至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得1年、2年、3.5年或5年總體存活率相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects caused a total of 1 year in the multiple human subjects. The survival rate is at least about 42% or higher, at least about 45% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher , At least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals results in a 2-year overall survival rate of at least about 67% or Higher, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals results in a 3.5-year overall survival rate of at least about 38% or Higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher , At least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals results in a 5-year overall survival rate of at least about 15% or Higher, at least about 20% or higher, at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher , At least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects results in a 1 year, 2 year, 3.5 year, or 5 year overall survival rate compared to administration Otuzumab, gemcitabine, and oxaliplatin correspondingly increased in multiple human individuals.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的2年無事件存活率係至少約44%或更高、至少約45%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得1年、2年、3.5年或5年無事件存活率相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體增加。In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects caused 2 years of absence in the multiple human subjects. Event survival rate is at least about 44% or higher, at least about 45% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher High, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human subjects results in a 1-year, 2-year, 3.5-year, or 5-year event-free survival rate compared to administration. Correspondingly, the number of human individuals with otuzumab, gemcitabine and oxaliplatin increased.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的客觀反應率係至少約44%或更高、至少約45%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。In some embodiments that can be combined with any of the foregoing embodiments, the objective response rate caused by the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals At least about 44% or higher, at least about 45% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher, at least About 90% or higher, at least about 95% or higher, or about 100%.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的完全反應率係至少約35%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。In some embodiments that can be combined with any of the foregoing embodiments, the complete response rate caused by the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals At least about 35% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher, at least About 90% or higher, at least about 95% or higher, or about 100%.

在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的部分反應率係至少約10%或更高、至少約20%或更高、至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、奧妥珠單抗、吉西他濱及奧沙利鉑使得部分反應率相較於投與奧妥珠單抗、吉西他濱及奧沙利鉑的相應多名人類個體之部分反應率增加。In some embodiments that can be combined with any of the foregoing embodiments, the partial response rate caused by the administration of immunoconjugates, otuzumab, gemcitabine, and oxaliplatin to multiple human individuals At least about 10% or higher, at least about 20% or higher, at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least About 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, oltuzumab, gemcitabine, and oxaliplatin to multiple human subjects makes the partial response rate compared to the administration of oltuzumab Corresponding partial response rates of multiple human individuals with monoclonal antibodies, gemcitabine, and oxaliplatin increased.

在另一個態樣中，本文提供一種套組，該套組包括含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合使用以治療患有彌漫性大B細胞淋巴瘤(DLBCL)的有需要之人類個體。In another aspect, this document provides a kit that includes an immunoconjugate containing the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and Touzumab, gemcitabine, and oxaliplatin are used in combination to treat human individuals in need with diffuse large B-cell lymphoma (DLBCL).

在另一個態樣中，本文提供一種套組，該套組包含帕妥珠單抗維多汀-piiq，其係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合使用以治療患有彌漫性大B細胞淋巴瘤(DLBCL)的有需要之人類個體。In another aspect, this document provides a kit comprising Pertuzumab Vidotin-piiq, which is combined with otuzumab, gemcitabine, and oxaliplatin according to any of the foregoing embodiments Used to treat human individuals in need with diffuse large B-cell lymphoma (DLBCL).

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8. The immunoconjugate is according to any of the foregoing embodiments, and The combination of touzumab, gemcitabine and oxaliplatin is used in the treatment of diffuse large B-cell lymphoma (DLBCL).

在另一個態樣中，本文提供奧妥珠單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間。In another aspect, provided herein is otuzumab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、奧妥珠單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, otuzumab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧妥珠單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間。In another aspect, provided herein is oxaliplatin, which is used in combination with immunoconjugates, gemcitabine and otuzumab for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8. The immunoconjugate is according to any of the foregoing embodiments, and The combination of touzumab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered After platinum, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8. The immunoconjugate is according to any of the foregoing embodiments, and The combination of touzumab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered It does not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8. The immunoconjugate is according to any of the foregoing embodiments, and The combination of touzumab, gemcitabine, and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, oxaliplatin is administered to a number of human individuals to be treated After touzumab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 within 14 days Or lower.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中向多名人類個體投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8. The immunoconjugate is according to any of the foregoing embodiments, and The combination of touzumab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, otuzumab, gemcitabine are administered to multiple human individuals With oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 or lower within 14 days.

在另一個態樣中，本文提供奧妥珠單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is otuzumab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered After anti-, gemcitabine, and oxaliplatin, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供奧妥珠單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is otuzumab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in this human individual, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供奧妥珠單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is otuzumab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein in the multiple human subjects to be treated, the administration After the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease could not be It subsides to grade 1 or lower within 14 days.

在另一個態樣中，本文提供奧妥珠單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is otuzumab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Otuzumab, gemcitabine, and oxaliplatin caused 33% or less of the multiple human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、奧妥珠單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, otuzumab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered After anti-, gemcitabine, and oxaliplatin, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、奧妥珠單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, otuzumab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in this human individual, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、奧妥珠單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, otuzumab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein in the multiple human subjects to be treated, the administration After the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease could not be It subsides to grade 1 or lower within 14 days.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、奧妥珠單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, otuzumab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Otuzumab, gemcitabine, and oxaliplatin caused 33% or less of the multiple human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧妥珠單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is oxaliplatin, which is used in combination with immunoconjugates, gemcitabine and otuzumab for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered After anti-, gemcitabine, and oxaliplatin, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧妥珠單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。In another aspect, provided herein is oxaliplatin, which is used in combination with immunoconjugates, gemcitabine and otuzumab for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in this human individual, and the disease cannot resolve to grade 1 or lower within 14 days.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧妥珠單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is oxaliplatin, which is used in combination with immunoconjugates, gemcitabine and otuzumab for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein in the multiple human subjects to be treated, the administration After the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease could not be It subsides to grade 1 or lower within 14 days.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧妥珠單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別。In another aspect, provided herein is oxaliplatin, which is used in combination with immunoconjugates, gemcitabine and otuzumab for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Otuzumab, gemcitabine, and oxaliplatin caused 33% or less of the multiple human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與1.8 mg/kg劑量之帕妥珠單抗維多汀-piiq、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 1.8 to the human individual Pertuzumab Vidotin-piiq at a mg/kg dose, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與1.8 mg/kg劑量之帕妥珠單抗維多汀-piiq、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑，其中該帕妥珠單抗維多汀-piiq、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中該帕妥珠單抗維多汀-piiq及利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 1.8 to the human individual Pertuzumab vedotine-piiq at mg/kg dose, rituximab at 375 mg/m 2 dose, gemcitabine at 1000 mg/m 2 dose, and oxaliplatin at 100 mg/m 2 dose, The Pertuzumab Vidotin-piiq, rituximab, gemcitabine and oxaliplatin were administered for at least one 21-day cycle, and the Pertuzumab Vidotin-piiq and rituximab The monoclonal antibody was administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤 (R/R DLBCL)的方法，該方法包括向該人類個體投與4.8 mg/kg劑量之依拉妥珠單抗維多汀、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 4.8 to the human individual Elatuzumab vedotine at a mg/kg dose, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2.

在另一個態樣中，本文提供一種用於有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤 (R/R DLBCL)的方法，該方法包括向該人類個體投與3.6 mg/kg劑量之依拉妥珠單抗維多汀、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑。In another aspect, this article provides a method for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 3.6 mg to the human individual Ilatuzumab vitotin at a dose per kg, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與4.8 mg/kg劑量之依拉妥珠單抗維多汀、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑，其中該依拉妥珠單抗維多汀、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中該依拉妥珠單抗維多汀與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 4.8 to the human individual Elatuzumab vedotine at a mg/kg dose, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2 The elatuzumab vidotin, rituximab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein the elatuzumab vidotin and rituximab are administered It was administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與3.6 mg/kg劑量之依拉妥珠單抗維多汀、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑，其中該依拉妥珠單抗維多汀、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中該依拉妥珠單抗維多汀與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 3.6 to the human individual Elatuzumab vedotine at a mg/kg dose, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2 The elatuzumab vidotin, rituximab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein the elatuzumab vidotin and rituximab are administered It was administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與1.8 mg/kg劑量之帕妥珠單抗維多汀-piiq、1000 mg劑量之奧妥珠單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 1.8 to the human individual Pertuzumab Vidotin-piiq at mg/kg dose, otuzumab at 1000 mg dose, gemcitabine at 1000 mg/m 2 dose, and oxaliplatin at 100 mg/m 2 dose.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與1.8 mg/kg劑量之帕妥珠單抗維多汀-piiq、1000 mg劑量之奧妥珠單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑，其中該帕妥珠單抗維多汀-piiq、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中該帕妥珠單抗維多汀-piiq及奧妥珠單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 1.8 to the human individual Pertuzumab Vidotin-piiq at a mg/kg dose, otuzumab at a 1000 mg dose, gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2 in which the Pa Touzumab vitotin-piiq, otuzumab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein the Pertuzumab vidotin-piiq and otuzumab are administered It was administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與4.8 mg/kg劑量之依拉妥珠單抗維多汀、1000 mg劑量之奧妥珠單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 4.8 to the human individual Elatuzumab vedotine at a mg/kg dose, otuzumab at a 1000 mg dose, gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與3.6 mg/kg劑量之依拉妥珠單抗維多汀、1000 mg劑量之奧妥珠單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 3.6 to the human individual Elatuzumab vedotine at mg/kg dose, otuzumab at 1000 mg dose, gemcitabine at 1000 mg/m 2 dose, and oxaliplatin at 100 mg/m 2 dose.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與4.8 mg/kg劑量之依拉妥珠單抗維多汀、1000 mg劑量之奧妥珠單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑，其中該依拉妥珠單抗維多汀、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中該依拉妥珠單抗維多汀及奧妥珠單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 4.8 to the human individual Ilatuzumab vedotine at a mg/kg dose, oltuzumab at a 1000 mg dose, gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2, wherein the elatuzumab Tocilizumab vedotine, oltuzumab, gemcitabine and oxaliplatin were administered for at least one 21-day cycle, wherein the elatuzumab vedotine and oltuzumab were administered in each It was administered intravenously on the first day of the 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與3.6 mg/kg劑量之依拉妥珠單抗維多汀、1000 mg劑量之奧妥珠單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑，其中該依拉妥珠單抗維多汀、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中該依拉妥珠單抗維多汀及奧妥珠單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering 3.6 to the human individual Ilatuzumab vedotine at a mg/kg dose, oltuzumab at a 1000 mg dose, gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2, wherein the elatuzumab Tocilizumab vedotine, oltuzumab, gemcitabine and oxaliplatin were administered for at least one 21-day cycle, wherein the elatuzumab vedotine and oltuzumab were administered in each It was administered intravenously on the first day of the 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)的方法中，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and A combination of tuximab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered And at least one 21-day cycle, wherein in each cycle, the dose of the immunoconjugate is about 1.8 mg/kg, the dose of rituximab is about 375 mg/m 2 , and the dose of gemcitabine The dose is about 1000 mg/m 2 , and the dose of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate and rituximab are on the first of each 21-day cycle It was administered intravenously every day, and gemcitabine and oxaliplatin were administered intravenously on the 2nd day of each 21-day cycle.

在另一個態樣中，本文提供利妥昔單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is rituximab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab, gemcitabine And oxaliplatin-based administration for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and the administration dose of rituximab is about 375 mg /m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate and rituximab are in each It was administered intravenously on the first day of a 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、利妥昔單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, rituximab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab, gemcitabine And oxaliplatin-based administration for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and the administration dose of rituximab is about 375 mg /m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate and rituximab are in each It was administered intravenously on the first day of a 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及利妥昔單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is oxaliplatin, which is used in the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with immunoconjugates, gemcitabine, and rituximab according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab, gemcitabine And oxaliplatin-based administration for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and the administration dose of rituximab is about 375 mg /m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate and rituximab are in each It was administered intravenously on the first day of a 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)的方法中，其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and The combination of tuximab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered After platinum, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days; and the immunoconjugate, rituximab, gemcitabine And oxaliplatin-based administration for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and the administration dose of rituximab is about 375 mg /m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate and rituximab are in each It was administered intravenously on the first day of a 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)的方法中，其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and A combination of tuximab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered Does not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, rituximab, gemcitabine And oxaliplatin-based administration for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and the administration dose of rituximab is about 375 mg /m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and the immunoconjugate and rituximab are in each It was administered intravenously on the first day of a 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)的方法中，其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and The combination of tuximab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein in a number of human individuals to be treated, the immunoconjugate, oxaliplatin is administered After tuximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 within 14 days Or lower grade; and wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate It is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg /m 2 ; and wherein the immunoconjugate and rituximab are administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin are administered on the first day of each 21-day cycle Administer intravenously in 2 days.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與利妥昔單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)的方法中，其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and A combination of tuximab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, rituximab, gemcitabine are administered to multiple human individuals And oxaliplatin caused 33% or less of the multiple human individuals to experience peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 or lower within 14 days; and wherein The immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, The dosage of rituximab is about 375 mg/m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; and The immunoconjugate and rituximab were administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供利妥昔單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is rituximab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered After anti-, gemcitabine, and oxaliplatin, the human individual did not experience peripheral neuropathy of grade 3 or higher, and the disease could not resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and that of rituximab The administration dose is about 375 mg/m 2 , the administration dose of gemcitabine is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 100 mg/m 2 ; Tuximab was administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供利妥昔單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is rituximab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered , Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and that of rituximab The administration dose is about 375 mg/m 2 , the administration dose of gemcitabine is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 100 mg/m 2 ; Tuximab was administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供利妥昔單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is rituximab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein in the multiple human subjects to be treated, the administration After the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease cannot be Regressed to grade 1 or lower within 14 days; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the immune The dosage of the conjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin The dosage is about 100 mg/m 2 ; and the immunoconjugate and rituximab are administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin are in It is administered intravenously on the 2nd day of each 21-day cycle.

在另一個態樣中，本文提供利妥昔單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is rituximab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Rituximab, gemcitabine, and oxaliplatin caused 33% or less of the human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower grade; and wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate It is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg /m 2 ; and wherein the immunoconjugate and rituximab are administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin are administered on the first day of each 21-day cycle Administer intravenously in 2 days.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、利妥昔單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, rituximab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered After anti-, gemcitabine, and oxaliplatin, the human individual did not experience peripheral neuropathy of grade 3 or higher, and the disease could not resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and that of rituximab The administration dose is about 375 mg/m 2 , the administration dose of gemcitabine is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 100 mg/m 2 ; Tuximab was administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、利妥昔單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, rituximab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered , Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and that of rituximab The administration dose is about 375 mg/m 2 , the administration dose of gemcitabine is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 100 mg/m 2 ; Tuximab was administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、利妥昔單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, rituximab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein in the multiple human subjects to be treated, the administration After the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease cannot be Regressed to grade 1 or lower within 14 days; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the immune The dosage of the conjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin The dosage is about 100 mg/m 2 ; and the immunoconjugate and rituximab are administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin are in It is administered intravenously on the 2nd day of each 21-day cycle.

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、利妥昔單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, rituximab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Rituximab, gemcitabine, and oxaliplatin caused 33% or less of the human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower grade; and wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate It is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg /m 2 ; and wherein the immunoconjugate and rituximab are administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin are administered on the first day of each 21-day cycle Administer intravenously in 2 days.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及利妥昔單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is oxaliplatin, which is used in the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with immunoconjugates, gemcitabine, and rituximab according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered After anti-, gemcitabine, and oxaliplatin, the human individual did not experience peripheral neuropathy of grade 3 or higher, and the disease could not resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and that of rituximab The administration dose is about 375 mg/m 2 , the administration dose of gemcitabine is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 100 mg/m 2 ; Tuximab was administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及利妥昔單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is oxaliplatin, which is used in the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with immunoconjugates, gemcitabine, and rituximab according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab is administered , Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and that of rituximab The administration dose is about 375 mg/m 2 , the administration dose of gemcitabine is about 1000 mg/m 2 , and the administration dose of oxaliplatin is about 100 mg/m 2 ; Tuximab was administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及利妥昔單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is oxaliplatin, which is used in the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with immunoconjugates, gemcitabine, and rituximab according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein in the multiple human subjects to be treated, the administration After the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease cannot be Regressed to grade 1 or lower within 14 days; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the immune The dosage of the conjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin The dosage is about 100 mg/m 2 ; and the immunoconjugate and rituximab are administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin are in It is administered intravenously on the 2nd day of each 21-day cycle.

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及利妥昔單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。In another aspect, provided herein is oxaliplatin, which is used in the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with immunoconjugates, gemcitabine, and rituximab according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Rituximab, gemcitabine, and oxaliplatin caused 33% or less of the human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower grade; and wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate It is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg /m 2 ; and wherein the immunoconjugate and rituximab are administered intravenously on the first day of each 21-day cycle, and gemcitabine and oxaliplatin are administered on the first day of each 21-day cycle Administer intravenously in 2 days.

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)的方法中，其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8. The immunoconjugate is according to any of the foregoing embodiments, and The combination of touzumab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered together And at least one 21-day cycle, wherein in each cycle, the dose of the immunoconjugate is about 1.8 mg/kg, the dose of otuzumab is about 1000 mg, and the dose of gemcitabine is about About 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供奧妥珠單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, provided herein is otuzumab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab, gemcitabine Administer at least one 21-day cycle with oxaliplatin, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, and the dosage of otuzumab is about 1000 mg The dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、奧妥珠單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, otuzumab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab, gemcitabine Administer at least one 21-day cycle with oxaliplatin, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, and the dosage of otuzumab is about 1000 mg The dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧妥珠單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, provided herein is oxaliplatin, which is used in combination with immunoconjugates, gemcitabine and otuzumab for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab, gemcitabine Administer at least one 21-day cycle with oxaliplatin, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, and the dosage of otuzumab is about 1000 mg The dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)的方法中，其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8. The immunoconjugate is according to any of the foregoing embodiments, and A combination of touzumab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered After platinum, the human individual did not experience grade 3 or higher peripheral neuropathy, and the disease could not resolve to grade 1 or lower within 14 days; and the immunoconjugate, otuzumab, gemcitabine Administer at least one 21-day cycle with oxaliplatin, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, and the dosage of otuzumab is about 1000 mg The dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)的方法中，其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and The combination of touzumab, gemcitabine and oxaliplatin is used in a method of treating diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered Does not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot resolve to grade 1 or lower within 14 days; and the immunoconjugate, otuzumab, gemcitabine Administer at least one 21-day cycle with oxaliplatin, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, and the dosage of otuzumab is about 1000 mg The dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)的方法中，其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8. The immunoconjugate is according to any of the foregoing embodiments, and The combination of touzumab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, oxaliplatin is administered to a number of human individuals to be treated After touzumab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 within 14 days Or lower grade; and wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate It is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係根據任何前述實施例，與奧妥珠單抗、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)的方法中，其中向多名人類個體投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, this article provides an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is based on any of the foregoing embodiments, and The combination of touzumab, gemcitabine and oxaliplatin is used in a method for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein the immunoconjugate, otuzumab, and gemcitabine are administered to multiple human individuals With oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease did not subside to grade 1 or lower within 14 days; and The immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, The dosage of otuzumab is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供奧妥珠單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, provided herein is otuzumab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered After anti-, gemcitabine and oxaliplatin, the human individual did not experience peripheral neuropathy of grade 3 or higher, and the disease could not resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Otuzumab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and the dose of otuzumab is about 1.8 mg/kg. The dosage of administration is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供奧妥珠單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, provided herein is otuzumab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered , Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Otuzumab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and that The dosage of administration is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供奧妥珠單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, provided herein is otuzumab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein in the multiple human subjects to be treated, the administration After the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease could not be It resolves to grade 1 or lower within 14 days; and wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the immune The dosage of the conjugate is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 1000 mg/m 2 It is about 100 mg/m 2 .

在另一個態樣中，本文提供奧妥珠單抗，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, provided herein is otuzumab, which is used in combination with immunoconjugates, gemcitabine and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Otuzumab, gemcitabine, and oxaliplatin caused 33% or less of the multiple human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower grade; and wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate It is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、奧妥珠單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, otuzumab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered After anti-, gemcitabine and oxaliplatin, the human individual did not experience peripheral neuropathy of grade 3 or higher, and the disease could not resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Otuzumab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and the dose of otuzumab is about 1.8 mg/kg. The dosage of administration is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、奧妥珠單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, otuzumab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered , Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Otuzumab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and that The dosage of administration is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、奧妥珠單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, otuzumab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein in the multiple human subjects to be treated, the administration After the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease could not be It resolves to grade 1 or lower within 14 days; and wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the immune The dosage of the conjugate is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 1000 mg/m 2 It is about 100 mg/m 2 .

在另一個態樣中，本文提供吉西他濱，其係根據任何前述實施例，與免疫偶聯物、奧妥珠單抗及奧沙利鉑組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, gemcitabine is provided herein, which is used in combination with immunoconjugates, otuzumab and oxaliplatin for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Otuzumab, gemcitabine, and oxaliplatin caused 33% or less of the multiple human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower grade; and wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate It is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧妥珠單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該人類個體未經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, provided herein is oxaliplatin, which is used in combination with immunoconjugates, gemcitabine and otuzumab for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered After anti-, gemcitabine and oxaliplatin, the human individual did not experience peripheral neuropathy of grade 3 or higher, and the disease could not resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Otuzumab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and the dose of otuzumab is about 1.8 mg/kg. The dosage of administration is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧妥珠單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑不會在該人類個體中引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, provided herein is oxaliplatin, which is used in combination with immunoconjugates, gemcitabine and otuzumab for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate, otuzumab is administered , Gemcitabine and oxaliplatin will not cause peripheral neuropathy of grade 3 or higher in the human individual, and the disease cannot resolve to grade 1 or lower within 14 days; and wherein the immunoconjugate, Otuzumab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate is about 1.8 mg/kg, and that The dosage of administration is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧妥珠單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中在所治療之多名人類個體中，在投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑之後，該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, provided herein is oxaliplatin, which is used in combination with immunoconjugates, gemcitabine and otuzumab for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein in the multiple human subjects to be treated, the administration After the immunoconjugate, otuzumab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals experienced peripheral neuropathy of grade 3 or higher, and the disease could not be It resolves to grade 1 or lower within 14 days; and wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the immune The dosage of the conjugate is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 1000 mg/m 2 It is about 100 mg/m 2 .

在另一個態樣中，本文提供奧沙利鉑，其係根據任何前述實施例，與免疫偶聯物、吉西他濱及奧妥珠單抗組合用於治療彌漫性大B細胞淋巴瘤(DLBCL)之方法中，其中該免疫偶聯物包含下式：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，其中向多名人類個體投與該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退成1級或更低級別；且其中該免疫偶聯物、奧妥珠單抗、吉西他濱與奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，奧妥珠單抗之投與劑量係約1000 mg，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。In another aspect, provided herein is oxaliplatin, which is used in combination with immunoconjugates, gemcitabine and otuzumab for the treatment of diffuse large B-cell lymphoma (DLBCL) according to any of the foregoing embodiments In the method, wherein the immunoconjugate comprises the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, wherein the immunoconjugate is administered to multiple human subjects, Otuzumab, gemcitabine, and oxaliplatin caused 33% or less of the multiple human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 within 14 days Or lower grade; and wherein the immunoconjugate, otuzumab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein in each cycle, the administration dose of the immunoconjugate It is about 1.8 mg/kg, the dosage of otuzumab is about 1000 mg, the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 .

相關申請案之交叉引用Cross-reference of related applications

本申請案主張2019年10月18日提交之美國臨時申請案62/923,359之權益，該案全部內容特此以全文引用之方式併入。以 ASCII 文本文件提交之序列表 This application claims the rights and interests of U.S. Provisional Application 62/923,359 filed on October 18, 2019, and the entire content of the case is hereby incorporated by reference in its entirety. Sequence table submitted as ASCII text file

以下以ASCII文本文件提交之內容係以全文引用之方式併入本文中：序列表之電腦可讀形式(CRF) (文件名：146392049141SEQLIST.TXT，記錄日期：2020年6月8日，大小：59 KB)。The following content submitted as an ASCII text file is incorporated into this article by reference in its entirety: Computer-readable form of sequence listing (CRF) (file name: 146392049141SEQLIST.TXT, record date: June 8, 2020, size: 59 KB).

如本文所使用，術語「帕妥珠單抗維多汀-piiq」係指IUPHAR/BPS編號為8404、KEGG編號為D10761或CAS登記號為1313206-42-6的抗CD79b免疫偶聯物。帕妥珠單抗維多汀-piiq亦可互換地稱為「帕妥珠單抗維多汀」、「huMA79bv28-MC-vc-PAB-MMAE」、「DCDS4501A」或「RG7596」。As used herein, the term "Pertuzumab Vidotin-piiq" refers to the anti-CD79b immunoconjugate with IUPHAR/BPS number 8404, KEGG number D10761, or CAS registration number 1313206-42-6. Pertuzumab Vidotin-piiq can also be interchangeably referred to as "Pertuzumab Vidotin", "huMA79bv28-MC-vc-PAB-MMAE", "DCDS4501A" or "RG7596".

本文提供用於治療個體(例如 人類)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性或難治性DLBCL)或延遲其進展的方法，該等方法包括向該個體投與有效量之抗CD79b免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20藥劑(例如 抗CD20抗體，諸如利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)。Provided herein are methods for treating or delaying the progression of diffuse large B-cell lymphoma (DLBCL, such as relapsed or refractory DLBCL) in an individual (e.g., human), the methods comprising administering to the individual an effective amount of anti-CD79b Immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 agents ( e.g. anti-CD20 antibodies, such as rituximab) and one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin) .

在一些實施例中，該方法包括治療患有彌漫性大B細胞淋巴瘤(DLBCL)，例如 復發性/難治性DLBCL之個體，其係藉由向該個體投與以下實現：(a)包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含GYTFSSYWIE (SEQ ID NO: 21)之胺基酸序列的HVR-H1；(ii)含GEILPGGGDTNYNEIFKG (SEQ ID NO: 22)之胺基酸序列的HVR-H2；(iii)含TRRVPIRLDY (SEQ ID NO: 23)之胺基酸序列的HVR-H3；(iv)含KASQSVDYEGDSFLN (SEQ ID NO: 24)之胺基酸序列的HVR-L1；(v)含AASNLES (SEQ ID NO: 25)之胺基酸序列的HVR-L2；及(vi)含QQSNEDPLT (SEQ ID NO:26)之胺基酸序列的HVR-L3，且其中p在1與8之間(例如 在2與5之間，或在3與4之間)；(b)抗CD20藥劑(例如 利妥昔單抗)；及(c)一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)。在一些實施例中，該免疫偶聯物之投與劑量係在約1.4 mg/kg與約1.8 mg/kg之間，該抗CD20藥劑(例如 利妥昔單抗)之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 。 I. 通用技術 In some embodiments, the method includes treating an individual suffering from diffuse large B-cell lymphoma (DLBCL), such as relapsed/refractory DLBCL, by administering to the individual: (a) comprising: Immunoconjugate
Figure 02_image001
, Where Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 21); (ii) containing the amino acid sequence of GEILPGGGDTNYNEIFKG (SEQ ID NO: 22) (Iii) HVR-H3 containing the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 23); (iv) HVR-L1 containing the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 24); ( v) HVR-L2 containing the amino acid sequence of AASNLES (SEQ ID NO: 25); and (vi) HVR-L3 containing the amino acid sequence of QQSNEDPLT (SEQ ID NO: 26), and where p is between 1 and 8 ( e.g., between 2 and 5, or between 3 and 4); (b) anti-CD20 agents ( e.g. , rituximab); and (c) one or more chemotherapeutic agents ( e.g., gemcitabine and Oxaliplatin). In some embodiments, the dosage of the immunoconjugate is between about 1.4 mg/kg and about 1.8 mg/kg, and the dosage of the anti-CD20 agent ( for example , rituximab) is about 375. mg/m 2 , the dosage of gemcitabine is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 . I. General technology

除非另外指示，否則本發明之實踐將採用分子生物學(包括重組技術)、微生物學、細胞生物學、生物化學及免疫學之習知技術，該等技術在此項技術之技能範圍內。此類技術在諸如「Molecular Cloning: A Laboratory Manual」，第二版(Sambrook等人，1989)；「Oligonucleotide Synthesis」(M. J. Gait編輯， 1984)；「Animal Cell Culture」(R. I. Freshney編輯， 1987)；「Methods in Enzymology」(Academic Press，Inc.)；「Current Protocols in Molecular Biology」(F. M. Ausubel等人編輯，1987，以及定期更新)；「PCR: The Polymerase Chain Reaction」，(Mullis等人編輯，1994)；「A Practical Guide to Molecular Cloning」(Perbal Bernard V.，1988)；「Phage Display: A Laboratory Manual」(Barbas等人，2001)之類文獻中有充分的解釋。II. 定義 Unless otherwise indicated, the practice of the present invention will use the conventional techniques of molecular biology (including recombinant technology), microbiology, cell biology, biochemistry, and immunology, which are within the skill range of this technology. Such techniques are described in "Molecular Cloning: A Laboratory Manual", second edition (Sambrook et al., 1989); "Oligonucleotide Synthesis" (MJ Gait editor, 1984); "Animal Cell Culture" (RI Freshney editor, 1987); "Methods in Enzymology" (Academic Press, Inc.); "Current Protocols in Molecular Biology" (Edited by FM Ausubel et al., 1987, and regularly updated); "PCR: The Polymerase Chain Reaction", (Edited by Mullis et al., 1994 ); "A Practical Guide to Molecular Cloning" (Perbal Bernard V., 1988); "Phage Display: A Laboratory Manual" (Barbas et al., 2001) and other documents have sufficient explanations. II. Definition

在詳細描述本發明之前，應當理解，本發明不限於特定組成物或生物系統，故其當然可以變化。還應理解，本文所使用的術語僅出於描述特定實施例的目的，而無意於進行限制。Before describing the present invention in detail, it should be understood that the present invention is not limited to a specific composition or biological system, so it can of course be changed. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to be limiting.

除非上下文另外清楚地規定，否則如本說明書及所附申請專利範圍中所使用，單數形式「一個」、「一種」及「該」包括複數個(種)對象。因此，例如提及「一個分子」視情況包括兩個或更多個此類分子之組合及類似物。Unless the context clearly dictates otherwise, as used in this specification and the scope of the appended application, the singular forms "a", "a" and "the" include plural (kind) objects. Thus, for example, reference to "a molecule" optionally includes combinations of two or more such molecules and the like.

如本文所使用，術語「約」係指本技術領域之技術人員易於了解之各別值的常見誤差範圍。本文中提及「約」一個值或參數包括(並描述)針對該值或參數本身的實施例。As used herein, the term "about" refers to the common error range of individual values that are easily understood by those skilled in the art. Reference herein to "about" a value or parameter includes (and describes) an embodiment for the value or parameter itself.

應當理解，本文所述的本發明之各態樣及實施例包括「包含各態樣及實施例」、「由各態樣及實施例組成」及「基本上由各態樣及實施例組成」。It should be understood that the various aspects and embodiments of the present invention described herein include "including various aspects and embodiments", "consisting of various aspects and embodiments" and "basically consisting of various aspects and embodiments" .

除非另外指示，否則如本文所使用，術語「CD79b」係指來自任何脊椎動物來源的任何天然CD79b，包括哺乳動物，諸如靈長類動物(例如 人類、食蟹獼猴(「cyno」))及囓齒動物(例如 小鼠及大鼠)。人CD79b在本文中亦稱為「Igβ」、「B29」、「DNA225786」或「PRO36249」。包括信號序列之示例性CD79b序列如SEQ ID NO: 1中所示。不含信號序列之示例性CD79b序列如SEQ ID NO: 2中所示。術語「CD79b」涵蓋「全長」未加工之CD79b，以及由細胞中加工產生的任何形式之CD79b。該術語還涵蓋CD79b的天然存在之變異體，例如 剪接變異體、對偶基因變異體及同功異型物。本文所述的CD79b多肽可自多種來源分離，諸如自人體組織類型或自另一種來源分離，或藉由重組或合成方法製備。「天然序列CD79b多肽」包含具有與源自於自然界之相應CD79b多肽相同之胺基酸序列的多肽。此類天然序列CD79b多肽可由自然界分離或可藉由重組或合成方式產生。術語「天然序列CD79b多肽」特定地涵蓋特定CD79b多肽的天然存在之截短或分泌形式(例如 細胞外域序列)，以及該多肽的天然存在之變異體形式(例如 替代性剪接形式)及其天然存在之對偶基因變異體。Unless otherwise indicated, as used herein, the term "CD79b" refers to any natural CD79b from any vertebrate source, including mammals, such as primates ( e.g., humans, cynomolgus monkeys ("cyno")) and rodents Animals ( e.g. mice and rats). Human CD79b is also referred to herein as "Igβ", "B29", "DNA225786" or "PRO36249". An exemplary CD79b sequence including the signal sequence is shown in SEQ ID NO:1. An exemplary CD79b sequence without a signal sequence is shown in SEQ ID NO: 2. The term "CD79b" encompasses "full-length" unprocessed CD79b, as well as any form of CD79b produced by processing in cells. The term also covers naturally-occurring variants of CD79b, such as splice variants, allele variants, and isoforms. The CD79b polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. "Native sequence CD79b polypeptide" includes a polypeptide having the same amino acid sequence as the corresponding CD79b polypeptide derived from nature. Such native sequence CD79b polypeptides can be isolated in nature or can be produced recombinantly or synthetically. The term "native sequence CD79b polypeptide" specifically encompasses the naturally occurring truncated or secreted form of a particular CD79b polypeptide ( for example , extracellular domain sequence), as well as naturally occurring variant forms of the polypeptide ( for example, alternative splicing forms) and naturally occurring The allele variants.

如本文所使用，「CD20」係指人B淋巴細胞抗原CD20 (又稱為CD20、B淋巴細胞表面抗原B1、Leu-16、Bp35、BM5及LF5；該序列以SwissProt資料庫登錄號P11836表徵)係位於前驅B淋巴細胞及成熟B淋巴細胞上分子量為約35 kD之疏水性跨膜蛋白。(Valentine，M.A.等人，J. Biol. Chem. 264(19) (1989 11282-11287；Tedder，T.F.等人，Proc.Natl. Acad. Sci. U.S.A. 85 (1988) 208-12；Stamenkovic，I.等人，J. Exp. Med. 167 (1988) 1975-80；Einfeld，D.A.等人，EMBO J. 7 (1988) 711-7；Tedder，T.F.等人，J. Immunol. 142 (1989) 2560-8)。相應的人類基因係4度跨膜蛋白域，亞家族A，成員1，又稱為MS4A1。此基因編碼4度跨膜蛋白亞型A基因家族之成員。該新生蛋白質家族之成員以共同結構特徵及類似內含子/外顯子剪接邊界為特徵且在造血細胞及非淋巴系組織間展示獨特的表現模式。該基因編碼B淋巴細胞表面分子，該分子在B細胞發育及分化為漿細胞中起到作用。在一組家族成員中，該家族成員位於係位於11q12。該基因之替代性剪接產生編碼相同蛋白質之兩種轉錄物變異體。As used herein, "CD20" refers to the human B lymphocyte antigen CD20 (also known as CD20, B lymphocyte surface antigen B1, Leu-16, Bp35, BM5 and LF5; this sequence is characterized by SwissProt database accession number P11836) It is a hydrophobic transmembrane protein with a molecular weight of about 35 kD located on precursor B lymphocytes and mature B lymphocytes. (Valentine, MA et al., J. Biol. Chem. 264(19) (1989 11282-11287; Tedder, TF et al., Proc. Natl. Acad. Sci. USA 85 (1988) 208-12; Stamenkovic, I. Et al., J. Exp. Med. 167 (1988) 1975-80; Einfeld, DA et al., EMBO J. 7 (1988) 711-7; Tedder, TF et al., J. Immunol. 142 (1989) 2560- 8). The corresponding human gene is the 4th degree transmembrane protein domain, subfamily A, member 1, also known as MS4A1. This gene encodes a member of the 4th degree transmembrane protein subtype A gene family. The members of this new protein family are Common structural features and similar intron/exon splicing boundaries are characteristic and display a unique expression pattern between hematopoietic cells and non-lymphoid tissues. This gene encodes a B lymphocyte surface molecule that develops and differentiates into B cells Play a role in plasma cells. In a group of family members, the family member is located at line 11q12. Alternative splicing of the gene produces two transcript variants encoding the same protein.

術語「CD20」及「CD20抗原」在本文可互換使用，且包括由細胞天然表現或在經CD20基因轉染之細胞上表現的人類CD20之任何變異體、同功型及物種同源物。本發明之抗體結合至CD20抗原，藉由使CD20失活來介導表現CD20之細胞(例如 腫瘤細胞)的殺滅。表現CD20之細胞可藉由以下一或多個機制發生：細胞死亡/細胞凋亡誘導、ADCC及CDC。如此項技術中所認識到的，CD20之同義詞包括B淋巴細胞抗原CD20、B淋巴細胞表面抗原B1、Leu-16、Bp35、BM5及LF5。The terms "CD20" and "CD20 antigen" are used interchangeably herein, and include any variants, isoforms, and species homologs of human CD20 that are naturally expressed by cells or on cells transfected with the CD20 gene. The antibody of the present invention binds to the CD20 antigen and mediates the killing of CD20-expressing cells (e.g., tumor cells) by inactivating CD20. CD20-expressing cells can occur through one or more of the following mechanisms: cell death/apoptosis induction, ADCC, and CDC. As recognized in the art, synonyms for CD20 include B lymphocyte antigen CD20, B lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5.

術語「CD20之表現」意圖指示細胞，例如 T細胞或B細胞中CD20抗原之相當大的表現量。在一個實施例中，擬根據本發明方法治療之患者在B細胞腫瘤或癌症上表現相當大量之CD20。患有「表現CD20之癌症」的患者可藉由此項技術中已知之標準檢定確定。例如 ，使用免疫組織化學(IHC)偵測、FACS或經由基於PCR之偵測相應mRNA來量測CD20抗原之表現。The term "CD20 expression" is intended to indicate a considerable amount of expression of CD20 antigen in cells, such as T cells or B cells. In one embodiment, patients to be treated according to the methods of the present invention exhibit a significant amount of CD20 on B-cell tumors or cancers. Patients with "cancer manifesting CD20" can be determined by standard tests known in the art. For example , using immunohistochemistry (IHC) detection, FACS or PCR-based detection of corresponding mRNA to measure the expression of CD20 antigen.

「親和力」係指分子(例如 抗體)之單個結合位點與其結合搭配物(例如 抗原)之間非共價相互作用之總和的強度。除非另外指示，如本文所使用，「結合親和力」係指反映結合對(例如 抗體與抗原)各成員之間之1:1相互作用的固有結合親和力。分子X對其搭配物Y之親和力一般可以用解離常數(Kd)表示。親和力可藉由此項技術中已知之常用方法量測，包括本文所述之方法。以下描述用於量測結合親和力之具體說明性且示例性的實施例。"Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (such as an antibody) and its binding partner ( such as an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the inherent binding affinity that reflects the 1:1 interaction between each member of a binding pair (e.g., antibody and antigen). The affinity of molecule X to its partner Y can generally be expressed by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including the methods described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

「親和力成熟」之抗體係指相較於不具有改變之親本抗體，在一或多個高變區(HVR)中具有一或多個該等改變的抗體，該等改變使該抗體對抗原之親和力改善。"Affinity maturation" antibody system refers to an antibody that has one or more of these changes in one or more hypervariable regions (HVR) compared to the parent antibody without changes, and the changes make the antibody to the antigen Improved affinity.

術語「抗體」在本文中係以最廣義使用，且涵蓋各種抗體結構，包括但不限於單株抗體、多株抗體、多特異性抗體(例如 雙特異性抗體)及抗體片段，只要其展現出所需抗原結合活性即可。The term "antibody" is used in the broadest sense herein, and encompasses various antibody structures, including but not limited to monoclonal antibodies, multi-strain antibodies, multispecific antibodies ( such as bispecific antibodies), and antibody fragments, as long as they exhibit The desired antigen binding activity is sufficient.

「抗體片段」係指除完整抗體外的分子，其包含完整抗體中結合該完整抗體所結合之抗原之一部分。抗體片段之實例包括但不限於Fv、Fab、Fab'、Fab'-SH、F(ab')2 ；雙功能抗體；線性抗體；單鏈抗體分子(例如 scFv)；及由抗體片段形成之多特異性抗體。"Antibody fragments" refer to molecules other than intact antibodies, which include a part of the intact antibody that binds to the antigen bound by the intact antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab') 2 ; bifunctional antibodies; linear antibodies; single-chain antibody molecules ( such as scFv); Specific antibodies.

與參照抗體「結合相同抗原決定基之抗體」係指在競爭檢定中阻斷參照抗體與其抗原之結合達50%或更高百分比的抗體，且相反地，參照抗體在競爭檢定中阻斷抗體與其抗原之結合達50%或更高百分比。本文提供示例性競爭檢定。The "antibody that binds to the same epitope" as the reference antibody refers to an antibody that blocks the binding of the reference antibody to its antigen by 50% or more in a competition assay. On the contrary, the reference antibody blocks the antibody and its antigen in a competition assay. The binding of antigen reaches 50% or higher. This article provides an exemplary competition test.

術語「抗原決定基」係指抗原分子上抗體所結合之特定位點。The term "antigenic determinant" refers to a specific site on an antigen molecule where an antibody binds.

術語「嵌合」抗體係指重鏈及/或輕鏈之一部分係來源於特定來源或物種，而重鏈及/或輕鏈之其餘部分係來源於不同來源或物種的抗體。The term "chimeric" antibody system means that a part of the heavy chain and/or light chain is derived from a specific source or species, and the rest of the heavy chain and/or light chain is an antibody derived from a different source or species.

抗體之「類別」係指其重鏈所具有之恆定域或恆定區的類型。抗體有五種主要類別：IgA、IgD、IgE、IgG及IgM，且其中有一些可進一步分為亞類(同型)，例如 IgG1 、IgG2 、IgG3 、IgG4 、IgA1 及IgA2 。對應於不同類別免疫球蛋白之重鏈恆定域分別稱為α、δ、ε、γ及μ。The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of them can be further divided into subclasses (isotypes), such as IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 and IgA 2 . The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

術語「抗CD79b抗體」或「結合至CD79b之抗體」係指能夠以足夠親和力結合CD79b的抗體，由此使該抗體可用作靶向CD79b之診斷劑及/或治療劑。較佳地，如例如 藉由放射免疫檢定(RIA)所量測，抗CD79b抗體與不相關的非CD79b蛋白質之結合程度小於該抗體與CD79b之結合的約10%。在某些實施例中，結合至CD79b之抗體的解離常數(Kd) ≤ 1 μM、≤ 100 nM、≤ 10 nM、≤ 1 nM或≤ 0.1 nM。在某些實施例中，抗CD79b抗體結合至在來自不同物種之CD79b間保守的CD79b之抗原決定基。The term "anti-CD79b antibody" or "antibody that binds to CD79b" refers to an antibody that can bind to CD79b with sufficient affinity, so that the antibody can be used as a diagnostic and/or therapeutic agent that targets CD79b. Preferably, the degree of binding of the anti-CD79b antibody to unrelated non-CD79b proteins is less than about 10% of the binding of the antibody to CD79b , as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the dissociation constant (Kd) of the antibody bound to CD79b is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, or ≤ 0.1 nM. In certain embodiments, the anti-CD79b antibody binds to the epitope of CD79b that is conserved among CD79b from different species.

根據本發明之術語「抗CD20抗體」係指能夠以足夠親和力結合CD20之抗體，由此使該抗體可用作靶向CD20之診斷劑及/或治療劑。較佳地，如例如 藉由放射免疫檢定(RIA)所量測，抗CD20抗體與不相關的非CD20蛋白質之結合程度小於該抗體與CD20之結合的約10%。在某些實施例中，結合至CD20之抗體的解離常數(Kd)≤1 μM、≤100 nM、≤10 nM、≤1 nM或≤0.1 nM。在某些實施例中，抗CD20抗體結合至在來自不同物種之CD20間保守的CD20之抗原決定基。The term "anti-CD20 antibody" according to the present invention refers to an antibody capable of binding to CD20 with sufficient affinity, so that the antibody can be used as a diagnostic and/or therapeutic agent targeting CD20. Preferably, the degree of binding of an anti-CD20 antibody to an irrelevant non-CD20 protein is less than about 10% of the binding of the antibody to CD20 , as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the dissociation constant (Kd) of the antibody bound to CD20 is ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM. In certain embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.

「經分離」之抗體係已自其天然環境之組分分離的抗體。在一些實施例中，如藉由例如電泳(例如 SDS-PAGE、等電聚焦(IEF)、毛細管電泳)或層析法(例如 離子交換或反相HPLC)所測定，抗體係純化至超過95%或99%純度。關於評估抗體純度之方法的評述，參見例如 Flatman等人，J. Chromatogr. B 848:79-87 (2007)。抗體之「可變區」或「可變域」係指抗體重鏈或輕鏈之胺基末端域。重鏈之可變域可稱為「VH」。輕鏈之可變域可稱為「VL」。此等域一般係抗體中變化最大的部分，並含有抗原結合位點。"Separated" Antibody System An antibody that has been separated from its natural environment. In some embodiments, as determined by, for example, electrophoresis ( such as SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography ( such as ion exchange or reverse phase HPLC), the antibody system is purified to more than 95% Or 99% purity. For a review of methods for assessing antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007). The "variable region" or "variable domain" of an antibody refers to the amino terminal domain of the heavy or light chain of the antibody. The variable domain of the heavy chain can be called "VH". The variable domain of the light chain can be referred to as "VL". These domains are generally the most variable part of the antibody and contain antigen binding sites.

「編碼抗CD79b抗體的經分離之核酸」係指編碼抗體重鏈及輕鏈(或其片段)之一或多個核酸分子，包括呈單一載體或單獨載體形式之此類核酸分子，以及存在於宿主細胞中一或多個位置處的此類核酸分子。"Isolated nucleic acid encoding an anti-CD79b antibody" refers to a nucleic acid molecule encoding one or more of the antibody heavy chain and light chain (or fragments thereof), including such nucleic acid molecules in the form of a single vector or a separate vector, and present in Such nucleic acid molecules at one or more locations in the host cell.

如本文所使用，術語「單株抗體」係指自基本上均質之抗體群體獲得的抗體，亦即 ，構成該群體之各個抗體除了可能的變異體抗體，例如 含有天然存在之突變或在製造單株抗體製劑過程中產生的變異體抗體外，其餘係一致的及/或結合同一抗原決定基，此類變異體一般係以微量存在。與典型地包括針對不同決定簇(抗原決定基)之不同抗體的多株抗體製劑相比，單株抗體製劑中之每種單株抗體針對抗原上的單一決定簇。因此，修飾語「單株」指示自基本上均質之抗體群體獲得的抗體之性質，且不應解釋為需要藉由任何特定方法來製造該抗體。舉例而言，可藉由多種技術製備根據本發明使用的單株抗體，該等技術包括但不限於融合瘤方法、重組DNA方法、噬菌體展示方法以及利用含有人類免疫球蛋白基因座之全部或一部分之轉殖基因動物的方法，此類方法及用於製備單株抗體之其他示例性方法描述於本文中。As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, that is , each antibody constituting the population except for possible variant antibodies, such as containing naturally-occurring mutations or in the manufacture of monoclonal antibodies. Except for the variant antibodies produced during the preparation of strain antibodies, the rest are identical and/or bind to the same epitope. Such variants generally exist in trace amounts. In contrast to multi-strain antibody preparations which typically include different antibodies directed against different determinants (antigenic determinants), each monoclonal antibody in the monoclonal antibody preparation is directed against a single determinant on the antigen. Therefore, the modifier "monoclonal" indicates the nature of the antibody obtained from a substantially homogeneous antibody population, and should not be construed as requiring the production of the antibody by any specific method. For example, the monoclonal antibodies used according to the present invention can be prepared by a variety of techniques, including but not limited to fusion tumor methods, recombinant DNA methods, phage display methods, and the use of all or part of human immunoglobulin loci. Methods of transgenic animals, such methods and other exemplary methods for preparing monoclonal antibodies are described herein.

「裸抗體」係指未與異源部分(例如 細胞毒性部分)或放射性標記結合的抗體。裸抗體可存在於醫藥調配物中。"Naked antibody" refers to an antibody that is not bound to a heterologous moiety (e.g., a cytotoxic moiety) or a radioactive label. Naked antibodies can be present in pharmaceutical formulations.

「天然抗體」係指具有不同結構的天然存在之免疫球蛋白分子。舉例而言，天然IgG抗體係約150,000道爾頓的異四聚糖蛋白，由二硫鍵鍵接的兩條一致輕鏈及兩條一致重鏈構成。自N末端至C末端，每條重鏈均具有可變區(VH)，又稱為可變重鏈域或重鏈可變域，後接三個恆定域(CH1、CH2及CH3)。類似地，自N末端至C末端，每條輕鏈均具有可變區(VL)，又稱為可變輕鏈域或輕鏈可變域，後接恆定輕鏈(CL)域。抗體之輕鏈可基於其恆定域之胺基酸序列而指定為稱為κ及λ的兩種類型之一。"Natural antibodies" refer to naturally occurring immunoglobulin molecules with different structures. For example, a heterotetrameric glycoprotein with a natural IgG antibody system of about 150,000 daltons is composed of two identical light chains and two identical heavy chains connected by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also known as a variable heavy chain domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also known as a variable light chain domain or a light chain variable domain, followed by a constant light chain (CL) domain. The light chain of an antibody can be assigned to one of two types called kappa and lambda based on the amino acid sequence of its constant domain.

術語「Fc區」在本文中用於定義含有恆定區之至少一部分的免疫球蛋白重鏈之C末端區域。該術語包括天然序列Fc區及變異體Fc區。在一個實施例中，人類IgG重鏈Fc區自Cys226或自Pro230延伸至重鏈之羧基末端。然而，Fc區之C末端離胺酸(Lys447)可以存在或可以不存在。除非本文另外說明，否則Fc區或恆定區中胺基酸殘基之編號係根據如Kabat等人， Sequences of Proteins of Immunological Interest ，第5版，Public Health Service，National Institutes of Health，Bethesda，MD，1991中所述的EU編號系統，又稱為EU索引。The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, the Fc region of a human IgG heavy chain extends from Cys226 or from Pro230 to the carboxy terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is based on, for example, Kabat et al ., Sequences of Proteins of Immunological Interest , 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD, The EU numbering system described in 1991 is also known as the EU index.

「構架」或「FR」係指除高變區(HVR)殘基以外的可變域殘基。可變域之FR一般由四個FR域組成：FR1、FR2、FR3及FR4。因此，HVR及FR序列一般按以下順序出現在VH (或VL)中：FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4。"Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, HVR and FR sequences generally appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

出於本文之目的，「受體人類構架」係包含來源於如下文所定義的人類免疫球蛋白構架或人類共同構架之輕鏈可變域(VL)構架或重鏈可變域(VH)構架之胺基酸序列的構架。「來源於」人類免疫球蛋白構架或人類共同構架之受體人類構架可包含其相同的胺基酸序列，或者其可含有胺基酸序列變化。在一些實施例中，胺基酸變化之數量係10個或更少、9個或更少、8個或更少、7個或更少、6個或更少、5個或更少、4個或更少、3個或更少、或2個或更少。在一些實施例中，VL受體人類構架之序列與VL人類免疫球蛋白構架序列或人類共同構架序列一致。For the purpose of this article, the "acceptor human framework" includes the light chain variable domain (VL) framework or the heavy chain variable domain (VH) framework derived from the human immunoglobulin framework or the human common framework as defined below The framework of the amino acid sequence. The acceptor human framework "derived from" the human immunoglobulin framework or the human common framework may contain the same amino acid sequence, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 One or less, 3 or less, or 2 or less. In some embodiments, the sequence of the VL receptor human framework is identical to the VL human immunoglobulin framework sequence or the human common framework sequence.

術語「全長抗體」、「完整抗體」及「全抗體」在本文中可互換使用，意思指具有與天然抗體結構基本上類似之結構或具有含如本文所定義之Fc區之重鏈的抗體。The terms "full-length antibody", "whole antibody" and "whole antibody" are used interchangeably herein and mean an antibody having a structure that is substantially similar to that of a natural antibody or having a heavy chain containing an Fc region as defined herein.

術語「宿主細胞」、「宿主細胞株」及「宿主細胞培養物」可互換使用且意思指已引入外源核酸之細胞，包括此類細胞之後代。宿主細胞包括「轉型株」及「轉型細胞」，其包括初代轉型細胞及來源於其之後代，而與傳代次數無關。後代之核酸含量可能與親代細胞不完全相同，而是可能含有突變。具有與關於原始轉型細胞篩選或選擇相同之功能或生物活性的突變後代包括在本文中。The terms "host cell", "host cell strain" and "host cell culture" are used interchangeably and mean cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformed strains" and "transformed cells", which include primary transformed cells and their descendants, regardless of the number of passages. The nucleic acid content of the offspring may not be exactly the same as the parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as the screening or selection of the original transformed cell are included herein.

「人類抗體」係胺基酸序列對應於由人類或人類細胞產生之抗體的胺基酸序列，或來源於利用人類抗體譜系之非人類來源或其他人類抗體編碼序列的抗體。此關於人類抗體之定義特別排除包含非人類抗原結合殘基之人類化抗體。"Human antibodies" are antibodies whose amino acid sequences correspond to those of antibodies produced by humans or human cells, or are derived from non-human sources using the human antibody lineage or other human antibody coding sequences. This definition of human antibodies specifically excludes humanized antibodies that contain non-human antigen-binding residues.

「人類共同構架」係表示選定之人類免疫球蛋白VL或VH構架序列中最常見之胺基酸殘基的構架。一般而言，人類免疫球蛋白VL或VH序列係選自可變域序列之亞群。一般而言，序列亞群係如Kabat等人，Sequences of Proteins of Immunological Interest ，第五版，NIH Publication 91-3242，Bethesda MD (1991)，第1-3卷中所述之亞群。 在一個實施例中，對於VL，該亞群係如Kabat等人，同上中之亞群 I 。 在一個實施例中，對於VH，該亞群係如Kabat等人，同上 中之亞群III。"Human common framework" refers to the framework of the most common amino acid residues in the selected human immunoglobulin VL or VH framework sequence. In general, human immunoglobulin VL or VH sequences are selected from a subgroup of variable domain sequences. Generally speaking, sequence subgroups are as described in Kabat et al., Sequences of Proteins of Immunological Interest , Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), Vols 1-3 . In one embodiment, for VL, the subgroup is such as Kabat et al ., subgroup I above . In one embodiment, for VH, the subgroup is such as Kabat et al ., subgroup III in the above.

「人類化」抗體係指包含來自非人類HVR之胺基酸殘基及來自人類FR之胺基酸殘基的嵌合抗體。在某些實施例中，人類化抗體將包含至少一個且典型地兩個可變域之基本上全部，其中全部或基本上全部的HVR(例如 CDR)對應於非人抗體之HVR，且全部或基本上全部的FR對應於人類抗體之FR。人類化抗體視情況可包含來源於人類抗體之抗體恆定區的至少一部分。抗體，例如 非人類抗體之「人類化形式」係指已經歷人類化的抗體。The "humanized" antibody system refers to a chimeric antibody containing amino acid residues from non-human HVR and amino acid residues from human FR. In certain embodiments, a humanized antibody will comprise substantially all of at least one and typically two variable domains, wherein all or substantially all of the HVR ( e.g., CDR) corresponds to the HVR of the non-human antibody, and all or Almost all FRs correspond to the FRs of human antibodies. The humanized antibody may optionally comprise at least a part of the constant region of an antibody derived from a human antibody. Antibodies, such as "humanized forms" of non-human antibodies, refer to antibodies that have undergone humanization.

如本文所使用，術語「高變區」或「HVR」係指抗體可變域中序列高變及/或形成結構確定之環(「高變環」)的每個區域。一般而言，天然的四鏈抗體包含六個HVR；VH (H1、H2、H3)中的三個及VL (L1、L2、L3)中的三個。HVR一般包含來自高變環及/或來自「互補決定區」(CDR)之胺基酸殘基，互補決定區具有最高序列變化及/或參與抗原識別。示例性高變環位於胺基酸殘基26-32 (L1)、50-52 (L2)、91-96 (L3)、26-32 (H1)、53-55(H2)及96-101 (H3) 處。(Chothia及Lesk，J. Mol. Biol. 196:901-917 (1987))。示例性CDR (CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3)位於L1之胺基酸殘基24-34、L2之50-56、L3之89-97、H1之31-35B、H2之50-65及H3之95-102處。(Kabat等人，Sequences of Proteins of Immunological Interest，第5版，Public Health Service，National Institutes of Health，Bethesda，MD (1991)。)除VH中的CDR1外，CDR一般包含形成高變環之胺基酸殘基。CDR還包含「特異性決定殘基」或「SDR」，該等殘基係與抗原接觸之殘基。SDR包含在以縮寫CDR或a-CDR命名之CDR區域內。示例性a-CDR (a-CDR-L1、a-CDR-L2、a-CDR-L3、a-CDR-H1、a-CDR-H2及a-CDR-H3)位於L1之胺基酸殘基31-34、L2之50-55、L3之89-96、H1之31-35B、H2之50-58及H3之95-102處。(請參閱 Almagro及Fransson，Front. Biosci . 13:1619-1633 (2008)。)除非另外指示，否則可變域中之HVR殘基及其他殘基(例如 FR殘基)在本文中係根據Kabat等人，同上 編號。As used herein, the term "hypervariable region" or "HVR" refers to each region in an antibody variable domain that is hypervariable in sequence and/or forms a structurally defined loop ("hypervariable loop"). Generally speaking, a natural four-chain antibody contains six HVRs; three of VH (H1, H2, H3) and three of VL (L1, L2, L3). HVR generally contains amino acid residues from the hypervariable loop and/or from the "complementarity determining region" (CDR). The complementarity determining region has the highest sequence change and/or participates in antigen recognition. Exemplary hypervariable rings are located at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2) and 96-101 ( H3) place. (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3) are located at amino acid residues 24-34 of L1, 50-56 of L2, 89- of L3 97, 31-35B of H1, 50-65 of H2 and 95-102 of H3. (Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991).) In addition to CDR1 in VH, CDR generally contains an amine group that forms a hypervariable ring Acid residues. CDRs also include "specificity determining residues" or "SDRs", which are residues in contact with the antigen. The SDR is contained in the CDR region named after the abbreviation CDR or a-CDR. Exemplary a-CDR (a-CDR-L1, a-CDR-L2, a-CDR-L3, a-CDR-H1, a-CDR-H2 and a-CDR-H3) is located at the amino acid residue of L1 31-34, 50-55 of L2, 89-96 of L3, 31-35B of H1, 50-58 of H2 and 95-102 of H3. ( See Almagro and Fransson, Front. Biosci . 13:1619-1633 (2008).) Unless otherwise indicated, HVR residues and other residues ( e.g., FR residues) in the variable domain are herein based on Kabat Et al., the same as above .

術語「可變區」或「可變域」係指抗體重鏈或輕鏈中參與抗體與抗原之結合的域。天然抗體之重鏈及輕鏈的可變域(分別為VH及VL)一般具有相似的結構，其中每個域均包含四個保守框架區(FR)及三個高變區(HVR)。(參見例如 Kindt等人，Kuby Immunology ，第6版，W.H. Freeman and Co.，第91頁(2007)。)單個VH或VL域可足以賦予抗原結合特異性。此外，結合特定抗原之抗體可使用來自結合該抗原之抗體的VH或VL域分別篩選互補VL或VH域文庫進行分離。參見例如 Portolano等人，J. Immunol. 150:880-887 (1993)；Clarkson等人，Nature 352:624-628 (1991)。The term "variable region" or "variable domain" refers to the domain in the heavy or light chain of an antibody that participates in the binding of the antibody to the antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, and each domain contains four conserved framework regions (FR) and three hypervariable regions (HVR). ( See, for example, Kindt et al., Kuby Immunology , 6th edition, WH Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen binding specificity. In addition, antibodies that bind to a specific antigen can be isolated by screening complementary VL or VH domain libraries using VH or VL domains from antibodies that bind the antigen, respectively. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

「效應功能」係指歸因於抗體Fc區之生物活性，其隨抗體同型而變化。抗體效應功能之實例包括：C1q結合及補體依賴性細胞毒性(CDC)；Fc受體結合；抗體依賴性細胞介導的細胞毒性(ADCC)；吞噬作用；細胞表面受體(例如 B細胞受體)下調；及B細胞活化。"Effector function" refers to the biological activity attributed to the Fc region of an antibody, which varies with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; cell surface receptors ( such as B cell receptors) ) Down-regulation; and B cell activation.

「CD79b多肽變異體」意思指與本文所揭示之全長天然序列CD79b多肽序列、如本文所揭示的不含信號肽之CD79b多肽序列、如本文所揭示的含或不含信號肽之CD79b多肽之胞外域或如本文所揭示之全長CD79b多肽序列之任何其他片段(諸如由僅表示全長CD79b多肽之完整編碼序列之一部分的核酸所編碼之片段)具有至少約80%胺基酸序列一致性的如本文所定義之CD79b多肽，較佳地為活性CD79b多肽。此類CD79b多肽變異體包括例如在全長天然胺基酸序列之N末端或C末端添加或缺失一或多個胺基酸殘基之CD79b多肽。通常，CD79b多肽變異體將與如本文揭示之全長原生序列CD79b多肽序列、如本文揭示之缺少信號肽之CD79b多肽序列、如本文揭示之具有或不具有信號肽的CD79b多肽之細胞外域、或如本文揭示之全長CD79b多肽序列之任何其他特別限定片段具有至少約80%胺基酸序列一致性，或者至少約81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%胺基酸序列一致性。通常，CD79b變異體多肽之長度係至少約10個胺基酸，或者至少約20、30、40、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、320、330、340、350、360、370、380、390、400、410、420、430、440、450、460、470、480、490、500、510、520、530、540、550、560、570、580、590、600個或更多個胺基酸。視情況，與天然CD79b多肽序列相比，CD79b變異體多肽將具有不超過一個保守胺基酸取代，或者與天然CD79b多肽序列相比，具有不超過2、3、4、5、6、7、8、9或10個保守胺基酸取代。"CD79b polypeptide variant" means a cell with the full-length native sequence CD79b polypeptide sequence disclosed herein, the CD79b polypeptide sequence without the signal peptide as disclosed herein, the CD79b polypeptide with or without the signal peptide as disclosed herein Exodomain or any other fragment of the full-length CD79b polypeptide sequence as disclosed herein (such as a fragment encoded by a nucleic acid representing only a part of the complete coding sequence of the full-length CD79b polypeptide) has at least about 80% amino acid sequence identity as herein The defined CD79b polypeptide is preferably an active CD79b polypeptide. Such CD79b polypeptide variants include, for example, CD79b polypeptides with one or more amino acid residues added or deleted at the N-terminus or C-terminus of the full-length natural amino acid sequence. Generally, the CD79b polypeptide variant will be the same as the full-length native sequence CD79b polypeptide sequence as disclosed herein, the CD79b polypeptide sequence lacking a signal peptide as disclosed herein, the extracellular domain of the CD79b polypeptide with or without a signal peptide as disclosed herein, or as Any other specifically limited fragments of the full-length CD79b polypeptide sequence disclosed herein have at least about 80% amino acid sequence identity, or at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88 %, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity. Generally, the length of the CD79b variant polypeptide is at least about 10 amino acids, or at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600 or more amino acids. Optionally, compared with the natural CD79b polypeptide sequence, the CD79b variant polypeptide will have no more than one conservative amino acid substitution, or compared with the natural CD79b polypeptide sequence, no more than 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions.

相對於參考多肽序列之「胺基酸序列一致性百分比(%)」定義為在比對序列並在必要時引入空位以達到最大序列一致性百分比後，且在不考慮任何保守取代作為序列一致性之一部分的情況下，候選序列中與參考多肽序列中之胺基酸殘基一致的胺基酸殘基之百分含量。為了達到確定胺基酸序列一致性百分比之目的，比對可藉由在此項技術之技能範圍內的多種方式實現，例如使用公開可用之電腦軟體，諸如BLAST、BLAST-2、ALIGN或Megalign (DNASTAR)軟體。熟習此項技術者可確定用於比對序列之適當參數，包括在所比較之序列的全長上實現最大比對所需的任何算法。然而，出於本文之目的，胺基酸序列一致性百分比值係使用序列比較電腦程式ALIGN-2生成。ALIGN-2序列比較電腦程式由Genentech，Inc.編寫，且源代碼已與使用者文件一起歸檔於位於華盛頓特區 (Washington D.C.) 20559的美國版權局(U.S. Copyright Office)中，其中其係以美國版權登記號TXU510087註冊。ALIGN-2程式自位於加利福尼亞南舊金山(South San Francisco，California)之Genentech，Inc.公開可用，或可由源代碼編譯。ALIGN-2程式應編譯成在UNIX操作系統，包括在數字式UNIX V4.0D上使用。所有序列比較參數均由ALIGN-2程式設定且沒有變化。"Amino acid sequence identity percentage (%)" relative to the reference polypeptide sequence is defined as the sequence identity after aligning the sequences and introducing gaps when necessary to achieve the maximum sequence identity percentage, and without considering any conservative substitutions as sequence identity In the case of one part, the percentage of amino acid residues in the candidate sequence that are consistent with the amino acid residues in the reference polypeptide sequence. In order to achieve the purpose of determining the percent identity of amino acid sequences, the alignment can be achieved in a variety of ways within the skill of this technology, such as using publicly available computer software, such as BLAST, BLAST-2, ALIGN or Megalign ( DNASTAR) software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithms required to achieve maximum alignment over the full length of the sequences being compared. However, for the purposes of this article, the percent identity of amino acid sequences is generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code has been archived in the US Copyright Office (Washington DC) 20559 along with user documentation, where it is under US copyright Registration number TXU510087 is registered. The ALIGN-2 program is publicly available from Genentech, Inc. in South San Francisco, California, or can be compiled from source code. The ALIGN-2 program should be compiled to be used on the UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and remain unchanged.

在使用ALIGN-2進行胺基酸序列比較的情況下，給定胺基酸序列A相對於、與或針對給定胺基酸序列B之胺基酸序列一致性百分比(可以替代地表述為具有或包含相對於、與或針對給定胺基酸序列B之給定胺基酸序列A)計算如下： 100乘以X/Y的比率 其中X係在序列比對程式ALIGN-2比對A與B時被該程式評分為一致匹配的胺基酸殘基之數量，且其中Y係B中胺基酸殘基之總數。應理解，在胺基酸序列A之長度不等於胺基酸序列B之長度時，A相對於B之胺基酸序列一致性百分比將不等於B相對於A之胺基酸序列一致性百分比。除非另外明確說明，否則本文所使用的所有胺基酸序列一致性百分比值均如剛剛前一段中所述，使用ALIGN-2電腦程式獲得。In the case of using ALIGN-2 for amino acid sequence comparison, a given amino acid sequence A is relative to, with or against the amino acid sequence identity percentage of a given amino acid sequence B (which can alternatively be expressed as having Or including a given amino acid sequence A) relative to, and or for a given amino acid sequence B) is calculated as follows: 100 times the ratio of X/Y Wherein X is the number of amino acid residues that are scored as unanimous matches when comparing A and B in the sequence alignment program ALIGN-2, and Y is the total number of amino acid residues in B. It should be understood that when the length of the amino acid sequence A is not equal to the length of the amino acid sequence B, the amino acid sequence identity percentage of A relative to B will not be equal to the amino acid sequence identity percentage of B relative to A. Unless explicitly stated otherwise, all amino acid sequence identity percentage values used herein are obtained using the ALIGN-2 computer program as described in the previous paragraph.

如本文所使用，術語「載體」係指這樣一種核酸分子，其能夠繁殖與其所連接之另一核酸。該術語包括作為自我複制核酸結構之載體，以及併入宿主細胞基因組中之載體，該宿主細胞中已引入該載體。某些載體能夠引導與其可操作地連接之核酸的表現。此類載體在本文中稱為「表現載體」。As used herein, the term "vector" refers to a nucleic acid molecule capable of multiplying another nucleic acid to which it is linked. The term includes a vector as a self-replicating nucleic acid structure, as well as a vector incorporated into the genome of a host cell into which the vector has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "performance vectors".

「免疫偶聯物」係與一或多個異源分子結合之抗體，該一或多個異源分子包括但不限於細胞毒性劑。An "immunoconjugate" is an antibody that binds to one or more heterologous molecules, including but not limited to cytotoxic agents.

在本文所提供各式之上下文中，「p」係指每個抗體之藥物部分的平均數量，其範圍可例如 為每個抗體約1至約20個藥物部分，且在某些實施例中，每個抗體1至約8個藥物部分。本發明包括一種組成物，該組成物包含式I之抗體-藥物化合物之混合物，其中每個抗體之平均藥物載量為約2至約5個，或約3至約4個，例如 約3.5個。In the context of the various formulae provided herein, "p" refers to the average number of drug moieties per antibody, and can range, for example, from about 1 to about 20 drug moieties per antibody, and in certain embodiments, From 1 to about 8 drug moieties per antibody. The present invention includes a composition comprising a mixture of an antibody-drug compound of formula I, wherein the average drug load of each antibody is about 2 to about 5, or about 3 to about 4, such as about 3.5 .

如本文所使用，術語「細胞毒性劑」係指抑製或阻止細胞功能及/或引起細胞死亡或破壞之物質。細胞毒性劑包括但不限於放射性同位素(例如 At211 、I131 、I125 、Y90 、Re186 、Re188 、Sm153 、Bi212 、P32 、Pb212 及Lu之放射性同位素)；化學治療劑或藥物(例如 甲胺蝶呤(methotrexate)、阿德里亞黴素(adriamicin)、長春花生物鹼(vinca alkaloid)(長春新鹼(vincristine)、長春鹼(vinblastine)、依托泊苷(etoposide))、小紅莓(doxorubicin)、美法蘭(melphalan)、絲裂黴素C(mitomycin C)、苯丁酸氮芥(chlorambucil)、柔紅黴素(daunorubicin)或其他嵌入劑)；生長抑製劑；酶及其片段，諸如溶核酶；抗生素；細菌、真菌、植物或動物來源之毒素，諸如小分子毒素或酶活性毒素，包括其片段及/或變異體；以及以下所揭示之各種抗腫瘤劑或抗癌劑。As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and/or causes cell death or destruction. Cytotoxic agents include but are not limited to radioisotopes ( such as At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents Or drugs ( e.g. methotrexate, adriamicin, vinca alkaloid (vincristine, vinblastine, etoposide)) , Cranberries (doxorubicin), melange (melphalan), mitomycin C (mitomycin C), chlorambucil (chlorambucil), daunorubicin (daunorubicin) or other intercalants); growth inhibitors ; Enzymes and fragments thereof, such as nucleolytic enzymes; antibiotics; toxins of bacterial, fungal, plant or animal origin, such as small molecule toxins or enzymatically active toxins, including fragments and/or variants thereof; and various anti-tumor agents disclosed below Agent or anticancer agent.

術語「癌症」及「癌性」係指或描述哺乳動物中典型地以細胞生長不受調控為特徵的生理狀況。癌症之實例包括但不限於B細胞淋巴瘤(包括低度惡性/濾泡性非霍奇金氏淋巴瘤(NHL)；小淋巴細胞性(SL)NHL；中度惡性/濾泡性NHL；中度惡性彌漫性NHL；高度惡性免疫母細胞性NHL；高度惡性淋巴母細胞性NHL；高度惡性小無裂細胞性NHL；大包塊疾病NHL；套細胞淋巴瘤；AIDS相關性淋巴瘤；及瓦爾登斯特倫氏巨球蛋白血症(Waldenstrom's Macroglobulinemia))；慢性淋巴細胞性白血病(CLL)；急性淋巴母細胞性白血病(ALL)；毛細胞白血病；慢性髓母細胞性白血病；及移植後淋巴增生性病症(PTLD)，以及異常血管增生伴斑痣病、水腫(諸如與腦腫瘤有關)及梅格斯氏症候群(Meigs' syndrome)。更具體之實例包括但不限於復發性或難治性NHL、一線低度惡性NHL、III期/IV期NHL、耐化學療法性NHL、前驅B淋巴母細胞性白血病及/或淋巴瘤、小淋巴細胞性淋巴瘤、B細胞慢性淋巴細胞性白血病及/或幼淋巴細胞性白血病及/或小淋巴細胞性淋巴瘤、B細胞幼淋巴細胞性淋巴瘤、免疫細胞瘤及/或淋巴漿細胞性淋巴瘤、淋巴漿細胞性淋巴瘤、邊緣區B細胞淋巴瘤、脾邊緣區淋巴瘤、結外邊緣區-MALT淋巴瘤、淋巴結邊緣區淋巴瘤、毛細胞白血病、漿細胞瘤及/或漿細胞骨髓瘤、低度惡性/濾泡性淋巴瘤、中度惡性/濾泡性NHL、套細胞淋巴瘤、濾泡中心性淋巴瘤(濾泡性)、濾泡性淋巴瘤(例如 復發性/難治性濾泡性淋巴瘤)、中度惡性彌漫性NHL、彌漫性大B細胞淋巴瘤(DLBCL)、復發性DLBCL、難治性DLBCL、復發性/難治性DLBCL、侵襲性NHL(包括侵襲性一線NHL及侵襲性復發性NHL)、自體幹細胞移植後復發之NHL或自體幹細胞移植難治性NHL、原發性縱隔大B細胞淋巴瘤、原發性滲出性淋巴瘤、高度惡性免疫母細胞性NHL、高度惡性淋巴母細胞性NHL、高度惡性小無裂細胞NHL、大包塊疾病NHL、伯基特氏淋巴瘤(Burkitt's lymphoma)、前驅(外周)大顆粒淋巴細胞性白血病、蕈樣真菌病及/或塞扎里氏症候群(Sezary syndrome)、皮膚(皮)淋巴瘤、間變性大細胞淋巴瘤、血管中心性淋巴瘤。The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, B-cell lymphoma (including low-grade/follicular non-Hodgkin’s lymphoma (NHL); small lymphocytic (SL) NHL; moderately malignant/follicular NHL; medium Highly malignant diffuse NHL; Highly malignant immunoblastic NHL; Highly malignant lymphoblastic NHL; Highly malignant small non-cleaved cell NHL; Large mass disease NHL; Mantle cell lymphoma; AIDS-related lymphoma; and Val Denstrom's Macroglobulinemia (Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic medulloblastic leukemia; and post-transplant lymph Proliferative disorders (PTLD), as well as abnormal vascular proliferation with spotted moles, edema (such as associated with brain tumors), and Meigs' syndrome. More specific examples include, but are not limited to, relapsed or refractory NHL, first-line low-grade NHL, stage III/IV NHL, chemotherapy-resistant NHL, precursor B lymphoblastic leukemia and/or lymphoma, small lymphocytes Lymphoma, B-cell chronic lymphocytic leukemia and/or young lymphocytic leukemia and/or small lymphocytic lymphoma, B-cell young lymphocytic lymphoma, immune cell tumor and/or lymphoplasmacytic lymphoma , Lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, splenic marginal zone lymphoma, extranodal marginal zone-MALT lymphoma, lymph node marginal zone lymphoma, hairy cell leukemia, plasmacytoma and/or plasma cell myeloma , Low-grade/follicular lymphoma, moderately malignant/follicular NHL, mantle cell lymphoma, follicular central lymphoma (follicular), follicular lymphoma ( e.g. relapsed/refractory Alveolar lymphoma), moderately malignant diffuse NHL, diffuse large B-cell lymphoma (DLBCL), relapsed DLBCL, refractory DLBCL, relapsed/refractory DLBCL, aggressive NHL (including aggressive first-line NHL and aggressive Recurrent NHL), relapsed NHL after autologous stem cell transplantation or refractory NHL after autologous stem cell transplantation, primary mediastinal large B-cell lymphoma, primary exudative lymphoma, high-grade immunoblastic NHL, high-grade Malignant lymphoblastic NHL, high-grade malignant small non-cleaved cell NHL, large mass disease NHL, Burkitt's lymphoma, precursor (peripheral) large granular lymphocytic leukemia, mycosis fungoides and/or Sezary syndrome, skin (cutaneous) lymphoma, anaplastic large cell lymphoma, angiocentric lymphoma.

「個體」或「受試者」係哺乳動物。哺乳動物包括但不限於家養動物(例如 牛、綿羊、貓、犬及馬)、靈長類動物(例如 人類及非人類靈長類動物，諸如猴)、兔及囓齒動物(例如小鼠及大鼠)。在某些實施例中，個體或受試者係人類。"Individual" or "subject" is a mammal. Mammals include, but are not limited to, domestic animals ( such as cows, sheep, cats, dogs, and horses), primates ( such as humans and non-human primates, such as monkeys), rabbits, and rodents (such as mice and large animals). mouse). In certain embodiments, the individual or subject is a human.

一種藥劑(例如 醫藥調配物)之「有效量」係指在所需劑量及時間段內有效達到所希望之治療或預防結果的量。The "effective amount" of a medicament ( such as a pharmaceutical formulation) refers to an amount that is effective to achieve the desired therapeutic or preventive result within the required dose and time period.

術語「醫藥調配物」係指這樣一種製劑，其形式允許其中所含活性成分之生物活性有效，且不含對將被投與該調配物之受試者產生不可接受之毒性的額外組分。The term "pharmaceutical formulation" refers to a preparation in a form that allows the biological activity of the active ingredients contained therein to be effective, and does not contain additional components that produce unacceptable toxicity to the subject to which the formulation is to be administered.

「醫藥學上可接受之載劑」係指醫藥調配物中除活性成分以外的對受試者無毒的成分。醫藥學上可接受之載劑包括但不限於緩沖劑、賦形劑、穩定劑或防腐劑。"Pharmaceutically acceptable carrier" refers to ingredients in pharmaceutical formulations that are non-toxic to subjects other than the active ingredients. Pharmaceutically acceptable carriers include but are not limited to buffers, excipients, stabilizers or preservatives.

如本文所使用，「治療」(及其語法變化形式，諸如「治療(treat/treating)」)係指試圖改變所治療個體之自然病程的臨床干預措施，且可被執行用於預防目的或在臨床病理過程期間執行。希望的治療效果包括但不限於減少游離輕鏈、預防疾病之發生或復發、緩解症狀、減輕疾病之任何直接或間接病理後果、降低疾病進展速率、改善或緩和疾病狀態、以及緩解或改善預後。在一些實施例中，本文所述之抗體係用於延遲疾病之發展或減慢疾病之進展。As used herein, "treatment" (and its grammatical variations, such as "treat/treating") refers to clinical interventions that attempt to change the natural course of the individual being treated, and can be performed for preventive purposes or in Performed during the clinical pathological process. The desired therapeutic effects include but are not limited to reducing free light chains, preventing the occurrence or recurrence of diseases, alleviating symptoms, alleviating any direct or indirect pathological consequences of the disease, reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving the prognosis. In some embodiments, the anti-system described herein is used to delay or slow the progression of a disease.

術語「CD79b陽性癌症」係指包含在表面上表現CD79b之細胞的癌症。在一些實施例中，細胞表面上CD79b之表現係例如在諸如免疫組織化學、FACS等方法中使用針對CD79b之抗體測定。或者，認為CD79b mRNA表現與細胞表面上CD79b之表現相關，且可藉由選自原位雜交及RT-PCR (包括定量RT-PCR)之方法測定。The term "CD79b-positive cancer" refers to cancers that contain cells expressing CD79b on the surface. In some embodiments, the expression of CD79b on the cell surface is determined by using antibodies against CD79b in methods such as immunohistochemistry, FACS, and the like. Alternatively, it is believed that the expression of CD79b mRNA is related to the expression of CD79b on the cell surface and can be determined by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR).

如本文所使用，「與……結合」或「與……組合」係指除投與一種治療方式之外，亦投與另一種治療方式。因此，「與……結合」或「與……組合」係指在向個體投與一種治療方式之前、期間或之後投與另一種治療方式。As used herein, "in combination with" or "in combination with" means that in addition to administration of one type of treatment, another type of treatment is also administered. Therefore, "in combination with" or "in combination with" refers to the administration of one treatment modality before, during, or after the administration of another treatment modality to the individual.

「化學治療劑」係可用於治療癌症之化合物。化學治療劑之實例包括厄洛替尼(erlotinib)(TARCEVA® ，Genentech/OSI Pharm.)；硼替佐米(bortezomib)(VELCADE® ，Millennium Pharm.)；二硫龍(disulfiram)；表沒食子兒茶素沒食子酸酯；鹽孢菌素A (salinosporamide A)；卡非佐米(carfilzomib)；17-AAG (格爾德黴素(geldanamycin))；根赤殼菌素(radicicol)；乳酸脫氫酶A (LDH-A)；氟維司群(fulvestrant)(FASLODEX® ，AstraZeneca)；舒尼替尼(sunitib)(SUTENT® ，Pfizer/Sugen)；來曲唑(letrozole)(FEMARA® ，Novartis)；甲磺酸伊馬替尼(imatinib mesylate)(GLEEVEC® ，Novartis)；菲那舒那(finasunate)(VATALANIB® ，Novartis)；奧沙利鉑(oxaliplatin)(益樂鉑(ELOXATIN)® ，Sanofi)；5-FU (5-氟尿嘧啶)；甲醯四氫葉酸(leucovorin)；雷帕黴素(Rapamycin)(西羅莫司(Sirolimus)，RAPAMUNE® ，Wyeth)；拉帕替尼(Lapatinib)(TYKERB® ，GSK572016，Glaxo Smith Kline)；洛那法尼(Lonafamib)(SCH 66336)；索拉非尼(sorafenib)(NEXAVAR® ，Bayer Labs)；吉非替尼(gefitinib)(IRESSA® ，AstraZeneca)；AG1478；烷基化劑，諸如噻替派(thiotepa)及CYTOXAN® 環磷醯胺；烷基磺酸酯，諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan)；氮丙啶，諸如苯并多巴(benzodopa)、卡巴醌(carboquone)、美妥多巴(meturedopa)及脲多巴(uredopa)；伸乙亞胺及甲基密胺，包括六甲密胺(altretamine)、三伸乙基密胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三羥甲基密胺；番荔枝內酯(acetogenin)(尤其是布拉它辛(bullatacin)及布拉它辛酮(bullatacinone))；喜樹鹼(camptothecin)(包括拓撲替康(topotecan)及伊立替康(irinotecan))；苔蘚蟲素(bryostatin)；卡利他汀(callystatin)；CC-1065 (包括其阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin)合成類似物)；念珠藻素(cryptophycin)(尤其是念珠藻素1及念珠藻素8)；腎上腺皮質類固醇(包括潑尼松(prednisone)及潑尼松龍(prednisolone))；乙酸環丙孕酮(cyproterone acetate)；5α-還原酶，包括非那雄胺(finasteride)及度他雄胺(dutasteride))；伏立諾他(vorinostat)；羅米地辛(romidepsin)；帕比司他(panobinostat)；丙戊酸；莫西司他(mocetinostat)；海兔毒素(dolastatin)；阿地介白素(aldesleukin)；滑石；倍癌黴素(duocarmycin)(包括合成類似物KW-2189及CB1-TM1)；艾榴塞洛素(eleutherobin)；水鬼蕉鹼(pancratistatin)；匍枝珊瑚醇(sarcodictyin)；海綿抑素(spongistatin)；氮芥，諸如苯丁酸氮芥(chlorambucil)、氯瑪法辛(chlomaphazine)、氯磷醯胺(chlorophosphamide)、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、甲氮芥(mechlorethamine)、甲氮芥氧化物鹽酸鹽、美法蘭(melphalan)、新恩比興(novembichin)、膽固醇苯乙酸氮芥(phenesterine)、潑尼莫斯汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥；亞硝基脲，諸如卡莫司汀(carmustine)、氯脲黴素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimnustine)；抗生素，諸如烯二炔抗生素(例如 卡奇黴素(calicheamicin)，尤其是卡奇黴素γ1I及卡奇黴素ω1I (Angew Chem.Intl. Ed. Engl. 1994 33:183-186)；達內黴素(dynemicin)，包括達內黴素A；雙膦酸鹽，諸如氯膦酸二鈉(clodronate)；埃斯培拉黴素(esperamicin)；以及新製癌菌素發色團(neocarzinostatin chromophore) 及相關色蛋白烯二炔抗生素發色團)、阿克拉黴素(aclacinomysins)、放線菌素(actinomycin)、安曲黴素(authramycin)、氮雜絲胺酸(azaserine)、博萊黴素(bleomycins)、放線菌素C (cactinomycin)、卡拉比星(carabicin)、洋紅黴素(caminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycinis)、放線菌素D (dactinomycin)、柔紅黴素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-側氧基-L-正白胺酸、ADRIAMYCIN® (小紅莓)、(N-嗎啉基)-小紅莓、氰基(N-嗎啉基)-小紅莓、2-吡咯啉基-小紅莓及脫氧小紅莓)、表柔比星(epirubicin)、依索比星(esorubicin)、依維莫斯(everolimus)、索曲托林(sotrataurin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycins)，諸如絲裂黴素C (mitomycin C)、黴酚酸(mycophenolic acid)、諾拉黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素(peplomycin)、泊非黴素(porfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲佐菌素(streptozocin)、殺結核菌素(tubercidin)、烏本美司(ubenimex)、淨司他汀(zinostatin)、佐柔比星(zorubicin)；抗代謝物，諸如甲胺喋呤及5-氟尿嘧啶(5-FU)；葉酸類似物，諸如二甲葉酸(denopterin)、甲胺喋呤、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate)；嘌呤類似物，諸如氟達拉濱(fludarabine)、6-巰基嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine)；嘧啶類似物，諸如安西他滨(ancitabine)、氮雜胞苷(azacitidine)、6-氮雜尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、雙脫氧尿苷(dideoxyuridine)、脫氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟脫氧尿苷(floxuridine)；雄激素，諸如卡魯睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯(testolactone)；抗腎上腺素，諸如胺格魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane)；葉酸補充劑，諸如亞葉酸(frolinic acid)；醋葡醛内酯(aceglatone)；醛磷醯胺糖苷(aldophosphamide glycoside)；胺基乙醯丙酸(aminolevulinic acid)；恩尿嘧啶(eniluracil)；胺苯吖啶(amsacrine)；比曲比新(bestrabucil)；比生群(bisantrene)；伊達曲沙(edatraxate)；地磷醯胺(defofamine)；地美可辛(demecolcine)；地吖醌(diaziquone)；艾弗米新(elfomithine)；依利醋铵(elliptinium acetate)；埃坡霉素(epothilone)；依托格鲁(etoglucid)；硝酸鎵(gallium nitrate)；羥基脲(hydroxyurea)；香菇多糖(lentinan)；氯尼达明(lonidainine)；類美登素(maytansinoids)，諸如美登素(maytansine)及安丝菌素(ansamitocins)；米托胍腙(mitoguazone)；米托蒽醌 (mitoxantrone)；莫哌达醇(mopidamnol)；二胺硝吖啶(nitraerine)；喷司他丁(pentostatin)；蛋胺氮芥(phenamet)；吡柔比星(pirarubicin)；洛索蒽醌(losoxantrone)；足叶草酸(podophyllinic acid)；2-乙基醯肼；丙卡巴嗪(procarbazine)；PSK® 多糖複合物(JHS Natural Products，Eugene，Oreg.)；雷佐生(razoxane)；根瘤菌素(rhizoxin)；西佐喃(sizofuran)；锗螺胺(spirogermanium)；细交链孢菌酮酸(tenuazonic acid)；三亚胺醌(triaziquone)；2,2',2''-三氯三乙胺；单端孢霉烯(trichothecenes) (尤其是T-2毒素，疣孢菌素A (verracurin A)；漆斑菌素A (roridin A)及蛇形菌素(anguidine))；烏瑞沙(urethan)；長春地辛 (vindesine)；達卡巴嗪(dacarbazine)；甘露莫司汀(mannomustine)；二溴甘露醇(mitobronitol)；二溴卫矛醇(mitolactol)；哌泊溴烷(pipobroman)；加胞嘧啶(gacytosine)；阿拉伯糖苷(arabinoside) (「Ara-C」)；環磷醯胺；噻替哌(thiotepa)；紫杉醇 (taxoids)，例如 TAXOL (太平洋紫杉醇(paclitaxel))；Bristol-Myers Squibb Oncology，Princeton，N.J.)，ABRAXANE® (無克列莫佛(Cremophor-free))、白蛋白工程改造的太平洋紫杉醇奈米粒子調配物(American Pharmaceutical Partners，Schaumberg，Ill.)及TAXOTERE® (多克他賽(docetaxel)、多西他賽(doxetaxel)；Sanofi-Aventis)；苯丁酸氮芥；健擇® (吉西他濱(gemcitabine))；6-硫鳥嘌呤；巰基嘌呤；甲胺喋呤；鉑類似物，諸如順鉑(cisplatin)及卡鉑(carboplatin)；长春碱 (vinblastine)；依托泊苷(etoposide) (VP-16)；異環磷醯胺；米托蒽醌；長春新鹼 (vincristine)；NAVELBINE® (長春瑞賓(vinorelbine))；诺消灵(novantrone)；替尼泊苷(teniposide)；伊達曲沙(edatrexate)；道諾黴素(daunomycin)；胺基喋呤(aminopterin)；卡培他濱 (capecitabine) (XELODA® )；依班膦酸鹽(ibandronate)；CPT-11；拓撲異構酶抑製劑RFS 2000；二氟甲基鳥胺酸(DMFO)；類視黃醇，諸如視黃酸(retinoic acid)；及上述任一種之醫藥學上可接受之鹽、酸及衍生物；以及上述兩種或更多種之組合，諸如CHOP(環磷醯胺、小紅莓、長春新鹼及潑尼松龍之組合療法的縮寫)及FOLFOX (利用奧沙利鉑(益樂鉑TM )與5-FU及亞葉酸之治療方案的縮寫)。化學治療劑之額外實例包括苯達莫司汀(或鹽酸苯達莫司汀) (TREANDA®)、依魯替尼、來那度胺及/或艾代拉裡斯(GS-1101)。"Chemotherapeutic agents" are compounds that can be used to treat cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA ® , Genentech/OSI Pharm.); bortezomib (VELCADE ® , Millennium Pharm.); disulfiram; epigallium Catechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; Lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX ® , AstraZeneca); sunitinib (SUTENT ® , Pfizer/Sugen); letrozole (FEMARA ® , Novartis); imatinib mesylate (GLEEVEC ® , Novartis); finasunate (VATALANIB ® , Novartis); oxaliplatin (ELOXATIN ® , Sanofi); 5-FU (5-fluorouracil); leucovorin; Rapamycin (Sirolimus, RAPAMUNE ® , Wyeth); Lapatinib ) (TYKERB ® , GSK572016, Glaxo Smith Kline); Lonafamib (SCH 66336); Sorafenib (NEXAVAR ® , Bayer Labs); Gefitinib (IRESSA ® , AstraZeneca); AG1478; alkylating agents, such as thiotepa and CYTOXAN ® cyclophosphamide; alkyl sulfonates, such as busulfan (busulfan), improsulfan (improsulfan) and piposol Where (piposulfan); aziridine, such as benzodopa (benzodopa), carboquone (carboquone), metodopa (meturedopa) and ureidopa (uredopa); ethyleneimine and methylmelamine, including Hexamethyl melamine (altretamine), triethylene melamine, triethylene phosphatidamide, tris ethylene thiophosphatidamide and trimethylol melamine; acetogenin (especially cloth Bullatacin and bulla Bullatacinone; camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including Its adozelesin, carzelesin, and bizelesin synthetic analogues); cryptophycin (especially nostridine 1 and nostrine 8); adrenal glands Corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase, including finasteride and dutasteride )); vorinostat; romidepsin; panobinostat; valproic acid; mocetinostat; dolastatin; aldesine Aldesleukin; talc; duocarmycin (including synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, and ifosphine Ifosfamide, mechlorethamine, mechlorethamine, chlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednisodine (prednimustine), trifosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine (lomustine), nimustine (nimustine) and ramustine (ranimnustine); antibiotics, such as enediyne antibiotics ( such as calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I ( Angew Chem.Intl. Ed. En gl. 1994 33:183-186); dynemicin, including danomycin A; bisphosphonates, such as clodronate; esperamicin; And neocarzinostatin chromophore (neocarzinostatin chromophore) and related chromoprotein endiyne antibiotic chromophore), aclacinomysins, actinomycin (actinomycin), atramycin (authramycin), nitrogen Azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin chromomycinis), actinomycin D (dactinomycin), daunorubicin (daunorubicin), detorubicin (detorubicin), 6-diazo-5-oxo-L-n-leucine, ADRIAMYCIN ® (Little Red Berry), (N-morpholinyl)-cranberry, cyano (N-morpholinyl)-cranberry, 2-pyrrololinyl-cranberry and deoxycranberry), epirubicin ( epirubicin, esorubicin, everolimus, sotrataurin, idarubicin, marcellomycin, mitomycins , Such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin , Puromycin (puromycin), tri-iron adriamycin (quelamycin), rhodoubicin (rodorubicin), streptomycin (streptonigrin), streptozocin (streptozocin), tubercidin (tubercidin), Ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folate analogs, such as dimethylfolate (denopterin), methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamine (thiamiprine), thioguanine (thioguanine); pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine ( cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, drotapropionate Androsterone (dromostanolone propionate), epithiosterol (epitiostanol), mepitiostane (mepitiostane), testolactone (testolactone); anti-adrenaline, such as aminoglutethimide (aminoglutethimide), mitotane (mitotane), triturate Trilostane; folic acid supplements, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; en Uracil (eniluracil); amsacrine (amsacrine); bestrabucil; bisantrene; edatraxate; defofamine; demecolcine ); diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea ( hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; rice Mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; loxo Anthraquinone (losoxantrone); podophyllinic acid; 2-ethylhydrazine; Procarbazine (proc arbazine); PSK ® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; Alternaria tenuis Tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verrucosporin) A (verracurin A); roridin A and anguidine; urethan; vindesine; dacarbazine; mannmostine (mannomustine); dibromomannitol (mitobronitol); mitolactol (mitolactol); pipobroman (pipobroman); plus cytosine (gacytosine); arabinoside ("Ara-C"); ring Phosphosamide; thiotepa; taxoids, such as TAXOL (paclitaxel); Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE ® (Cremophor-free) ), albumin engineered paclitaxel nanoparticle formulations (American Pharmaceutical Partners, Schaumberg, Ill.) and TAXOTERE ® (docetaxel, doxetaxel; Sanofi-Aventis); benzene chlorambucil; Gemzar ® (gemcitabine (gemcitabine)); 6- thioguanine; mercaptopurine; methotrexate; platinum analogs such as cis-platinum (cisplatin) and carboplatin (carboplatin in); vinblastine (vinblastine ); etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (vincristine); NAVELBINE ® (vinorelbine); novantrone; Teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XEL ODA ® ); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids, such as retinoic acid ; And any of the above pharmaceutically acceptable salts, acids and derivatives; and combinations of two or more of the above, such as CHOP (cyclophosphamide, cranberry, vincristine and prednisolone abbreviations of combination therapy) and FOLFOX (oxaliplatin using (Yi lobaplatin (TM)) with a treatment regimen abbreviations 5-FU and the leucovorin). Additional examples of chemotherapeutic agents include bendamustine (or bendamustine hydrochloride) (TREANDA®), ibrutinib, lenalidomide, and/or aidelaris (GS-1101).

化學治療劑之額外實例包括抗激素劑，用於調節、降低、阻斷或抑制可促進癌症生長之之激素的作用，且通常呈系統性或全身治療形式。其本身可能為激素。實例包括抗雌激素及選擇性雌激素受體調節劑(SERM)，包括例如他莫昔芬(包括NOLVADEX®他莫昔芬)、雷洛昔芬(EVISTA®)、屈落昔芬、4-羥基他莫昔芬、曲沃昔芬、凱奧昔芬、LY117018、奥那司酮及托瑞米芬(FARESTON®)；抗孕激素；雌激素受體下調劑(ERD)；雌激素受體拮抗劑，諸如氟維司群(FASLODEX®)；用於抑製或關閉卵巢功能之藥劑，例如促黃體激素釋放激素(LHRH)促效劑，諸如醋酸亮丙瑞林(LUPRON®及ELIGARD®)、醋酸戈舍瑞林、醋酸布塞林及雷公藤甲素；抗雄激素，諸如氟他胺、尼魯米特及比卡魯胺；以及抑制可調節腎上腺雌激素生成之酶芳香化酶的芳香化酶抑製劑，例如4(5)-咪唑、胺格魯米特、醋酸甲地孕酮(MEGASE®)、依西美坦(AROMASIN®)、甲芬斯坦、法卓唑、伏洛唑(RIVISOR®)、來曲唑(FEMARA®)及阿那曲唑(ARIMIDEX®)。另外，此類化學治療劑之定義包括雙膦酸鹽，諸如氯膦酸二鈉(例如BONEFOS®或OSTAC®)、依替膦酸鹽(DIDROCAL®)、NE-58095、唑來膦酸/唑來膦酸鹽(ZOMETA®)、阿崙膦酸鹽(FOSAMAX®)、帕米膦酸鹽(AREDIA®)、替洛膦酸鹽(SKELID®)或利塞膦酸鹽(ACTONEL®)；以及曲沙他滨(1,3-二氧雜環己烷核苷胞嘧啶類似物)；反義寡核苷酸，特別是抑制與異常細胞增殖有關之信號傳導途徑中之基因表現的寡核苷酸，例如PKC-α、Raf、H-Ras及表皮生長因子受體(EGF-R)；疫苗，諸如THERATOPE®疫苗及基因治療疫苗，例如ALLOVECTIN®疫苗、LEUVECTIN®疫苗及VAXID®疫苗。Additional examples of chemotherapeutic agents include antihormonal agents, which are used to modulate, reduce, block or inhibit the effects of hormones that can promote cancer growth, and are usually in the form of systemic or systemic therapy. It may be a hormone by itself. Examples include anti-estrogen and selective estrogen receptor modulators (SERM), including, for example, tamoxifen (including NOLVADEX® tamoxifen), raloxifene (EVISTA®), droloxifene, 4- Hydroxytamoxifen, Travoxifene, Cheoxifene, LY117018, Onlastone and Toremifene (FARESTON®); Antiprogestin; Estrogen receptor downregulator (ERD); Estrogen receptor Antagonists, such as Fulvestrant (FASLODEX®); agents used to inhibit or shut down ovarian function, such as luteinizing hormone releasing hormone (LHRH) agonists, such as leuprolide acetate (LUPRON® and ELIGARD®), Goserelin acetate, buserin acetate and triptolide; antiandrogens such as flutamide, nilutamide and bicalutamide; and aromatase that inhibits the enzyme aromatase that regulates adrenal estrogen production Enzyme inhibitors, such as 4(5)-imidazole, amineglumid, megestrol acetate (MEGASE®), exemestane (AROMASIN®), mefenstein, fazrozole, volazole ( RIVISOR®), letrozole (FEMARA®) and anastrozole (ARIMIDEX®). In addition, the definition of such chemotherapeutic agents includes bisphosphonates, such as clodronate disodium (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/azole Ledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tilodronate (SKELID®) or risedronate (ACTONEL®); and Traxatabine (1,3-dioxane nucleoside cytosine analogue); antisense oligonucleotides, especially oligonucleotides that inhibit gene expression in signal transduction pathways related to abnormal cell proliferation Acids, such as PKC-α, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines, such as THERATOPE® vaccines and gene therapy vaccines, such as ALLOVECTIN® vaccines, LEUVECTIN® vaccines and VAXID® vaccines.

在一些實施例中，化學治療劑包括拓撲異構酶1抑製劑(例如 LURTOTECAN®)；抗雌激素，諸如氟維司群；Kit抑製劑，諸如伊馬替尼或EXEL-0862(酪胺酸激酶抑製劑)；EGFR抑製劑，諸如厄洛替尼或西妥昔單抗；抗VEGF抑製劑，諸如貝伐單抗(bevacizumab)；阿立替康(arinotecan)；rmRH (例如 ABARELIX®)；拉帕替尼及二甲苯磺酸拉帕替尼(一種ErbB-2及EGFR雙重酪胺酸激酶小分子抑製劑，又稱為GW572016)；17AAG (作為熱休克蛋白(Hsp)90毒素之格爾德黴素衍生物)，以及上述任一種之醫藥學上可接受之鹽，酸或衍生物。In some embodiments, chemotherapeutic agents include topoisomerase 1 inhibitors ( e.g. LURTOTECAN®); anti-estrogens, such as fulvestrant; Kit inhibitors, such as imatinib or EXEL-0862 (tyrosine kinase Inhibitors); EGFR inhibitors, such as erlotinib or cetuximab; anti-VEGF inhibitors, such as bevacizumab; arinotecan; rmRH ( e.g., ABARELIX®); Lapa Tinib and lapatinib ditosylate (a small molecule inhibitor of ErbB-2 and EGFR dual tyrosine kinase, also known as GW572016); 17AAG (Gold's mold as heat shock protein (Hsp) 90 toxin) Derivatives), and any of the above-mentioned pharmaceutically acceptable salts, acids or derivatives.

化學治療劑還包括抗體，諸如阿崙單抗(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(rituximab)(RITUXAN®，Genentech/Biogen Idec)、乌妥昔单抗(ublituximab)、奧法木單抗(ofatumumab)、替伊莫單抗(ibritumomab tiuxetan)、帕妥珠单抗(pertuzumab)(OMNITARG®，2C4，Genentech)、曲妥珠單抗(trastuzumab)(HERCEPTIN®，Genentech)、托西莫單抗(tositumomab)(Bexxar，Corixia)及抗體藥物偶聯物吉妥珠單抗奧唑米星(gemtuzumab ozogamicin)(MYLOTARG®, Wyeth)。與該等化合物組合的作為藥劑具有治療潛力之額外人類化單株抗體包括：阿泊珠单抗、阿塞珠单抗、阿特利单抗、巴匹珠单抗、比伐单抗美登素、莫坎妥珠单抗美登素、西地珠单抗、聚乙二醇结合赛妥珠单抗、西斯妥珠單抗、西妥珠單抗、達西珠單抗、依库珠单抗、艾法珠單抗、依帕珠单抗、艾利珠單抗、非维珠单抗、弗妥利珠單抗、吉妥珠單抗奧佐米星、奥英妥珠单抗奧佐米星、伊匹单抗、拉贝珠单抗、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、諾維珠單抗、努維珠單抗、奧瑞珠單抗、奧馬珠單抗、帕利珠單抗、帕考珠單抗、培斯妥珠單抗、培妥珠單抗、培克珠單抗、拉維珠單抗、蘭尼單抗、瑞維珠單抗、瑞替珠单抗、瑞賽珠單抗、洛維珠單抗、魯匹單抗、西罗珠单抗、西匹珠單抗、索妥珠單抗、他珠单抗四氢西泮、他度珠單抗、他利珠單抗、替巴珠單抗、托利珠單抗、妥拉珠單抗、圖克珠單抗西莫白介素、圖西妥單抗、奧馬珠單抗、優妥珠單抗、乌司奴单抗、维西珠单抗、及抗介白素-12 (ABT-874/J695，Wyeth Research and Abbott Laboratories)，其係一種經基因修飾成識別介白素-12 p40蛋白質的重組僅人類序列之全長IgG1λ抗體。Chemotherapeutics also include antibodies, such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), Rituximab (RITUXAN®, Genentech/Biogen Idec), ublituximab, ofatumumab, ibritumomab tiuxetan, Pertuzumab Anti (pertuzumab) (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Colixia) and the antibody drug conjugate gemtuzumab The monoclonal antibody gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies that have therapeutic potential as medicaments in combination with these compounds include: apolizumab, atezolizumab, atlizumab, bapiizumab, bivacizumab maytan Cetuzumab, Mocantuzumab, Maytansine, Cidizumab, Polyethylene Glycol Combination Certuzumab, Cistuzumab, Cetuzumab, Daclizumab, Ecuador Lizumab, ifazizumab, ipalizumab, elizumab, felizumab, fltolizumab, gemtuzumab ozogamicin, otuzumab Anti-Ozomicin, Ipilimumab, Rabelizumab, Lintuzumab, Matuzumab, Mepolizumab, Movizumab, Motuzumab, Natalizumab Mab, Nituzumab, Novizumab, Nuvizumab, Orrelizumab, Omalizumab, Palivizumab, Pascolizumab, Perstuzumab , Pertuzumab, pexelizumab, lavelizumab, ranibizumab, revizumab, retilizumab, reseizumab, lovizumab, lupi Mab, Sirolizumab, Cipilizumab, Sotuzumab, Talizumab, Tetrahydrozepam, Taduzumab, Taclizumab, Tibazizumab, Tolizumab Ruzumab, tolatuzumab, tuctilizumab, simo interleukin, tucetuzumab, omalizumab, eutumuzumab, usnuzumab, vesizizumab, and anti Interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories), which is a recombinant human-only full-length IgG1λ antibody genetically modified to recognize the interleukin-12 p40 protein.

術語「包裝插頁」用於指通常包括在治療產品之商業包裝中的說明書，其含有關於適應症、用法、劑量、投藥、組合療法、禁忌症及/或有關使用此類治療產品之警告的資訊。The term "package insert" is used to refer to the instructions usually included in the commercial packaging of therapeutic products, which contain information about indications, usage, dosage, administration, combination therapy, contraindications, and/or warnings about the use of such therapeutic products News.

「烷基」係含有正碳原子、二級碳原子、三級碳原子或環狀碳原子之C1 -C18 烴。實例為甲基(Me、-CH3 )、乙基(Et、-CH2 CH3 )、1-丙基(n-Pr、正丙基、-CH2 CH2 CH3 )、2-丙基(i-Pr、異丙基、-CH(CH3 )2 )、1-丁基(n-Bu、正丁基、-CH2 CH2 CH2 CH3 )、2-甲基-1-丙基(i-Bu、異丁基、-CH2 CH(CH3 )2 )、2-丁基(s-Bu、第二丁基、-CH(CH3 )CH2 CH3 )、2-甲基-2-丙基(t-Bu、第三丁基、-C(CH3 )3 )、1-戊基(正-戊基、-CH2 CH2 CH2 CH2 CH3 )、2-戊基(-CH(CH3 )CH2 CH2 CH3 )、3-戊基(-CH(CH2 CH3 )2 )、2-甲基-2-丁基(-C(CH3 )2 CH2 CH3 )、3-甲基-2-丁基(-CH(CH3 )CH(CH3 )2 )、3-甲基-1-丁基(-CH2 CH2 CH(CH3 )2 )、2-甲基-1-丁基(-CH2 CH(CH3 )CH2 CH3 )、1-己基(-CH2 CH2 CH2 CH2 CH2 CH3 )、2-己基(-CH(CH3 )CH2 CH2 CH2 CH3 )、3-己基(-CH(CH2 CH3 )(CH2 CH2 CH3 ))、2-甲基-2-戊基(-C(CH3 )2 CH2 CH2 CH3 )、3-甲基-2-戊基(-CH(CH3 )CH(CH3 )CH2 CH3 )、4-甲基-2-戊基(-CH(CH3 )CH2 CH(CH3 )2 )、3-甲基-3-戊基(-C(CH3 )(CH2 CH3 )2 )、2-甲基-3-戊基(-CH(CH2 CH3 )CH(CH3 )2 )、2,3-二甲基-2-丁基(-C(CH3 )2 CH(CH3 )2 )、3,3-二甲基-2-丁基(-CH(CH3 )C(CH3 )3 。 "Alkyl" is a C 1 -C 18 hydrocarbon containing normal carbon atoms, secondary carbon atoms, tertiary carbon atoms or cyclic carbon atoms. Examples are methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, isopropyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propane Group (i-Bu, isobutyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, second butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl Base-2-propyl (t-Bu, tertiary butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2- Pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl(-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl ( -CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl(-C (CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl ( -CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-di Methyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 .

如本文所使用，術語「C1 -C8 烷基」係指具有1至8個碳原子的直鏈或支鏈的飽和或不飽和烴。代表性「C1 -C8 烷基」包括但不限於-甲基、-乙基、-正丙基、-正丁基、-正戊基、-正己基、-正庚基，-正辛基、-正壬基及-正癸基；而支鏈C1 -C8 烷基包括但不限於-異丙基、-第二丁基 、-異丁基、-第三 丁基、-異戊基、2-甲基丁基；不飽和C1 -C8 烷基包括但不限於-乙烯基、-烯丙基、-1-丁烯基、-2-丁烯基、-異丁烯基、-1-戊烯基、-2-戊烯基、-3-甲基-1-丁烯基、-2-甲基-2-丁烯基、-2,3-二甲基-2-丁烯基、1-己基、2-己基、3-己基、-乙炔基、-丙炔基、-1-丁炔基、-2-丁炔基、-1-戊炔基、-2-戊炔基、-3-甲基-1丁炔基。C1 -C8 烷基可未經取代或經一或多個基團取代，該一或多個基團包括但不限於-C1 -C8 烷基、-O-(C1 -C8 烷基)、-芳基、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2 、-C(O)NHR'、-C(O)N(R')2 -NHC(O)R'、-SO3 R'、-S(O)2 R'、-S(O)R'、-OH、-鹵素、-N3 、-NH2 、-NH(R')、-N(R')2 及-CN；其中各R′獨立地選自H、-C1 -C8 烷基及芳基。As used herein, the term "C 1 -C 8 alkyl" refers to a linear or branched saturated or unsaturated hydrocarbon having 1 to 8 carbon atoms. Representative "C 1 -C 8 alkyl groups" include but are not limited to -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl group, - n-nonyl group, and - n-decyl; while branched C 1 -C 8 alkyl groups include, but are not limited to - isopropyl - butyl, - iso -butyl, - tert-butyl, - iso Pentyl, 2-methylbutyl; Unsaturated C 1 -C 8 alkyl groups include but are not limited to -vinyl, -allyl,-1-butenyl, -2-butenyl, -isobutenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl Alkenyl, 1-hexyl, 2-hexyl, 3-hexyl, -ethynyl, -propynyl,-1-butynyl,-2-butynyl,-1-pentynyl,-2-pentynyl Group, -3-methyl-1 butynyl. The C 1 -C 8 alkyl group may be unsubstituted or substituted with one or more groups including but not limited to -C 1 -C 8 alkyl, -O-(C 1 -C 8 Alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH 2 , -C(O)NHR', -C (O)N(R') 2 -NHC(O)R', -SO 3 R', -S(O) 2 R', -S(O)R', -OH, -halogen, -N 3 , -NH 2 , -NH(R'), -N(R') 2 and -CN; wherein each R'is independently selected from H, -C 1 -C 8 alkyl and aryl.

如本文所使用，術語「C1 -C12 烷基」係指具有1至12個碳原子之直鏈或支鏈飽和或不飽和烴。C1 -C12 烷基可未經取代或經一或多個基團取代，該一或多個基團包括但不限於-C1 -C8 烷基、-O-(C1 -C8 烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2 、-C(O)NHR’、-C(O)N(R’)2 -NHC(O)R’、-SO3 R’、-S(O)2 R’、-S(O)R’、-OH、-鹵素、-N3 、-NH2 、-NH(R’)、-N(R’)2 及-CN；其中各R’獨立地選自H、-C1 -C8 烷基及芳基。As used herein, the term "C 1 -C 12 alkyl" refers to a linear or branched saturated or unsaturated hydrocarbon having 1 to 12 carbon atoms. The C 1 -C 12 alkyl group may be unsubstituted or substituted with one or more groups including but not limited to -C 1 -C 8 alkyl, -O-(C 1 -C 8 Alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH 2 , -C(O)NHR', -C (O)N(R') 2 -NHC(O)R', -SO 3 R', -S(O) 2 R', -S(O)R', -OH, -halogen, -N 3 , -NH 2 , -NH(R'), -N(R') 2 and -CN; wherein each R'is independently selected from H, -C 1 -C 8 alkyl and aryl.

如本文所使用，術語「C1 -C6 烷基」係指具有1至6個碳原子之直鏈或支鏈飽和或不飽和烴。代表性「C1 -C6 烷基」包括但不限於-甲基、-乙基、-正丙基、-正丁基、-正戊基及-正己基；而支鏈C1 -C6 烷基包括但不限於-異丙基、-第二 丁基、-異丁基、- 第三 丁基、-異戊基及2-甲基丁基；不飽和C1 -C6 烷基包括但不限於-乙烯基、-烯丙基、-1-丁烯基，-2-丁烯基及-異丁烯基、-1-戊烯基、-2-戊烯基、-3-甲基-1-丁烯基、-2-甲基-2-丁烯基、-2,3-二甲基-2-丁烯基、1-己基、2-己基及3-己基。C1 -C6 烷基可未經取代或經一或多個如上文關於C1 -C8 烷基所描述之基團取代。As used herein, the term "C 1 -C 6 alkyl" refers to a straight or branched chain saturated or unsaturated hydrocarbon having 1 to 6 carbon atoms. Representative "C 1 -C 6 alkyl groups" include but are not limited to -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; and branched C 1 -C 6 groups include, but are not limited to - isopropyl - butyl, - iso -butyl, - tert-butyl, - isopentyl, and 2-methylbutyl; unsaturated C 1 -C 6 alkyl groups include But not limited to -vinyl, -allyl,-1-butenyl,-2-butenyl and -isobutenyl,-1-pentenyl,-2-pentenyl,-3-methyl- 1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl and 3-hexyl. The C 1 -C 6 alkyl group may be unsubstituted or substituted with one or more groups as described above for the C 1 -C 8 alkyl group.

如本文所使用，術語「C1 -C4 烷基」係指具有1至4個碳原子之直鏈或支鏈飽和或不飽和烴。代表性「C1 -C4 烷基」包括但不限於-甲基、-乙基、-正丙基、-正丁基；而支鏈C1 -C4 烷基包括但不限於-異丙基、-第二 -丁基、-異丁基、-第三 丁基；不飽和C1 -C4 烷基包括但不限於-乙烯基、-烯丙基、-1-丁烯基、-2-丁烯基及異丁烯基。C1 -C4 烷基可未經取代或經一或多個如上文關於C1 -C8 烷基所描述之基團取代。As used herein, the term "C 1 -C 4 alkyl" refers to a straight or branched chain saturated or unsaturated hydrocarbon having 1 to 4 carbon atoms. Representative "C 1 -C 4 alkyl groups" include but are not limited to -methyl, -ethyl, -n-propyl, -n-butyl; and branched C 1 -C 4 alkyl groups include but are not limited to -isopropyl group, - second - butyl, - iso -butyl, - tert-butyl; C 1 -C 4 unsaturated alkyl groups include, but are not limited to - vinyl - allyl, 1-butenyl, - 2-butenyl and isobutenyl. The C 1 -C 4 alkyl group may be unsubstituted or substituted with one or more groups as described above for the C 1 -C 8 alkyl group.

「烷氧基」係以單鍵鍵接至氧之烷基。示例性烷氧基包括但不限於甲氧基(-OCH3 )及乙氧基(-OCH2 CH3 )。「C1 -C5 烷氧基」係具有1至5個碳原子之烷氧基。烷氧基可未經取代或經一或多個如上文關於烷基所描述之基團取代。"Alkoxy" is an alkyl group bonded to oxygen with a single bond. Exemplary alkoxy groups include, but are not limited to, methoxy (-OCH 3 ) and ethoxy (-OCH 2 CH 3 ). The "C 1 -C 5 alkoxy group" is an alkoxy group having 1 to 5 carbon atoms. Alkoxy groups may be unsubstituted or substituted with one or more groups as described above for alkyl groups.

「烯基」係含有正碳原子、二級碳原子、三級碳原子或環狀碳原子且帶有至少一個不飽和位點，亦即 碳-碳sp2 雙鍵之C2 -C18 烴。實例包括但不限於：乙烯或乙烯基(-CH=CH2 )、烯丙基(-CH2 CH=CH2 )、環戊烯基(-C5 H7 )及5-己烯基(-CH2 CH2 CH2 CH2 CH=CH2 )。「C2 -C8 烯基」係含有2至8個正碳原子、二級碳原子、三級碳原子或環狀碳原子且帶有至少一個不飽和位點，亦即碳-碳sp2 雙鍵之烴。 "Alkenyl" is a C 2 -C 18 hydrocarbon containing a normal carbon atom, a secondary carbon atom, a tertiary carbon atom or a cyclic carbon atom with at least one unsaturation site, that is, a carbon-carbon sp 2 double bond . Examples include, but are not limited to: ethylene or vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), cyclopentenyl (-C 5 H 7 ), and 5-hexenyl (- CH 2 CH 2 CH 2 CH 2 CH=CH 2 ). "C 2 -C 8 alkenyl" contains 2 to 8 normal carbon atoms, secondary carbon atoms, tertiary carbon atoms or cyclic carbon atoms and has at least one site of unsaturation, that is, carbon-carbon sp 2 Hydrocarbons with double bonds.

「炔基」係含有正碳原子、二級碳原子、三級碳原子或環狀碳原子且帶有至少一個不飽和位點，亦即 碳-碳sp 參鍵之C2 -C18 烴。實例包括但不限於：乙炔基(-C≡CH)及炔丙基(-CH2 C≡CH)。「C2 -C8 炔基」係含有2至8個正碳原子、二級碳原子、三級碳原子或環狀碳原子且帶有至少一個不飽和位點，亦即 碳-碳sp 參鍵之烴。"Alkynyl" is a C 2 -C 18 hydrocarbon containing a normal carbon atom, a secondary carbon atom, a tertiary carbon atom or a cyclic carbon atom and has at least one site of unsaturation, that is, a carbon-carbon sp-bond. Examples include, but are not limited to: ethynyl (-C≡CH) and propargyl (-CH 2 C≡CH). "C 2 -C 8 alkynyl" contains 2 to 8 normal carbon atoms, secondary carbon atoms, tertiary carbon atoms or cyclic carbon atoms and has at least one site of unsaturation, that is, carbon-carbon sp reference The bond of the hydrocarbon.

「伸烷基」係指具有1-18個碳原子且具有藉由自母烷烴之統一碳原子或兩個不同碳原子移除兩個氫原子得到的兩個單價基團中心的飽和、支鏈或直鏈或環狀烴基。典型的伸烷基包括但不限於：亞甲基(-CH2 -)、1,2-乙基(-CH2 CH2 -)、1,3-丙基(-CH2 CH2 CH2 -)、1,4-丁基(-CH2 CH2 CH2 CH2 -)及類似基團。"Alkane" refers to a saturated, branched chain with 1-18 carbon atoms and two monovalent group centers obtained by removing two hydrogen atoms from the unified carbon atom or two different carbon atoms of the parent alkane Or linear or cyclic hydrocarbon groups. Typical alkylene groups include but are not limited to: methylene (-CH 2 -), 1,2-ethyl (-CH 2 CH 2 -), 1,3-propyl (-CH 2 CH 2 CH 2 -) ), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -) and similar groups.

「C1 -C10 伸烷基」係具有式-(CH2 )1-10 -的直鏈飽和烴基。C1 -C10 伸烷基之實例包括亞甲基、伸乙基、伸丙基、伸丁基、伸戊基、伸己基、伸庚基、伸辛基、伸壬基及伸癸基。"C 1 -C 10 alkylene" is a linear saturated hydrocarbon group having the formula -(CH 2 ) 1-10 -. Examples of C 1 -C 10 alkylene include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylylene, and decylene.

「伸烯基」係指具有2-18個碳原子且具有藉由自母烯烴之同一碳原子或兩個不同碳原子移除兩個氫原子得到的兩個單價基團中心之不飽和、支鏈或直鏈或環狀烴基。典型的伸烯基包括但不限於1,2-伸烯基(-CH=CH-)。"Alkenylene" refers to an unsaturated, branched group having 2-18 carbon atoms and having two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkene. Chain or straight chain or cyclic hydrocarbon group. Typical alkenylene groups include but are not limited to 1,2-alkenylene groups (-CH=CH-).

「伸炔基」係指具有2-18個碳原子且具有藉由自母炔烴之同一碳原子或兩個不同碳原子移除兩個氫原子得到的兩個單價基團中心之不飽和、支鏈或直鏈或環狀烴基。典型的伸炔基包括但不限於：乙炔(-C≡C-)、炔丙基(-CH2 C≡C-)及4-戊炔基(-CH2 CH2 CH2 C≡C-)。"Alkynylene" refers to an unsaturated group with two monovalent groups having 2-18 carbon atoms and having two monovalent groups obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkyne, Branched or straight chain or cyclic hydrocarbon group. Typical alkynylene groups include but are not limited to: acetylene (-C≡C-), propargyl (-CH 2 C≡C-) and 4-pentynyl (-CH 2 CH 2 CH 2 C≡C-) .

「芳基」係指碳環芳族基團。芳基之實例包括但不限於苯基、萘基及蒽基。碳環芳族基團或雜環芳族基團可未經取代或經一或多個基團取代，該一或多個基團包括但不限於-C1 -C8 烷基、-O-(C1 -C8 烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2 、-C(O)NHR’、-C(O)N(R’)2 -NHC(O)R’、-S(O)2 R’、-S(O)R’、-OH、-鹵素、-N3 、-NH2 、-NH(R’)、-N(R’)2 及-CN；其中各R’獨立地選自H、-C1 -C8 烷基及芳基。"Aryl" refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The carbocyclic aromatic group or heterocyclic aromatic group may be unsubstituted or substituted with one or more groups including but not limited to -C 1 -C 8 alkyl, -O- (C 1 -C 8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH 2 , -C(O )NHR', -C(O)N(R') 2 -NHC(O)R', -S(O) 2 R', -S(O)R', -OH, -halogen, -N 3 , -NH 2 , -NH(R'), -N(R') 2 and -CN; wherein each R'is independently selected from H, -C 1 -C 8 alkyl and aryl.

「C5 -C20 芳基」係在碳環芳族環中具有5至20個碳原子的芳基。C5 -C20 芳基之實例包括但不限於苯基、萘基及蒽基。如上文關於芳基所描述，C5 -C20 芳基可為經取代或未經取代的。「C5 -C14 芳基」係在碳環芳族環中具有5至14個碳原子之芳基。C5 -C14 芳基之實例包括但不限於苯基、萘基及蒽基。如上文關於芳基所描述，C5 -C14 芳基可為經取代或未經取代的。The "C 5 -C 20 aryl group" is an aryl group having 5 to 20 carbon atoms in the carbocyclic aromatic ring. Examples of C 5 -C 20 aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. As described above for aryl groups, C 5 -C 20 aryl groups may be substituted or unsubstituted. The "C 5 -C 14 aryl group" is an aryl group having 5 to 14 carbon atoms in the carbocyclic aromatic ring. Examples of C 5 -C 14 aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. As described above for aryl groups, C 5 -C 14 aryl groups may be substituted or unsubstituted.

「伸芳基」係具有兩個共價鍵之芳基，且其可呈鄰位、間位或對位構型，如以下結構所示：

Figure 02_image007
， 其中苯基可未經取代或經至多四個基團取代，該等基團包括但不限於-C1 -C8 烷基、-O-(C1 -C8 烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2 、-C(O)NHR’、-C(O)N(R’)2 -NHC(O)R’、-S(O)2 R’、-S(O)R’、-OH、-鹵素、-N3 、-NH2 、-NH(R’)、-N(R’)2 及-CN；其中各R’獨立地選自H、-C1 -C8 烷基及芳基。"Aryl" is an aryl group with two covalent bonds, and it can be in the ortho, meta or para configuration, as shown in the following structure:
Figure 02_image007
, Wherein the phenyl group may be unsubstituted or substituted with up to four groups, such groups including but not limited to -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -aryl , -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH 2 , -C(O)NHR', -C(O)N(R' ) 2 -NHC(O)R', -S(O) 2 R', -S(O)R', -OH, -halogen, -N 3 , -NH 2 , -NH(R'), -N (R') 2 and -CN; wherein each R'is independently selected from H, -C 1 -C 8 alkyl and aryl.

「芳基烷基」係指鍵接至碳原子，典型地鍵接至末端或sp3 碳原子之氫原子之一經芳基取代的無環烷基。典型的芳基烷基包括但不限於苯甲基、2-苯基乙-1-基、2-苯基乙烯-1-基、萘甲基、2-萘基乙-1-基、2-萘基乙烯-1-基、萘并苯甲基、2 -萘并苯基乙-1-基及類似基團。芳基烷基包含6至20個碳原子，例如 芳基烷基之烷基部分，包括烷烴基、烯基或炔基，為1至6個碳原子，而芳基部分為5至14個碳原子。"Arylalkyl" refers to an acyclic alkyl group bonded to a carbon atom, typically one of the hydrogen atoms bonded to a terminal or sp 3 carbon atom substituted with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethyl-1-yl, 2-phenylvin-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, 2- Naphthylethylene-1-yl, naphthobenzyl, 2-naphthophenylethyl-1-yl and similar groups. The arylalkyl group contains 6 to 20 carbon atoms, for example , the alkyl portion of an arylalkyl group, including alkane, alkenyl or alkynyl, is 1 to 6 carbon atoms, and the aryl portion is 5 to 14 carbons atom.

「雜芳基烷基」係指鍵接至碳原子，典型地鍵接至末端或sp3 碳原子之氫原子之一經雜芳基置換的無環烷基。典型的雜芳基烷基包括但不限於2-苯并咪唑基甲基、2-呋喃基乙基及類似基團。雜芳基烷基包含6至20個碳原子，例如 雜芳基烷基之烷基部分，包括烷烴基、烯基或炔基，為1至6個碳原子，而雜芳基部分為5至14個碳原子且具有1至3個選自N、O、P及S之雜原子。雜芳基烷基之雜芳基部分可為具有3至7個環成員(2至6個碳原子)之單環或具有7至10個環成員(4至9個碳原子及1至3個選自N、O、P及S之雜原子)，例如：雙環[4,5]、[5,5]、[5,6]或[6,6]系統。"Heteroarylalkyl" refers to an acyclic alkyl group bonded to a carbon atom, typically one of the hydrogen atoms bonded to a terminal or sp 3 carbon atom replaced by a heteroaryl group. Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl, 2-furylethyl and similar groups. Heteroarylalkyl contains 6 to 20 carbon atoms, for example , the alkyl portion of heteroarylalkyl, including alkane, alkenyl or alkynyl, has 1 to 6 carbon atoms, and the heteroaryl portion is 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S. The heteroaryl portion of the heteroarylalkyl group can be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms) or having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 Heteroatoms selected from N, O, P and S), for example: bicyclic [4,5], [5,5], [5,6] or [6,6] systems.

「經取代烷基」、「經取代芳基」及「經取代芳基烷基」分別係指一或多個氫原子各自獨立地經取代基置換的烷基、芳基及芳基烷基。典型的取代基包括但不限於-X、-R、-O- 、-OR、-SR、-S- 、-NR2 、-NR3 、=NR、-CX3 、-CN、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2 、=N2 、-N3 、NC(=O)R、-C(=O)R、-C(=O)NR2 、-SO3 -、-SO3 H、-S(=O)2 R、-OS(=O)2 OR、-S(=O)2 NR、-S(=O)R、-OP(=O)(OR)2 、-P(=O)(OR)2 、-PO-3 、-PO3 H2 、-C(=O)R、-C(=O)X、-C(=S)R、-CO2 R、-CO2 -、-C(=S)OR、-C(=O)SR、-C(=S)SR、-C(=O)NR2 、-C(=S)NR2 、-C(=NR)NR2 ，其中各X獨立地為鹵素：F、Cl、Br或I；各R獨立地為-H、C2 -C18 烷基、C6 -C20 芳基、C3 -C14 雜環、保護基或前藥部分。上文所述之伸烷基、伸烯基及伸炔基亦可類似地經取代。"Substituted alkyl", "substituted aryl" and "substituted arylalkyl" respectively refer to alkyl, aryl, and arylalkyl in which one or more hydrogen atoms are each independently replaced by a substituent. Typical substituents include but are not limited to -X, -R, -O - , -OR, -SR, -S - , -NR 2 , -NR 3 , =NR, -CX 3 , -CN, -OCN,- SCN, -N=C=O, -NCS, -NO, -NO 2 , =N 2 , -N 3 , NC(=O)R, -C(=O)R, -C(=O)NR 2 , -SO 3 -, -SO 3 H, -S(=O) 2 R, -OS(=O) 2 OR, -S(=O) 2 NR, -S(=O)R, -OP(= O)(OR) 2 , -P(=O)(OR) 2 , -PO- 3 , -PO 3 H 2 , -C(=O)R, -C(=O)X, -C(=S )R, -CO 2 R, -CO 2 -, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NR 2 , -C(= S)NR 2 , -C(=NR)NR 2 , wherein each X is independently halogen: F, Cl, Br or I; each R is independently -H, C 2 -C 18 alkyl, C 6 -C 20 aryl, C 3 -C 14 heterocycle, protecting group or prodrug moiety. The alkylene, alkenylene and alkynylene groups described above can also be similarly substituted.

「雜芳基」及「雜環」係指一或多個環原子為雜原子，例如 氮、氧及硫之環系統。雜環基團包含3至20個碳原子及1至3個選自N、O、P、及S之雜原子。雜環可為具有3至7個環成員(2至6個碳原子及1至3個選自N、O、P及S之雜原子)之單環或具有7至10個環成員(4至9個碳原子及1至3個選自N、O、P及S之雜原子)之雙環，例如：雙環[4,5]、[5,5]、[5,6]或[6,6]系統。"Heteroaryl" and "heterocyclic ring" refer to a ring system in which one or more ring atoms are heteroatoms, such as nitrogen, oxygen, and sulfur. The heterocyclic group contains 3 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. The heterocyclic ring can be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S) or having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S) bicyclic ring, for example: bicyclic ring [4,5], [5,5], [5,6] or [6,6 ]system.

示例性雜環描述於例如 Paquette，Leo A.，「Principles of Modern Heterocyclic Chemistry」 (W.A. Benjamin，New York，1968)，具體言之，第1、3、4、6、7及9章；「The Chemistry of Heterocyclic Compounds，A series of Monographs」 (John Wiley & Sons，New York，1950至今)，具體言之，第13、14、16、19及28卷；及J. Am. Chem. Soc. (1960) 82:5566中。Exemplary heterocycles are described in, for example, Paquette, Leo A., "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), specifically, Chapters 1, 3, 4, 6, 7 and 9; Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), specifically, Volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960 ) 82:5566.

雜環之實例包括例如但不限於吡啶基、二氫吡啶基、四氫吡啶基(哌啶基)、噻唑基、四氫噻吩基、硫氧化之四氫噻吩基，嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、四唑基、苯并呋喃基、噻萘基、吲哚基、吲哚烯基、喹啉基、異喹啉基、苯并咪唑基、哌啶基、4-哌啶酮基、吡咯啶基、2-吡咯啶酮基、吡咯啶基、四氫呋喃基、雙-四氫呋喃基、四氫哌喃基、雙-四氫哌喃基、四氫喹啉基、四氫異喹啉基、十氫喹啉基、八氫異喹啉基、氮雜環辛四烯基、三嗪基、6H-1,2,5-噻二嗪基、2H,6H-1,5,2-二噻嗪基、噻吩基、噻蒽基、哌喃基、異苯并呋喃基、色烯基、氧雜蒽基、啡噁噻基、2H-吡咯基、異噻唑基、異噁唑基、吡嗪基、噠嗪基、吲哚嗪基、異吲哚基、3H-吲哚基、1H-吲唑基、嘌呤基、4H-喹啉嗪基、酞嗪基、萘啶基、喹喔啉基、喹唑啉基、噌啉基、喋啶基、4aH-咔唑基、咔唑基、β-咔啉基、啡啶基、吖啶基、嘧啶基、啡咯啉基、吩嗪基、吩噻嗪基、呋咱基、啡噁嗪基、異色滿基、色滿基、咪唑啶基、咪唑啉基、吡唑啶基、吡唑啉基、哌嗪基、吲哚啉基、異吲哚啉基、奎寧環基、嗎啉基、噁唑啶基、苯并三唑基、苯并噁唑基、羥吲哚基、苯并噁唑啉基及靛红醯基。Examples of heterocycles include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridinyl (piperidinyl), thiazolyl, tetrahydrothienyl, sulfoxylated tetrahydrothienyl, pyrimidinyl, furyl, thiophene Group, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thionaphthyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidine Group, 4-piperidinone, pyrrolidinyl, 2-pyrrolidinone, pyrrolidinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropiperanyl, bis-tetrahydropiperanyl, tetrahydroquinoline Group, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azacyclooctatetraenyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H -1,5,2-Dithiazinyl, thienyl, thioanthranyl, piperanyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiyl, 2H-pyrrolyl, isothiazole Group, isoxazolyl, pyrazinyl, pyridazinyl, indolazinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolinazinyl, phthalazinyl , Naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridine, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, Phanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenanthrazinyl, isochromanyl, chromanyl, imidazolinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazine Azinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzoxazolyl, oxindolinyl, benzoxazoline Base and isatin base.

作為示例而非限制，碳鍵接之雜環係在吡啶之2、3、4、5或6位；噠嗪之3、4、5或6位；嘧啶之2、4、5或6位；吡嗪之2、3、5或6位；呋喃、四氫呋喃、硫代呋喃、噻吩、吡咯或四氫吡咯之2、3、4或5位；噁唑、咪唑或噻唑之2、4或5位；異噁唑、吡唑或異噻唑之3、4或5位；氮丙啶之2或3位；氮雜環丁烷之2、3或4位；喹啉之2、3、4、5、6、7或8位；或異喹啉的位置1、3、4、5、6、7或8位鍵接。又更典型地，碳鍵接之雜環包括2-吡啶基、3-吡啶基，4-吡啶基、5-吡啶基、6-吡啶基、3-噠嗪基、4-噠嗪基、5-噠嗪基、6-噠嗪基、2-嘧啶基、4-嘧啶基、5-嘧啶基、6-嘧啶基、2-吡嗪基、3-吡嗪基、5-吡嗪基、6-吡嗪基、2-噻唑基、4-噻唑基或5-噻唑基。By way of example and not limitation, the carbon-bonded heterocyclic ring is at the 2, 3, 4, 5 or 6 position of pyridine; the 3, 4, 5 or 6 position of pyridazine; the 2, 4, 5 or 6 position of pyrimidine; 2, 3, 5 or 6 position of pyrazine; 2, 3, 4 or 5 position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole; 2, 4 or 5 position of oxazole, imidazole or thiazole ; 3, 4 or 5 positions of isoxazole, pyrazole or isothiazole; 2 or 3 positions of aziridine; 2, 3 or 4 positions of azetidine; 2, 3, 4, 5 of quinolines , 6, 7 or 8 positions; or bonding at positions 1, 3, 4, 5, 6, 7 or 8 of isoquinoline. More typically, carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5 -Pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6 -Pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

作為示例而非限制，氮鍵接之雜環在氮丙啶、氮雜環丁烷、吡咯、吡咯啶、2-吡咯啉、3-吡咯啉、咪唑、咪唑啶、2-咪唑啉、3-咪唑啉、吡唑、吡唑啉、2-吡唑啉、3-吡唑啉、哌啶、哌嗪、吲哚、吲哚啉、1H-吲唑之1位；異吲哚或異吲哚之2位；嗎啉之4位；及咔唑或β-咔啉之9位鍵接。又更典型地，氮鍵接之雜環包括1-氮丙啶基、1-氮杂环丁二烯基、1-吡咯基、1-咪唑基、1-吡唑基及1-哌啶基。By way of example and not limitation, nitrogen-bonded heterocycles are in aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazoline, 2-imidazoline, 3- Position 1 of imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole; isoindole or isoindole The 2-position; the 4-position of morpholine; and the bonding of the 9-position of carbazole or β-carboline. More typically, the nitrogen-bonded heterocycle includes 1-aziridinyl, 1-azetidinyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl .

「C3 -C8 雜環」係指芳族或非芳族C3 -C8 碳環，其中一至四個環碳原子獨立地經選自由O、S及N組成之群的雜原子置換。C3 -C8 雜環之代表性實例包括但不限於苯并呋喃基、苯并噻吩、吲哚基、苯并吡唑基、香豆基、異喹啉基、吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、吡唑基、三唑基、喹啉基、嘧啶基、吡啶基、吡啶酮基、吡嗪基、噠嗪基、異噻唑基、異噁唑基及四唑基。C3 -C8 雜環可未經取代或經至多七個基團取代，該等基團包括但不限於-C1 -C8 烷基、-O-(C1 -C8 烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2 、-C(O)NHR’、-C(O)N(R’)2 、-NHC(O)R’、-S(O)2 R’、-S(O)R’、-OH、-鹵素、-N3 、-NH2 、-NH(R’)、-N(R’)2 及-CN；其中各R’獨立地選自H、-C1 -C8 烷基及芳基。"C 3 -C 8 heterocyclic ring" refers to an aromatic or non-aromatic C 3 -C 8 carbocyclic ring in which one to four ring carbon atoms are independently replaced by heteroatoms selected from the group consisting of O, S, and N. Representative examples of C 3 -C 8 heterocycles include, but are not limited to, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, coumarin, isoquinolinyl, pyrrolyl, thienyl, furan Group, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl and tetrazolyl . The C 3 -C 8 heterocycle may be unsubstituted or substituted with up to seven groups, such groups including but not limited to -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -Aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH 2 , -C(O)NHR', -C(O)N (R') 2 , -NHC(O)R', -S(O) 2 R', -S(O)R', -OH, -halogen, -N 3 , -NH 2 , -NH(R' ), -N(R') 2 and -CN; wherein each R'is independently selected from H, -C 1 -C 8 alkyl and aryl.

「C3 -C8 雜環」係指雜環基之一個氫原子經鍵結置換的以上所定義之C3 -C8 雜環基。C3 -C8 雜環-可未經取代或經至多六個基團取代，該等基團包括但不限於-C1 -C8 烷基、-O-(C1 -C8 烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2 、-C(O)NHR’、-C(O)N(R’)2 、-NHC(O)R’、-S(O)2 R’、-S(O)R’、-OH、-鹵素、-N3 、-NH2 、-NH(R’)、-N(R’)2 及-CN；其中各R’獨立地選自H、-C1 -C8 烷基及芳基。"C 3 -C 8 heterocyclic ring" refers to the above-defined C 3 -C 8 heterocyclic group in which one hydrogen atom of the heterocyclic group is replaced by a bond. C 3 -C 8 heterocycle-may be unsubstituted or substituted with up to six groups, these groups include but are not limited to -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl) , -Aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH 2 , -C(O)NHR', -C(O) N(R') 2 , -NHC(O)R', -S(O) 2 R', -S(O)R', -OH, -halogen, -N 3 , -NH 2 , -NH(R '), -N(R') 2 and -CN; wherein each R'is independently selected from H, -C 1 -C 8 alkyl and aryl.

「C3 -C20 雜環」係指 芳族或非芳族C3 -C8 碳環，其中一至四個環碳原子獨立地經選自由O、S及N組成之群之雜原子置換。C3 -C20 雜環可未經取代或經至多七個基團取代，該等基團包括但不限於-C1 -C8 烷基、-O-(C1 -C8 烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2 、-C(O)NHR’、-C(O)N(R’)2 、-NHC(O)R’、-S(O)2 R’、-S(O)R’、-OH、-鹵素、-N3 、-NH2 、-NH(R’)、-N(R’)2 及-CN；其中各R’獨立地選自H、-C1 -C8 烷基及芳基。"C 3 -C 20 heterocycle" refers to an aromatic or non-aromatic C 3 -C 8 carbocyclic ring in which one to four ring carbon atoms are independently replaced by heteroatoms selected from the group consisting of O, S and N. The C 3 -C 20 heterocyclic ring may be unsubstituted or substituted with up to seven groups, including but not limited to -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -Aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH 2 , -C(O)NHR', -C(O)N (R') 2 , -NHC(O)R', -S(O) 2 R', -S(O)R', -OH, -halogen, -N 3 , -NH 2 , -NH(R' ), -N(R') 2 and -CN; wherein each R'is independently selected from H, -C 1 -C 8 alkyl and aryl.

「C3 -C20 雜環-」係指 雜環基團之一個氫原子經鍵結置換的以上所定義之C3 -C20 雜環基。The "C 3 -C 20 heterocyclic ring-" refers to the C 3 -C 20 heterocyclic group defined above in which one hydrogen atom of the heterocyclic group is replaced by a bond.

「碳環」係指呈單環形式具有3至7個碳原子或呈雙環形式具有7至12個碳原子的飽和或不飽和環。單環碳環具有3至6個環原子，更典型地具有5或6個環原子。雙環碳環具有7至12個環原子，例如 排列成雙環[4,5]、[5,5]、[5,6]或[6,6]系統，或具有9或10個環原子，排列成雙環[5,6]或[6,6]系統。單環碳環之實例包括環丙基、環丁基、環戊基、1-環戊-1-烯基、1-環戊-2-烯基、1-環戊-3-烯基、環己基、1-環己-1-烯基、1-環己-2 -烯基、1-環己-3-烯基、環庚基及環辛基。"Carbocyclic ring" refers to a saturated or unsaturated ring having 3 to 7 carbon atoms in the form of a monocyclic ring or 7 to 12 carbon atoms in the form of a bicyclic ring. Monocyclic carbocyclic rings have 3 to 6 ring atoms, more typically 5 or 6 ring atoms. The bicyclic carbocyclic ring has 7 to 12 ring atoms, for example arranged in a bicyclic [4,5], [5,5], [5,6] or [6,6] system, or has 9 or 10 ring atoms, arranged Into a double ring [5,6] or [6,6] system. Examples of monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, ring Hexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cycloheptyl and cyclooctyl.

「C3 -C8 碳環」係3、4、5、6、7或8員飽和或不飽和非芳族碳環。代表性C3 -C8 碳環包括但不限於-環丙基、-環丁基、-環戊基、-環戊二烯基、-環己基，-環己烯基，-1,3-環己二烯基、-1,4-環己二烯基、-環庚基、-1,3-環庚二烯基、-1,3,5-環庚三烯基、-環辛基及-環辛二烯基。C3 -C8 碳環基團可未經取代或經一或多個基團取代，該一或多個基團包括但不限於-C1 -C8 烷基、-O-(C1 -C8 烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2 、-C(O)NHR’、-C(O)N(R’)2 、-NHC(O)R’、-S(O)2 R’、-S(O)R’、-OH、-鹵素、-N3 、-NH2 、-NH(R’)、-N(R’)2 及-CN；其子各R’獨立地選自H、-C1 -C8 烷基及芳基。"C 3 -C 8 carbocyclic ring" is a 3, 4, 5, 6, 7 or 8 member saturated or unsaturated non-aromatic carbocyclic ring. Representative C 3 -C 8 carbocyclic rings include but are not limited to -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1,3- Cyclohexadienyl, -1,4-cyclohexadienyl, -cycloheptyl, -1,3-cycloheptadienyl, -1,3,5-cycloheptatrienyl, -cyclooctyl And-cyclooctadienyl. The C 3 -C 8 carbocyclic group may be unsubstituted or substituted with one or more groups including but not limited to -C 1 -C 8 alkyl, -O-(C 1- C 8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH 2 , -C(O)NHR', -C(O)N(R') 2 , -NHC(O)R', -S(O) 2 R', -S(O)R', -OH, -halogen, -N 3 , -NH 2 , -NH(R'), -N(R') 2 and -CN; each R'of its children is independently selected from H, -C 1 -C 8 alkyl and aryl.

「C3 -C8 碳環-」係指碳環基團之一個氫原子經鍵結置換的上文所定義之C3 -C8 碳環基團。"C 3 -C 8 carbocyclic-" refers to a C 3 -C 8 carbocyclic group defined above in which one hydrogen atom of a carbocyclic group is replaced by a bond.

「連接子」係指將抗體共價連接至藥物部分的包含共價鍵或原子鏈之化學部分。在各種實施例中，連接子包括二價基團，諸如烷基二基、芳基二基、雜芳基二基，及諸如以下部分：-(CR2 )n O(CR2 )n -、烷氧基(例如 聚伸乙基氧基、PEG、聚亞甲氧基)及烷基胺基(例如 聚伸乙基胺基，JeffamineTM )之重複單元；以及二酸酯及醯胺，包括琥珀酸酯、琥珀醯胺、二甘醇酸酯、丙二酸酯及己醯胺。在各種實施例中，連接子可包含一或多個胺基酸殘基，諸如纈胺酸、苯丙胺酸、離胺酸及高離胺酸。"Linker" refers to a chemical moiety containing a covalent bond or chain of atoms that covalently connects an antibody to a drug moiety. In various embodiments, the linker includes divalent groups, such as alkyldiyl, aryldiyl, heteroaryldiyl, and moieties such as: -(CR 2 ) n O(CR 2 ) n -, Repeating units of alkoxy ( for example, polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino ( for example , Jeffamine TM ); and diacid esters and amides, including Succinate, succinamide, diglycolate, malonate and hexanamide. In various embodiments, the linker may include one or more amino acid residues, such as valine, phenylalanine, lysine, and homolysine.

術語「對掌性」係指分子具有鏡像搭配物之不可重疊性質，而術語「非對掌性」係指分子可重疊於其鏡像搭配物上。The term "opposite" refers to the non-superimposability of the molecule with the mirror image partner, and the term "non-opposite" means that the molecule can be superimposed on its mirror partner.

術語「立體異構體」係指具有相同化學組成，但原子或原子團於空間中之排列不同之化合物。The term "stereoisomers" refers to compounds that have the same chemical composition but differ in the arrangement of atoms or groups of atoms in space.

「非鏡像異構體」係指具有兩個或更多個對掌性中心且分子不互為鏡像之立體異構體。非鏡像異構體具有不同物理性質，例如 熔點、沸點、光譜性質及反應性。非鏡像異構體之混合物可依據諸如電泳及層析之類高解析度分析程序分離。A "diastereomer" refers to a stereoisomer with two or more opposing centers and the molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated according to high-resolution analysis procedures such as electrophoresis and chromatography.

「對映異構體」係指互為不可重疊之鏡像的化合物之兩種立體異構體。"Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.

本文使用之立體化學定義及慣例一般遵循S. P. Parker，編，McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company，New York；以及Eliel，E.及Wilen，S.，Stereochemistry of Organic Compounds (1994) John Wiley & Sons，Inc.，New York。許多有機化合物以光學活性形式存在，亦即 ，其具有使平面偏振光之平面旋轉的能力。在描述光學活性化合物時，前綴D及L、或R 及S 用於表示分子關於其對掌性中心之絕對構型。前綴d及l或(+)及(-)係用於指定化合物使平面偏振光旋轉之標志，其中(-)或1意謂化合物係左旋的。帶有前綴(+)或d之化合物係右旋的。對於給定化學結構，此等立體異構體相同，不過其互為鏡像。特定立體異構體亦可稱為對映異構體，且此類異構體之混合物常常稱為對映異構體混合物。對映異構體之50:50混合物稱為外消旋混合物或外消旋物，其可在化學反應或製程中不存在立體選擇或立體特異性時存在。術語「外消旋混合物」及「外消旋物」係指兩種對映異構物質之等莫耳濃度混合物，不具有光學活性。The definitions and conventions of stereochemistry used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds ( 1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, that is , they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L, or R and S are used to indicate the absolute configuration of the molecule with respect to its opposing center. The prefixes d and 1 or (+) and (-) are used to designate the signs that the compound rotates plane-polarized light, where (-) or 1 means that the compound is left-handed. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are the same, but they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can exist when there is no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to equal molar concentration mixtures of two enantiomers, which do not have optical activity.

「離去基團」係指可經另一官能基取代之官能基。某些離去基團係此項技術中熟知的，且實例包括但不限於鹵基(例如 氯基、溴基或碘基)、甲烷磺醯基(甲磺醯基)、對甲苯磺醯基(甲苯磺醯基)、三氟甲基磺醯基(三氟甲磺酸酯基)及三氟甲基磺酸酯基。The "leaving group" refers to a functional group that can be substituted with another functional group. Certain leaving groups are well known in the art, and examples include, but are not limited to, halo ( e.g., chloro, bromo or iodo), methanesulfonyl (methylsulfonyl), p-toluenesulfonyl (Toluenesulfonyl), trifluoromethanesulfonyl (trifluoromethanesulfonate) and trifluoromethanesulfonate.

術語「保護基」係指通常用於在化合物上之其他官能基反應時阻擋或保護特定官能基的取代基。舉例而言，「胺基保護基」係連接至胺基且阻擋或保護化合物中之胺基官能基的取代基。適合胺基保護基包括但不限於乙醯基、三氟乙醯基、第三丁氧基羰基(BOC)、苯甲基氧基羰基(CBZ)及9-茀基亞甲基氧基羰基(Fmoc)。有關保護基及其使用之整體描述，參見 T. W. Greene，Protective Groups in Organic Synthesis，John Wiley & Sons，New York，1991或後期版本。III. 方法 The term "protecting group" refers to a substituent that is generally used to block or protect a specific functional group when other functional groups on a compound react. For example, the "amino protecting group" is a substituent that is connected to the amino group and blocks or protects the amino functional group in the compound. Suitable amine protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tertiary butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-tinylmethyleneoxycarbonyl ( Fmoc). For an overall description of protecting groups and their use, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 or later editions. III. Method

本文提供治療有需要之個體(例如 人類個體)之B細胞增殖性疾病(諸如彌漫性大B細胞淋巴瘤(DLBCL)，例如 復發性/難治性DLBCL)的方法，其包括向該個體投與有效量之(a)包含結合CD79b之抗體的免疫偶聯物，該CD79b連接至細胞毒性劑；(b)抗CD20抗體；及(c)一或多種化學治療劑。Provided herein is a method for treating a B-cell proliferative disease (such as diffuse large B-cell lymphoma (DLBCL), such as relapsed/refractory DLBCL) in an individual in need (such as a human individual), which includes administering an effective The quantity (a) comprises an immunoconjugate that binds to CD79b-binding antibody, the CD79b being linked to a cytotoxic agent; (b) an anti-CD20 antibody; and (c) one or more chemotherapeutic agents.

在一些實施例中，抗CD79b免疫偶聯物係帕妥珠單抗維多汀-piiq。在一些實施例中，抗CD20抗體係利妥昔單抗。在一些實施例中，該一或多種化學治療劑包含吉西他濱。在一些實施例中，該一或多種化學治療劑包含奧沙利鉑。在一些實施例中，該一或多種化學治療劑係吉西他濱及奧沙利鉑。In some embodiments, the anti-CD79b immunoconjugate is Pertuzumab Vidotin-piiq. In some embodiments, the anti-CD20 antibody system is rituximab. In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine. In some embodiments, the one or more chemotherapeutic agents comprise oxaliplatin. In some embodiments, the one or more chemotherapeutic agents are gemcitabine and oxaliplatin.

術語「共投與(co-administration/co-administering)」係指將抗CD79b免疫偶聯物、抗CD20抗體及該一或多種化學治療劑以兩種(或更多種)獨立調配物形式(或以包含抗CD79b免疫偶聯物、抗CD20抗體及該一或多種化學治療劑之單一調配物形式)投與。在使用獨立調配物之情況下，共投與可為同時或以任何次序依序進行，其中較佳地存在所有活性劑同時發揮其生物活性之時間段。在一些實施例中，抗CD79b免疫偶聯物、抗CD20抗體及該一或多種化學治療劑係同時或依序共投與。在一些實施例中，當依序共投與所有治療劑時，劑量係在同一天分兩次或更多次獨立投藥進行投與，或一或多種藥劑係在第1天(例如 在21天週期之第1天)投與，而其他藥劑在約第2天(例如 在21天週期之第2天)共投與。在一些實施例中，術語「依序地」係指在給與第一組分之後7天內，例如 在給與第一組分之後4天、3天、2天或1天內；且術語「同時地」係指在同一時間。在一些實施例中，術語「依序地」係指在給與第一組分之後低於1天內，例如 在給與第一組分之後低於24小時、低於20小時、低於15小時、低於10小時、低於12小時、低於8小時、低於6小時、低於3小時、低於2小時或低於1小時中之任一時間內。在一些實施例中，抗CD79b免疫偶聯物和抗CD20抗體係在每個21天週期之約第1天依序地共投與，且該一或多種化學治療劑係在每個21天週期之約第2天依序地共投與。The term "co-administration/co-administering" refers to the anti-CD79b immunoconjugate, anti-CD20 antibody and the one or more chemotherapeutic agents in the form of two (or more) independent formulations ( Or it can be administered in the form of a single formulation comprising an anti-CD79b immunoconjugate, an anti-CD20 antibody and the one or more chemotherapeutic agents. In the case of using separate formulations, the co-administration can be performed simultaneously or sequentially in any order, wherein there is preferably a time period during which all active agents simultaneously exert their biological activities. In some embodiments, the anti-CD79b immunoconjugate, anti-CD20 antibody, and the one or more chemotherapeutic agents are co-administered simultaneously or sequentially. In some embodiments, when all the therapeutic agents are co-administered sequentially, the dosage is administered in two or more separate administrations on the same day, or one or more agents are administered on day 1 ( e.g., on day 21). The first day of the cycle) is administered, while the other drugs are co-administered about the second day (e.g., on the second day of the 21-day cycle). In some embodiments, the term "sequentially" refers to within 7 days after administration of the first component, for example within 4 days, 3 days, 2 days, or 1 day after administration of the first component; and the term "Simultaneously" means at the same time. In some embodiments, the term "sequentially" refers to less than 1 day after the first component is administered, for example less than 24 hours, less than 20 hours, less than 15 hours after the first component is administered. Hours, less than 10 hours, less than 12 hours, less than 8 hours, less than 6 hours, less than 3 hours, less than 2 hours, or less than 1 hour. In some embodiments, the anti-CD79b immunoconjugate and the anti-CD20 antibody system are co-administered sequentially on about day 1 of each 21-day cycle, and the one or more chemotherapeutic agents are administered in each 21-day cycle. On the second day of the contract, they will be co-invested sequentially.

本文所提供的用於本文所描述之任何治療方法的抗CD79b免疫偶聯物、抗CD20抗體及該一或多種化學治療劑將以與良好醫學實踐一致之方式調配、定劑量及投與。在此情況下考慮之因素包括所治療之特定病症、所治療之特定哺乳動物、個別患者之臨床病況、病症起因、藥劑之遞送部位、投與方法、投與時程及醫學從業者已知之其他因素。免疫偶聯物未必但視情況與一或多種當前用於預防或治療所論及疾病之藥劑一起調配。The anti-CD79b immunoconjugates, anti-CD20 antibodies, and the one or more chemotherapeutic agents provided herein for any of the treatment methods described herein will be formulated, dosed, and administered in a manner consistent with good medical practice. In this case, the factors to be considered include the specific disease to be treated, the specific mammal to be treated, the clinical condition of individual patients, the cause of the disease, the location of the drug delivery, the method of administration, the time course of administration, and others known to the medical practitioner factor. The immunoconjugate may not necessarily be formulated with one or more agents currently used to prevent or treat the disease in question, but as appropriate.

抗CD79b免疫偶聯物、抗CD20抗體及該一或多種化學治療劑的共投與量以及共投與之時程將取決於所治療患者之類型(物種、性別、年齡、體重等)及病況以及所治療疾病或病況之嚴重程度。抗CD79b免疫偶聯物、抗CD20抗體及該一或多種化學治療劑適合一次性或經一系列治療，例如 在同一天或之後一天共投與患者。The co-administration amount and time course of the anti-CD79b immunoconjugate, anti-CD20 antibody and the one or more chemotherapeutic agents will depend on the type (species, sex, age, weight, etc.) and condition of the patient being treated And the severity of the disease or condition being treated. The anti-CD79b immunoconjugate, anti-CD20 antibody, and the one or more chemotherapeutic agents are suitable for one-time or a series of treatments, for example , co-administered to the patient on the same day or a day after.

在一些實施例中，抗CD79b免疫偶聯物(諸如帕妥珠單抗維多汀-piiq)之劑量係在約1.4-5 mg/kg、1.4-4 mg/kg、1.4-3.2 mg/kg、1.4-2.4 mg/kg或1.4-1.8 mg/kg中任一種之間。在該等方法中任一種之一些實施例中，抗CD79b免疫偶聯物之劑量係約以下任一種：1.4 mg/kg、1.5 mg/kg、1.6 mg/kg、1.7 mg/kg、1.8 mg/kg、1.9 mg/kg、2.0 mg/kg、2.2 mg/kg、2.4 mg/kg、2.6 mg/kg、2.8 mg/kg、3.0 mg/kg、3.2 mg/kg、3.4 mg/kg、3.6 mg/kg、3.8 mg/kg、4.0 mg/kg、4.2 mg/kg、4.4 mg/kg、4.6 mg/kg及/或4.8 mg/kg。在一些實施例中，抗CD79b免疫偶聯物之劑量係約1.4 mg/kg。在一些實施例中，抗CD79b免疫偶聯物之劑量係約1.8 mg/kg。在一些實施例中，抗CD79b免疫偶聯物之劑量係約2.4 mg/kg。在一些實施例中，抗CD79b免疫偶聯物之劑量係約3.2 mg/kg。在一些實施例中，抗CD79b免疫偶聯物之劑量係約3.6 mg/kg。在該等方法中任一種之一些實施例中，抗CD79b免疫偶聯物係q3wk投與。在該等方法中任一種之一些實施例中，抗CD79b免疫偶聯物在每個21天週期中投與一次。在該等方法中任一種之一些實施例中，抗CD79b免疫偶聯物係在每個21天週期之約第1天投與。在一些實施例中，抗CD79b免疫偶聯物係經由靜脈內輸注投與。在一些實施例中，經由輸注投與之劑量在每劑約1 mg至約2,000 mg範圍內，一般每三週一次投與(例如 在每個21天週期之第1天)，持續總共1、2、3，4、5、6、7、8、9、10、11、12、13、14、15、16次或更多次劑量。在一些實施例中，經由輸注投與之劑量在每劑約1 mg至約2,000 mg範圍內，一般在每個21天週期之約第1天投與，持續至多八個21天週期。或者，劑量範圍係約1 mg至約2,000 mg、約1 mg至約1,800 mg、約400 mg至約1200 mg、約600 mg至約1000 mg、約10 mg至約500 mg、約10 mg至約300 mg、約10 mg至約200 mg及約1 mg至約200 mg。在一些實施例中，經由輸注投與之劑量在每劑約1 µg/m2 至約10,000 µg/m2 範圍內，一般在每個21天週期之約第1天投與，持續總共1、2、3，4、5、6、7、8、9、10、11、12、13、14、15、16次或更多次劑量。在一些實施例中，經由輸注投與之劑量在每劑約1 µg/m2 至約10,000 µg/m2 範圍內，一般每三週一次劑量(例如 在每個21天週期之第1天)投與，持續至多八個21天週期。或者，劑量範圍係約1 µg/m2 至約1000 µg/m2 、約1 µg/m2 至約800 µg/m2 、約1 µg/m2 至約600 µg/m2 、約1 µg/m2 至約400 µg/m2 、10 µg/m2 至約500 µg/m2 、約10 µg/m2 至約300 µg/m2 、約10 µg/m2 至約200 µg/m2 及約1 µg/m2 至約200 µg/m2 。劑量可每週一次、每週多次但每天少於一次、每月多次但每天少於一次、每月多次但每周少於一次、每月一次、每三週一次、每21天一次、每個21天週期一次、在每個21天週期之第1天或間歇性投與，以減輕或緩解疾病之症狀。投與可按任何所揭示之時間間隔繼續進行，持續至多八個21天週期，或直至所治療的腫瘤或B細胞增殖性病症(例如 DLBCL)之症狀緩解。投與可在達成症狀緩解或減輕後繼續進行，其中此類緩解或減輕因此持續給藥而延長。In some embodiments, the dose of anti-CD79b immunoconjugate (such as Pertuzumab Vidotin-piiq) is about 1.4-5 mg/kg, 1.4-4 mg/kg, 1.4-3.2 mg/kg , 1.4-2.4 mg/kg or 1.4-1.8 mg/kg. In some embodiments of any of these methods, the dose of the anti-CD79b immunoconjugate is about any of the following: 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg kg, 1.9 mg/kg, 2.0 mg/kg, 2.2 mg/kg, 2.4 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.2 mg/kg, 3.4 mg/kg, 3.6 mg/ kg, 3.8 mg/kg, 4.0 mg/kg, 4.2 mg/kg, 4.4 mg/kg, 4.6 mg/kg and/or 4.8 mg/kg. In some embodiments, the dose of anti-CD79b immunoconjugate is about 1.4 mg/kg. In some embodiments, the dose of anti-CD79b immunoconjugate is about 1.8 mg/kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 2.4 mg/kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 3.2 mg/kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 3.6 mg/kg. In some embodiments of any of these methods, the anti-CD79b immunoconjugate is administered by q3wk. In some embodiments of any of these methods, the anti-CD79b immunoconjugate is administered once in every 21-day cycle. In some embodiments of any of these methods, the anti-CD79b immunoconjugate is administered on about day 1 of each 21-day cycle. In some embodiments, the anti-CD79b immunoconjugate is administered via intravenous infusion. In some embodiments, the dose is administered by infusion in the range of about 1 mg to about 2,000 mg per dose, generally once every three weeks ( for example, on day 1 of each 21-day cycle) for a total of 1. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or more doses. In some embodiments, the dosage is administered via infusion in the range of about 1 mg to about 2,000 mg per dose, generally on about day 1 of each 21-day cycle, for up to eight 21-day cycles. Alternatively, the dosage range is about 1 mg to about 2,000 mg, about 1 mg to about 1,800 mg, about 400 mg to about 1200 mg, about 600 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, and about 1 mg to about 200 mg. In some embodiments, the dose is administered via infusion in the range of about 1 µg/m 2 to about 10,000 µg/m 2 per dose, generally on about day 1 of each 21-day cycle, for a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or more doses. In some embodiments, the dose is administered via infusion in the range of about 1 µg/m 2 to about 10,000 µg/m 2 per dose, generally once every three weeks ( for example, on day 1 of each 21-day cycle) The administration lasts up to eight 21-day cycles. Alternatively, the dosage range is about 1 µg/m 2 to about 1000 µg/m 2 , about 1 µg/m 2 to about 800 µg/m 2 , about 1 µg/m 2 to about 600 µg/m 2 , about 1 µg /m 2 to about 400 µg/m 2 , 10 µg/m 2 to about 500 µg/m 2 , about 10 µg/m 2 to about 300 µg/m 2 , about 10 µg/m 2 to about 200 µg/m 2 and about 1 µg/m 2 to about 200 µg/m 2 . The dosage can be once a week, multiple times a week but less than once a day, multiple times a month but less than once a day, multiple times a month but less than once a week, once a month, once every three weeks, once every 21 days , Once every 21-day cycle, on the first day of each 21-day cycle or intermittently administered to reduce or alleviate the symptoms of the disease. Administration can continue at any disclosed time interval, for up to eight 21-day cycles, or until the symptoms of the tumor or B cell proliferative disorder (such as DLBCL) being treated are alleviated. Administration can be continued after symptom relief or relief is achieved, where such relief or relief is prolonged due to continued administration.

在一些實施例中，抗CD20抗體(例如 利妥昔單抗)之劑量在約300-1600 mg/m2 及/或300-2000 mg之間。在一些實施例中，抗CD20抗體之劑量係約以下任一種：300 mg/m2 、375 mg/m2 、600 mg/m2 、1000 mg/m2 或1250 mg/m2 及/或300 mg、1000 mg或2000 mg。在一些實施例中，抗CD20抗體係利妥昔單抗，且投與劑量係375 mg/m2 。在一些實施例中，抗CD20抗體係q3w (亦即 ，每3週)投與。在一些實施例中，抗CD20抗體在每個21天週期投與一次(例如 在每個21天週期之第1天)。在一些實施例中，抗CD20抗體係利妥昔單抗。在一些實施例中，利妥昔單抗之劑量可為在每個21天週期之第1天375 mg/m2 。在一些實施例中，利妥昔單抗之劑量可為在每個21天週期之第1天375 mg/m2 ，持續至多八個21天週期。在一些實施例中，利妥昔單抗之劑量可為在每個21天週期之第1天375 mg/m2 ，持續八個21天週期。In some embodiments, the dose of anti-CD20 antibody ( e.g. , rituximab) is between about 300-1600 mg/m 2 and/or 300-2000 mg. In some embodiments, the dosage of the anti-CD20 antibody is about any of the following: 300 mg/m 2 , 375 mg/m 2 , 600 mg/m 2 , 1000 mg/m 2 or 1250 mg/m 2 and/or 300 mg, 1000 mg or 2000 mg. In some embodiments, the anti-CD20 antibody system is rituximab, and the dosage is 375 mg/m 2 . In some embodiments, the anti-CD20 antibody system q3w ( ie , every 3 weeks) is administered. In some embodiments, the anti-CD20 antibody is administered once every 21-day cycle (e.g., on day 1 of every 21-day cycle). In some embodiments, the anti-CD20 antibody system is rituximab. In some embodiments, the dose of rituximab may be 375 mg/m 2 on the 1st day of each 21-day cycle. In some embodiments, the dose of rituximab may be 375 mg/m 2 on the first day of each 21-day cycle for up to eight 21-day cycles. In some embodiments, the dose of rituximab may be 375 mg/m 2 on the first day of each 21-day cycle for eight 21-day cycles.

在一些實施例中，抗CD20抗體(例如 利妥昔單抗)可每週一次、每月多次但每週少於一次、每月一次、每三週一次、每21天一次、每個21天週期一次、在每個21天週期之第1天或間歇性投與，以減輕或緩解疾病之症狀。投與可按任何所揭示之時間間隔繼續進行，持續至多八個21天週期，或直至所治療的腫瘤或B細胞增殖性病症(例如 DLBCL)之症狀緩解。投與可在達成症狀緩解或減輕後繼續進行，其中此類緩解或減輕因此持續給藥而延長。In some embodiments, the anti-CD20 antibody ( e.g. , rituximab) can be used once a week, multiple times a month but less than once a week, once a month, once every three weeks, once every 21 days, every 21 days. It is administered once a day, on the first day of each 21-day cycle or intermittently to reduce or relieve the symptoms of the disease. Administration can continue at any disclosed time interval, for up to eight 21-day cycles, or until the symptoms of the tumor or B cell proliferative disorder (such as DLBCL) being treated are alleviated. Administration can be continued after symptom relief or relief is achieved, where such relief or relief is prolonged due to continued administration.

在一些實施例中，該一或多種化學治療劑之劑量在約50 mg/m2 至約2000 mg/m2 之間。在一些實施例中，該一或多種化學治療劑之劑量在約50 mg/m2 至約100 mg/m2 之間、在約100 mg/m2 至約200 mg/m2 之間、在約200 mg/m2 至約300 mg/m2 之間、在約300 mg/m2 至約400 mg/m2 之間、在約400 mg/m2 至約500 mg/m2 之間、在約500 mg/m2 至約600 mg/m2 之間、在約600 mg/m2 至約700 mg/m2 之間、在約700 mg/m2 至約800 mg/m2 之間、在約800 mg/m2 至約900 mg/m2 之間、在約900 mg/m2 至約1000 mg/m2 之間、在約1000 mg/m2 至約1100 mg/m2 之間、在約1100 mg/m2 至約1200 mg/m2 之間、在約1200 mg/m2 至約1300 mg/m2 之間、在約1300 mg/m2 至約1400 mg/m2 之間、在約1400 mg/m2 至約1500 mg/m2 、或在約1500 mg/m2 至約2000 mg/m2 之間。In some embodiments, the dosage of the one or more chemotherapeutic agents is between about 50 mg/m 2 to about 2000 mg/m 2 . In some embodiments, the dose of the one or more chemotherapeutic agents is between about 50 mg/m 2 and about 100 mg/m 2 , between about 100 mg/m 2 and about 200 mg/m 2 , Between about 200 mg/m 2 and about 300 mg/m 2 , between about 300 mg/m 2 and about 400 mg/m 2 , between about 400 mg/m 2 and about 500 mg/m 2 , Between about 500 mg/m 2 and about 600 mg/m 2 , between about 600 mg/m 2 and about 700 mg/m 2 , between about 700 mg/m 2 and about 800 mg/m 2 , Between about 800 mg/m 2 and about 900 mg/m 2 , between about 900 mg/m 2 and about 1000 mg/m 2 , between about 1000 mg/m 2 and about 1100 mg/m 2 Between about 1100 mg/m 2 and about 1200 mg/m 2 , between about 1200 mg/m 2 and about 1300 mg/m 2 , between about 1300 mg/m 2 and about 1400 mg/m 2 Between about 1400 mg/m 2 to about 1500 mg/m 2 , or between about 1500 mg/m 2 to about 2000 mg/m 2 .

在一些實施例中，該一或多種化學治療劑之劑量包含約500 mg/m2 至約1500 mg/m2 (例如 約500 mg/m2 至約600 mg/m2 、約600 mg/m2 至約700 mg/m2 、約700 mg/m2 至約800 mg/m2 、約800 mg/m2 至約 900 mg/m2 、約900 mg/m2 至約1000 mg/m2 、約1000 mg/m2 至約1100 mg/m2 、約1100 mg/m2 至約1200 mg/m2 、約1200 mg/m2 至約1300 mg/m2 、約1300 mg/m2 至約1400 mg/m2 、約1400 mg/m2 至約1500 mg/m2 )之吉西他濱劑量。在一些實施例中，該一或多種化學治療劑之劑量包含約1000 mg/m2 之吉西他濱劑量。在一些實施例中，吉西他濱之劑量係q3w投與或在每個21天週期投與約一次(例如 在每個21天週期之第2天)。在一些實施例中，吉西他濱之劑量係每個21天週期投與一次(例如 在每個21天週期之第2天)，持續至多八個21天週期。在一些實施例中，吉西他濱之劑量係在每個21天週期投與一次(例如 在每個21天週期之第2天)，持續八個21天週期。在一些實施例中，該一或多種化學治療劑之劑量包含在約50 mg/m2 至約200 mg/m2 之間(例如 50 mg/m2 至約100 mg/m2 、或約100 mg/m2 至約200 mg/m2 )之奧沙利鉑劑量。在一些實施例中，該一或多種化學治療劑之劑量包含約100 mg/m2 之奧沙利鉑劑量。在一些實施例中，奧沙利鉑之劑量係q3w投與或在每個21天週期投與約一次(例如 在每個21天週期之第2天)。在一些實施例中，奧沙利鉑之劑量係在每個21天週期投與一次(例如 在每個21天週期之第2天)，持續至多八個21天週期。在一些實施例中，吉西他濱之劑量係在每個21天週期投與一次(例如 在每個21天週期之第2天)，持續八個21天週期。在一些實施例中，該一或多種化學治療劑包含吉西他濱及奧沙利鉑，且吉西他濱及奧沙利鉑在每個21天週期之約第2天靜脈內投與。在一些實施例中，該一或多種化學治療劑包含吉西他濱及奧沙利鉑，且吉西他濱及奧沙利鉑在每個21天週期之約第2天靜脈內投與，持續至多八個週期。In some embodiments, the dosage of the one or more chemotherapeutic agents comprises about 500 mg/m 2 to about 1500 mg/m 2 ( e.g., about 500 mg/m 2 to about 600 mg/m 2 , about 600 mg/m 2 2 to about 700 mg/m 2 , about 700 mg/m 2 to about 800 mg/m 2 , about 800 mg/m 2 to about 900 mg/m 2 , about 900 mg/m 2 to about 1000 mg/m 2 , About 1000 mg/m 2 to about 1100 mg/m 2 , about 1100 mg/m 2 to about 1200 mg/m 2 , about 1200 mg/m 2 to about 1300 mg/m 2 , about 1300 mg/m 2 to About 1400 mg/m 2 , about 1400 mg/m 2 to about 1500 mg/m 2 ) of gemcitabine dose. In some embodiments, the dose of the one or more chemotherapeutic agents comprises a dose of gemcitabine of about 1000 mg/m 2. In some embodiments, the dose of gemcitabine is administered q3w or approximately once in every 21-day cycle (e.g., on day 2 of every 21-day cycle). In some embodiments, the dose of gemcitabine is administered once every 21-day cycle (e.g., on the second day of each 21-day cycle) for up to eight 21-day cycles. In some embodiments, the dose of gemcitabine is administered once every 21-day cycle (e.g., on the second day of each 21-day cycle) for eight 21-day cycles. In some embodiments, the dosage of the one or more chemotherapeutic agents is comprised between about 50 mg/m 2 to about 200 mg/m 2 ( for example, 50 mg/m 2 to about 100 mg/m 2, or about 100 mg/m 2 ). mg/m 2 to about 200 mg/m 2 ) of oxaliplatin dose. In some embodiments, the dosage of the one or more chemotherapeutic agents comprises an oxaliplatin dosage of about 100 mg/m 2. In some embodiments, the dose of oxaliplatin is administered q3w or approximately once in every 21-day cycle (e.g., on day 2 of every 21-day cycle). In some embodiments, the dose of oxaliplatin is administered once every 21-day cycle (e.g., on the second day of each 21-day cycle) for up to eight 21-day cycles. In some embodiments, the dose of gemcitabine is administered once every 21-day cycle (e.g., on the second day of each 21-day cycle) for eight 21-day cycles. In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine and oxaliplatin, and gemcitabine and oxaliplatin are administered intravenously on about day 2 of each 21-day cycle. In some embodiments, the one or more chemotherapeutic agents include gemcitabine and oxaliplatin, and gemcitabine and oxaliplatin are administered intravenously on about day 2 of each 21-day cycle for up to eight cycles.

在一些實施例中，該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)係每週一次、每週多次但每天少於一次、每月多次但每天少於一次、每月多次但每周少於一次、每月一次、每三週一次、每個21天週期一次、在每個21天週期之約第2天或間歇性投與，以減輕或緩解疾病之症狀。投與可按任何所揭示之時間間隔繼續進行，持續至多約八個21天週期，或直至所治療的腫瘤或B細胞增殖性病症之症狀緩解。投與可在達成症狀緩解或減輕後繼續進行，其中此類緩解或減輕因此持續給藥而延長。In some embodiments, the one or more chemotherapeutic agents ( such as gemcitabine and oxaliplatin) are once a week, multiple times a week but less than once a day, multiple times a month but less than once a day, more than once a month. Times but less than once a week, once a month, once every three weeks, once every 21-day cycle, on about the second day of each 21-day cycle, or intermittently to reduce or alleviate the symptoms of the disease. Administration can continue at any disclosed time interval for up to about eight 21-day cycles, or until the symptoms of the tumor or B-cell proliferative disorder being treated are alleviated. Administration can be continued after symptom relief or relief is achieved, where such relief or relief is prolonged due to continued administration.

抗CD79b免疫偶聯物(諸如帕妥珠單抗維多汀-piiq)及其他藥劑之組合療法的示例性給藥方案包括但不限於在每個21天週期之約第1天以約1.4-5 mg/kg投與的抗CD79b免疫偶聯物(諸如huMA79bv28-MC-vc-PAB-MMAE)，加在每個21天週期之約第1天以約300-1600 mg/m2 投與的抗CD20抗體(例如 利妥昔單抗)，加在每個21天週期之約第2天以約50 mg/m2 至約2000 mg/m2 投與之一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)(例如 以約500 mg/m2 至約2000 mg/m2 投與之吉西他濱及以約50 mg/m2 至約200 mg/m2 投與之奧沙利鉑)。在一些實施例中，抗CD79b免疫偶聯物(諸如帕妥珠單抗維多汀-piiq)係在每個21天週期之約第1天以約1.8 mg/kg投與，抗CD20抗體(例如 利妥昔單抗)係在每個21天週期之約第1天以約375 mg/m2 投與，且該一或多種化學治療劑係在每個21天週期之約第2天投與(例如 吉西他濱以約1000 mg/m2 投與及奧沙利鉑以約100 mg/m2 投與)。在一些實施例中，抗CD79b免疫偶聯物係以約1.8 mg/kg投與。在一些實施例中，抗CD79b免疫偶聯物係帕妥珠單抗維多汀-piiq且以約1.8 mg/kg投與。在一些實施例中，抗CD20抗體係以約375 mg/m2 投與。在一些實施例中，抗CD20抗體係利妥昔單抗且以約375 mg/m2 投與。在一些實施例中，該一或多種化學治療劑包含以約1000 mg/m2 投與之吉西他濱及以約100 mg/m2 投與之奧沙利鉑。在一些實施例中，抗CD79b免疫偶聯物係帕妥珠單抗維多汀-piiq且以約1.8 mg/kg投與，抗CD20抗體係利妥昔單抗且以約375 mg/m2 投與，且該一或多種化學治療劑係以約1000 mg/m2 投與之吉西他濱及以約100 mg/m2 投與之奧沙利鉑。Exemplary dosing regimens for combination therapy of anti-CD79b immunoconjugates (such as Pertuzumab Vidotin-piiq) and other agents include, but are not limited to, a dose of about 1.4 to about 1 day of each 21-day cycle. Anti-CD79b immunoconjugate (such as huMA79bv28-MC-vc-PAB-MMAE) administered at 5 mg/kg, added at about 300-1600 mg/m 2 on the first day of each 21-day cycle Anti-CD20 antibody ( e.g. rituximab) is added to one or more chemotherapeutics ( e.g. gemcitabine) at about 50 mg/m 2 to about 2000 mg/m 2 on about the second day of each 21-day cycle And oxaliplatin) ( for example, gemcitabine is administered at about 500 mg/m 2 to about 2000 mg/m 2 and oxaliplatin is administered at about 50 mg/m 2 to about 200 mg/m 2 ). In some embodiments, an anti-CD79b immunoconjugate (such as Pertuzumab Vidotin-piiq) is administered at about 1.8 mg/kg on about the first day of each 21-day cycle. The anti-CD20 antibody ( For example , rituximab) is administered at about 375 mg/m 2 on about the first day of each 21-day cycle, and the one or more chemotherapeutic agents are administered on about the second day of each 21-day cycle And ( for example, gemcitabine is administered at about 1000 mg/m 2 and oxaliplatin is administered at about 100 mg/m 2 ). In some embodiments, the anti-CD79b immunoconjugate is administered at about 1.8 mg/kg. In some embodiments, the anti-CD79b immunoconjugate is Pertuzumab Vidotin-piiq and is administered at about 1.8 mg/kg. In some embodiments, the anti-CD20 antibody is about 375 mg / m 2 administered. In some embodiments, the anti-CD20 antibody system is rituximab and is administered at about 375 mg/m 2. In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine administered at about 1000 mg/m 2 and oxaliplatin administered at about 100 mg/m 2. In some embodiments, the anti-CD79b immunoconjugate is Pertuzumab Vidotin-piiq and is administered at about 1.8 mg/kg, and the anti-CD20 anti-system rituximab is administered at about 375 mg/m 2 And the one or more chemotherapeutic agents are administered with gemcitabine at about 1000 mg/m 2 and oxaliplatin at about 100 mg/m 2.

用於本文所述之任何治療方法中的本文所提供之免疫偶聯物、本文所提供之抗CD20抗體及本文所提供之一或多種化學治療劑可藉由任何適合方式投與，包括非經腸、肺內及鼻內投與，且若需要局部治療，則經病灶內投與。非經腸輸注包括肌肉內、靜脈內(例如 靜脈內輸注)、動脈內、腹膜內或皮下投與。部分取決於投藥係短暫的抑或長期的，給藥可藉由任何適合途徑進行，例如 藉由注射，諸如靜脈內或皮下注射進行。本文涵蓋各種給藥時程，包括但不限於經各種時間點進行之單次或多次投藥、快速注射投藥及脈衝輸注。The immunoconjugates provided herein, the anti-CD20 antibodies provided herein, and one or more chemotherapeutics provided herein used in any of the treatment methods described herein can be administered by any suitable means, including non-administrative Intestinal, intrapulmonary, and intranasal administration, and if local treatment is needed, administration is via intralesional administration. Parenteral infusion includes intramuscular, intravenous ( e.g., intravenous infusion), intraarterial, intraperitoneal, or subcutaneous administration. Depending in part on whether the administration is short-term or long-term, the administration can be carried out by any suitable route, for example by injection, such as intravenous or subcutaneous injection. This article covers various administration schedules, including but not limited to single or multiple administrations, bolus administrations, and pulse infusions at various time points.

本文提供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO:26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)抗CD20抗體；及(c)一或多種化學治療劑。在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO:19之胺基酸序列的重鏈可變域(VH)及含SEQ ID NO:20之胺基酸序列的輕鏈可變域(VL)。Provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (a human individual), which comprises administering to the individual an effective amount of the following: (a) Contains immunoconjugates of the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) anti-CD20 antibody; and (c) one or more Chemotherapeutics. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 19 and an amino acid containing SEQ ID NO: 20 Sequence of the light chain variable domain (VL).

本文亦提供用於治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This document also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (human individual), which comprises administering to the individual an effective amount of the following: (a) An immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) Rituximab; (c) Gemcitabine; And (d) oxaliplatin; wherein after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human individual has not experienced grade 3 or higher (for example, grade 3 or higher , Grade 4 or higher, or grade 5 or higher) peripheral neuropathy, the disease cannot be within 14 days ( for example , 14 days, 13 days, 12 days, 11 days, 10 days, 9 days , 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day) subside to grade 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

本文亦提供用於治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This document also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (human individual), which comprises administering to the individual an effective amount of the following: (a) An immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) Rituximab; (c) Gemcitabine; And (d) Oxaliplatin; wherein the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not cause grade 3 or higher (e.g. grade 3 or higher) in the human individual , Grade 4 or higher, or grade 5 or higher) peripheral neuropathy, the disease cannot be within 14 days ( for example , 14 days, 13 days, 12 days, 11 days, 10 days, 9 days , 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day) subside to grade 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

本文亦提供用於治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少(例如 以下任一種：約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中少於約40% (例如 以下任一種：少於約40%、約39%或更少、約38%或更少、約37%或更少、約36%或更少、約35%或更少、約34%或更少、約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This document also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (human individual), which comprises administering to the individual an effective amount of the following: (a) An immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) Rituximab; (c) Gemcitabine; And (d) oxaliplatin; wherein among the multiple human subjects treated, after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, 33 of the multiple human subjects % Or less ( for example, any of the following: about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or more Less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less , About 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, About 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) A human individual experiences peripheral neuropathy of grade 3 or higher (for example, any of grade 3 or higher, grade 4 or higher, or grade 5 or higher), the disease cannot be within 14 days ( for example, in 14 days , 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) subside to grade 1 or Lower level. In some embodiments, after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin in the plurality of human subjects treated, less than about 40% of the plurality of human subjects ( For example, any of the following: less than about 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% Or less, about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or Less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or more Less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less , About 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, About 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human individuals experiencing Grade 3 or Peripheral neuropathy of higher grade (for example, any of grade 3 or higher, grade 4 or higher, or grade 5 or higher), the disease cannot be within 14 days ( for example, in 14 days, 13 days, 12 days) , 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) regress to grade 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

本文亦提供用於治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中33%或更少(例如 以下任一種：約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)之人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中少於約40% (例如 以下任一種：少於約40%、約39%或更少、約38%或更少、約37%或更少、約36%或更少、約35%或更少、約34%或更少、約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This document also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (human individual), which comprises administering to the individual an effective amount of the following: (a) An immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8; (b) Rituximab; (c) Gemcitabine; And (d) Oxaliplatin; wherein administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin to multiple human individuals makes 33% or less of the multiple human individuals ( e.g., the following Any: about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or more Less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less , About 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, About 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human individuals experiencing grade 3 or more High-grade peripheral neuropathy (for example, any one of grade 3 or higher, grade 4 or higher, or grade 5 or higher), the disease cannot be within 14 days ( for example, in 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) regressed to grade 1 or lower. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in less than about 40% of the multiple human subjects ( e.g., any of the following: less About 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% or less, about 33% Or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or Less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or more Less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less , About 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, About 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human individuals experience grade 3 or higher (e.g., grade 3 or Peripheral neuropathy of higher grade, grade 4 or higher, or grade 5 or higher), the disease cannot be within 14 days ( for example, on 14 days, 13 days, 12 days, 11 days, 10 days, Within any of 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day), it regressed to grade 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，p在2至7之間、在2至6之間、在2至5之間、在3至5之間、或在3至4之間。在一些實施例中，p在2至5之間。在一些實施例中，p在3與4之間。在一些實施例中，p係3.5。在一些實施例中，抗CD79b免疫偶聯物係帕妥珠單抗維多汀-piiq。在一些實施例中，抗CD20抗體係利妥昔單抗。在一些實施例中，該一或多種化學治療劑包含本文所提供之化學治療劑中的任一種。在一些實施例中，該一或多種化學治療劑包含吉西他濱。在一些實施例中，該一或多種化學治療劑包含奧沙利鉑。在一些實施例中，該一或多種化學治療劑係吉西他濱及奧沙利鉑。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 38. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, p is between 2 and 7, between 2 and 6, between 2 and 5, between 3 and 5, or between 3 and 4. In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.5. In some embodiments, the anti-CD79b immunoconjugate is Pertuzumab Vidotin-piiq. In some embodiments, the anti-CD20 antibody system is rituximab. In some embodiments, the one or more chemotherapeutic agents include any of the chemotherapeutic agents provided herein. In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine. In some embodiments, the one or more chemotherapeutic agents comprise oxaliplatin. In some embodiments, the one or more chemotherapeutic agents are gemcitabine and oxaliplatin.

在一些實施例中，抗CD79b抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，抗CD79b抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。在一些實施例中，免疫偶聯物係依拉妥珠單抗維多汀。在某些實施例中，p在2與5之間。在某些實施例中，p係2。在一些實施例中，該免疫偶聯物係以約1 mg/kg至約5 mg /kg之劑量投與。在一些實施例中，該免疫偶聯物係以約1.2 mg/kg、約1.8 mg/kg、約2.4 mg/kg、約3.6 mg/kg或約4.8 mg/kg之劑量投與。在一些實施例中，該免疫偶聯物係以約1.8 mg/kg之劑量投與。In some embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 38. In some embodiments, the immunoconjugate is elatuzumab vedotine. In some embodiments, p is between 2 and 5. In certain embodiments, p is 2. In some embodiments, the immunoconjugate is administered at a dose of about 1 mg/kg to about 5 mg/kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.2 mg/kg, about 1.8 mg/kg, about 2.4 mg/kg, about 3.6 mg/kg, or about 4.8 mg/kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg.

如本文所使用，術語「依拉妥珠單抗維多汀」係指具有國際非專利醫藥物質名稱(INN)編號10647或CAS登記號1906205-77-3的抗CD79b免疫偶聯物。依拉妥珠單抗維多汀亦可互換地稱為「DCDS0780A」或「RO7032005」。As used herein, the term "Elatuzumab Vidotin" refers to an anti-CD79b immunoconjugate with International Non-Patent Drug Name (INN) No. 10647 or CAS Registration No. 1906205-77-3. Elatuzumab vedotine can also be referred to interchangeably as "DCDS0780A" or "RO7032005".

抗CD79b免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)可藉由相同投藥途徑或藉由不同投藥途徑投與。在一些實施例中，抗CD79b免疫偶聯物係經靜脈內、肌肉內、皮下、表面、經口、經皮、腹膜內、眶內、藉由植入、藉由吸入、鞘內、室內或鼻內投與。在一些實施例中，抗CD20抗體(諸如利妥昔單抗)係經靜脈內、肌肉內、皮下、表面、經口、經皮、腹膜內、眶內、藉由植入、藉由吸入、鞘內、室內或鼻內投與。在一些實施例中，該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)係經靜脈內、肌肉內、皮下、表面、經口、經皮、腹膜內、眶內、藉由植入、藉由吸入、鞘內、室內或鼻內投與。在一些實施例中，抗CD79b免疫偶聯物、抗CD20抗體(諸如利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)各自經由靜脈內輸注投與。抗CD79b免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)可經投與用於預防或治療疾病。Anti-CD79b immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies (e.g. rituximab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin) can be used They are administered by the same route of administration or by different routes of administration. In some embodiments, the anti-CD79b immunoconjugate is intravenous, intramuscular, subcutaneous, surface, oral, transdermal, intraperitoneal, intraorbital, by implantation, by inhalation, intrathecal, intrathecal, or intravenous Intranasal administration. In some embodiments, the anti-CD20 antibody (such as rituximab) is administered intravenously, intramuscularly, subcutaneously, superficially, orally, percutaneously, intraperitoneally, intraorbitally, by implantation, by inhalation, Intrathecal, indoor, or intranasal administration. In some embodiments, the one or more chemotherapeutic agents ( such as gemcitabine and oxaliplatin) are administered intravenously, intramuscularly, subcutaneously, superficially, orally, percutaneously, intraperitoneally, intraorbitally, by implantation , By inhalation, intrathecal, indoor or intranasal administration. In some embodiments, the anti-CD79b immunoconjugate, anti-CD20 antibody (such as rituximab), and the one or more chemotherapeutic agents ( such as gemcitabine and oxaliplatin) are each administered via intravenous infusion. Anti-CD79b immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies (e.g. Rituximab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin) can be used Administration is used to prevent or treat diseases.

在一些實施例中，抗CD79b免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)係以在約1.4 mg/kg至約2 mg/kg之間(例如 約1.4 mg/kg至約1.6 mg/kg、約1.6 mg/kg至約1.8 mg/kg、或約1.8 mg/kg至約2 mg/kg)之劑量投與。在一些實施例中，抗CD79b免疫偶聯物係以約1.8 mg/kg之劑量投與。在一些實施例中，抗CD79b免疫偶聯物係帕妥珠單抗維多汀-piiq。在一些實施例中，帕妥珠單抗維多汀-piiq係以約1.8 mg/kg之劑量投與。替代地或另外，在一些實施例中，抗CD20抗體(例如 利妥昔單抗)係以在約300-1800 mg/m2 之間(例如 約300 mg/m2 至約600 mg/m2 、約600 mg/m2 至約900 mg/m2 、約900 mg/m2 至約1200 mg/m2 、約1200 mg/m2 至約1500 mg/m2 、或約1500 mg/m2 至約1800 mg/m2 )及/或在約300-2000 mg之間(例如 約300 mg至約600 mg、約600 mg至約900 mg、約900 mg至約1200 mg、約1200 mg至約1500 mg、約1500 mg至約1750 mg、或約1750 mg至約2000 mg)之劑量投與。在一些實施例中，抗CD20抗體係利妥昔單抗。在一些實施例中，利妥昔單抗係以約375 mg/m2 之劑量投與。替代地或另外，在一些實施例中，該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)係以在約50 mg/m2 至約2000 mg/m2 之間(例如 約50 mg/m2 至約100 mg/m2 、約100 mg/m2 至約200 mg/m2 、約200 mg/m2 至約400 mg/m2 、約400 mg/m2 至約600 mg/m2 、約600 mg/m2 至約800 mg/m2 、約800 mg/m2 至約1000 mg/m2 、約1000 mg/m2 至約1200 mg/m2 、約1200 mg/m2 至約1400 mg/m2 、約1400 mg/m2 至約1600 mg/m2 、約1600 mg/m2 至約1800 mg/m2 、或約1800 mg/m2 至約2000 mg/m2 )之劑量投與。在一些實施例中，該一或多種化學治療劑包含吉西他濱。在一些實施例中，吉西他濱係以約1000 mg/m2 之劑量投與。在一些實施例中，該一或多種化學治療劑包含奧沙利鉑。在一些實施例中，奧沙利鉑係以約100 mg/m2 之劑量投與。在一些實施例中，該一或多種化學治療劑係吉西他濱及奧沙利鉑，且吉西他濱係以約1000 mg/m2 之劑量投與且奧沙利鉑係以約100 mg/m2 之劑量投與。In some embodiments, the anti-CD79b immunoconjugate ( e.g. Pertuzumab Vidotin-piiq) is provided at between about 1.4 mg/kg to about 2 mg/kg ( e.g., about 1.4 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, or about 1.8 mg/kg to about 2 mg/kg). In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.8 mg/kg. In some embodiments, the anti-CD79b immunoconjugate is Pertuzumab Vidotin-piiq. In some embodiments, Pertuzumab Vidotin-piiq is administered at a dose of about 1.8 mg/kg. Alternatively or in addition, in some embodiments, the anti-CD20 antibody ( e.g. , rituximab) is provided at between about 300-1800 mg/m 2 ( e.g., about 300 mg/m 2 to about 600 mg/m 2 , About 600 mg/m 2 to about 900 mg/m 2 , about 900 mg/m 2 to about 1200 mg/m 2 , about 1200 mg/m 2 to about 1500 mg/m 2 , or about 1500 mg/m 2 To about 1800 mg/m 2 ) and/or between about 300-2000 mg ( e.g., about 300 mg to about 600 mg, about 600 mg to about 900 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1500 mg, about 1500 mg to about 1750 mg, or about 1750 mg to about 2000 mg). In some embodiments, the anti-CD20 antibody system is rituximab. In some embodiments, rituximab is administered at a dose of about 375 mg/m 2. Alternatively or in addition, in some embodiments, the one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) are set to be between about 50 mg/m 2 and about 2000 mg/m 2 ( e.g., about 50 mg /m 2 to about 100 mg/m 2 , about 100 mg/m 2 to about 200 mg/m 2 , about 200 mg/m 2 to about 400 mg/m 2 , about 400 mg/m 2 to about 600 mg/ m 2 , about 600 mg/m 2 to about 800 mg/m 2 , about 800 mg/m 2 to about 1000 mg/m 2 , about 1000 mg/m 2 to about 1200 mg/m 2 , about 1200 mg/m 2 to about 1400 mg/m 2 , about 1400 mg/m 2 to about 1600 mg/m 2 , about 1600 mg/m 2 to about 1800 mg/m 2 , or about 1800 mg/m 2 to about 2000 mg/m 2 ) The dosage of administration. In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine. In some embodiments, gemcitabine is administered at a dose of about 1000 mg/m 2. In some embodiments, the one or more chemotherapeutic agents comprise oxaliplatin. In some embodiments, oxaliplatin is administered at a dose of about 100 mg/m 2. In some embodiments, the one or more chemotherapeutic agents are gemcitabine and oxaliplatin, and gemcitabine is administered at a dose of about 1000 mg/m 2 and oxaliplatin is administered at a dose of about 100 mg/m 2 Contribute.

在一些實施例中，抗CD20抗體係利妥昔單抗。在一些實施例中，該免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與且奧沙利鉑係以約100 mg/m2 之劑量投與。在一些實施例中，帕妥珠單抗維多汀-piiq係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與。In some embodiments, the anti-CD20 antibody system is rituximab. In some embodiments, the immunoconjugate ( for example , Pertuzumab Vidotin-piiq) is administered at a dose of about 1.8 mg/kg, and rituximab is administered at a dose of about 375 mg/m 2 Dosage administration, gemcitabine is administered at a dose of about 1000 mg/m 2 and oxaliplatin is administered at a dose of about 100 mg/m 2 . In some embodiments, Pertuzumab vedotine-piiq is administered at a dose of about 1.8 mg/kg, rituximab is administered at a dose of about 375 mg/m 2 , and gemcitabine is administered at a dose of about The dose of 1000 mg/m 2 is administered, and the oxaliplatin is administered at a dose of about 100 mg/m 2 .

在一些實施例中，抗CD79b免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)係投與至少一個21天週期(例如 約一個、約兩個、約三個、約四個、約五個、約六個、約七個或約八個或更多個21天週期中的任一個)。In some embodiments, the anti-CD79b immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), the anti-CD20 antibody ( e.g. Rituximab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and ol Thaliplatin) is administered for at least one 21-day cycle ( e.g., about one, about two, about three, about four, about five, about six, about seven, or about eight or more 21 days Any one of the cycles).

在一些實施例中，抗CD79b免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)係投與至多八個21天週期(例如 約一個、約兩個、約三個、約四個、約五個、約六個、約七個或約八個21天週期中之任一個)。在一些實施例中，該免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)係在每個21天週期之約第1天靜脈內投與。在一些實施例中，該免疫偶聯物係帕妥珠單抗維多汀-piiq且該帕妥珠單抗維多汀-piiq係在每個21天週期之約第1天靜脈內投與。替代地或另外地，在一些實施例中，抗CD20抗體(例如 利妥昔單抗)係在每個21天週期之約第1天靜脈內投與。在一些實施例中，抗CD20抗體係利妥昔單抗且利妥昔單抗係在每個21天週期之約第1天投與。替代地或另外，在一些實施例中，該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)係在每個21天週期之約第2天靜脈內投與。在一些實施例中，該等化學治療劑係吉西他濱及奧沙利鉑，且吉西他濱及奧沙利鉑係在每個21天週期之約第2天靜脈內投與。In some embodiments, the anti-CD79b immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), the anti-CD20 antibody ( e.g. Rituximab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and ol Thaliplatin) is administered in up to eight 21-day cycles ( e.g., about one, about two, about three, about four, about five, about six, about seven, or about eight 21-day cycles Either). In some embodiments, the immunoconjugate ( e.g. , Pertuzumab Vidotin-piiq) is administered intravenously on about day 1 of each 21-day cycle. In some embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq and the Pertuzumab Vidotin-piiq is administered intravenously on about day 1 of each 21-day cycle . Alternatively or additionally, in some embodiments, an anti-CD20 antibody ( e.g. , rituximab) is administered intravenously on about day 1 of each 21-day cycle. In some embodiments, the anti-CD20 antibody system is rituximab and rituximab is administered on about day 1 of each 21-day cycle. Alternatively or additionally, in some embodiments, the one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) are administered intravenously on about day 2 of each 21-day cycle. In some embodiments, the chemotherapeutic agents are gemcitabine and oxaliplatin, and gemcitabine and oxaliplatin are administered intravenously on about day 2 of each 21-day cycle.

在一些實施例中，該免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)係投與至少一個21天週期，其中該免疫偶聯物與該抗CD20抗體係在每個21天週期之約第1天靜脈內投與，且其中該一或多種化學治療劑係在每個21天週期之約第2天靜脈內投與。在一些實施例中，該免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)係投與至多八個21天週期，其中該免疫偶聯物與該抗CD20抗體係在每個21天週期之約第1天靜脈內投與，且其中該一或多種化學治療劑係在每個21天週期之約第2天靜脈內投與。在一些實施例中，該一或多種化學治療劑係吉西他濱及奧沙利鉑。在一些實施例中，抗CD20抗體係利妥昔單抗。在一些實施例中，該免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中該免疫偶聯物與利妥昔單抗係在每個21天週期之約第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之約第2天靜脈內投與。在一些實施例中，該免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天投與。在一些實施例中，該免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中該免疫偶聯物與利妥昔單抗係在每個21天週期之約第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之約第2天靜脈內投與。在一些實施例中，該免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，且其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天投與。In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. Rituximab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxa) Liplatin) is administered for at least one 21-day cycle, wherein the immunoconjugate and the anti-CD20 antibody system are administered intravenously on about day 1 of each 21-day cycle, and wherein the one or more chemotherapeutic agents are administered It is administered intravenously on approximately day 2 of each 21-day cycle. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. Rituximab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxa) Liplatin) is administered up to eight 21-day cycles, wherein the immunoconjugate and the anti-CD20 antibody system are administered intravenously on about day 1 of each 21-day cycle, and wherein the one or more chemotherapeutic agents It is administered intravenously on about the second day of each 21-day cycle. In some embodiments, the one or more chemotherapeutic agents are gemcitabine and oxaliplatin. In some embodiments, the anti-CD20 antibody system is rituximab. In some embodiments, the immunoconjugate ( such as Pertuzumab Vidotin-piiq), rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein the immune system The conjugate and rituximab were administered intravenously on approximately day 1 of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously approximately on day 2 of each 21-day cycle . In some embodiments, the immunoconjugate ( for example , Pertuzumab Vidotin-piiq) is administered at a dose of about 1.8 mg/kg, and rituximab is administered at a dose of about 375 mg/m 2 Dosage administration, gemcitabine is administered at a dose of about 1000 mg/m 2 , and oxaliplatin is administered at a dose of about 100 mg/m 2 , wherein the immunoconjugate, rituximab, gemcitabine And oxaliplatin are administered up to eight 21-day cycles, and the immunoconjugate and rituximab are administered on the first day of each 21-day cycle, and gemcitabine and oxaliplatin are administered on the first day of each 21-day cycle. It is administered on the second day of each 21-day cycle. In some embodiments, the immunoconjugate ( for example , Pertuzumab Vidotin-piiq), rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein the immunoconjugate The conjugate and rituximab were administered intravenously on approximately day 1 of each 21-day cycle, and gemcitabine and oxaliplatin were administered intravenously on approximately day 2 of each 21-day cycle. In some embodiments, the immunoconjugate ( for example , Pertuzumab Vidotin-piiq) is administered at a dose of about 1.8 mg/kg, and rituximab is administered at a dose of about 375 mg/m 2 Dosage administration, gemcitabine is administered at a dose of about 1000 mg/m 2 , and oxaliplatin is administered at a dose of about 100 mg/m 2 , wherein the immunoconjugate, rituximab, gemcitabine And oxaliplatin-based administration for at least one 21-day cycle, and wherein the immunoconjugate and rituximab are administered on the first day of each 21-day cycle, and wherein gemcitabine and oxaliplatin-based Administer on the 2nd day of each 21-day cycle.

本文提供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。在一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。Provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (a human individual), which comprises administering to the individual an effective amount of the following: (a) Contains immunoconjugates of the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate is administered at a dose of about 1.8 mg/kg, ritux Ciximab is administered at a dose of about 375 mg/m 2 , gemcitabine is administered at a dose of about 1000 mg/m 2 , and oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein The immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for up to eight 21-day cycles, wherein the immunoconjugate and rituximab are administered at the first of each 21-day cycle It was administered intravenously every day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle. In some embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

本文提供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與；且其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。在一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。Provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (a human individual), which comprises administering to the individual an effective amount of the following: (a) Contains immunoconjugates of the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate is administered at a dose of about 1.8 mg/kg, ritux Ciximab is administered at a dose of about 375 mg/m 2 , gemcitabine is administered at a dose of about 1000 mg/m 2 , and oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein The immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein the immunoconjugate and rituximab are administered on the first day of each 21-day cycle It was administered intravenously, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle. In some embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

本文亦提供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO：36之胺基酸序列的重鏈及(ii)含SEQ ID NO：35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This article also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (a human individual), which comprises administering to the individual an effective amount of the following: (a ) Contains immunoconjugates of the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the 21st day of each cycle. 1 day intravenous administration, and wherein gemcitabine and oxaliplatin are administered intravenously on the 2nd day of each 21-day cycle; and wherein the immunoconjugate, rituximab, gemcitabine and After oxaliplatin, the human individual has not experienced peripheral neuropathy of grade 3 or higher (for example, any of grade 3 or higher, grade 4 or higher, or grade 5 or higher). The disease cannot be Within 14 days ( e.g., any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) One kind of inner) regressed to level 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

本文亦提供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO：36之胺基酸序列的重鏈及(ii)含SEQ ID NO：35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This article also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (a human individual), which comprises administering to the individual an effective amount of the following: (a ) Contains immunoconjugates of the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the first of each 21-day cycle And oxaliplatin is administered intravenously on the second day of each 21-day cycle; and wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered intravenously. After thaliplatin, the human individual has not experienced peripheral neuropathy of grade 3 or higher (for example, any of grade 3 or higher, grade 4 or higher, or grade 5 or higher), and the disease cannot be in 14 Within days ( e.g. in any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) (Inside) fades to level 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

本文亦提供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO：36之胺基酸序列的重鏈及(ii)含SEQ ID NO：35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This article also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (a human individual), which comprises administering to the individual an effective amount of the following: (a ) Contains immunoconjugates of the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the 21st day of each cycle. It was administered intravenously on 1 day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle; and the immunoconjugate, rituximab, gemcitabine, and oxaliplatin were administered intravenously. Thaliplatin does not cause peripheral neuropathy of grade 3 or higher (for example, any of grade 3 or higher, grade 4 or higher, or grade 5 or higher) in the human individual, and the disease cannot be Within 14 days ( e.g., any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) One kind of inner) fades to level 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

本文亦提供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO：36之胺基酸序列的重鏈及(ii)含SEQ ID NO：35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This article also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (a human individual), which comprises administering to the individual an effective amount of the following: (a ) Contains immunoconjugates of the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the first of each 21-day cycle It was administered intravenously on the same day, and where gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle; and where the immunoconjugate, rituximab, gemcitabine and oxali were administered Libaplatin does not cause peripheral neuropathy of grade 3 or higher (for example, any of grade 3 or higher, grade 4 or higher, or grade 5 or higher) in the human individual, and the disease cannot be in 14 Within days ( e.g. in any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) (Inside) fades to level 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

本文亦提供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO：36之胺基酸序列的重鏈及(ii)含SEQ ID NO：35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中33%或更少(例如 以下任一種：約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。在一些實施例中，在所治療之多名人類個體中，在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該多名人類個體中少於約40% (例如 以下任一種：少於約40%、約39%或更少、約38%或更少、約37%或更少、約36%或更少、約35%或更少、約34%或更少、約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This article also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (a human individual), which comprises administering to the individual an effective amount of the following: (a ) Contains immunoconjugates of the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the first 21-day cycle One day of intravenous administration, and wherein gemcitabine and oxaliplatin are administered intravenously on the second day of each 21-day cycle; and wherein among the multiple human subjects being treated, the immunoconjugate is administered After drugs, rituximab, gemcitabine, and oxaliplatin, 33% or less of the multiple human individuals ( e.g., any of the following: about 33% or less, about 32% or less, about 31% Or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or Less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or more Less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less , About 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, About 2% or less, about 1% or less, or about 0.5% or less) of human individuals experience grade 3 or higher (e.g., grade 3 or higher, grade 4 or higher, or grade 5 or higher) Any one of high-grade peripheral neuropathy, the disease cannot be within 14 days ( for example , 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days , 4 days, 3 days, 2 days or 1 day) subside to grade 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles. In some embodiments, after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin in the plurality of human subjects treated, less than about 40% of the plurality of human subjects ( For example, any of the following: less than about 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% Or less, about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or Less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or more Less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less , About 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, About 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human individuals experiencing Grade 3 or Peripheral neuropathy of higher grade (for example, any of grade 3 or higher, grade 4 or higher, or grade 5 or higher), the disease cannot be within 14 days ( for example, in 14 days, 13 days, 12 days) , 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) regress to grade 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

本文亦提供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO：36之胺基酸序列的重鏈及(ii)含SEQ ID NO：35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中33%或更少(例如 以下任一種：約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。在一些實施例中，向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中少於約40% (例如 以下任一種：少於約40%、約39%或更少、約38%或更少、約37%或更少、約36%或更少、約35%或更少、約34%或更少、約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This article also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (a human individual), which comprises administering to the individual an effective amount of the following: (a ) Contains immunoconjugates of the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administration is at most eight 21-day cycles, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , gemcitabine The dosage of oxaliplatin is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the first 21-day cycle It was administered intravenously on 1 day, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle; and the immunoconjugate and rituxima were administered to multiple human subjects Antibodies, gemcitabine, and oxaliplatin make 33% or less of the plurality of human individuals ( e.g., any of the following: about 33% or less, about 32% or less, about 31% or less, about 30% Or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or Less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or more Less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less , About 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, About 1% or less, or about 0.5% or less) of human individuals experience level 3 or higher (e.g., any of level 3 or higher, level 4 or higher, or level 5 or higher) Peripheral neuropathy, the disease cannot be within 14 days ( for example , 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, Within 2 days or 1 day) subside to grade 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in less than about 40% of the multiple human subjects ( e.g., any of the following: less About 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% or less, about 33% Or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or Less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or more Less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less , About 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, About 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human individuals experience grade 3 or higher (e.g., grade 3 or Peripheral neuropathy of higher grade, grade 4 or higher, or grade 5 or higher), the disease cannot be within 14 days ( for example, on 14 days, 13 days, 12 days, 11 days, 10 days, Within any of 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day), it regressed to grade 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

本文亦提供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法，其包括向該個體投與有效量之以下各物：(a)包含下式之免疫偶聯物：

Figure 02_image001
，其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO：36之胺基酸序列的重鏈及(ii)含SEQ ID NO：35之胺基酸序列的輕鏈，且其中p在2與5之間；(b)利妥昔單抗；(c)吉西他濱；及(d)奧沙利鉑；其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期中，該免疫偶聯物之投與劑量係約1.8 mg/kg，利妥昔單抗之投與劑量係約375 mg/m2 ，吉西他濱之投與劑量係約1000 mg/m2 ，且奧沙利鉑之投與劑量係約100 mg/m2 ；其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中33%或更少(例如 以下任一種：約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。在一些實施例中，向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中少於約40% (例如 以下任一種：少於約40%、約39%或更少、約38%或更少、約37%或更少、約36%或更少、約35%或更少、約34%或更少、約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。This article also provides a method for treating diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (a human individual), which comprises administering to the individual an effective amount of the following: (a ) Contains immunoconjugates of the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein in each cycle, the dosage of the immunoconjugate is about 1.8 mg/kg, the dosage of rituximab is about 375 mg/m 2 , and the dosage of gemcitabine is The dosage of administration is about 1000 mg/m 2 , and the dosage of oxaliplatin is about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are on the first of each 21-day cycle It was administered intravenously every day, and gemcitabine and oxaliplatin were administered intravenously on the 2nd day of each 21-day cycle; and the immunoconjugate, rituximab were administered to multiple human subjects , Gemcitabine and oxaliplatin make 33% or less of the plurality of human individuals ( for example, any of the following: about 33% or less, about 32% or less, about 31% or less, about 30% or Less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or more Less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less , About 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, About 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human individuals experiencing level 3 or higher (for example, any of level 3 or higher, level 4 or higher, or level 5 or higher) Neuropathy, the disease cannot be within 14 days ( for example , 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 Within one day or one day) subside to level 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in less than about 40% of the multiple human subjects ( e.g., any of the following: less About 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% or less, about 33% Or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or Less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or more Less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less , About 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, About 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human individuals experience grade 3 or higher (e.g., grade 3 or Peripheral neuropathy of higher grade, grade 4 or higher, or grade 5 or higher), the disease cannot be within 14 days ( for example, on 14 days, 13 days, 12 days, 11 days, 10 days, Within any of 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day), it regressed to grade 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

在一些實施例中，抗CD20抗體(例如 利妥昔單抗)係在免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)之前(例如 至多約1小時、至多約2小時、至多約4小時、至多約6小時、至多約12小時、至多約16小時、至多約18小時、至多約22小時、至多約24小時、或至多約1天、至多約2天、至多約3天中之任一種或更長時間之前)投與。在一些實施例中，該抗CD20抗體係利妥昔單抗，且利妥昔單抗係在該免疫偶聯物之前投與。在一些實施例中，該免疫偶聯物係在抗CD20抗體之前(例如 至多約1小時、至多約2小時、至多約4小時、至多約6小時、至多約12小時、至多約16小時、至多約18小時、至多約22小時、至多約24小時、或至多約1天、至多約2天、至多約3天中之任一種或更長時間之前)投與。在一些實施例中，該抗CD20抗體係利妥昔單抗，且該免疫偶聯物係在利妥昔單抗之前投與。In some embodiments, the anti-CD20 antibody (e.g. rituximab) in the immunoconjugate-based (e.g. pertuzumab Wei Duoting -piiq) prior to (e.g., up to about 1 hour, up to about 2 hours, up to About 4 hours, up to about 6 hours, up to about 12 hours, up to about 16 hours, up to about 18 hours, up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days Any of them or more) before). In some embodiments, the anti-CD20 antibody system is rituximab, and rituximab is administered before the immunoconjugate. In some embodiments, the immunoconjugate is before the anti-CD20 antibody ( e.g., at most about 1 hour, at most about 2 hours, at most about 4 hours, at most about 6 hours, at most about 12 hours, at most about 16 hours, at most About 18 hours, up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days or more) before administration. In some embodiments, the anti-CD20 antibody system is rituximab, and the immunoconjugate is administered before rituximab.

在一些實施例中，該一或多種化學治療劑係依序投與的。在一些實施例中，該等化學治療劑係吉西他濱及奧沙利鉑。在一些實施例中，吉西他濱係在奧沙利鉑之前(例如 至多約1小時、至多約2小時、至多約4小時、至多約6小時、至多約12小時、至多約16小時、至多約18小時、至多約22小時、至多約24小時、或至多約1天、至多約2天、至多約3天中之任一種或更長時間之前)投與。在一些實施例中，奧沙利鉑係在吉西他濱之前(例如 至多約1小時、至多約2小時、至多約4小時、至多約6小時、至多約12小時、至多約16小時、至多約18小時、至多約22小時、至多約24小時、或至多約1天、至多約2天、至多約3天中之任一種或更長時間之前)投與。In some embodiments, the one or more chemotherapeutic agents are administered sequentially. In some embodiments, the chemotherapeutic agents are gemcitabine and oxaliplatin. In some embodiments, gemcitabine precedes oxaliplatin ( e.g., up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 12 hours, up to about 16 hours, up to about 18 hours. , Up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days, or any of them) before administration. In some embodiments, oxaliplatin precedes gemcitabine ( e.g., up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 12 hours, up to about 16 hours, up to about 18 hours. , Up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days, or any of them) before administration.

在一些實施例中，該免疫偶聯物、該抗CD20抗體及該一或多種化學治療劑係投與一個、兩個、三個、四個、五個、六個、七個或八個21天週期中之任一個。在一些實施例中，該等化學治療劑係吉西他濱及奧沙利鉑。在一些實施例中，抗CD20抗體係利妥昔單抗。在一些實施例中，該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與一個、兩個、三個、四個、五個、六個、七個或八個21天週期中之任一個。在一些實施例中，將免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑投與八個21天週期。In some embodiments, the immunoconjugate, the anti-CD20 antibody, and the one or more chemotherapeutic agents are administered with one, two, three, four, five, six, seven, or eight 21 Any of the days in the cycle. In some embodiments, the chemotherapeutic agents are gemcitabine and oxaliplatin. In some embodiments, the anti-CD20 antibody system is rituximab. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered in one, two, three, four, five, six, seven, or eight 21 Any of the days in the cycle. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for eight 21-day cycles.

在可與任何前述實施例組合的一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少兩個、至少三個、至少四個、至少五個、至少六個或至少七個21天週期。在一些實施例中，將免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑投與八個21天週期。在一些實施例中，利妥昔單抗係在該免疫偶聯物之前投與。在一些實施例中，吉西他濱係在奧沙利鉑之前投與。在一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。In some embodiments that can be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered at least two, at least three, at least four, at least five, At least six or at least seven 21-day cycles. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for eight 21-day cycles. In some embodiments, rituximab is administered before the immunoconjugate. In some embodiments, gemcitabine is administered before oxaliplatin. In some embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

在一些實施例中，該人類個體已接受至少一種針對DLBCL之先前療法。在一些實施例中，該人類個體係成人。在一些實施例中，該人類個體患有經組織學確定的非特指型(NOS)彌漫性大B細胞淋巴瘤，或者該人類個體有惰性疾病轉化為DLBCL之病史。在一些實施例中，該人類人類個體已接受至少一種針對DLBCL之先前全身性療法。在一些實施例中，該人類個體已接受至少兩種針對DLBCL之先前療法。舉例而言，在一些情況下，人類個體已預先接受自體造血幹細胞移植(HSCT)(化學療法之後進行鞏固性自體HSCT被視為一線先前療法)。在另一個實例中，人類個體已接受先前同種異體HSCT，且該人類個體不再接受免疫抑制療法，並且沒有活動性移植物抗宿主病(GVHD)(化學療法之後進行同種異體HSCT被視為一線先前療法)。在一些實施例中，人類個體接受先前局部療法，例如 放射療法。在一些實施例中，DLBCL係復發性或難治性DLBCL。在一些實施例中，若DLBCL在自完成最後一線療法開始持續≥6個月之反應後復發，則其係復發性的。在一些實施例中，若DLBCL在先前療法期間進展或在先前療法之6個月內(＜ 6個月)進展，則其係難治性的。在一些實施例中，人類個體具有至少一個二維可量測之病灶，例如 最長尺寸大於1.5 cm之病變，此係藉由電腦斷層攝影(CT)或磁共振成像(MRI)量測。在一些實施例中，該人類個體的美國東岸癌症臨床研究合作組織(ECOG)體能狀態係0、1或2。在一些實施例中，該人類個體沒有計劃進行自體或同種異體幹細胞移植(SCT)。在一些實施例中，該人類個體未曾接受用吉西他濱及鉑基藥劑之組合進行之先前療法。在一些實施例中，根據5.0版國家癌症研究院常見不良事件評價準則，該人類個體之周圍神經病變不大於1級。在一些實施例中，該人類個體未患原發性或繼發性中樞神經系統(CNS)淋巴瘤。在一些實施例中，該人類個體未患里希特氏轉化(Richter’s transformation)或先前未患毛細管滲漏症候群(CLL)。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前，該人類個體並非造血幹細胞移植(HSCT)之候選人。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前，該人類個體並非自體造血幹細胞移植(HSCT)之候選人。在一些實施例中，該人類個體已接受至少兩種針對DLBCL之先前療法。在一些實施例中，該人類個體未接受針對DLBCL之帕妥珠單抗維多汀-piiq先前療法。在一些實施例中，該人類個體係成人。在一些實施例中，若未另外說明，否則該成人患有復發性或難治性彌漫性大B細胞淋巴瘤。In some embodiments, the human individual has received at least one previous therapy for DLBCL. In some embodiments, the human is an adult. In some embodiments, the human individual has histologically determined non-specified type (NOS) diffuse large B-cell lymphoma, or the human individual has a history of indolent disease converted to DLBCL. In some embodiments, the human human individual has received at least one previous systemic therapy for DLBCL. In some embodiments, the human individual has received at least two previous therapies for DLBCL. For example, in some cases, human individuals have previously received autologous hematopoietic stem cell transplantation (HSCT) (consolidating autologous HSCT followed by chemotherapy is considered a first-line prior therapy). In another example, the human individual has received previous allogeneic HSCT, and the human individual is no longer receiving immunosuppressive therapy, and does not have active graft versus host disease (GVHD) (allogeneic HSCT after chemotherapy is considered first-line Previous therapy). In some embodiments, the human individual receives previous local therapy, such as radiation therapy. In some embodiments, DLBCL is relapsed or refractory DLBCL. In some embodiments, if DLBCL recurs after a response lasting ≥ 6 months since the completion of the last-line therapy, it is recurrent. In some embodiments, if DLBCL progresses during the previous therapy or within 6 months (<6 months) of the previous therapy, it is refractory. In some embodiments, the human individual has at least one two-dimensional measurable lesion, such as a lesion with a longest dimension greater than 1.5 cm, which is measured by computer tomography (CT) or magnetic resonance imaging (MRI). In some embodiments, the ECOG performance status of the human individual is 0, 1, or 2. In some embodiments, the human individual has no plans to undergo autologous or allogeneic stem cell transplantation (SCT). In some embodiments, the human individual has not received prior therapy with a combination of gemcitabine and platinum-based agents. In some embodiments, the peripheral neuropathy of the human individual is not greater than Grade 1 according to the Common Adverse Event Evaluation Guidelines of the National Cancer Institute Version 5.0. In some embodiments, the human individual does not suffer from primary or secondary central nervous system (CNS) lymphoma. In some embodiments, the human individual has not suffered from Richter's transformation or has not previously suffered from capillary leak syndrome (CLL). In some embodiments, the human individual is not a candidate for hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human individual is not a candidate for autologous hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human individual has received at least two previous therapies for DLBCL. In some embodiments, the human individual has not received Pertuzumab Vidotin-piiq prior therapy for DLBCL. In some embodiments, the human is an adult. In some embodiments, unless otherwise specified, the adult has relapsed or refractory diffuse large B-cell lymphoma.

在一些實施例中，非特指型(NOS)彌漫性大B細胞淋巴瘤(DLBCL)(例如非特指型復發性或難治性彌漫性大B細胞淋巴瘤)係指不符合其他DLBCL亞型之獨特臨床表現、組織形態學、腫瘤細胞表型及/或病原體相關標準的DLBCL。DLBC NOS一般係一種侵襲性疾病，佔所有DLBCL病例約80-85%。使用標準化學療法方案治療的DLBCL NOS患者的總體長期存活率為 約65%。參見例如 Grimm等人 (2019) Annals of Diagnostic Pathology，38:6-10。In some embodiments, non-specific (NOS) diffuse large B-cell lymphoma (DLBCL) (e.g., non-specific relapsed or refractory diffuse large B-cell lymphoma) refers to the uniqueness of other DLBCL subtypes Clinical manifestations, histomorphology, tumor cell phenotype and/or pathogen-related standard DLBCL. DLBC NOS is generally an aggressive disease, accounting for about 80-85% of all DLBCL cases. The overall long-term survival rate of DLBCL NOS patients treated with standard chemotherapy regimens is approximately 65%. See, for example, Grimm et al. (2019) Annals of Diagnostic Pathology, 38:6-10.

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級(例如4級或更高級、或5級或更高級中之任一種)的周圍神經病變。在一些實施例中，向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中33%或更少(例如 以下任一種：約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中少於約40% (例如 以下任一種：少於約40%、約39%或更少、約38%或更少、約37%或更少、約36%或更少、約35%或更少、約34%或更少、約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在某些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause grade 3 or higher (e.g. grade 3 or higher, grade 4 or higher) in the human individual. High grade, or any one of grade 5 or higher) peripheral neuropathy, which does not subside to grade 1 or lower within 14 days. In some embodiments, administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause grade 4 or higher (e.g., grade 4 or higher, or grade 5 or Any of the higher grades) peripheral neuropathy. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals makes 33% or less of the multiple human individuals ( e.g., any of the following: about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26 % Or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% Or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or Less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less Few, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human individuals experience level 3 or higher (e.g., 3 Grade or higher, grade 4 or higher, or grade 5 or higher) peripheral neuropathy, the disease can not be within 14 days ( for example , 14 days, 13 days, 12 days, 11 days, 10 Within any of days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) regressed to grade 1 or lower. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in less than about 40% of the multiple human subjects ( e.g., any of the following: less About 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% or less, about 33% Or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or Less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or more Less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less , About 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, About 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human individuals experience grade 3 or higher (e.g., grade 3 or Peripheral neuropathy of higher grade, grade 4 or higher, or grade 5 or higher), the disease cannot be within 14 days ( for example, on 14 days, 13 days, 12 days, 11 days, 10 days, Within any of 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day), it regressed to grade 1 or lower. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約8% (例如 低於約8%、7%、6%、5%、4%、3%、2%或1%中之任一百分比)的個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中低於約6% (例如 低於約6%、5%、4%、3%、2%或1%中之任一百分比)的個體經歷周圍神經病變，該疾病導致用該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑進行之治療中止。在一些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered to multiple human individuals such that less than about 8% ( e.g., less than about 8%, Individuals with 7%, 6%, 5%, 4%, 3%, 2%, or 1%) experience level 3 or higher (e.g., level 3 or higher, level 4 or higher, or 5 Grade or higher) peripheral neuropathy. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered to multiple human individuals such that less than about 6% ( e.g., less than about 6%, 5%, 4%, 3%, 2%, or 1%) of individuals who experience peripheral neuropathy that leads to treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin The treatment was discontinued. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，在該人類個體未經歷4級或更高級(例如4級或更高級、或5級或更高級中之任一種)的周圍神經病變。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級(例如4級或更高級、或5級或更高級中之任一種)的周圍神經病變。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷4級或更高級(例如4級或更高級、或5級或更高級中之任一種)的周圍神經病變。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級(例如4級或更高級、或5級或更高級中之任一種)的神經毒性。在一些實施例中，神經毒性係指感覺及/或運動周圍神經病變。在某些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。In some embodiments, after the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human individual has not experienced grade 4 or higher (for example, grade 4 or higher, or grade 5). Or higher) peripheral neuropathy. In some embodiments, administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause grade 4 or higher (e.g., grade 4 or higher, or grade 5 or Any of the higher grades) peripheral neuropathy. In some embodiments, after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human individual has not experienced grade 4 or higher (e.g., grade 4 or higher, or grade 5 or Any of the higher grades) peripheral neuropathy. In some embodiments, administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause grade 4 or higher (e.g., grade 4 or higher, or grade 5 or Any of the higher levels) neurotoxicity. In some embodiments, neurotoxicity refers to sensory and/or peripheral motor neuropathy. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後存活至少約10個月或更長時間、至少約11個月或更長時間、至少約12個月或更長時間、至少約13個月或更長時間、至少約14個月或更長時間、或至少約15個月或更長時間。在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑引起該多名人類個體中之人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後至少約10個月或更長時間、至少約11個月或更長時間、至少約12個月或更長時間、至少約13個月或更長時間、至少約14個月或更長時間、或至少約15個月或更長時間的中值總體存活期。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得總體存活(OS)時間例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加。OS係自首次投與免疫偶聯物、抗CD20抗體及該一或多種化學治療劑至因任何原因導致死亡之時間量測。在一些實施例中，OS，例如 中值OS係以天數、週數、月份數或年份數量度。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得OS，例如 中值OS，例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。OS，例如 中值OS，可根據此項技術中已知之任何方法估計。在一些情況下，OS，例如 中值OS係使用Kaplan-Meier方法估算。在一些實施例中，治療效果之估計係使用分層Cox比例風險分析(例如 包括95%信賴限值)，以死亡風險比表示。在一些實施例中，使用Brookmeyer-Crowley方法構造中值OS之95%信賴區間。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使人類個體之存活期相較於向相應人類個體投與利妥昔單抗、吉西他濱及奧沙利鉑增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中之人類個體的總體存活期，例如 中值OS，相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體增加例如至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的1年總體存活率係至少約42%或更高、至少約45%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的2年總體存活率係至少約67%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的3.5年總體存活率係至少約38%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的5年總體存活率係至少約15%或更高、至少約20%或更高、至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得1年、2年、3.5年或5年總體存活率相較於投與利妥昔單抗、吉西他濱及奧沙利鉑之相應多名人類個體增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，1年總體存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後1年因任何原因而發生死亡的人類個體之比例。在一些實施例中，2年總體存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後2年因任何原因而發生死亡的人類個體之比例。在一些實施例中，3.5年總體存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後3.5年因任何原因而發生死亡的人類個體之比例。在一些實施例中，5年總體存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後5年因任何原因而發生死亡的人類個體之比例。In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin Survive at least about 10 months or longer, at least about 11 months or longer, at least about 12 months or longer, at least about 13 months or longer, at least about 14 months or longer , Or at least about 15 months or more. In some embodiments that can be combined with any of the foregoing embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals causes the human individuals of the multiple human individuals to start Immunoconjugates, rituximab, gemcitabine, and oxaliplatin after treatment at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least A median overall survival of about 13 months or more, at least about 14 months or more, or at least about 15 months or more. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) make overall survival (OS) time, for example, compared to administration of anti-CD20 antibodies ( e.g. , rituximab) and one or more chemotherapeutics ( e.g., gemcitabine and oxaliplatin) increase. OS is a measurement of the time from the first administration of the immunoconjugate, anti-CD20 antibody and the one or more chemotherapeutic agents to death due to any cause. In some embodiments, the OS, such as the median OS, is measured in days, weeks, months, or years. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) make OS, such as median OS, for example, compared to administration of anti-CD20 antibodies ( e.g. , rituximab) and one or more chemotherapeutics ( e.g., gemcitabine and oxaliplatin) ) Increased by at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 Times or at least about 6 times or higher. OS, such as median OS, can be estimated according to any method known in the art. In some cases, OS, such as median OS, is estimated using the Kaplan-Meier method. In some embodiments, the treatment effect is estimated using a stratified Cox proportional hazard analysis ( e.g., including a 95% confidence limit), expressed as a risk ratio for death. In some embodiments, the Brookmeyer-Crowley method is used to construct the 95% confidence interval of the median OS. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin makes the survival of the human individual compared to the administration of rituximab, gemcitabine, and oxaliplatin to the corresponding human individual Liplatin is increased by, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least Any one of about 5.5 times or at least about 6 times or higher. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in the overall survival of the human individuals among the multiple human individuals, such as median OS, Compared to the corresponding multiple human subjects administered rituximab, gemcitabine and oxaliplatin, the increase is, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, Any one of at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times or higher. In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects caused a total of 1 year in the multiple human subjects. The survival rate is at least about 42% or higher, at least about 45% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher , At least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a 2-year overall survival rate of at least about 67% or Higher, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a 3.5-year overall survival rate of at least about 38% or Higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher , At least about 95% or higher, or about 100%. In some embodiments, administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a 5-year overall survival rate of at least about 15% or Higher, at least about 20% or higher, at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher , At least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in a 1 year, 2 year, 3.5 year, or 5 year overall survival rate compared to administration The corresponding human subjects of rituximab, gemcitabine and oxaliplatin increase, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, Any one of at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times or higher. In some embodiments, the 1-year overall survival rate refers to the number of human subjects administered immunoconjugate, rituximab, gemcitabine and oxaliplatin in the beginning of immunoconjugate, rituximab The proportion of human individuals who died of any cause one year after treatment with gemcitabine and oxaliplatin. In some embodiments, the 2-year overall survival rate refers to the start of immunoconjugate, rituximab among multiple human subjects who were administered immunoconjugate, rituximab, gemcitabine, and oxaliplatin. The proportion of human individuals who died of any cause 2 years after gemcitabine and oxaliplatin treatment. In some embodiments, the 3.5-year overall survival rate refers to the start of immunoconjugate, rituximab among a number of human subjects administered immunoconjugate, rituximab, gemcitabine, and oxaliplatin The proportion of human individuals who died of any cause 3.5 years after treatment with gemcitabine and oxaliplatin. In some embodiments, the 5-year overall survival rate refers to the start of immunoconjugate, rituximab among multiple human subjects administered immunoconjugate, rituximab, gemcitabine, and oxaliplatin The proportion of human individuals who died from any cause within 5 years after treatment with gemcitabine and oxaliplatin.

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑引起該人類個體之無進展存活。在一些實施例中、投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約13個月、至少約14個月、至少約15個月、至少約16個月、至少約17個月、至少約18個月、至少約19個月、至少約20個月、至少約21個月、至少約22個月、至少約23個月、至少約24個月或至少約25個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約5個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約6個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約9.5個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約11個月的無進展存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約14個月的無進展存活期。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得無進展存活(PFS)時間例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加。在一些實施例中，PFS係自首次投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)至根據Lugano 2014反應標準(Cheson等人 ，(2014) J Clin Oncol 32:3059-3068)判斷首次出現疾病進展，或由任何原因引起之死亡的時間量測。在一些實施例中，PFS係以天數、週數、月份數或年份數量度。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得PFS例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，PFS係使用Kaplan-Meier方法計算。在一些實施例中，治療效果之估計係使用分層Cox比例風險分析(例如 包括95%信賴限值)，以風險比表示。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使無進展存活期相較於向相應人類個體投與利妥昔單抗、吉西他濱及奧沙利鉑增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中之人類個體的無進展存活期(例如 中值無進展存活期)相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體之無進展存活期(例如 中值無進展存活期)增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，無進展存活期係自首次投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑至根據Lugano 2014反應標準判斷首次出現疾病進展(基於包括PET CT資料或不包括任何PET資料之反應)，或由任何原因引起之死亡的時間量測。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中之人類個體中引起的1年無進展存活率係至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的2年無進展存活率係至少約63%或更高、至少約65%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的5年無進展存活率係至少約14%或更高、至少約15%或更高、至少約20%或更高、至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得1年、2年、3.5年或5年無進展存活率相較於投與利妥昔單抗、吉西他濱及奧沙利鉑之相應多名人類個體增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，1年無進展存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後1年根據Lugano 2014反應標準而未發生疾病進展(基於包括PET CT資料或不包括任何PET資料之反應)或由任何原因引起之死亡的人類個體之比例。在一些實施例中，2年無進展存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後2年根據Lugano 2014反應標準而未發生疾病進展(基於包括PET CT資料或不包括任何PET資料之反應)或由任何原因引起之死亡的人類個體之比例。在一些實施例中，3.5年無進展存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後3.5年根據Lugano 2014反應標準而未發生疾病進展(基於包括PET CT資料或不包括任何PET資料之反應)或由任何原因引起之死亡的人類個體之比例。在一些實施例中，5年無進展存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後5年根據Lugano 2014反應標準而未發生疾病進展(基於包括PET CT資料或不包括任何PET資料之反應)或由任何原因引起之死亡的人類個體之比例。In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin causes progression-free survival of the human individual. In some embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin allows the human individual to start treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin Have lasting at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, At least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about A progression-free survival period of 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 4 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period that lasts at least about 5 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period that lasts at least about 6 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 9.5 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 11 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is a progression-free survival period lasting at least about 14 months. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) make progression-free survival (PFS) time, for example, compared to administration of an anti-CD20 antibody ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin). )increase. In some embodiments, the PFS is administered from the first administration of the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. Rituximab) and the one or more chemotherapeutic agents ( For example, gemcitabine and oxaliplatin) to the Lugano 2014 response criteria (Cheson et al . (2014) J Clin Oncol 32:3059-3068) to determine the first disease progression or death from any cause. In some embodiments, the PFS is measured in days, weeks, months, or years. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) increase PFS, for example , by at least about 1.1 times compared to administration of anti-CD20 antibodies ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) , At least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times Any of them or higher multiples. In some embodiments, PFS is calculated using the Kaplan-Meier method. In some embodiments, the treatment effect is estimated using a stratified Cox proportional hazard analysis ( for example, including a 95% confidence limit), expressed as a hazard ratio. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin results in progression-free survival compared to the administration of rituximab, gemcitabine, and oxaliplatin to the corresponding human individual Platinum increases, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about Any one of 5.5 times or at least about 6 times or higher. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a progression-free survival ( e.g. , a median value of none) of the human individuals among the multiple human individuals. Progression-free survival) compared to the corresponding multiple human subjects administered rituximab, gemcitabine and oxaliplatin, the progression-free survival ( e.g. median progression-free survival) increased, for example, at least about 1.1 times, at least about Any of 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times One or higher multiples. In some embodiments, the progression-free survival period is from the first administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the first occurrence of disease progression based on the Lugano 2014 response criteria (based on PET CT data or Does not include any PET data response), or the time measurement of death caused by any cause. In some embodiments, administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals causes a 1-year progression-free survival rate in human individuals among the multiple human individuals. At least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a 2-year progression-free survival rate of at least about 63% in the multiple human individuals. Or higher, at least about 65% or higher, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in a 5-year progression-free survival rate of at least about 14% in the multiple human individuals. Or higher, at least about 15% or higher, at least about 20% or higher, at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher High, at least about 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in a 1-year, 2-year, 3.5-year, or 5-year progression-free survival rate compared to the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. The corresponding multiple human subjects with rituximab, gemcitabine, and oxaliplatin increase, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times , At least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times, any one or higher multiples. In some embodiments, the 1-year progression-free survival rate refers to the number of human subjects administered immunoconjugates, rituximab, gemcitabine, and oxaliplatin at the beginning of immunoconjugates, rituximab The proportion of human individuals who did not progress (based on the response including PET CT data or not including any PET data) or died from any cause according to the Lugano 2014 response criteria 1 year after treatment with anti-gemcitabine and oxaliplatin. In some embodiments, the 2-year progression-free survival rate refers to the number of human subjects administered immunoconjugate, rituximab, gemcitabine, and oxaliplatin in the beginning of immunoconjugate, rituximab The proportion of human individuals who have not progressed (based on the response including PET CT data or excluding any PET data) or died from any cause according to the Lugano 2014 response criteria 2 years after treatment with anti-gemcitabine and oxaliplatin. In some embodiments, the 3.5-year progression-free survival rate refers to the number of human subjects administered immunoconjugates, rituximab, gemcitabine, and oxaliplatin at the beginning of immunoconjugates, rituximab The proportion of human individuals who did not progress (based on the response including PET CT data or not including any PET data) or died from any cause according to the Lugano 2014 response criteria after 3.5 years of treatment with anti-gemcitabine and oxaliplatin. In some embodiments, the 5-year progression-free survival rate refers to the number of human subjects administered immunoconjugates, rituximab, gemcitabine, and oxaliplatin at the beginning of immunoconjugates, rituximab The proportion of human individuals who have not progressed (based on the response including PET CT data or excluding any PET data) or died from any cause according to the Lugano 2014 response criteria for 5 years after treatment with anti-gemcitabine and oxaliplatin.

在一些實施例中，OS及PFS係在經歷HSCT之患者中評估。In some embodiments, OS and PFS are evaluated in patients undergoing HSCT.

在一些實施例中，針對根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)的反應係藉由此項技術中已知之任何方法量測。在一些實施例中，針對根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)的反應係藉由正電子發射電腦斷層攝影術(PET)及/或電腦斷層攝影術(CT)掃描量測。在一些實施例中，針對根據本文所提供之方法之治療的反應係使用2014 Lugano標準(Cheson等人 ，(2014) J Clin Oncol 32:3059-3068)評估。在一些實施例中，針對根據本文所提供之方法之治療的反應係在治療期間或在治療結束時評估。在一些實施例中，針對根據本文所提供之方法之治療的反應係在患者中與在根據本文所提供之方法投與治療之前的評估相比較來評估。在一些實施例中，CT掃描係每6個月執行一次。在一些實施例中，PET掃描係在根據本文所提供之方法投與治療之前及結束時執行。在一些實施例中，PET及/或CT (例如 PET-CT)掃描包括顱底到大腿中部。在一些實施例中，執行全身PET-CT掃描。在一些實施例中，CT掃描包括靜脈內造影，其可包括但不限於胸部、頸部、腹部及盆骨掃描。在一些實施例中，例如，若懷疑疾病進展或復發，則執行腫瘤之放射照相評估。在一些實施例中，針對根據本文所提供之方法之治療的反應係使用骨髓活檢評估，骨髓活檢可根據此項技術中已知之任何方法執行。在一些情況下，骨髓活檢係在患者中用PET-CT上之陰性骨信號執行。在一些實施例中，PET-CT及/或CT掃描係根據本文所提供之方法投與治療之前且根據臨床指示，在根據本文所提供之方法投與治療期間及之後獲得。在一些實施例中，PET-CT及/或CT掃描在根據本文所提供之方法投與治療之後執行至多兩年。 In some embodiments, the immunoconjugate (e.g. Pertuzumab Vidotin-piiq), an anti-CD20 antibody ( e.g. rituximab) and the one or more chemical agents are administered according to the methods provided herein. The response of therapeutic agents ( such as gemcitabine and oxaliplatin) is measured by any method known in the art. In some embodiments, the immunoconjugate (e.g. Pertuzumab Vidotin-piiq), an anti-CD20 antibody ( e.g. rituximab) and the one or more chemical agents are administered according to the methods provided herein. The response to therapeutic agents ( such as gemcitabine and oxaliplatin) is measured by positron emission computed tomography (PET) and/or computed tomography (CT) scanning. In some embodiments, the response to treatment according to the methods provided herein is assessed using the 2014 Lugano criteria (Cheson et al . (2014) J Clin Oncol 32:3059-3068). In some embodiments, the response to treatment according to the methods provided herein is assessed during the treatment or at the end of the treatment. In some embodiments, the response to treatment according to the methods provided herein is evaluated in the patient compared to an evaluation before the treatment according to the methods provided herein. In some embodiments, CT scans are performed every 6 months. In some embodiments, the PET scan is performed before and at the end of the treatment according to the methods provided herein. In some embodiments, PET and/or CT ( eg, PET-CT) scans include the base of the skull to the middle of the thigh. In some embodiments, a whole body PET-CT scan is performed. In some embodiments, the CT scan includes intravenous angiography, which may include, but is not limited to, chest, neck, abdomen, and pelvic scans. In some embodiments, for example, if disease progression or recurrence is suspected, a radiographic evaluation of the tumor is performed. In some embodiments, the response to treatment according to the methods provided herein is assessed using bone marrow biopsy, which can be performed according to any method known in the art. In some cases, bone marrow biopsy is performed in patients with negative bone signals on PET-CT. In some embodiments, PET-CT and/or CT scans are obtained before and after treatment according to the methods provided herein, and according to clinical instructions, during and after treatment according to the methods provided herein. In some embodiments, PET-CT and/or CT scans are performed up to two years after administering treatment according to the methods provided herein.

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該人類個體中引起完全反應。在一些實施例中，根據Lugano 2014反應標準(Cheson等人 ，(2014) J Clin Oncol 32:3059-3068)，完全反應包含基於PET-CT之完全代謝反應。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得完全反應率(CRR)例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加。在一些實施例中，CRR係指根據Lugano 2014反應標準，例如 基於正電子發射斷層攝影術及電腦斷層攝影(PET-CT)分析，在用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)治療結束時實現完全代謝反應的患者比例。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得CRR例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，CRR係在不包括PET資料情況下確定。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得完全反應率(CRR)相較於投與利妥昔單抗、吉西他濱及奧沙利鉑之相應多名人類個體增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的完全反應率係至少約35%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin elicits a complete response in the human individual. In some embodiments, according to the Lugano 2014 reaction standard (Cheson et al . (2014) J Clin Oncol 32:3059-3068), the complete reaction includes a complete metabolic reaction based on PET-CT. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) make the complete response rate (CRR), for example, compared to administration of an anti-CD20 antibody ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) increase. In some embodiments, CRR refers to the use of immunoconjugates (e.g. Pertuzumab Vidotin ) based on Lugano 2014 response criteria, for example, based on positron emission tomography and computer tomography (PET-CT) analysis. -piiq), anti-CD20 antibody ( e.g. , rituximab), and the proportion of patients who achieve a complete metabolic response at the end of treatment with one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin). In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) increase CRR, for example , by at least about 1.1 times compared to administration of anti-CD20 antibodies ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) , At least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times Any of them or higher multiples. In some embodiments, CRR is determined without including PET data. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects makes the complete response rate (CRR) compared to the administration of rituximab, gemcitabine, and oxaliplatin. The corresponding increase in oxaliplatin in a plurality of human individuals is, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 Times, at least about 5 times, at least about 5.5 times, or at least about 6 times, or higher. In some embodiments that can be combined with any of the foregoing embodiments, the complete response rate caused by the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals At least about 35% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher, at least About 90% or higher, at least about 95% or higher, or about 100%.

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該人類個體中引起部分反應。在一些實施例中，根據Lugano 2014反應標準，部分反應包括含PET CT資料之部分代謝反應。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得客觀反應率(ORR)例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加。在一些實施例中，ORR係指根據Lugano 2014反應標準，例如 基於正電子發射斷層攝影術及電腦斷層攝影(PET-CT)分析，在用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)治療結束時實現完全或部分代謝反應的患者比例。在一些實施例中，ORR係指例如 根據Lugano 2014反應標準，在用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)治療結束時實現完全或部分代謝反應的患者比例。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得ORR例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，ORR係在不包括PET資料情況下確定。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得客觀反應率(ORR)相較於投與利妥昔單抗、吉西他濱及奧沙利鉑之相應多名人類個體增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的客觀反應率係至少約44%或更高、至少約45%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的部分反應率係至少約10%或更高、至少約20%或更高、至少約30%或更高、至少約40%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在可與前述實施例中之任一個組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得部分反應率相較於投與利妥昔單抗、吉西他濱及奧沙利鉑之相應多名人類個體增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，部分反應率係指根據Lugano 2014反應標準，例如 基於正電子發射斷層攝影術及電腦斷層攝影(PET-CT)分析，在用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)治療結束時實現部分代謝反應的患者比例。在一些實施例中，部分反應率係指例如 根據Lugano 2014反應標準，在用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)治療結束時實現部分代謝反應的患者比例。In some embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin elicits a partial response in the human individual. In some embodiments, according to the Lugano 2014 reaction standard, the partial reaction includes a partial metabolic reaction including PET CT data. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) make the objective response rate (ORR), for example, compared to administration of an anti-CD20 antibody ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) increase. In some embodiments, ORR refers to the use of immunoconjugates (e.g. Pertuzumab Vidotin ) based on Lugano 2014 reaction criteria, for example, based on positron emission tomography and computer tomography (PET-CT) analysis. -piiq), an anti-CD20 antibody ( e.g. , rituximab), and the proportion of patients with a complete or partial metabolic response at the end of treatment with one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin). In some embodiments, ORR refers to, for example, according to Lugano 2014 reaction criteria, immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. rituximab) and the same The proportion of patients who achieved a complete or partial metabolic response at the end of treatment with multiple chemotherapeutic agents ( such as gemcitabine and oxaliplatin). In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g., gemcitabine and oxaliplatin) increase ORR, for example , by at least about 1.1 times compared to administration of anti-CD20 antibodies ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) , At least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times Any of them or higher multiples. In some embodiments, the ORR is determined without including PET data. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects makes the objective response rate (ORR) compared to the administration of rituximab, gemcitabine, and oxaliplatin. The corresponding increase in oxaliplatin in a plurality of human individuals is, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 Times, at least about 5 times, at least about 5.5 times, or at least about 6 times, or higher. In some embodiments that can be combined with any of the foregoing embodiments, the objective response rate of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin caused by the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals At least about 44% or higher, at least about 45% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher, at least About 90% or higher, at least about 95% or higher, or about 100%. In some embodiments that can be combined with any of the foregoing embodiments, the partial response rate caused by the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals At least about 10% or higher, at least about 20% or higher, at least about 30% or higher, at least about 40% or higher, at least about 50% or higher, at least about 60% or higher, at least About 70% or higher, at least about 80% or higher, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments that can be combined with any of the preceding embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects makes the partial response rate compared to administration The corresponding human subjects of rituximab, gemcitabine and oxaliplatin increase, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, Any one of at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times or higher. In some embodiments, the partial response rate refers to the Lugano 2014 response standard, for example, based on positron emission tomography and computer tomography (PET-CT) analysis, using immunoconjugates ( such as Pertuzumab Vitamin Dotin-piiq), an anti-CD20 antibody ( e.g. , rituximab), and the proportion of patients who achieved a partial metabolic response at the end of treatment with one or more chemotherapeutics ( e.g., gemcitabine and oxaliplatin). In some embodiments, the partial response rate refers to, for example , the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and The proportion of patients who achieved a partial metabolic response at the end of the treatment with the one or more chemotherapeutic agents ( for example, gemcitabine and oxaliplatin).

在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得最佳總體反應(BOR)比率例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加。在一些實施例中，BOR係指根據Lugano 2014反應標準，例如 基於正電子發射斷層攝影術及電腦斷層攝影(PET-CT)分析，在用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)治療期間的最佳反應。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得BOR比率例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得最佳總體反應率(BOR)相較於投與利妥昔單抗、吉西他濱及奧沙利鉑之相應多名人類個體增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) make the best overall response (BOR) ratio, for example, compared to administration of an anti-CD20 antibody ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin). Platinum) increase. In some embodiments, BOR refers to the use of immunoconjugates (e.g. Pertuzumab Vidotin ) based on Lugano 2014 reaction criteria, for example, based on positron emission tomography and computer tomography (PET-CT) analysis. -piiq), anti-CD20 antibody ( e.g. rituximab) and the best response during treatment with the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin). In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) increase the BOR ratio, for example , by at least about 1.1 compared to administration of an anti-CD20 antibody ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) Times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times Any one of multiples or a higher multiple. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals results in the best overall response rate (BOR) compared to administration of rituximab, The corresponding multiple human individuals of gemcitabine and oxaliplatin increase, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least Any one of about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times or higher.

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑引起該人類個體之無事件存活。在一些實施例中、投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約13個月、至少約14個月、至少約15個月、至少約16個月、至少約17個月、至少約18個月、至少約19個月、至少約20個月、至少約21個月、至少約22個月、至少約23個月、至少約24個月或至少約25個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約4個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約5個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約6個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約9.5個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約11個月的無事件存活期。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該人類個體在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後有持續至少約14個月的無事件存活期。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得無事件存活(EFSeff )時間例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加。在一些實施例中，EFSeff 係指自首次投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)的時間至發生疾病進展或復發、由任何原因引起之死亡或起始另一種抗淋巴瘤治療中之任一種的時間。在一些實施例中，EFSeff 係以天數、週數、月份數或年份數量度。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得EFSeff 例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，用於PFS分析之方法(例如 ，如上所述)用於分析EFSeff 。在一些實施例中，無事件存活期係自首次投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑的時間至首次發生以下任一種情形的時間量測：(i)疾病進展或復發(基於包括PET CT資料或不包括任何PET資料之反應)；(ii)由任何原因引起之死亡；或(iii)起始新的抗淋巴瘤治療(NALT)。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使人類個體之無事件存活期相較於向相應人類個體投與利妥昔單抗、吉西他濱及奧沙利鉑增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中之人類個體的無事件存活期相較於投與利妥昔單抗、吉西他濱及奧沙利鉑的相應多名人類個體增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在可與任何前述實施例組合的一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑在該多名人類個體中引起的2年無事件存活率係至少約44%或更高、至少約45%或更高、至少約50%或更高、至少約60%或更高、至少約70%或更高、至少約80%或更高、至少約90%或更高、至少約95%或更高、或約100%。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得1年、2年、3.5年或5年無事件存活率相較於投與利妥昔單抗、吉西他濱及奧沙利鉑之相應多名人類個體增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，1年無事件存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後1年未發生以下任一種情形之人類個體的比例：(i)疾病進展或復發(基於包括PET CT資料或不包括任何PET資料之反應)；(ii)由任何原因引起之死亡；或(iii)起始新的抗淋巴瘤治療(NALT)。在一些實施例中，2年無事件存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後2年未發生以下任一種情形之人類個體的比例：(i)疾病進展或復發(基於包括PET CT資料或不包括任何PET資料之反應)；(ii)由任何原因引起之死亡；或(iii)起始新的抗淋巴瘤治療(NALT)。在一些實施例中，3.5年無事件存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後3.5年未發生以下任一種情形之人類個體的比例：(i)疾病進展或復發(基於包括PET CT資料或不包括任何PET資料之反應)；(ii)由任何原因引起之死亡；或(iii)起始新的抗淋巴瘤治療(NALT)。在一些實施例中，5年無事件存活率係指投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之多名人類個體中在開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療後5年未發生以下任一種情形之人類個體的比例：(i)疾病進展或復發(基於包括PET CT資料或不包括任何PET資料之反應)；(ii)由任何原因引起之死亡；或(iii)起始新的抗淋巴瘤治療(NALT)。In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes event-free survival of the human individual. In some embodiments, the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin allows the human individual to start treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin Have lasting at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, At least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about An event-free survival period of 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival that lasts at least about 4 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival period that lasts at least about 5 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 6 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 9.5 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 11 months. In some embodiments, the administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin causes the human individual to start treatment with immunoconjugate, rituximab, gemcitabine, and oxaliplatin There is an event-free survival period lasting at least about 14 months. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) make event-free survival (EFS eff ) time, for example, compared to administration of anti-CD20 antibodies ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) Platinum) increase. In some embodiments, EFS eff refers to the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy treatments since the first administration. The time of treatment ( e.g. gemcitabine and oxaliplatin) to the onset of disease progression or recurrence, death from any cause, or the initiation of another anti-lymphoma treatment. In some embodiments, EFS eff is measured in days, weeks, months, or years. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) increase the EFS eff, for example , by at least about 1.1 compared to administration of an anti-CD20 antibody ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) Times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times Any one of multiples or a higher multiple. In some embodiments, the method used for PFS analysis ( eg , as described above) is used to analyze EFS eff . In some embodiments, the event-free survival period is measured from the time when the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are first administered to the time when any of the following occurs for the first time: (i) disease Progression or recurrence (based on the response including PET CT data or not including any PET data); (ii) death from any cause; or (iii) initiation of new anti-lymphoma therapy (NALT). In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin makes the event-free survival of the human individual compared to the administration of rituximab, gemcitabine, and oxaliplatin to the corresponding human individual. Oxaliplatin is increased by, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times , At least about 5.5 times or at least about 6 times any one or higher multiples. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human individuals makes the event-free survival of the human individuals of the multiple human individuals compared to the administration The corresponding human subjects of rituximab, gemcitabine, and oxaliplatin increase, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, Any one of at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times or higher. In some embodiments that can be combined with any of the foregoing embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects caused 2 years of non-existence in the multiple human subjects. Event survival rate is at least about 44% or higher, at least about 45% or higher, at least about 50% or higher, at least about 60% or higher, at least about 70% or higher, at least about 80% or higher High, at least about 90% or higher, at least about 95% or higher, or about 100%. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects results in a 1-year, 2-year, 3.5-year, or 5-year event-free survival rate compared to the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. The corresponding multiple human subjects with rituximab, gemcitabine, and oxaliplatin increase, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times , At least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times, any one or higher multiples. In some embodiments, the 1-year event-free survival rate refers to the number of human subjects administered immunoconjugates, rituximab, gemcitabine, and oxaliplatin at the beginning of immunoconjugates, rituximab The proportion of human individuals who have not experienced any of the following conditions within 1 year after anti-, gemcitabine and oxaliplatin treatment: (i) disease progression or recurrence (based on the response including PET CT data or not including any PET data); (ii) Death caused by any reason; or (iii) initiation of new anti-lymphoma therapy (NALT). In some embodiments, the 2-year event-free survival rate refers to the number of human subjects administered immunoconjugates, rituximab, gemcitabine, and oxaliplatin at the beginning of immunoconjugates, rituximab The proportion of human individuals who have not experienced any of the following conditions after 2 years of anti-, gemcitabine and oxaliplatin treatment: (i) disease progression or recurrence (based on the response that includes PET CT data or does not include any PET data); (ii) Death caused by any reason; or (iii) initiation of new anti-lymphoma therapy (NALT). In some embodiments, the 3.5-year event-free survival rate refers to the number of human subjects administered immunoconjugates, rituximab, gemcitabine, and oxaliplatin at the start of immunoconjugates, rituximab The proportion of human individuals who have not had any of the following conditions after 3.5 years of anti-, gemcitabine and oxaliplatin treatment: (i) disease progression or recurrence (based on the response including PET CT data or not including any PET data); (ii) Death caused by any reason; or (iii) initiation of new anti-lymphoma therapy (NALT). In some embodiments, the 5-year event-free survival rate refers to the number of human subjects administered immunoconjugates, rituximab, gemcitabine, and oxaliplatin at the beginning of immunoconjugates, rituximab The proportion of human individuals who have not experienced any of the following conditions after 5 years of anti-, gemcitabine and oxaliplatin treatment: (i) disease progression or recurrence (based on the response including PET CT data or not including any PET data); (ii) Death caused by any reason; or (iii) initiation of new anti-lymphoma therapy (NALT).

在一些實施例中，無事件存活率係自首次投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑、或自開始免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑治療的時間至首次發生以下任一種情形之時間量測：(i)疾病進展或復發(基於包括PET CT資料或不包括任何PET資料之反應)；(ii)由任何原因引起之死亡；或(iii)起始新的抗淋巴瘤治療(NALT)。In some embodiments, the event-free survival rate is based on the first administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin, or since the initial administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin. The measurement of the time from the time of thaliplatin treatment to the first occurrence of any of the following conditions: (i) disease progression or recurrence (based on the response including PET CT data or excluding any PET data); (ii) death caused by any cause ; Or (iii) Initiate a new anti-lymphoma treatment (NALT).

在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得反應持續時間(DOR)例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加。在一些實施例中，DOR係在根據本文所提供之方法投與治療之患者中量測，該等患者自首次發生完全或部分反應之日期直至發生進行性疾病或死亡之首個日期，具有使用Lugano 2014標準確定之客觀反應。在一些實施例中，DOR係以天數、週數、月份數或年份數量度。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)使得DOR例如 相較於投與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)增加至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。在一些實施例中，用於PFS分析之方法(例如 ，如上所述)用於分析DOR，不過DOR分析未經分層。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得反應持續時間(DOR)相較於投與利妥昔單抗、吉西他濱及奧沙利鉑之相應多名人類個體增加例如 至少約1.1倍、至少約1.5倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍或至少約6倍中之任一種或更高倍數。In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) make the duration of response (DOR), for example, compared to administration of an anti-CD20 antibody ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) increase. In some embodiments, DOR is measured in patients who are administered treatment according to the methods provided herein, and these patients have use from the date of the first full or partial response until the first date of the onset of progressive disease or death. The objective response determined by the Lugano 2014 standard. In some embodiments, DOR is measured in days, weeks, months, or years. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein Agents ( e.g. gemcitabine and oxaliplatin) increase DOR, for example , by at least about 1.1 times compared to administration of an anti-CD20 antibody ( e.g. , rituximab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) , At least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times Any of them or higher multiples. In some embodiments, the method used for PFS analysis ( eg , as described above) is used to analyze DOR, but DOR analysis is not stratified. In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin to multiple human subjects makes the duration of response (DOR) compared to the administration of rituximab, gemcitabine, and oxaliplatin. The corresponding increase in oxaliplatin in a plurality of human individuals is, for example, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 Times, at least about 5 times, at least about 5.5 times, or at least about 6 times, or higher.

在一些實施例中，針對根據本文所提供之方法用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)治療的反應係使用患者報告結果(PRO)工具評估。PRO工具之實例包括但不限於FACT/GOG-Ntx12神經病(Kopec等人 ，(2006) J Supportive Oncol，4:W1-W8；Calhoun等人 ，(2003) Int J Gynecol Cancer，13:741-748)、EQ-5D-5L (EuroQol (1990) Health Policy，16:199-208；Brooks (1996) Health Policy，37:53-72；Herdman等人 ，(2011) 20:1727-1736；Janssen等人 ，(2013) Qual Life Res，22:1717-1727；http://www(dot)euroqol(dot)org/about-eq-5d/valuation-of-eq-5d；Devlin等人， (2017) Health Economics，1-16)、EORTC QLQ-C30 (Aaronson等人 ，(1993) J Natl Cancer Inst，85:365-376；Fitzsimmons等人 ，(1999) 35:939-941)及FACT/Lym (Cella等人 ，(1993) J Clin ONcol，11:570-579；Cella等人 ，(2005) Blood，106:750；Carter等人 ，(2008) Blood，112:2376；Hlubocky等人 ，(2013) Lymphoma，ID147176；Webster等人 ，(2003) Health Qual Life Outcomes，1:79)。 In some embodiments, immunoconjugates (e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. rituximab) and the one or more chemotherapeutics are used in some embodiments according to the methods provided herein The response to treatment with drugs ( such as gemcitabine and oxaliplatin) is assessed using the Patient Reported Outcome (PRO) tool. Examples of PRO tools include, but are not limited to, FACT/GOG-Ntx12 neuropathy (Kopec et al ., (2006) J Supportive Oncol, 4: W1-W8; Calhoun et al ., (2003) Int J Gynecol Cancer, 13:741-748) , EQ-5D-5L (EuroQol (1990) Health Policy, 16:199-208; Brooks (1996) Health Policy, 37:53-72; Herdman et al ., (2011) 20:1727-1736; Janssen et al ., (2013) Qual Life Res, 22:1717-1727; http://www(dot)euroqol(dot)org/about-eq-5d/valuation-of-eq-5d; Devlin et al., (2017) Health Economics , 1-16), EORTC QLQ-C30 (Aaronson et al ., (1993) J Natl Cancer Inst, 85:365-376; Fitzsimmons et al ., (1999) 35:939-941), and FACT/Lym (Cella et al. , (1993) J Clin ONcol, 11:570-579; Cella et al ., (2005) Blood, 106:750; Carter et al ., (2008) Blood, 112:2376; Hlubocky et al ., (2013) Lymphoma, ID147176 ; Webster et al ., (2003) Health Qual Life Outcomes, 1:79).

在一些實施例中，在根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之後的不良事件係根據國家癌症研究院常見不良事件評價準則第5版(National Cancer Institute Common Terminology Criteria for Adverse Events，Version 5；NCI CTCAE v5.0)、癌症療法功能評估/婦科腫瘤學組-神經毒性12項量表(Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item Scale，FACT/GOG-Ntx12)、臨床實驗室測試結果、心電圖(ECG)及/或生命體徵評估。在一些實施例中，對導致治療終止之不良事件、導致劑量減少或中止之不良事件、≥3級不良事件、導致死亡之不良事件、嚴重不良事件及/或特別關注之不良事件進行分析。在一些實施例中，本文所提供之不良事件係針對暴露於免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及/或該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)分析。 In some embodiments, the immunoconjugate (e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemical compounds are administered according to the methods provided herein. Adverse events following therapeutic agents ( such as gemcitabine and oxaliplatin) are based on the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5; NCI CTCAE v5.0), Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item Scale (FACT/GOG-Ntx12), clinical laboratory test results, electrocardiogram (ECG) And/or vital signs assessment. In some embodiments, analysis is performed on adverse events leading to treatment termination, adverse events leading to dose reduction or discontinuation, ≥ grade 3 adverse events, adverse events leading to death, serious adverse events, and/or adverse events of special concern. In some embodiments, the adverse events provided herein are directed to exposure to immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. Rituximab), and/or this one. Or a variety of chemotherapeutic agents ( such as gemcitabine and oxaliplatin) analysis.

在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化療劑(例如 吉西他濱及奧沙利鉑)之患者中周圍神經病變之發生係藉由FACT/GOG-Ntx12得分及/或NCI CTCAE v5.0評估。周圍神經病變(感覺及/或運動神經病)之症狀包括但不限於感覺減退、感覺亢進、感覺異常、感覺遲鈍、不適、灼燒感、無力、步態不穩或神經病變性疼痛。在一些實施例中，周圍神經病變之發生率係基於例如 不良事件分析計算。在一些實施例中，發生周圍神經病變之所有患者在終止根據本文所提供之方法進行之治療後經歷隨訪，直至疾病消退或穩定。在一些實施例中，小於50% (例如 小於約50%、45%、40%、35%、34%、33%、32%、31%、30%、29%、28%、27%、26%、25%、24%、23%、22%、21%、20%、19%、18%、17%、16%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%或0.5%中任一百分比)的根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之患者經歷≥3級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內(例如 14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成≤1級。在一些實施例中，小於約40%的根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之患者經歷≥3級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內消退成≤1級。在一些實施例中，小於約33%的根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之患者經歷≥3級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內消退成≤1級。在一些實施例中，小於約30%的根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之患者經歷≥3級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內消退成≤1級。在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起4級或更高級(例如4級或更高級、或5級或更高級中之任一種)的周圍神經病變。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，在該人類個體未經歷4級或更高級(例如4級或更高級、或5級或更高級中之任一種)的周圍神經病變。在一些實施例中，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之後，該人類個體未經歷4級或更高級(例如4級或更高級、或5級或更高級中之任一種)的周圍神經病變。在一些實施例中，神經毒性係指感覺及/或運動周圍神經病變。在一些實施例中，向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使該多名人類個體中33%或更少(例如 以下任一種：約33%或更少、約32%或更少、約31%或更少、約30%或更少、約29%或更少、約28%或更少、約27%或更少、約26%或更少、約25%或更少、約24%或更少、約23%或更少、約22%或更少、約21%或更少、約20%或更少、約19%或更少、約18%或更少、約17%或更少、約16%或更少、約15%或更少、約14%或更少、約13%或更少、約12%或更少、約11%或更少、約10%或更少、約9%或更少、約8%或更少、約7%或更少、約6%或更少、約5%或更少、約4%或更少、約3%或更少、約2%或更少、約1%或更少、或約0.5%或更少)的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中的任一種)的周圍神經病變，該疾病不能在14天內(例如 在14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在一些實施例中，向多名人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中小於約40% (例如 小於約40%、35%、34%、33%、32%、31%、30%、29%、28%、27%、26%、25%、24%、23%、22%、21%、20%、19%、18%、17%、16%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%或0.5%中任一百分比) 的人類個體經歷3級或更高級(例如3級或更高級、4級或更高級、或5級或更高級中之任一種)的周圍神經病變，該疾病不能在14天內(例如 14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天中之任一種內)消退成1級或更低級別。在某些實施例中，免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。 In some embodiments, the immunoconjugate (e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapeutic agents are administered according to the methods provided herein The occurrence of peripheral neuropathy in patients ( such as gemcitabine and oxaliplatin) is assessed by FACT/GOG-Ntx12 score and/or NCI CTCAE v5.0. Symptoms of peripheral neuropathy (sensory and/or motor neuropathy) include but are not limited to hypoesthesia, hyperesthesia, paresthesia, hypoesthesia, discomfort, burning sensation, weakness, gait instability, or neuropathic pain. In some embodiments, the incidence of peripheral neuropathy is calculated based on, for example, adverse event analysis. In some embodiments, all patients with peripheral neuropathy undergo follow-up after termination of treatment according to the methods provided herein until the disease resolves or stabilizes. In some embodiments, less than 50% ( e.g., less than about 50%, 45%, 40%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26% %, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0.5%) of the immunoconjugate ( e.g. Patients with tocilizumab vidotin-piiq), anti-CD20 antibodies ( e.g. rituximab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin) experienced ≥ grade 3 (e.g. grade 3 or Peripheral neuropathy of higher grade, grade 4 or higher, or grade 5 or higher), the disease cannot be within 14 days ( for example, 14 days, 13 days, 12 days, 11 days, 10 days, 9 Within days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day), it regressed to grade ≤1. In some embodiments, less than about 40% of the immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. rituximab) and the immunoconjugates administered according to the methods provided herein Patients with one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin) experience peripheral neuropathy ≥ grade 3 (e.g., any of grade 3 or higher, grade 4 or higher, or grade 5 or higher) , The disease cannot subside to grade ≤1 within 14 days. In some embodiments, less than about 33% of the immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. rituximab) and the immunoconjugate administered according to the methods provided herein Patients with one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin) experience peripheral neuropathy ≥ grade 3 (e.g., any of grade 3 or higher, grade 4 or higher, or grade 5 or higher) , The disease cannot subside to grade ≤1 within 14 days. In some embodiments, less than about 30% of the immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. rituximab) and the immunoconjugates administered according to the methods provided herein Patients with one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin) experience peripheral neuropathy ≥ grade 3 (e.g., any of grade 3 or higher, grade 4 or higher, or grade 5 or higher) , The disease cannot subside to grade ≤1 within 14 days. In some embodiments, administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause grade 4 or higher (e.g., grade 4 or higher, or grade 5 or Any of the higher grades) peripheral neuropathy. In some embodiments, after the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human individual has not experienced grade 4 or higher (for example, grade 4 or higher, or grade 5). Or higher level) peripheral neuropathy. In some embodiments, after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human individual has not experienced grade 4 or higher (e.g., grade 4 or higher, or grade 5 or Any of the higher grades) peripheral neuropathy. In some embodiments, neurotoxicity refers to sensory and/or peripheral motor neuropathy. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to multiple human individuals makes 33% or less of the multiple human individuals ( e.g., any of the following: about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26 % Or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% Or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or Less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less Few, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human individuals experience level 3 or higher (e.g., 3 Grade or higher, grade 4 or higher, or grade 5 or higher) peripheral neuropathy, the disease can not be within 14 days ( for example , 14 days, 13 days, 12 days, 11 days, 10 Within any of days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) regressed to grade 1 or lower. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered to multiple human individuals such that less than about 40% ( e.g., less than about 40%, 35% , 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18 %, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0.5%) of human individuals who experience grade 3 or higher (for example, any of grade 3 or higher, grade 4 or higher, or grade 5 or higher) peripheral neuropathy, the Illness cannot be within 14 days ( e.g., 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) (Within any of them) fade to level 1 or lower. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day cycles.

在一些實施例中，對藥物誘發之肝損傷的發生進行評估。In some embodiments, the occurrence of drug-induced liver injury is evaluated.

在一些實施例中，評估當根據本文所提供之方法投與時免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)之免疫原性。在一些實施例中，藉由量測針對免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)之抗藥物抗體(ADA)來評估當根據本文所提供之方法投與時該免疫偶聯物的免疫原性。在一些實施例中，ADA係使用經驗證之抗體橋接酶聯免疫吸附分析(ELISA)在患者血清樣品中量測。In some embodiments, the immunogenicity of the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq) when administered according to the methods provided herein is assessed. In some embodiments, the anti-drug antibody (ADA) against the immunoconjugate (such as Pertuzumab Vidotin-piiq) is measured to evaluate the immunoconjugate when administered according to the methods provided herein. The immunogenicity of the conjugate. In some embodiments, ADA is measured in patient serum samples using a validated antibody-bridged enzyme-linked immunosorbent assay (ELISA).

在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之患者的不良事件發生率係在完成至少一個21天治療週期之後評估。在一些實施例中，根據本文所提供之方法投與免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之患者的不良事件發生率係在完成至少兩個21天治療週期之後評估In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein The incidence of adverse events in patients with drugs ( eg gemcitabine and oxaliplatin) is assessed after completing at least one 21-day treatment cycle. In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemotherapy are administered according to the methods provided herein The incidence of adverse events in patients with drugs ( e.g. gemcitabine and oxaliplatin) is assessed after completing at least two 21-day treatment cycles

在一些實施例中，免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及/或該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之劑量係根據不良事件之發生來改變。在一些實施例中，不良事件係基於在一個週期之第1天輸注之前72小時內獲得的實驗室測試結果。在某些實施例中，根據國家癌症研究院常見不良事件評價準則第5版(NCI CTCAE v5.0)對症狀分級。In some embodiments, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. Rituximab), and/or the one or more chemotherapeutic agents ( e.g., gemcitabine and ozone) The dose of thaliplatin is changed according to the occurrence of adverse events. In some embodiments, the adverse event is based on laboratory test results obtained within 72 hours before the infusion on day 1 of a cycle. In some embodiments, the symptoms are graded according to the National Cancer Institute's Common Adverse Events Evaluation Guidelines 5th Edition (NCI CTCAE v5.0).

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起嗜中性白血球減少症。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與針對嗜中性白血球減少症之預防性治療。在一些實施例中，針對嗜中性白血球減少症之預防性治療包括例如 在每個治療週期中投與G-CSF。在一些實施例中，若發生3級或4級嗜中性白血球減少症，則持續用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)治療直至絕對嗜中性白血球計數(ANC)恢復至 ＞1000個/μl。在一些實施例中，若需要管理嗜中性白血球減少症，則投與生長因子(例如 G-CSF)。參見例如 Smith等人 ，(2016) J Clin Oncol，24:3187-205。在一些實施例中，若在第7天或之前人類個體之ANC恢復至＞ 1000個/μl，則重新開始用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)進行之治療，無需任何額外劑量減少。在一些實施例中，若在第7天後人類個體之ANC恢復至＞ 1000個/μl，則帕妥珠單抗維多汀-piiq之劑量減少至1.4 mg/kg。在一些實施例中，若發生先前帕妥珠單抗維多汀-piiq劑量減少，則中止用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)進行之治療。In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause neutropenia in the human individual. In some embodiments, the methods provided herein further comprise administering to the human subject before, during, and/or after administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human subject Preventive treatment for neutropenia. In some embodiments, preventive treatment for neutropenia includes, for example , administration of G-CSF in each treatment cycle. In some embodiments, if grade 3 or 4 neutropenia occurs, continue to use immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. Rituxan Anti) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin) are treated until the absolute neutrophil count (ANC) returns to >1000/μl. In some embodiments, if neutropenia needs to be managed, growth factors ( e.g., G-CSF) are administered. See, for example, Smith et al ., (2016) J Clin Oncol, 24: 3187-205. In some embodiments, if the ANC of the human individual recovers to> 1000/μl on or before the 7th day, the immunoconjugate ( such as Pertuzumab Vidotin-piiq), anti-CD20 antibody is restarted ( Such as rituximab) and the one or more chemotherapeutics ( such as gemcitabine and oxaliplatin) without any additional dose reduction. In some embodiments, if the ANC of the human individual recovers to> 1000/μl after the 7th day, the dose of Pertuzumab Vidotin-piiq is reduced to 1.4 mg/kg. In some embodiments, if a previous reduction in the dose of Pertuzumab Vidotin-piiq occurs, discontinue the use of immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. Ritux) Cixiimab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin).

在一些實施例中，若發生3級或4級血小板減少症，則持續用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)治療直至血小板恢復至＞ 75,000個/μl。在一些實施例中，若在第7天或之前血小板恢復至＞ 75,000個/μl，則重新開始用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)進行之治療，無需任何額外劑量減少。在一些實施例中，若在第7天後血小板恢復至＞ 75,000個/μl，則帕妥珠單抗維多汀-piiq之劑量減少至1.4 mg/kg。在一些實施例中，若發生先前帕妥珠單抗維多汀-piiq劑量減少，則中止用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)進行之治療。In some embodiments, if grade 3 or 4 thrombocytopenia occurs, continue to use immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. Rituximab) and The one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) are treated until platelets recover to> 75,000/μl. In some embodiments, if the platelets recover to> 75,000/μl on or before day 7, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. Rib Tuximab) and the one or more chemotherapeutic agents ( such as gemcitabine and oxaliplatin) do not require any additional dose reduction. In some embodiments, if the number of platelets recovered to> 75,000/μl after the 7th day, the dose of Pertuzumab Vidotin-piiq was reduced to 1.4 mg/kg. In some embodiments, if a previous reduction in the dose of Pertuzumab Vidotin-piiq occurs, discontinue the use of immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. Ritux) Cixiimab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin).

在一些實施例中，若發生2級或3級周圍神經病變，則延遲用免疫偶聯物(例如帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如利妥昔單抗)及該一或多種化學治療劑(例如吉西他濱及奧沙利鉑)治療)進行之治療直至改善成≤1級。在一些實施例中，若2級或3級周圍神經病變在14天內恢復至級別≤ 1級，則用1.4 mg/kg的持久減少之劑量的帕妥珠單抗維多汀-piiq及75 mg/m2 劑量之奧沙利鉑重新開始用免疫偶聯物(例如帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如利妥昔單抗)及該一或多種化學治療劑(例如吉西他濱及奧沙利鉑)進行之治療。在一些實施例中，若2級或3級周圍神經病變在第14天或之前未恢復成級別≤ 1，若患者先前患有2級周圍神經病變及/或若帕妥珠單抗維多汀-piiq先前劑量減少至1.4 mg/kg或奧沙利鉑先前劑量減少至75 mg/m2 ，則中止用單獨帕妥珠單抗維多汀-piiq之治療。在一些實施例中，若受試者患有先前3級周圍神經病變，則中止治療。在一些實施例中，若2級或3級周圍神經病變直至＞ 14天或在下一個週期之時程日期之後才恢復成≤1級，則持久地中止奧沙利鉑及帕妥珠單抗維多汀-piiq。在一些實施例中，若發生4級周圍神經病變，則中止用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。In some embodiments, if grade 2 or grade 3 peripheral neuropathy occurs, the use of immunoconjugates (such as Pertuzumab Vidotin-piiq), anti-CD20 antibodies (such as rituximab), and The one or more chemotherapeutic agents (such as gemcitabine and oxaliplatin) are treated until the improvement becomes ≤ Grade 1. In some embodiments, if grade 2 or grade 3 peripheral neuropathy recovers to grade ≤ grade 1 within 14 days, a sustained reduced dose of 1.4 mg/kg of Pertuzumab Verdotin-piiq and 75 The mg/m 2 dose of oxaliplatin was restarted with immunoconjugates (e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies (e.g. Rituximab) and the one or more chemotherapeutic agents (Such as gemcitabine and oxaliplatin). In some embodiments, if grade 2 or grade 3 peripheral neuropathy does not return to grade ≤ 1 on or before the 14th day, if the patient has previously suffered grade 2 peripheral neuropathy and/or if pertuzumab vedotine -If the previous dose of piiq is reduced to 1.4 mg/kg or the previous dose of oxaliplatin is reduced to 75 mg/m 2 , the treatment with Pertuzumab Verdotin-piiq alone should be discontinued. In some embodiments, if the subject has previous grade 3 peripheral neuropathy, treatment is discontinued. In some embodiments, if grade 2 or grade 3 peripheral neuropathy does not return to grade ≤ 1 until> 14 days or after the schedule date of the next cycle, oxaliplatin and pertuzumab are permanently discontinued Duotin-piiq. In some embodiments, if grade 4 peripheral neuropathy occurs, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or Treatment of various chemotherapeutics ( such as gemcitabine and oxaliplatin).

在一些實施例中，若發生咽喉感覺異常，則將奧沙利鉑輸注延長至6小時。In some embodiments, if throat paresthesia occurs, the oxaliplatin infusion is extended to 6 hours.

在一些實施例中，若發生1-2級輸注相關反應(IRR)，則減慢或保持輸注。在一些實施例中，給予受試者支持治療。在一些實施例中，支持治療包括對乙醯胺基酚(acetaminophen)/撲熱息痛(paracetamol)，及抗組胺藥，諸如苯海拉明(diphenhydramine)及/或靜脈內生理食鹽水。在一些實施例中，針對支氣管痙攣、蕁麻疹或呼吸困難之支持治療包括抗組胺藥、氧氣、皮質類固醇(例如 100 mg IV潑尼松龍(prednisolone)或等效物)及/或支氣管擴張藥。在一些實施例中，在症狀消退後，恢復輸注速率之增加。在一些實施例中，對於在症狀完全消退後重新開始輸注之後的輸注速率增加，輸注係以達到中止之前速率之50%的速率重新開始。在一些實施例中，在不存在輸注相關症狀的情況下，每30分鐘，以每小時50 mg之增量增加輸注速率。在一些實施例中，若發生1-2級IRR，則在下一個週期中經90分鐘輸注帕妥珠單抗維多汀。在一些實施例中，若未發生輸注相關反應，則在30分鐘內投與後續帕妥珠單抗維多汀輸注。在一些實施例中，在所有周期均投與前驅給藥。在一些實施例中，若再發生喘鳴或蕁麻疹症狀，則中止用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。In some embodiments, if a grade 1-2 infusion-related reaction (IRR) occurs, the infusion is slowed down or maintained. In some embodiments, supportive treatment is given to the subject. In some embodiments, supportive treatment includes acetaminophen/paracetamol, and antihistamines, such as diphenhydramine and/or intravenous saline. In some embodiments, supportive treatments for bronchospasm, urticaria, or dyspnea include antihistamines, oxygen, corticosteroids ( e.g. 100 mg IV prednisolone or equivalent) and/or bronchiectasis medicine. In some embodiments, the increase in the infusion rate is restored after the symptoms subsided. In some embodiments, for an increase in the infusion rate after resuming the infusion after the symptoms have completely subsided, the infusion is restarted at a rate that reaches 50% of the rate before the discontinuation. In some embodiments, in the absence of infusion-related symptoms, the infusion rate is increased in increments of 50 mg per hour every 30 minutes. In some embodiments, if grade 1-2 IRR occurs, pertuzumab vedotine is infused over 90 minutes in the next cycle. In some embodiments, if an infusion-related reaction does not occur, a subsequent pertuzumab vitotine infusion is administered within 30 minutes. In some embodiments, the prodrug is administered in all cycles. In some embodiments, if wheezing or urticaria symptoms occur again, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one Or a variety of chemotherapeutic agents ( such as gemcitabine and oxaliplatin) treatment.

在一些實施例中，若發生3級IRR，則中止輸注。在一些實施例中，給予受試者支持治療。在一些實施例中，支持治療包括對乙醯胺基酚(acetaminophen)/撲熱息痛(paracetamol)，及抗組胺藥，諸如苯海拉明(diphenhydramine)及/或靜脈內生理食鹽水。在一些實施例中，針對支氣管痙攣、蕁麻疹或呼吸困難之支持治療包括抗組胺藥、氧氣、皮質類固醇(例如 100 mg IV潑尼松龍(prednisolone)或等效物)及/或支氣管擴張藥。在一些實施例中，在症狀消退後，恢復輸注速率之增加。在一些實施例中，對於在症狀完全消退後重新開始輸注之後的輸注速率增加，輸注係以達到中止之前速率之50%的速率重新開始。在一些實施例中，在不存在輸注相關症狀的情況下，每30分鐘，以每小時50 mg之增量增加輸注速率。在一些實施例中，若再發生相同嚴重程度的相同不良事件，則中止用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。In some embodiments, if a grade 3 IRR occurs, the infusion is discontinued. In some embodiments, supportive treatment is given to the subject. In some embodiments, supportive treatment includes acetaminophen/paracetamol, and antihistamines, such as diphenhydramine and/or intravenous saline. In some embodiments, supportive treatments for bronchospasm, urticaria, or dyspnea include antihistamines, oxygen, corticosteroids ( e.g. 100 mg IV prednisolone or equivalent) and/or bronchiectasis medicine. In some embodiments, the increase in the infusion rate is restored after the symptoms subsided. In some embodiments, for an increase in the infusion rate after resuming the infusion after the symptoms have completely subsided, the infusion is restarted at a rate that reaches 50% of the rate before the discontinuation. In some embodiments, in the absence of infusion-related symptoms, the infusion rate is increased in increments of 50 mg per hour every 30 minutes. In some embodiments, if the same adverse event of the same severity occurs again, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. Rituximab) and The treatment of the one or more chemotherapeutic agents ( for example, gemcitabine and oxaliplatin).

在一些實施例中，若發生4級IRR，則中止用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。In some embodiments, if grade 4 IRR occurs, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or more chemical compounds are discontinued. Treatment with therapeutic agents ( such as gemcitabine and oxaliplatin).

在一些實施例中，若觀察到總膽紅素＞ 3.0 mg/dL，則延遲用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療，直至在≤ 14天內消退成≤ 1.5 mg/dL。在一些實施例中，若觀察到肝轉胺酶增加 ＞ 3×基線且直接膽紅素增加 ＞ 2×ULN，而未發現任何膽汁淤積或黃疸或肝功能障礙病徵，且不存在促成因素(例如 轉移性疾病之惡化或同時暴露於已知的肝毒性劑或有記錄的感染病源)，則中止用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。In some embodiments, if total bilirubin>3.0 mg/dL is observed, the use of immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. rituximab) is delayed. ) And the one or more chemotherapeutic agents ( such as gemcitabine and oxaliplatin) until it resolves to ≤ 1.5 mg/dL within ≤ 14 days. In some embodiments, if an increase in liver transaminases> 3× baseline and an increase in direct bilirubin> 2×ULN are observed, without any signs of cholestasis or jaundice or liver dysfunction, and there are no contributing factors ( eg For exacerbation of metastatic disease or simultaneous exposure to a known hepatotoxic agent or a documented source of infection), discontinue the use of immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. Rib Tuximab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin).

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起腫瘤溶解症候群。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與針對腫瘤溶解症候群之預防性治療。在一些實施例中，預防性治療包括水合，例如 每天3公升流體，例如 在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前約1天或2天開始。在一些實施例中，預防性治療包括別嘌醇(allopurinol)(例如 每天口服300 mg)或適合替代性治療(例如 拉布立酶(rasburicase))，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前約48小時至72小時開始。在一些實施例中，預防性治療包括水合，例如 每天3公升流體，例如 在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前約1天或2天開始；及別嘌醇(例如 每天口服300 mg)或適合替代性治療(例如 拉布立酶)，在投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前約48小時至72小時開始。在一些實施例中，若人類個體有患腫瘤溶解症候群之風險，例如若該人類個體人具有高腫瘤負擔(例如 淋巴細胞計數 ≥ 25 × 109 /L或顯著淋巴結腺體腫大)，則向該人類個體投與針對腫瘤溶解症候群之預防性治療。在一些實施例中，針對腫瘤溶解症候群之預防性治療係在每次投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前投與。在一些實施例中，若發生3級或4級腫瘤溶解症候群(TLS)，則持續用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。在一些實施例中，下一次劑量被延遲至多14天。在一些實施例中，在TLS完全消退後，在下一時程之輸注結合預防性療法期間，以全劑量重新開始用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause tumor lysis syndrome in the human individual. In some embodiments, the method provided herein further comprises administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human individual before, during and/or after the human individual Preventive treatment for tumor lysis syndrome. In some embodiments, prophylactic treatment includes hydration, for example, 3 liters of fluid per day, for example , starting about 1 or 2 days before the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, prophylactic treatment includes allopurinol ( for example, 300 mg orally per day) or suitable alternative treatment ( for example , rasburicase), in the administration of immunoconjugates, rituximab The monoclonal antibody, gemcitabine, and oxaliplatin start approximately 48 hours to 72 hours before. In some embodiments, prophylactic treatment includes hydration, such as 3 liters of fluid per day, for example , starting about 1 or 2 days before the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin; and Purinol ( e.g. 300 mg orally per day) or alternative treatments ( e.g. labrizyme), starting approximately 48 hours to 72 hours before the administration of immunoconjugates, rituximab, gemcitabine and oxaliplatin . In some embodiments, if a human individual is at risk of suffering from tumor lysis syndrome, for example, if the human individual has a high tumor burden ( for example, lymphocyte count ≥ 25 × 10 9 /L or significant lymph node gland enlargement), then The human individual is administered a preventive treatment for tumor lysis syndrome. In some embodiments, the preventive treatment for tumor lysis syndrome is administered before each administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, if grade 3 or grade 4 tumor lysis syndrome (TLS) occurs, continue to use immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. rituximab) Anti) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin). In some embodiments, the next dose is delayed up to 14 days. In some embodiments, after the TLS has completely resolved, during the next course of infusion combined with preventive therapy, the immunoconjugate ( for example , Pertuzumab Vidotin-piiq), anti-CD20 antibody is restarted at the full dose. ( E.g. rituximab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin).

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起感染。在一些實施例中，感染係肺孢子蟲感染或皰疹病毒感染。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與針對感染之預防性治療。在一些實施例中，針對感染之預防性治療包括一或多種適合的抗病毒藥物。在一些實施例中，如例如 Flowers等人，2013；National Comprehensive Cancer Network (NCCN) 2017中所述，向人類個體投與針對B型肝炎再活化之預防性治療。In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause infection in the human individual. In some embodiments, the infection is a Pneumocystis infection or a herpes virus infection. In some embodiments, the methods provided herein further comprise administering to the human subject before, during, and/or after administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human subject Preventive treatment for infection. In some embodiments, the prophylactic treatment for infection includes one or more suitable antiviral drugs. In some embodiments, as described in, for example, Flowers et al., 2013; National Comprehensive Cancer Network (NCCN) 2017, a human subject is administered a preventive treatment for hepatitis B reactivation.

在一些實施例中，若發生3級或4級非血液學毒性(不包括脫髮、噁心及嘔吐)，則延遲用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療，持續至多14天。在一些實施例中，若觀察到改善成級別≤ 1或基線，則以減少之劑量或全劑量重新開始用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。In some embodiments, if grade 3 or grade 4 non-hematological toxicity (excluding hair loss, nausea, and vomiting) occurs, the use of immunoconjugates ( such as Pertuzumab Vidotin-piiq), anti-CD20 The treatment of the antibody ( e.g. rituximab) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin) lasts up to 14 days. In some embodiments, if improvement is observed to a level ≤ 1 or baseline, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( For example , rituximab) and the one or more chemotherapeutic agents ( for example, gemcitabine and oxaliplatin).

在一些實施例中，若發生2級非血液學毒性，則延遲用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療，持續至多14天。在一些實施例中，若觀察到改善成級別 ≤ 1或基線，則以先前劑量投與用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。In some embodiments, if Grade 2 non-hematological toxicity occurs, the use of immunoconjugates ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibodies ( e.g. rituximab), and the Or a variety of chemotherapeutic agents ( such as gemcitabine and oxaliplatin) treatment lasts up to 14 days. In some embodiments, if an improvement of grade ≤ 1 or baseline is observed, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) will be administered at the previous dose. Monoclonal antibody) and the one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin).

在一些實施例中，若發生1級非血液學毒性，則不改變用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。In some embodiments, if grade 1 non-hematological toxicity occurs, the immunoconjugate ( for example , Pertuzumab Vidotin-piiq), anti-CD20 antibody ( for example , rituximab) and the Treatment of one or more chemotherapeutics ( e.g. gemcitabine and oxaliplatin).

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會在該人類個體中引起B型肝炎再活化。在一些實施例中，本文所提供之方法進一步包括在向人類個體投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前、期間及/或之後，向該人類個體投與B型肝炎再活化之預防性治療。在一些實施例中，對人進行乙型肝炎再活化的預防性治療，如例如 Flowers等人，2013；National Comprehensive Cancer Network (NCCN) 2017中所述，針對B型肝炎再活化之預防性治療包含抗病毒藥物。在一些實施例中，本文所提供之方法進一步包括當在人類個體中偵測到B型肝炎再活化時，向該人類個體投與抗病毒藥物，例如 適合核苷類似物。在一些實施例中，B型肝炎再活化係由新的可偵測HBV-DNA水準確定。在一些實施例中，若HBV-DNA水準在世界衛生組織(WHO)推薦的29 IU/mL 與100 IU/mL範圍之間，則在2週內重新測試HBV-DNA水準。在一些實施例中，若HBV-DNA水準呈陽性，則持續用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療並用核苷類似物治療受試者。在一些實施例中，若觀察到HBV-DNA水準在WHO推薦的＞ 100 IU/mL之截止值，則持續用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療並投與核苷類似物。在一些實施例中，若在適當抗病毒療法後觀察到HBV-DNA負荷升高(超過100 IU/mL)，則中止用免疫偶聯物(例如 帕妥珠單抗維多汀-piiq)、抗CD20抗體(例如 利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之治療。In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause hepatitis B reactivation in the human individual. In some embodiments, the methods provided herein further comprise administering to the human subject before, during, and/or after administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human subject Preventive treatment for hepatitis B reactivation. In some embodiments, the prophylactic treatment for reactivation of hepatitis B is performed on humans, as described in, for example, Flowers et al., 2013; National Comprehensive Cancer Network (NCCN) 2017, and the prophylactic treatment for reactivation of hepatitis B includes anti-viral drug. In some embodiments, the methods provided herein further include administering to the human subject an antiviral drug, such as a suitable nucleoside analog, when hepatitis B reactivation is detected in the human subject. In some embodiments, hepatitis B reactivation is determined by the new detectable HBV-DNA level. In some embodiments, if the HBV-DNA level is between 29 IU/mL and 100 IU/mL recommended by the World Health Organization (WHO), the HBV-DNA level is retested within 2 weeks. In some embodiments, if the HBV-DNA level is positive, the immunoconjugate ( e.g. Pertuzumab Vidotin-piiq), anti-CD20 antibody ( e.g. rituximab) and the one or Treatment of multiple chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin) and treatment of subjects with nucleoside analogs. In some embodiments, if it is observed that the HBV-DNA level is above the cut-off value of 100 IU/mL recommended by the WHO, continue to use immunoconjugates ( such as Pertuzumab Vidotin-piiq), anti-CD20 antibody ( E.g. , rituximab) and the one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) and administration of nucleoside analogs. In some embodiments, if an increase in HBV-DNA load (more than 100 IU/mL) is observed after appropriate antiviral therapy, the use of immunoconjugates ( such as Pertuzumab Verdotin-piiq), Treatment of anti-CD20 antibodies ( e.g. , rituximab) and the one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin).

在一些實施例中，投與免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會引起選自由以下組成之群的一或多例不良事件：藥物誘發之肝損傷、進行性多灶性腦白質病、全身性超敏反應、過敏性反應、類過敏性反應及第二惡性疾病。在一些實施例中，人類個體中藥物誘發之肝損傷包含根據Hy定律所確定的ALT或AST升高以及膽紅素升高或顯性黃疸。在一些實施例中，人類個體中藥物誘發之肝損傷包含治療中出現之ALT或AST＞3×基線值以及總膽紅素＞2×ULN(其中≥35%為直接膽紅素)。在一些實施例中，人類個體中藥物誘發之肝損傷包含治療中出現之ALT或AST＞3×基線值以及顯性黃疸。在一些實施例中，全身性超敏反應、過敏性反應及類過敏性反應係使用桑普森標準(Sampson’s criteria)評估。In some embodiments, the administration of immunoconjugates, rituximab, gemcitabine, and oxaliplatin does not cause one or more adverse events selected from the group consisting of: drug-induced liver injury, progressive Multifocal leukoencephalopathy, systemic hypersensitivity reactions, allergic reactions, allergic reactions and second malignant diseases. In some embodiments, drug-induced liver injury in a human individual includes an increase in ALT or AST and an increase in bilirubin or dominant jaundice as determined by Hy's law. In some embodiments, drug-induced liver injury in a human individual includes ALT or AST>3×baseline value and total bilirubin>2×ULN (where ≥35% is direct bilirubin) during treatment. In some embodiments, drug-induced liver injury in a human individual includes ALT or AST> 3×baseline value and dominant jaundice during treatment. In some embodiments, systemic hypersensitivity reactions, allergic reactions, and anaphylactoid reactions are assessed using Sampson's criteria.

提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係用於治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之方法中。在一些實施例中，免疫偶聯物係根據本文所提供之任何方法使用。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 19之胺基酸序列的VH及(ii)含SEQ ID NO: 20之胺基酸序列的VL。在一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。Provide an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8. This immunoconjugate is used to treat individuals in need ( Diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in a human individual). In some embodiments, the immunoconjugate is used according to any of the methods provided herein. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising (i) a VH containing the amino acid sequence of SEQ ID NO: 19 and (ii) a VH containing the amino acid sequence of SEQ ID NO: 20 VL. In some embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

亦提供包含下式之免疫偶聯物的用途

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係用於製造供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)之藥物，其中該藥物係供(例如 經調配以供)與抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)組合投與。在一些實施例中，該藥物(亦即，包含免疫偶聯物之藥物)係用於本文所述之方法中。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 19之胺基酸序列的VH及(ii)含SEQ ID NO: 20之胺基酸序列的VL。在一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。The use of immunoconjugates comprising the following formula is also provided
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is used for the manufacture of therapeutically needed A drug for diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) of an individual (human individual), wherein the drug is provided ( e.g., formulated for) and an anti-CD20 antibody ( e.g. , rituximab) ) And one or more chemotherapeutic agents ( e.g. gemcitabine and oxaliplatin). In some embodiments, the drug (ie, a drug comprising an immunoconjugate) is used in the methods described herein. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising (i) a VH containing the amino acid sequence of SEQ ID NO: 19 and (ii) a VH containing the amino acid sequence of SEQ ID NO: 20 VL. In some embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

提供一種包含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 19之胺基酸序列的VH及(ii)含SEQ ID NO: 20之胺基酸序列的VL，其中p在2與5之間，該免疫偶聯物係用於治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)的方法中，該方法包括向該個體投與有效量之(a)免疫偶聯物、(b)利妥昔單抗、(c)一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)，其中該免疫偶聯物係以在約1.4與約1.8 mg/kg之間之劑量投與，利妥昔單抗係以375 mg/m2 之劑量投與，且該一或多種化學治療劑係以在50-2000 mg/m2 之間之劑量投與(例如 吉西他濱係以1000 mg/m2 之劑量投與且奧沙利鉑係以100 mg/m2 之劑量投與)。在一些實施例中，免疫偶聯物係根據本文所描述之方法使用。在一些實施例中，p在3與4之間。在一些實施例中，p係3.5。在一些實施例中，該免疫偶聯物包含抗CD79抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。在一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。Provide an immunoconjugate comprising the following formula:
Figure 02_image001
, Where Ab is an anti-CD79b antibody, which includes (i) VH containing the amino acid sequence of SEQ ID NO: 19 and (ii) VL containing the amino acid sequence of SEQ ID NO: 20, where p is between 2 and Between 5, the immunoconjugate is used to treat diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in an individual in need (human individual), and the method includes giving the individual Administer an effective amount of (a) immunoconjugate, (b) rituximab, (c) one or more chemotherapeutics ( such as gemcitabine and oxaliplatin), wherein the immunoconjugate is in It is administered at a dose between about 1.4 and about 1.8 mg/kg, rituximab is administered at a dose of 375 mg/m 2 and the one or more chemotherapeutic agents are administered at a dosage of 50-2000 mg/m 2 Between the doses (for example, gemcitabine is administered at a dose of 1000 mg/m 2 and oxaliplatin is administered at a dose of 100 mg/m 2 ). In some embodiments, the immunoconjugate is used according to the methods described herein. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.5. In some embodiments, the immunoconjugate comprises an anti-CD79 antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 38. In some embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq.

亦提供一種包含下式之免疫偶聯物

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 19之胺基酸序列的VH及(ii)含SEQ ID NO: 20之胺基酸序列的VL，其中p在2與5之間，該免疫偶聯物係用於製造供治療有需要之個體(人類個體)之彌漫性大B細胞淋巴瘤(DLBCL，例如 復發性/難治性DLBCL)的藥物，其中該藥物係用於(例如 經調配用於)與利妥昔單抗及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)組合投與，其中該藥物係調配成投與劑量在約1.4與約1.8 mg/kg之間的該免疫偶聯物，利妥昔單抗係以375 mg/m2 之劑量投與，且該一或多種化學治療劑係以50-2000 mg/m2 之劑量投與(例如 吉西他濱係以1000 mg/m2 之劑量投與且奧沙利鉑係以100 mg/m2 之劑量投與)。在一些實施例中，該藥物(亦即，包含免疫偶聯物之藥物)係根據本文所述之方法使用。在一些實施例中，p在3與4之間。在一些實施例中，p係3.5。在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。在一些實施例中，免疫偶聯物係帕妥珠單抗維多汀-piiq。IV. 包含抗 CD79b 抗體及藥物 / 細胞毒性劑之免疫偶聯物 ( 「抗 CD79b 免疫偶聯物」 ) There is also provided an immunoconjugate comprising the formula
Figure 02_image001
, Where Ab is an anti-CD79b antibody, which includes (i) VH containing the amino acid sequence of SEQ ID NO: 19 and (ii) VL containing the amino acid sequence of SEQ ID NO: 20, where p is between 2 and Between 5, the immunoconjugate is used to manufacture drugs for the treatment of diffuse large B-cell lymphoma (DLBCL, such as relapsed/refractory DLBCL) in individuals in need (human individuals), wherein the drug is used In ( for example, formulated for) administration in combination with rituximab and one or more chemotherapeutic agents ( for example gemcitabine and oxaliplatin), wherein the drug is formulated to be administered at a dosage of between about 1.4 and about 1.8 mg /kg of the immunoconjugate, rituximab is administered at a dose of 375 mg/m 2 , and the one or more chemotherapeutic agents are administered at a dose of 50-2000 mg/m 2 ( For example, gemcitabine is administered at a dose of 1000 mg/m 2 and oxaliplatin is administered at a dose of 100 mg/m 2 ). In some embodiments, the drug (ie, a drug containing an immunoconjugate) is used according to the methods described herein. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.5. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 38. In some embodiments, the immunoconjugate is Pertuzumab Vidotin-piiq. IV. Immunoconjugates containing anti- CD79b antibodies and drugs / cytotoxic agents ( "anti- CD79b immunoconjugates" )

在一些實施例中，抗CD79b免疫偶聯物包含靶向癌細胞(諸如彌漫性大B細胞淋巴瘤(DLBCL)細胞)之抗CD79b抗體(Ab)、藥物部分(D)及將Ab連接至D之連接子部分(L)。在一些實施例中，抗CD79b抗體經由一或多個胺基酸殘基，諸如離胺酸及/或半胱胺酸連接至連接子部分(L)。在一些實施例中，該免疫偶聯物包含式Ab-(LD)p，其中：(a) Ab係抗CD79b抗體；(b) L係連接子；(c) D係細胞毒性劑；(d) p在1-8之範圍內。In some embodiments, the anti-CD79b immunoconjugate comprises an anti-CD79b antibody (Ab) that targets cancer cells (such as diffuse large B-cell lymphoma (DLBCL) cells), a drug moiety (D), and a linking Ab to D The linker part (L). In some embodiments, the anti-CD79b antibody is linked to the linker moiety (L) via one or more amino acid residues, such as lysine and/or cysteine. In some embodiments, the immunoconjugate comprises the formula Ab-(LD)p, wherein: (a) Ab series anti-CD79b antibody; (b) L series linker; (c) D series cytotoxic agent; (d) ) p is in the range of 1-8.

示例性抗CD79b免疫偶聯物包含式I： (I)   Ab-(L-D)p 其中p係1至約20 (例如 1至15、1至10、1至8、2至5或3至4)。在一些實施例中，可與抗CD79b抗體結合的藥物部分之數量受游離半胱胺酸殘基數量限制。在一些實施例中，游離半胱胺酸殘基係藉由本文別處所描述之方法引入抗體胺基酸序列中。式I之示例性抗CD79b免疫偶聯物包含但不限於含1、2、3或4個工程改造之半胱胺酸胺基酸的抗CD79b抗體(Lyon，R.等人(2012)Methods in Enzym . 502:123-138)。在一些實施例中，一個或多個游離半胱胺酸殘基已存在於抗CD79b抗體中，無需使用工程改造技術，在此情況下，可使用現有的游離半胱胺酸殘基使抗CD79b抗體與藥物/細胞毒性劑結合。在一些實施例中，在抗CD79b抗體與藥物/細胞毒性劑結合之前，使該抗體暴露於還原條件，以便產生一或多個游離半胱胺酸殘基。A. 示例性連接子 Exemplary anti-CD79b immunoconjugates comprise formula I: (I) Ab-(LD) p where p is 1 to about 20 ( e.g., 1 to 15, 1 to 10, 1 to 8, 2 to 5, or 3 to 4) . In some embodiments, the number of drug moieties that can bind to the anti-CD79b antibody is limited by the number of free cysteine residues. In some embodiments, free cysteine residues are introduced into the antibody amino acid sequence by methods described elsewhere herein. Exemplary anti-CD79b immunoconjugates of Formula I include, but are not limited to, anti-CD79b antibodies containing 1, 2, 3, or 4 engineered cysteine amino acids (Lyon, R. et al. (2012) Methods in Enzym 502:. 123-138). In some embodiments, one or more free cysteine residues are already present in the anti-CD79b antibody, without the use of engineering techniques, in this case, the existing free cysteine residues can be used to make anti-CD79b The antibody binds to the drug/cytotoxic agent. In some embodiments, before the anti-CD79b antibody binds to the drug/cytotoxic agent, the antibody is exposed to reducing conditions in order to generate one or more free cysteine residues. A. Exemplary linkers

「連接子」(L)係一種雙官能或多官能部分，其可用於將一或多個藥物部分(D)連接至抗CD79b抗體(Ab)以形成式I之抗CD79b免疫偶聯物。在一些實施例中，抗CD79b免疫偶聯物可使用連接子製備，該連接子具有用於共價連接至藥物及抗CD79b抗體之反應性官能基。舉例而言，在一些實施例中，抗CD79b抗體(Ab)之半胱胺酸硫醇可與連接子或藥物-連接子中間物之反應性官能基形成鍵結，以製備抗CD79b免疫偶聯物。The "linker" (L) is a bifunctional or multifunctional moiety that can be used to link one or more drug moieties (D) to the anti-CD79b antibody (Ab) to form an anti-CD79b immunoconjugate of formula I. In some embodiments, anti-CD79b immunoconjugates can be prepared using linkers that have reactive functional groups for covalent attachment to drugs and anti-CD79b antibodies. For example, in some embodiments, the cysteine thiol of an anti-CD79b antibody (Ab) can form a bond with a linker or a reactive functional group of a drug-linker intermediate to prepare an anti-CD79b immunoconjugate Things.

在一個態樣中，連接子具有能夠與抗CD79b抗體上存在之游離半胱胺酸反應形成共價鍵的官能基。示例性反應性官能基包括但不限於例如 順丁烯二醯亞胺、鹵代乙醯胺、α-鹵代乙醯基、活性酯如琥珀醯亞胺酯、4-硝基苯基酯、五氟苯基酯、四氟苯基酯、酸酐、醯氯化物、磺醯氯、異氰酸酯及異硫氰酸酯。參見例如 Klussman等人(2004)，Bioconjugate Chemistry 15(4):765-773第766頁及其中之實例的結合方法。In one aspect, the linker has a functional group capable of reacting with free cysteine present on the anti-CD79b antibody to form a covalent bond. Exemplary reactive functional groups include, but are not limited to, for example , maleimide, haloacetamide, α-haloacetamide, active esters such as succinimidyl ester, 4-nitrophenyl ester, Pentafluorophenyl ester, tetrafluorophenyl ester, acid anhydride, sulfonate chloride, sulfonate chloride, isocyanate and isothiocyanate. See, for example, Klussman et al. (2004), Bioconjugate Chemistry 15(4): 765-773, page 766 and the binding method of the examples therein.

在一些實施例中，連接子具有能夠與抗CD79b抗體上存在之親電子基團反應的官能基。示例性親電子基團包括但不限於例如 醛及酮羰基。在一些實施例中，連接子之反應性官能基的雜原子可與抗體上之親電子基團反應並與抗體單元形成共價鍵。示例性反應性官能基包括但不限於例如 醯肼、肟、胺基、肼、硫代半脲、肼羧酸酯及芳基醯肼。In some embodiments, the linker has a functional group capable of reacting with electrophilic groups present on the anti-CD79b antibody. Exemplary electrophilic groups include, but are not limited to, for example, aldehyde and ketone carbonyl groups. In some embodiments, the heteroatom of the reactive functional group of the linker can react with the electrophilic group on the antibody and form a covalent bond with the antibody unit. Exemplary reactive functional groups include, but are not limited to, for example, hydrazine, oxime, amine, hydrazine, thiosemiurea, hydrazine carboxylate, and arylhydrazine.

在一些實施例中，連接子包含一或多種連接子組分。示例性連接子組分包括例如 6-馬來醯亞胺基己醯基(「MC」)、馬來醯亞胺基丙醯基(「MP」)、纈胺酸-瓜胺酸(「val-cit」或「vc」)、丙胺酸-苯丙胺酸(「ala-phe」)、對胺基苯甲氧基羰基(「PAB」)、N-琥珀醯亞胺基4-(2-吡啶基硫基)戊酸酯(「SPP」)及4-(N-馬來醯亞胺甲基)環己烷-1甲酸酯(「MCC」)。此項技術中已知各種連接子組分，其中有一些在下文中描述。In some embodiments, the linker includes one or more linker components. Exemplary linker components include, for example, 6-maleiminohexanyl ("MC"), maleiminopropionyl ("MP"), valine-citrulline ("val -cit" or "vc"), alanine-phenylalanine ("ala-phe"), p-aminobenzyloxycarbonyl ("PAB"), N-succinimidyl 4-(2-pyridyl) Sulfo) valerate ("SPP") and 4-(N-maleiminomethyl)cyclohexane-1 carboxylate ("MCC"). Various linker components are known in the art, some of which are described below.

在一些實施例中，連接子係「可裂解連接子」，促進藥物之釋放。非限制性示例性可裂解連接子包括酸不穩定性連接子(例如 包含腙)、蛋白酶敏感性(例如 肽酶敏感性)連接子、光不穩定性連接子或含二硫鍵之連接子(Chari等人，Cancer Research 52:127-131 (1992)；US 5208020)。In some embodiments, the linker is a "cleavable linker" to promote drug release. Non-limiting exemplary cleavable linkers include acid-labile linkers ( e.g., containing hydrazone), protease-sensitive ( e.g., peptidase-sensitive) linkers, photolabile linkers, or disulfide bond-containing linkers ( Chari et al., Cancer Research 52:127-131 (1992); US 5208020).

在某些實施例中，連接子(L)具有下式II： (II)

Figure 02_image012
其中A係「延伸物單元」，且a係0至1之間的整數；W係「胺基酸單位」，且w係0至12的整數。Y係「間隔子單元」，且y係0、1或2；且Ab、D及p如上文關於式I所定義。此類連接子之示例性實施例描述於美國專利第7,498,298號，其以引用之方式明確地併入本文中。In certain embodiments, the linker (L) has the following formula II: (II)
Figure 02_image012
Wherein A is an "extension unit", and a is an integer between 0 and 1; W is an "amino acid unit", and w is an integer from 0 to 12. Y is a “spacer subunit”, and y is 0, 1, or 2; and Ab, D, and p are as defined above with respect to formula I. Exemplary embodiments of such linkers are described in US Patent No. 7,498,298, which is expressly incorporated herein by reference.

在一些實施例中，連接子組分包含將抗體連接至另一個連接子組分或連接至藥物部分的「延伸物單元」。非限制性示例性延伸物單元如下所示(其中波浪線指示與抗體、藥物或額外連接子組分共價連接之位點)：

Figure 02_image014
MC
Figure 02_image016
MP
Figure 02_image018
mPEG
Figure 02_image020
。In some embodiments, the linker component includes an "extension unit" that connects the antibody to another linker component or to a drug moiety. A non-limiting exemplary extension unit is shown below (where the wavy line indicates the site of covalent attachment to the antibody, drug, or additional linker component):
Figure 02_image014
MC
Figure 02_image016
MP
Figure 02_image018
mPEG
Figure 02_image020
.

在一些實施例中，連接子組分包含「胺基酸單元」。在一些此類實施例中，胺基酸單元允許蛋白酶裂解連接子，由此在暴露於細胞內蛋白酶，諸如溶酶體酶後，促進藥物/細胞毒性劑自抗CD79b免疫偶聯物釋放(Doronina等人(2003)Nat. Biotechnol. 21:778-784)。示例性胺基酸單元包括但不限於二肽、三肽、四肽及五肽。示例性二肽包括但不限於纈胺酸-瓜胺酸(vc或val-cit)、丙胺酸-苯丙胺酸(af或ala-phe)、苯丙胺酸-離胺酸(fk或phe-lys)、苯丙胺酸-高離胺酸(phe-homolys)及N-甲基纈胺酸-瓜胺酸(Me-val-cit)。示例性三肽包括但不限於甘胺酸-纈胺酸-瓜胺酸(gly-val-cit)及甘胺酸-甘胺酸-甘胺酸(gly-gly-gly)。胺基酸單元可包含天然存在之胺基酸殘基及/或次要胺基酸及/或非天然存在之胺基酸類似物，諸如瓜胺酸。可設計並優化胺基酸單元以藉由特定酶，例如腫瘤相關蛋白酶、組織蛋白酶B、C及D、或纖溶酶蛋白酶進行酶裂解。In some embodiments, the linker component includes "amino acid units." In some such embodiments, the amino acid unit allows the protease to cleave the linker, thereby facilitating the release of the drug/cytotoxic agent from the anti-CD79b immunoconjugate after exposure to intracellular proteases, such as lysosomal enzymes (Doronina Et al. (2003) Nat. Biotechnol. 21:778-784). Exemplary amino acid units include, but are not limited to, dipeptides, tripeptides, tetrapeptides, and pentapeptides. Exemplary dipeptides include, but are not limited to, valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe), phenylalanine-lysine (fk or phe-lys), Phenylalanine-homolysine (phe-homolys) and N-methylvaline-citrulline (Me-val-cit). Exemplary tripeptides include, but are not limited to, glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). The amino acid unit may include naturally occurring amino acid residues and/or minor amino acids and/or non-naturally occurring amino acid analogs, such as citrulline. The amino acid unit can be designed and optimized for enzymatic cleavage by specific enzymes, such as tumor-associated protease, cathepsin B, C and D, or plasmin protease.

在一些實施例中，連接子組分包含直接或經由延伸物單元及/或胺基酸單元將抗體連接至藥物部分的「間隔子」單元。間隔子單元可為「自分解型」或「非自分解型」間隔子單元。「非自分解型」間隔子單元係間隔子單元之一部分或全部在ADC裂解後仍結合至藥物部分的單元。非自分解型間隔子單元之實例包括但不限於甘胺酸間隔子單元及甘胺酸-甘胺酸間隔子單元。在一些實施例中，藉由腫瘤細胞相關蛋白酶對含甘胺酸-甘胺酸間隔子單元之ADC進行酶裂解使得甘胺酸-甘胺酸-藥物部分自ADC之其餘部分釋放。在一些此類實施例中，甘胺酸-甘胺酸-藥物部分在腫瘤細胞中經歷水解步驟，由此將甘胺酸-甘胺酸間隔子單元自藥物部分裂解。In some embodiments, the linker component includes a "spacer" unit that connects the antibody to the drug moiety either directly or via an extender unit and/or an amino acid unit. The spacer unit can be a "self-decomposing type" or a "non-self-decomposing type" spacer unit. The "non-self-degradable" spacer unit is a unit in which part or all of the spacer unit is still bound to the drug moiety after ADC cleavage. Examples of non-self-decomposing spacer units include, but are not limited to, glycine spacer units and glycine-glycine spacer units. In some embodiments, the enzymatic cleavage of the ADC containing the glycine-glycine spacer unit by tumor cell-related proteases allows the glycine-glycine-drug portion to be released from the rest of the ADC. In some such embodiments, the glycine-glycine-drug moiety undergoes a hydrolysis step in the tumor cell, thereby cleaving the glycine-glycine-drug spacer unit from the drug moiety.

「自分解型」間隔子單元允許釋放出藥物部分。在某些實施例中，連接子之間隔子單元包含對胺基苯甲基單元。在一些此類實施例中，對胺基苯甲醇經由醯胺鍵連接至胺基酸單元，且在苯甲醇與藥物之間產生胺基甲酸酯、甲基胺基甲酸酯或碳酸酯(Hamann等人(2005)Expert Opin. Ther. Patents (2005) 15:1087-1103)。在一些實施例中，間隔子單元係對胺基苯甲氧基羰基(PAB)。在一些實施例中，抗CD79b免疫偶聯物包括含以下結構之自分解型連接子：

Figure 02_image022
其中Q係-C1 -C8 烷基、-O-(C1 -C8 烷基)、-鹵素、-硝基或-氰基；m係在0至4範圍內之整數；p的範圍係1至約20。在一些實施例中，p的範圍係1至10、1至7、1至5或1至4。The "self-decomposing" spacer unit allows the release of the drug portion. In certain embodiments, the spacer unit of the linker comprises a p-aminobenzyl unit. In some such embodiments, the p-aminobenzyl alcohol is connected to the amino acid unit via an amide bond, and a carbamate, methyl carbamate, or carbonate is produced between the benzyl alcohol and the drug ( Hamann et al. (2005) Expert Opin. Ther. Patents (2005) 15: 1087-1103). In some embodiments, the spacer unit is p-aminobenzyloxycarbonyl (PAB). In some embodiments, the anti-CD79b immunoconjugate includes a self-decomposing linker having the following structure:
Figure 02_image022
Wherein Q is -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -halogen, -nitro or -cyano; m is an integer in the range of 0 to 4; the range of p Line 1 to about 20. In some embodiments, p ranges from 1 to 10, 1 to 7, 1 to 5, or 1 to 4.

自分解型間隔子之其他實例包括但不限於在電子上類似於PAB基團之芳族化合物，諸如2-胺基咪唑-5-甲醇衍生物(美國專利第7,375,078號；Hay等人(1999)Bioorg. Med. Chem. Lett . 9:2237)及鄰胺基苯甲基縮醛或對胺基苯甲基縮醛。在一些實施例中，可使用在醯胺鍵水解後經歷環化之間隔子，諸如經取代及未經取代之4-胺基丁酸醯胺(Rodrigues等人(1995)Chemistry Biology 2:223)、經適當取代之雙環[2.2.1]及雙環[2.2.2]環形系統(Storm等人(1972)J. Amer. Chem. Soc. 94:5815)及2-胺基苯基丙酸醯胺(Amsberry等人(1990)J. Org. Chem . 55:5867)。藥物與甘胺酸殘基之α-碳的連接係在ADC中可能有用的自分解型間隔子之另一個實例(Kingsbury等人(1984)J. Med. Chem . 27:1447)。Other examples of self-decomposing spacers include, but are not limited to, aromatic compounds that are electronically similar to the PAB group, such as 2-aminoimidazole-5-methanol derivatives (US Patent No. 7,375,078; Hay et al. (1999) Bioorg. Med. Chem. Lett . 9:2237) and o-aminobenzyl acetal or p-aminobenzyl acetal. In some embodiments, spacers that undergo cyclization after hydrolysis of the amide bond can be used, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al. (1995) Chemistry Biology 2:223) , Appropriately substituted bicyclic [2.2.1] and bicyclic [2.2.2] ring systems (Storm et al. (1972) J. Amer. Chem. Soc. 94:5815) and 2-aminophenyl propionate (Amsberry et al. (1990) J. Org. Chem . 55:5867). The linkage of the drug to the α-carbon of the glycine residue is another example of a self-decomposing spacer that may be useful in ADCs (Kingsbury et al. (1984) J. Med. Chem . 27:1447).

在一些實施例中，連接子L可為樹突狀連接子，用於經由分支、多官能連接子部分將多個藥物部分共價連接至抗體(Sun等人(2002)Bioorganic & Medicinal Chemistry Letters 12:2213-2215；Sun等人(2003)Bioorganic & Medicinal Chemistry 11:1761-1768)。樹突狀連接子可增加藥物與抗體之莫耳比，亦即 負載量，此與ADC之效力有關。因此，在抗體僅帶有一個反應性半胱胺酸硫醇基之情況下，可經由樹突狀連接子連接多個藥物部分。In some embodiments, the linker L may be a dendritic linker for covalently linking multiple drug moieties to the antibody via a branched, multifunctional linker moiety (Sun et al. (2002) Bioorganic & Medicinal Chemistry Letters 12 :2213-2215; Sun et al. (2003) Bioorganic & Medicinal Chemistry 11:1761-1768). Dendritic linkers can increase the molar ratio of drug to antibody, that is, the load, which is related to the effectiveness of ADC. Therefore, in the case where the antibody has only one reactive cysteine thiol group, multiple drug moieties can be connected via a dendritic linker.

在式III、IV、V之抗CD79免疫偶聯物的情況下，非限制性示例性連接子顯示於下： (III)

Figure 02_image024
val-cit (IV)
Figure 02_image026
MC-val-cit (V)
Figure 02_image028
MC-val-cit-PAB 其中(Ab)係抗CD79b抗體，(D)係藥物/細胞毒性劑，「Val-Cit」係纈胺酸-瓜胺酸二肽，MC係6-馬來醯亞胺基己醯基，PAB係對胺基苯甲氧基羰基，p係1至約20 (例如 1至15、1至10、1至8、2至5或3至4)。In the case of anti-CD79 immunoconjugates of formula III, IV, V, non-limiting exemplary linkers are shown below: (III)
Figure 02_image024
val-cit (IV)
Figure 02_image026
MC-val-cit (V)
Figure 02_image028
MC-val-cit-PAB (Ab) is an anti-CD79b antibody, (D) is a drug/cytotoxic agent, "Val-Cit" is a valine-citrulline dipeptide, and MC is a 6-maleia Aminohexyl, PAB is a p-aminobenzyloxycarbonyl group, and p is 1 to about 20 ( for example, 1 to 15, 1 to 10, 1 to 8, 2 to 5, or 3 to 4).

在一些實施例中，抗CD79b免疫偶聯物包含以下式VI-V中之任一個的結構： (VI)

Figure 02_image030
、(VII)
Figure 02_image032
、 (VIII)
Figure 02_image034
、(IX)
Figure 02_image036
、 (X)
Figure 02_image038
， 其中X係：
Figure 02_image040
； Y係：
Figure 02_image042
； 各R獨立地為H或C1 -C6 烷基；且n係1至12。In some embodiments, the anti-CD79b immunoconjugate comprises the structure of any one of the following formula VI-V: (VI)
Figure 02_image030
, (VII)
Figure 02_image032
, (VIII)
Figure 02_image034
, (IX)
Figure 02_image036
, (X)
Figure 02_image038
, Where X series:
Figure 02_image040
; Y series:
Figure 02_image042
; Each R is independently H or C 1 -C 6 alkyl; and n is 1-12.

典型地，肽型連接子可藉由在兩個或更多個胺基酸及/或肽片段之間形成肽鍵來製備。此類肽鍵可例如根據液相合成方法(例如 E. Schröder及K. Lübke (1965)「The Peptides」，第1卷，第76-136頁，Academic Press)製備。Typically, peptide linkers can be prepared by forming peptide bonds between two or more amino acids and/or peptide fragments. Such peptide bonds can be prepared, for example, according to a liquid phase synthesis method ( for example, E. Schröder and K. Lübke (1965) "The Peptides", vol. 1, pages 76-136, Academic Press).

在一些實施例中，連接子經調節溶解性及/或反應性之基團取代。作為非限制性實例，帶電取代基，諸如磺酸根(-SO3 -)或銨可增加連接子藥劑之水溶性並促進連接子藥劑與抗體及/或藥物部分之偶合反應，或促進Ab-L (抗CD79b抗體-連接子中間物)與D、或D-L (藥物/細胞毒劑-連接子中間物)與Ab之偶合反應，此取決於用於製備抗CD79b免疫偶聯物之合成途徑。在一些實施例中，連接子之一部分與抗體偶合且連接子之一部分與藥物偶合，且接著抗CD79 Ab-(連接子部分)a 與藥物/細胞毒性劑-(連接子部分)b 偶合形成式I之抗CD79b免疫偶聯物。在一些此類實施例中，抗CD79b抗體包含多個(連接子部分)a 取代基，使得多個藥物/細胞毒性劑與式I之抗CD79b免疫偶聯物中的抗CD79b抗體偶合。In some embodiments, the linker is substituted with a group that adjusts solubility and/or reactivity. As a non-limiting example, charged substituents such as sulfonate (-SO 3 -) or ammonium can increase the water solubility of the linker agent and promote the coupling reaction of the linker agent with the antibody and/or drug moiety, or promote Ab-L The coupling reaction between (anti-CD79b antibody-linker intermediate) and D, or DL (drug/cytotoxic agent-linker intermediate) and Ab depends on the synthetic route used to prepare the anti-CD79b immunoconjugate. In some embodiments, part of the linker is coupled to the antibody and part of the linker is coupled to the drug, and then anti-CD79 Ab-(linker portion) a is coupled to the drug/cytotoxic agent-(linker portion) b to form the formula I anti-CD79b immunoconjugate. In some such embodiments, the anti-CD79b antibody comprises multiple (linker portion) a substituents such that multiple drugs/cytotoxic agents are coupled to the anti-CD79b antibody in the anti-CD79b immunoconjugate of Formula I.

本文所提供之抗CD79b免疫偶聯物明確地包含但不限於用以下連接子藥劑製備之抗CD79b免疫偶聯物：雙馬來醯亞胺基三氧乙二醇(BMPEO)、N-(β-馬來醯亞胺基丙氧基)-N-羥基琥珀醯亞胺酯(BMPS)、N-(ε-馬來醯亞胺基己醯氧基)琥珀醯亞胺酯(EMCS)、N-[γ-馬來醯亞胺基丁醯氧基]琥珀醯亞胺酯(GMBS)、1,6-己烷雙乙烯基砜(HBVS)、琥珀醯亞胺基4-(N-馬來醯亞胺甲基)環己烷-1-羧基-(6-醯胺基己酸酯)(LC-SMCC)、間馬來醯亞胺基苯甲醯基-N-羥基琥珀醯亞胺酯(MBS)、4-(4-N-馬來醯亞胺基苯基)丁酸醯肼(MPBH)、琥珀醯亞胺基3-(溴乙醯胺基)丙酸酯(SBAP)、琥珀醯亞胺基碘乙酸酯(SIA)、琥珀醯亞胺基(4-碘乙醯基)胺基苯甲酸酯(SIAB)、N-琥珀醯亞胺基-3-(2-吡啶基二硫基)丙酸酯(SPDP)、N-琥珀醯亞胺基-4-(2-吡啶基硫基)戊酸酯(SPP)、琥珀醯亞胺基4-(N-馬來醯亞胺基甲基)環己烷-1-甲酸酯(SMCC)、琥珀醯亞胺基4-(對馬來醯亞胺基苯基)丁酸酯(SMPB)、琥珀醯亞胺基6-[(β-馬來醯亞胺基丙醯胺基)己酸酯](SMPH)、亞胺基硫雜環戊烷(IT)、磺基-EMCS、磺基-GMBS、磺基-KMUS、磺基-MBS、磺基-SIAB、磺基-SMCC及磺基-SMPB，以及琥珀醯亞胺基-(4-乙烯基砜)苯甲酸酯(SVSB)，且包括雙馬來醯亞胺藥劑：二硫基雙馬來醯亞胺基乙烷(DTME)、1,4-雙馬來醯亞胺基丁烷(BMB)、1,4-雙馬來醯亞胺基-2,3-二羥基丁烷(BMDB)、雙馬來醯亞胺基己烷(BMH)、雙馬來醯亞胺基乙烷(BMOE)、BM(PEG)2 (如下所示)及BM(PEG)3 (如下所示)；醯亞胺酯之雙官能衍生物(諸如二亞胺基己二酸二甲酯鹽酸鹽)、活性酯(諸如辛二酸二琥珀醯亞胺酯)、醛(諸如戊二醛)、雙疊氮化合物(諸如雙(對疊氮苯甲醯基)己二胺)、雙-重氮衍生物(諸如雙-(對重氮苯甲醯基)-乙二胺)、二異氰酸酯(諸如甲苯2,6-二異氰酸酯)及雙活性氟化合物(諸如1,5-二氟-2,4-二硝基苯)。在一些實施例中，雙馬來醯亞胺藥劑允許抗體中半胱胺酸之巰基與含巰基之藥物部分、連接子或連接子-藥物中間物連接。與巰基具有反應性之其他官能基包括但不限於碘乙醯胺、溴乙醯胺、乙烯基吡啶、二硫化物、吡啶基二硫化物、異氰酸酯及異硫氰酸酯。

Figure 02_image044
The anti-CD79b immunoconjugates provided herein specifically include, but are not limited to, anti-CD79b immunoconjugates prepared with the following linker agents: bismaleiminotrioxyethylene glycol (BMPEO), N-(β -Maleiminopropoxy)-N-hydroxysuccinimide (BMPS), N-(ε-maleiminohexyloxy)succinimide (EMCS), N -[γ-Maleiminobutyroxy] succinimidyl ester (GMBS), 1,6-hexane divinylsulfone (HBVS), succinimidyl 4-(N-maleimide) (Aminomethyl) cyclohexane-1-carboxy-(6-aminohexanoate) (LC-SMCC), m-maleiminobenzyl-N-hydroxysuccinimidyl ester (MBS), 4-(4-N-maleiminophenyl) hydrazine butyrate (MPBH), succinimidyl 3-(bromoacetamido) propionate (SBAP), amber Succinimidyl iodoacetate (SIA), succinimidyl (4-iodoacetyl) aminobenzoate (SIAB), N-succinimidyl-3-(2-pyridyl) Disulfide) propionate (SPDP), N-succinimidyl-4-(2-pyridylthio) pentanoate (SPP), succinimidyl 4-(N-maleic acid Amino methyl) cyclohexane-1-carboxylate (SMCC), succinimidyl 4-(p-maleiminophenyl) butyrate (SMPB), succinimidyl 6-[ (β-Maleiminopropylamino)hexanoate) (SMPH), iminothiolane (IT), sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfur -MBS, sulfo-SIAB, sulfo-SMCC and sulfo-SMPB, and succinimidyl-(4-vinylsulfone) benzoate (SVSB), including bismaleimide agents ：Disulfide bismaleiminoethane (DTME), 1,4-bismaleiminobutane (BMB), 1,4-bismaleimino-2,3- Dihydroxybutane (BMDB), bismaleimid hexane (BMH), bismaleimidethane (BMOE), BM(PEG) 2 (shown below) and BM(PEG) 3 (Shown below); difunctional derivatives of imine esters (such as diimino dimethyl adipate hydrochloride), active esters (such as disuccinimidyl suberate), aldehydes (such as Glutaraldehyde), bisazide compounds (such as bis(p-azidobenzyl)hexamethylene diamine), bis-diazo derivatives (such as bis-(p-diazobenzyl)-ethylenediamine) , Diisocyanates (such as toluene 2,6-diisocyanate) and dual active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). In some embodiments, the bismaleimide agent allows the sulfhydryl group of cysteine in the antibody to be linked to the sulfhydryl-containing drug moiety, linker or linker-drug intermediate. Other functional groups reactive with mercapto groups include, but are not limited to, iodoacetamide, bromoacetamide, vinyl pyridine, disulfide, pyridyl disulfide, isocyanate, and isothiocyanate.
Figure 02_image044

某些有用的連接子藥劑可自各種商業渠道獲得，諸如Pierce Biotechnology，Inc. (Rockford，IL)、Molecular Biosciences Inc.(Boulder，CO)或根據此項技術中描述之程序合成；例如，參見Toki等人(2002)J. Org. Chem . 67:1866-1872；Dubowchik等人(1997)Tetrahedron Letters ，38:5257-60；Walker，M.A. (1995)J. Org. Chem . 60:5352-5355；Frisch等人(1996)Bioconjugate Chem . 7:180-186；US 6214345；WO 02/088172；US 2003130189；US2003096743；WO 03/026577；WO 03/043583；及WO 04/032828。Some useful linker agents are available from various commercial sources, such as Pierce Biotechnology, Inc. (Rockford, IL), Molecular Biosciences Inc. (Boulder, CO) or synthesized according to procedures described in this technology; for example, see Toki (2002) J. Org. Chem . 67:1866-1872; Dubowchik et al. (1997) Tetrahedron Letters , 38:5257-60; Walker, MA (1995) J. Org. Chem . 60:5352-5355; Frisch et al. (1996) Bioconjugate Chem . 7:180-186; US 6214345; WO 02/088172; US 2003130189; US2003096743; WO 03/026577; WO 03/043583; and WO 04/032828.

碳14標記之1-異硫氰基苯甲基-3-甲基二伸乙三胺五乙酸(MX-DTPA)係用於使放射性核苷酸與抗體結合之示例性螯合劑。參見例如 WO 94/11026。B. 抗 CD79b 抗體 Carbon-14 labeled 1-isothiocyanobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for binding radionucleotides to antibodies. See, for example, WO 94/11026. B. Anti- CD79b antibody

在一些實施例中，免疫偶聯物(例如 抗CD79b免疫偶聯物)包含抗CD79b抗體，該抗體包含選自以下之至少一個、兩個、三個、四個、五個或六個HVR：(a)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(b)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(c)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(d)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(e)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(f)含SEQ ID NO: 26之胺基酸序列的HVR-L3。在一些此類實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含以下至少一個：(i)含SEQ ID NO: 23之胺基酸序列的HVR-H3及/或(ii)含SEQ ID NO: 24之胺基酸序列的HVR-L1。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含以下至少一個：(i)含SEQ ID NO: 23之胺基酸序列的HVR-H3及/或(ii)含SEQ ID NO: 24之胺基酸序列的HVR-L1。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含選自以下之至少一個、至少兩個或全部三個VH HVR序列：(a)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(b)含SEQ ID NO: 22之胺基酸序列的HVR-H2；及(c)含SEQ ID NO: 23之胺基酸序列的HVR-H3。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 23之胺基酸序列的HVR-H3。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 23之胺基酸序列的HVR-H3及含SEQ ID NO: 26之胺基酸序列的HVR-L3。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 23之胺基酸序列的HVR-H3、含SEQ ID NO: 26之胺基酸序列的HVR-L3、及含SEQ ID NO: 22之胺基酸序列的HVR-H2。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括(a)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(b)含SEQ ID NO: 22之胺基酸序列的HVR-H2；及(c)含SEQ ID NO: 23之胺基酸序列的HVR-H3。In some embodiments, the immunoconjugate ( e.g., anti-CD79b immunoconjugate) comprises an anti-CD79b antibody comprising at least one, two, three, four, five, or six HVRs selected from: (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; (c) containing the amino acid sequence of SEQ ID NO: 23 Acid sequence HVR-H3; (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 25; and (f) HVR-L3 of the amino acid sequence of SEQ ID NO: 26. In some such embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising at least one of the following: (i) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23 and/or (ii) containing SEQ ID NO: 23 ID NO: HVR-L1 of the amino acid sequence of 24. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising at least one of the following: (i) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23 and/or (ii) containing SEQ ID NO : HVR-L1 of 24 amino acid sequence. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising at least one, at least two, or all three VH HVR sequences selected from the group consisting of: (a) an amino acid sequence containing SEQ ID NO: 21 (B) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody including HVR-H3 containing the amino acid sequence of SEQ ID NO: 23. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody including HVR-H3 containing the amino acid sequence of SEQ ID NO: 23 and HVR-L3 containing the amino acid sequence of SEQ ID NO: 26. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody including HVR-H3 containing the amino acid sequence of SEQ ID NO: 23, HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, And HVR-H2 containing the amino acid sequence of SEQ ID NO: 22. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (b) containing the amino acid of SEQ ID NO: 22 Sequence HVR-H2; and (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括選自以下之至少一個、至少兩個或全部三個VL HVR序列：(a)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(b)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(c)含SEQ ID NO: 26之胺基酸序列的HVR-L3。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含選自以下之至少一個、至少兩個或全部三個VL HVR序列：(a)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(b)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(c)含SEQ ID NO: 26之胺基酸序列的HVR-L3。在一些實施例中，免疫偶聯物包括(a)含SEQ ID NO:24之胺基酸序列的HVR-L1；(b)含SEQ ID NO:25之胺基酸序列的HVR-L2；及(c)含SEQ ID NO:26之胺基酸序列的HVR-L3。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 24之胺基酸序列的HVR-L1。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括(a)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(b)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(c)含SEQ ID NO: 26之胺基酸序列的HVR-L3。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising at least one, at least two, or all three VL HVR sequences selected from the group consisting of: (a) an amino acid sequence containing SEQ ID NO: 24 (B) HVR-L2 containing the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising at least one, at least two, or all three VL HVR sequences selected from the group consisting of: (a) an amino acid sequence containing SEQ ID NO: 24 (B) HVR-L2 containing the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26. In some embodiments, the immunoconjugate includes (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 containing the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO:26. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody including HVR-L1 containing the amino acid sequence of SEQ ID NO: 24. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (b) containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (c) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括(a)含選自以下之至少一個、至少兩個或全部三個VH HVR序列的VH域：(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1、(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2及(iii)含SEQ ID NO:23之胺基酸序列的HVR-H3；以及(b)含選自以下之至少一個、至少兩個或全部三個VL HVR序列的VL域：(i)含SEQ ID NO: 24之胺基酸序列的HVR-L1、(ii)含SEQ ID NO: 25之胺基酸序列的HVR-L2及(iii)含SEQ ID NO: 26之胺基酸序列的HVR-L3。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含以下至少一個：(i)含SEQ ID NO: 23之胺基酸序列的HVR-H3及/或(ii)含SEQ ID NO: 24之胺基酸序列的HVR-L1。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising (a) a VH domain containing at least one, at least two, or all three VH HVR sequences selected from the group consisting of: (i) containing SEQ ID NO : HVR-H1 with the amino acid sequence of 21, (ii) HVR-H2 with the amino acid sequence of SEQ ID NO: 22, and (iii) HVR-H3 with the amino acid sequence of SEQ ID NO: 23; And (b) a VL domain containing at least one, at least two, or all three VL HVR sequences selected from the group consisting of: (i) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24, (ii) containing SEQ HVR-L2 with the amino acid sequence of ID NO: 25 and (iii) HVR-L3 with the amino acid sequence of SEQ ID NO: 26. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising at least one of the following: (i) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23 and/or (ii) containing SEQ ID NO : HVR-L1 of 24 amino acid sequence.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括(a)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(b)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(c)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(d)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(e)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(f)含SEQ ID NO: 26之胺基酸序列的HVR-L3(參見 表 A )。在一些實施例中，免疫偶聯物包含以下至少一個：含SEQ ID NO: 23之胺基酸序列的HVR-H3及/或含SEQ ID NO: 24之胺基酸序列的HVR-L1(參見 表 A )。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括(a)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(b)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(c)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(d)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(e)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(f)含SEQ ID NO: 26之胺基酸序列的HVR-L3(參見 表 A )。 表 A ： HVR 胺基酸序列 . 名稱 序列 SEQ ID NO huMA79bv28 HVR H1 GYTFSSYWIE 21 huMA79bv28 HVR H2 GEILPGGGDTNYNEIFKG 22 huMA79bv28 HVR H3 TRRVPIRLDY 23 huMA79bv28 HVR L1 KASQSVDYEGDSFLN 24 huMA79bv28 HVR L2 AASNLES 25 huMA79bv28 HVR L3 QQSNEDPLT 26 In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (b) containing the amino acid of SEQ ID NO: 22 Sequence HVR-H2; (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (e) containing SEQ ID NO: 25 amino acid sequence of HVR-L2; and (f) comprising SEQ ID NO: 26 amino acid sequence of HVR-L3 (see table a). In some embodiments, the immunoconjugate comprises at least one of the following: HVR-H3 containing the amino acid sequence of SEQ ID NO: 23 and/or HVR-L1 containing the amino acid sequence of SEQ ID NO: 24 ( see Table A ). In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (b) containing the amino acid of SEQ ID NO: 22 Sequence HVR-H2; (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (e) containing SEQ ID NO: 25 amino acid sequence of HVR-L2; and (f) comprising SEQ ID NO: 26 amino acid sequence of HVR-L3 (see table a). Table A : HVR amino acid sequence . name sequence SEQ ID NO huMA79bv28 HVR H1 GYTFSSYWIE twenty one huMA79bv28 HVR H2 GEILPGGGDTNYNEIFKG twenty two huMA79bv28 HVR H3 TRRVPIRLDY twenty three huMA79bv28 HVR L1 KASQSVDYEGDSFLN twenty four huMA79bv28 HVR L2 AASNLES 25 huMA79bv28 HVR L3 QQSNEDPLT 26

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體根據Kabat等人之編號包含帕妥珠單抗維多汀-piiq中之抗CD79b抗體的CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, which comprises the CDR-H1, CDR-H2, and CDR-H2 of the anti-CD79b antibody in Pertuzumab Vidotin-piiq according to the numbering of Kabat et al. H3, CDR-L1, CDR-L2 and CDR-L3.

在一些實施例中，抗CD79b免疫偶聯物包含人類化抗CD79b抗體。在一些實施例中，抗CD79b抗體包含如本文所提供之任何實施例中的HVR，且還包含人類受體構架，例如 人類免疫球蛋白構架或人類共同構架。在一些實施例中，人類受體構架係人類VL κ 1(VLKI )構架及/或VH構架VHIII 。在一些實施例中，人類化抗CD79b抗體包括(a)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(b)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(c)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(d)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(e)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(f)含SEQ ID NO: 26之胺基酸序列的HVR-L3。In some embodiments, the anti-CD79b immunoconjugate comprises a humanized anti-CD79b antibody. In some embodiments, the anti-CD79b antibody comprises the HVR as in any of the embodiments provided herein, and further comprises a human receptor framework, such as a human immunoglobulin framework or a human common framework. In some embodiments, the human receptor framework is human VL κ 1 (VL KI ) framework and/or VH framework VH III . In some embodiments, the humanized anti-CD79b antibody includes (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (e) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 The acid sequence of HVR-L2; and (f) the HVR-L3 containing the amino acid sequence of SEQ ID NO: 26.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含選自以下之至少一個、兩個、三個、四個、五個、六個、七個或八個框架區(FR)：(a)含SEQ ID NO: 27之胺基酸序列的重鏈FR (HC FR) 1；(b)含SEQ ID NO: 28之胺基酸序列的HC FR2；(c)含SEQ ID NO: 29之胺基酸序列的HC FR3；(d)含SEQ ID NO: 30之胺基酸序列HC FR4；(e)，其包含SEQ ID NO: 31之胺基酸序列的輕鏈FR (LC FR)1；(f)含SEQ ID NO: 32之胺基酸序列的LC FR2；(g)含SEQ ID NO: 33之胺基酸序列的LC FR3；及(h)含SEQ ID NO: 34之胺基酸序列的LC FR4 (參見 表 B )。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising at least one, two, three, four, five, six, seven or eight framework regions (FR) selected from : (A) heavy chain FR (HC FR) 1 containing the amino acid sequence of SEQ ID NO: 27; (b) HC FR2 containing the amino acid sequence of SEQ ID NO: 28; (c) containing SEQ ID NO : HC FR3 of the amino acid sequence of 29; (d) HC FR4 containing the amino acid sequence of SEQ ID NO: 30; (e), the light chain FR (LC FR)1; (f) LC FR2 containing the amino acid sequence of SEQ ID NO: 32; (g) LC FR3 containing the amino acid sequence of SEQ ID NO: 33; and (h) containing SEQ ID NO: 34 the amino acid sequence of the LC FR4 (see table B).

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含選自以下之至少一個、至少兩個、至少三個或全部四個HC FR序列：(a)含SEQ ID NO: 27之胺基酸序列的HC FR1；(b)含SEQ ID NO: 28之胺基酸序列的HC FR2；(c)含SEQ ID NO: 29之胺基酸序列的HC FR3；及(d)含SEQ ID NO: 30之胺基酸序列的HC FR4。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含選自以下之至少一個、至少兩個、至少三個或全部四個LC FR序列：(a)含SEQ ID NO: 31之胺基酸序列的LC FR1；(b)含SEQ ID NO: 32之胺基酸序列的LC FR2；(c)含SEQ ID NO: 33之胺基酸序列的LC FR3；及(d)含SEQ ID NO: 34之胺基酸序列的LC FR4。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising at least one, at least two, at least three or all four HC FR sequences selected from the group consisting of: (a) comprising SEQ ID NO: 27 HC FR1 of the amino acid sequence; (b) HC FR2 containing the amino acid sequence of SEQ ID NO: 28; (c) HC FR3 containing the amino acid sequence of SEQ ID NO: 29; and (d) containing SEQ ID NO: 30 amino acid sequence HC FR4. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising at least one, at least two, at least three, or all four LC FR sequences selected from the group consisting of: (a) containing SEQ ID NO: 31 LC FR1 of the amino acid sequence; (b) LC FR2 containing the amino acid sequence of SEQ ID NO: 32; (c) LC FR3 containing the amino acid sequence of SEQ ID NO: 33; and (d) containing SEQ ID NO: LC FR4 of 34 amino acid sequence.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含(a)含SEQ ID NO: 27之胺基酸序列的HC FR 1；(b)含SEQ ID NO: 28之胺基酸序列的HC FR2；(c)含SEQ ID NO: 29之胺基酸序列的HC FR3；及(d)含SEQ ID NO: 30之胺基酸序列的HC FR4。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含(a)含SEQ ID NO: 31之胺基酸序列的LC FR1；(b)含SEQ ID NO: 32之胺基酸序列的LC FR2；(c)含SEQ ID NO: 33之胺基酸序列的LC FR3；及(d)含SEQ ID NO: 34之胺基酸序列的LC FR4。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising (a) HC FR 1 containing the amino acid sequence of SEQ ID NO: 27; (b) containing the amino acid of SEQ ID NO: 28 Sequence HC FR2; (c) HC FR3 containing the amino acid sequence of SEQ ID NO: 29; and (d) HC FR4 containing the amino acid sequence of SEQ ID NO: 30. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising (a) LC FR1 containing the amino acid sequence of SEQ ID NO: 31; (b) containing the amino acid sequence of SEQ ID NO: 32 (C) LC FR3 containing the amino acid sequence of SEQ ID NO: 33; and (d) LC FR4 containing the amino acid sequence of SEQ ID NO: 34.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括(a)含選自以下之至少一個、至少兩個、至少三個或全部四個HC FR序列的VH域：(i)含SEQ ID NO: 27之胺基酸序列的HC FR1、(ii)含SEQ ID NO: 28之胺基酸序列的HC FR2；(iii)含SEQ ID NO:29之胺基酸序列的HC FR3，及(iv)含SEQ ID NO: 30之胺基酸序列的HC FR4；以及(b)含選自以下之至少一個、至少兩個、至少三個或全部四個LC FR序列的VL域：(i)含SEQ ID NO: 31之胺基酸序列的LC FR1、(ii)含SEQ ID NO: 32之胺基酸序列的LC FR2、(iii)含SEQ ID NO: 33之胺基酸序列的LC FR3，及(iv)含SEQ ID NO: 34之胺基酸序列的LC FR4。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising (a) a VH domain containing at least one, at least two, at least three, or all four HC FR sequences selected from: (i) HC FR1 containing the amino acid sequence of SEQ ID NO: 27, (ii) HC FR2 containing the amino acid sequence of SEQ ID NO: 28; (iii) HC FR3 containing the amino acid sequence of SEQ ID NO: 29 , And (iv) an HC FR4 containing the amino acid sequence of SEQ ID NO: 30; and (b) a VL domain containing at least one, at least two, at least three or all four LC FR sequences selected from: (i) LC FR1 containing the amino acid sequence of SEQ ID NO: 31, (ii) LC FR2 containing the amino acid sequence of SEQ ID NO: 32, (iii) containing the amino acid sequence of SEQ ID NO: 33 (Iv) LC FR4 containing the amino acid sequence of SEQ ID NO: 34.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括(a)含SEQ ID NO: 27之胺基酸序列的HC FR1；(b)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(c)含SEQ ID NO: 28之胺基酸序列的HC FR2；(d)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(e)含SEQ ID NO: 29之胺基酸序列的HC FR3；(f)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(g)含SEQ ID NO: 30之胺基酸序列的HC FR4；(h)含SEQ ID NO: 31之胺基酸序列的LC FR1；(i)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(j)含SEQ ID NO: 32之胺基酸序列的LC FR2；(k)含SEQ ID NO: 25之胺基酸序列的HVR-L2；(l)含SEQ ID NO: 33之胺基酸序列的LC FR3；(m)含SEQ ID NO: 26之胺基酸序列的HVR-L3；及(n)含SEQ ID NO: 34之胺基酸序列的LC FR4。 表 B ：重鏈及輕鏈框架區胺基酸序列 . 名稱 序列 SEQ ID NO huMA79bv28重鏈(HC)框架區(FR)1 EVQLVESGGGLVQPGGSLRLSCAAS 27 huMA79bv28 HC FR2 WVRQAPGKGLEWI 28 huMA79bv28 HC FR3 RATFSADTSKNTAYLQMNSLRAEDTAVYYC 29 huMA79bv28 HC FR4 WGQGTLVTVSS 30 huMA79bv28輕鏈(LC)FR1 DIQLTQSPSSLSASVGDRVTITC 31 huMA79bv28 LC FR2 WYQQKPGKAPKLLIY 32 huMA79bv28 LC FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC 33 huMA79bv28 LC FR4 FGQGTKVEIKR 34 In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising (a) HC FR1 containing the amino acid sequence of SEQ ID NO: 27; (b) containing the amino acid sequence of SEQ ID NO: 21 HVR-H1; (c) HC FR2 containing the amino acid sequence of SEQ ID NO: 28; (d) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; (e) containing SEQ ID NO: HC FR3 with the amino acid sequence of 29; (f) HVR-H3 with the amino acid sequence of SEQ ID NO: 23; (g) HC FR4 with the amino acid sequence of SEQ ID NO: 30; (h) LC FR1 containing the amino acid sequence of SEQ ID NO: 31; (i) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (j) LC containing the amino acid sequence of SEQ ID NO: 32 FR2; (k) HVR-L2 containing the amino acid sequence of SEQ ID NO: 25; (1) LC FR3 containing the amino acid sequence of SEQ ID NO: 33; (m) amine containing SEQ ID NO: 26 HVR-L3 with the base acid sequence; and (n) LC FR4 with the amino acid sequence of SEQ ID NO: 34. Table B : Amino acid sequences of heavy and light chain framework regions . name sequence SEQ ID NO huMA79bv28 heavy chain (HC) framework region (FR) 1 EVQLVESGGGLVQPGGSLRLSCAAS 27 huMA79bv28 HC FR2 WVRQAPGKGLEWI 28 huMA79bv28 HC FR3 RATFSADTSKNTAYLQMNSLRAEDTAVYYC 29 huMA79bv28 HC FR4 WGQGTLVTVSS 30 huMA79bv28 light chain (LC) FR1 DIQLTQSPSSLSASVGDRVTITC 31 huMA79bv28 LC FR2 WYQQKPGKAPKLLIY 32 huMA79bv28 LC FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC 33 huMA79bv28 LC FR4 FGQGTKVEIKR 34

在一些實施例中，免疫偶聯物(例如 抗CD79b免疫偶聯物)包含抗CD79b抗體，該抗體包含與SEQ ID NO: 19之胺基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性的重鏈可變域(VH)序列。在一些實施例中，與SEQ ID NO: 19之胺基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的VH序列相對於參考序列含有取代(例如 保守取代)、插入或缺失，但包含該序列之抗CD79b免疫偶聯物保留結合至CD79b之能力。在一些實施例中，SEQ ID NO: 19中總計1至10個胺基酸經取代、插入及/或缺失。在一些實施例中，SEQ ID NO: 19中總計1至5個胺基酸經取代、插入及/或缺失。在一些實施例中，取代、插入或缺失係在HVR之外部區域(亦即 ，在FR中)發生。在一些實施例中，免疫偶聯物(例如 抗CD79b免疫偶聯物)包含SEQ ID NO: 19之VH序列，包括該序列之轉譯後修飾。在一些實施例中，VH包含選自以下之一個、兩個或三個HVR：(a)含SEQ ID NO:21之胺基酸序列的HVR-H1、(b)含SEQ ID NO:22之胺基酸序列的HVR-H2、及(c)含SEQ ID NO:17或SEQ ID NO:23之胺基酸序列的HVR-H3。 EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSS (SEQ ID NO: 19)In some embodiments, the immunoconjugate ( e.g., anti-CD79b immunoconjugate) comprises an anti-CD79b antibody, the antibody comprising at least 90%, 91%, 92%, 93% of the amino acid sequence of SEQ ID NO: 19 %, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity of the heavy chain variable domain (VH) sequence. In some embodiments, the amino acid sequence of SEQ ID NO: 19 has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity The sexual VH sequence contains substitutions ( e.g. conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-CD79b immunoconjugates containing the sequence retain the ability to bind to CD79b. In some embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 19 are substituted, inserted, and/or deleted. In some embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 19 are substituted, inserted, and/or deleted. In some embodiments, the substitution, insertion, or deletion occurs in the outer region of the HVR (ie , in the FR). In some embodiments, the immunoconjugate ( e.g., anti-CD79b immunoconjugate) comprises the VH sequence of SEQ ID NO: 19, including post-translational modifications of the sequence. In some embodiments, the VH comprises one, two or three HVRs selected from the group consisting of: (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21, (b) HVR-H containing the amino acid sequence of SEQ ID NO: 22 The amino acid sequence of HVR-H2 and (c) the HVR-H3 containing the amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23. EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSS (SEQ ID NO: 19)

在一些實施例中，免疫偶聯物(例如 抗CD79b免疫偶聯物)包含抗CD79b抗體，該抗體包含與SEQ ID NO: 20之胺基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之輕鏈可變域(VL)。在某些實施例中，相對於參照序列，與胺基酸序列SEQ ID NO: 20具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性之VL序列含有取代(例如 保守性取代)、插入或缺失，但包含彼序列之抗CD79b免疫偶聯物保留結合於CD79b之能力。在某些實施例中，SEQ ID NO: 20中總計1至10個胺基酸經取代、插入及/或缺失。在某些實施例中，SEQ ID NO: 20中總計1至5個胺基酸經取代、插入及/或缺失。在某些實施例中，取代、插入或缺失係在HVR之外部區域中(亦即， 在FR中)發生。在一些實施例中，抗CD79b免疫偶聯物包含抗CD79b抗體，該抗體包含SEQ ID NO: 20之VL序列，包括該序列之轉譯後修飾。在一些實施例中，VL包含選自以下之一個、兩個或三個HVR：(a)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(b)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(c)含SEQ ID NO: 26之胺基酸序列的HVR-L3。在一些實施例中，VL包含選自以下之一個、兩個或三個HVR：(a)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(b)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(c)含SEQ ID NO: 26之胺基酸序列的HVR-L3。 DIQLTQSPSS LSASVGDRVT ITCKASQSVD YEGDSFLNWY QQKPGKAPKL LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPL TFGQGTKVEI KR (SEQ ID NO: 20)In some embodiments, the immunoconjugate ( e.g., anti-CD79b immunoconjugate) comprises an anti-CD79b antibody comprising an amino acid sequence of at least 90%, 91%, 92%, 93% with the amino acid sequence of SEQ ID NO: 20. %, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity of the light chain variable domain (VL). In certain embodiments, relative to the reference sequence, the amino acid sequence SEQ ID NO: 20 has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% Or 99% identical VL sequences contain substitutions ( eg conservative substitutions), insertions or deletions, but the anti-CD79b immunoconjugates containing that sequence retain the ability to bind to CD79b. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 20 are substituted, inserted, and/or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 20 are substituted, inserted, and/or deleted. In certain embodiments, the substitution, insertion, or deletion occurs in the outer region of the HVR (ie, in the FR). In some embodiments, the anti-CD79b immunoconjugate comprises an anti-CD79b antibody comprising the VL sequence of SEQ ID NO: 20, including post-translational modifications of the sequence. In some embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (b) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 with the amino acid sequence; and (c) HVR-L3 with the amino acid sequence of SEQ ID NO: 26. In some embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (b) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 with the amino acid sequence; and (c) HVR-L3 with the amino acid sequence of SEQ ID NO: 26. DIQLTQSPSS LSASVGDRVT ITCKASQSVD YEGDSFLNWY QQKPGKAPKL LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPL TFGQGTKVEI KR (SEQ ID NO: 20)

在一些實施例中，免疫偶聯物(例如 抗CD79b免疫偶聯物)包含抗CD79b抗體，該抗體包含如本文所提供之任何實施例中的VH及如本文所提供之任何實施例中的VL。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含分別如SEQ ID NO: 19及SEQ ID NO: 20中所示之VH序列及VL序列，包括該等序列之轉譯後修飾。In some embodiments, the immunoconjugate ( e.g., anti-CD79b immunoconjugate) comprises an anti-CD79b antibody comprising VH as in any embodiment provided herein and VL as in any embodiment provided herein . In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising the VH sequence and VL sequence as shown in SEQ ID NO: 19 and SEQ ID NO: 20, respectively, including post-translational modifications of these sequences.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含帕妥珠單抗維多汀-piiq中之抗CD79b抗體的VH及VL。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising the VH and VL of the anti-CD79b antibody in Pertuzumab Vidotin-piiq.

在一些實施例中，免疫偶聯物(例如 抗CD79b免疫偶聯物)包含與本文所述之抗CD79b抗體結合至相同抗原決定基的抗CD79b抗體。舉例而言，在一些實施例中，免疫偶聯物(例如 抗CD79b免疫偶聯物)包含抗CD79b抗體，該抗體與含SEQ ID NO:19之VH序列及SEQ ID NO:20之VL序列的抗CD79b抗體結合至相同的抗原決定基。In some embodiments, the immunoconjugate ( e.g., anti-CD79b immunoconjugate) comprises an anti-CD79b antibody that binds to the same epitope as the anti-CD79b antibody described herein. For example, in some embodiments, the immunoconjugate ( e.g., anti-CD79b immunoconjugate) comprises an anti-CD79b antibody, which is combined with an anti-CD79b antibody containing the VH sequence of SEQ ID NO: 19 and the VL sequence of SEQ ID NO: 20 The anti-CD79b antibody binds to the same epitope.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體係單株抗體、嵌合抗體、人類化抗體或人類抗體。在一些實施例中，免疫偶聯物包含本文所述之抗CD79b抗體的抗原結合片段，例如 Fv、Fab、Fab'、scFv、雙功能抗體或F(ab')2 片段。在一些實施例中，免疫偶聯物包含基本上全長抗CD79b抗體，例如 IgG1抗體或如本文別處所述之其他抗體類別或同型。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, which is a monoclonal antibody, a chimeric antibody, a humanized antibody, or a human antibody. In some embodiments, the immunoconjugate comprises an antigen-binding fragment of the anti-CD79b antibody described herein, such as Fv, Fab, Fab', scFv, bifunctional antibody, or F(ab') 2 fragment. In some embodiments, the immunoconjugate comprises a substantially full-length anti-CD79b antibody, such as an IgG1 antibody or other antibody class or isotype as described elsewhere herein.

在一些實施例中，免疫偶聯物包含抗CD79抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及/或含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及/或含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及/或含SEQ ID NO: 38之胺基酸序列的輕鏈。在一些實施例中，該免疫偶聯物包含抗CD79抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在一些實施例中，該免疫偶聯物包含抗CD79b抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。In some embodiments, the immunoconjugate comprises an anti-CD79 antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and/or a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and/or a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and/or a light chain containing the amino acid sequence of SEQ ID NO: 38. In some embodiments, the immunoconjugate comprises an anti-CD79 antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 38.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含帕妥珠單抗維多汀-piiq中之抗CD79b抗體的重鏈及輕鏈。In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, which comprises the heavy chain and light chain of the anti-CD79b antibody in Pertuzumab Vidotin-piiq.

在一些實施例中，免疫偶聯物包含抗CD79b抗體，該抗體包含依拉妥珠單抗維多汀中之抗CD79b抗體的重鏈及輕鏈。在一些實施例中，抗CD79b抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。C. 藥物 / 細胞毒性劑 In some embodiments, the immunoconjugate comprises an anti-CD79b antibody, and the antibody comprises the heavy chain and light chain of the anti-CD79b antibody in elatuzumab vedotin. In some embodiments, the anti-CD79b antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 35. C. Drugs / cytotoxic agents

抗CD79免疫偶聯物包含結合至與一或多種藥物/細胞毒性劑，諸如化學治療劑或藥物、生長抑製劑、毒素(例如 蛋白質毒素、細菌、真菌、植物或動物來源之酶活性毒素，或其片段)或放射性同位素(亦即 ，放射性偶聯物)結合的抗CD79b抗體(例如 本文所述之抗CD79b抗體)。此類免疫偶聯物係經靶向之化學治療分子，其藉由使強效細胞毒性藥物靶向表現抗原之癌細胞(諸如腫瘤細胞)來組合抗體及細胞毒性藥物之性質(Teicher，B.A. (2009)Current Cancer Drug Targets 9:982-1004)，由此藉由使功效達到最大且使脫靶毒性減到最小來增大治療指數(Carter，P.J.及Senter P.D. (2008)The Cancer Jour . 14(3):154-169；Chari，R.V. (2008)Acc. Chem. Res . 41:98-107。亦即，抗CD79免疫偶聯物將有效劑量之藥物選擇性遞送至癌細胞/組織，藉此在增加治療指數(「治療窗」)的同時，可實現較高的選擇性(亦即 ，較低的有效劑量)(Polakis P. (2005)Current Opinion in Pharmacology 5:382-387)。Anti-CD79 immunoconjugates include binding to one or more drugs/cytotoxic agents, such as chemotherapeutics or drugs, growth inhibitors, toxins ( eg protein toxins, bacterial, fungal, plant or animal-derived enzymatic toxins, or Fragments thereof) or radioisotope ( i.e. , radioconjugate) conjugated anti-CD79b antibodies ( e.g. , anti-CD79b antibodies described herein). Such immunoconjugates are targeted chemotherapeutic molecules that combine the properties of antibodies and cytotoxic drugs by targeting potent cytotoxic drugs to cancer cells (such as tumor cells) that express antigens (Teicher, BA ( 2009) Current Cancer Drug Targets 9:982-1004), thereby increasing the therapeutic index by maximizing efficacy and minimizing off-target toxicity (Carter, PJ and Senter PD (2008) The Cancer Jour . 14(3) ):154-169; Chari, RV (2008) Acc. Chem. Res . 41:98-107. That is, the anti-CD79 immunoconjugate selectively delivers an effective dose of the drug to cancer cells/tissues, thereby While increasing the therapeutic index ("therapeutic window"), higher selectivity ( ie , lower effective dose) can be achieved (Polakis P. (2005) Current Opinion in Pharmacology 5:382-387).

在本文所提供之方法中使用的抗CD79免疫偶聯物包括具有抗癌活性之免疫偶聯物。在一些實施例中，抗CD79免疫偶聯物包含與藥物部分結合，亦即 共價連接的抗CD79b抗體。在一些實施例中，抗CD79b抗體經由連接子共價連接至藥物部分。抗CD79免疫偶聯物之藥物部分(D)可包括具有細胞毒性或細胞抑製作用的任何化合物、部分或基團。藥物部分可藉由以下機制來發揮其細胞毒性及細胞生長抑制作用，該等機制包括但不限於微管蛋白結合、DNA結合或嵌入、以及RNA聚合酶、蛋白質合成及/或拓撲異構酶之抑制。示範性藥物部分包括但不限於類美登素、海兔毒素(dolastatin)、奧瑞他汀、卡奇黴素、蒽環黴素(anthracycline)、倍癌黴素(duocarmycin)、長春花生物鹼、紫杉烷(taxane)、新月毒素(trichothecene)、CC1065、喜樹鹼(camptothecin)、依利奈法德(elinafide)及其具有細胞毒性活性之立體異構體、同電子排列體、類似物及衍生物。(i) 美登素及類美登素 The anti-CD79 immunoconjugates used in the methods provided herein include immunoconjugates with anticancer activity. In some embodiments, the anti-CD79 immunoconjugate comprises an anti-CD79b antibody bound to the drug moiety, that is, covalently linked. In some embodiments, the anti-CD79b antibody is covalently linked to the drug moiety via a linker. The drug portion (D) of the anti-CD79 immunoconjugate may include any compound, portion or group that has cytotoxic or cytostatic effects. The drug part can exert its cytotoxicity and cell growth inhibitory effects through the following mechanisms, including but not limited to tubulin binding, DNA binding or intercalation, and RNA polymerase, protein synthesis and/or topoisomerase inhibition. Exemplary drugs include, but are not limited to, maytansinoid, dolastatin, auristatin, calicheamicin, anthracycline, duocarmycin, vinca alkaloid, Taxane, trichothecene, CC1065, camptothecin, elinafide and their stereoisomers, homoelectron arrays, analogs and their cytotoxic activity derivative. (i) Maytansinoids and maytansinoids

在一些實施例中，抗CD79b免疫偶聯物包含與一或多個類美登素分子結合之抗CD79b抗體。類美登素係美登鹼之衍生物，且為藉由抑制微管蛋白聚合來起作用的有絲分裂抑制劑。美登素最初自東非灌木齒葉美登木(Maytenus serrata)分離(美國專利第3896111號)。隨後，發現某些微生物亦產生類美登素，諸如美登醇(maytansinol)及C-3美登醇酯(美國專利第4,151,042號)。合成的類美登素揭示於例如美國專利第4,137,230號；第4,248,870號；第4,256,746號；第4,260,608號；第4,265,814號；第4,294,757號；第4,307,016號；第4,308,268號；第4,308,269號；第4,309,428號；第4,313,946號；第4,315,929號；第4,317,821號；第4,322,348號；第4,331,598號；第4,361,650號；第4,364,866號；第4,424,219號；第4,450,254號；第4,362,663號；及第4,371,533號中。In some embodiments, the anti-CD79b immunoconjugate comprises an anti-CD79b antibody that binds to one or more maytansinoid molecules. Maytansinoids are derivatives of maytansine and are mitotic inhibitors that act by inhibiting tubulin polymerization. Maytansine was originally isolated from the East African shrub Maytenus serrata (US Patent No. 3896111). Subsequently, it was discovered that certain microorganisms also produce maytansinoids, such as maytansinol and C-3 maytansinol esters (US Patent No. 4,151,042). Synthetic maytansinoids are disclosed in, for example, U.S. Patent Nos. 4,137,230; No. 4,248,870; No. 4,256,746; No. 4,260,608; No. 4,265,814; No. 4,294,757; No. 4,307,016; No. 4,308,268; No. 4,308,269; No. 4,309,428 ; No. 4,313,946; No. 4,315,929; No. 4,317,821; No. 4,322,348; No. 4,331,598; No. 4,361,650; No. 4,364,866; No. 4,424,219; No. 4,450,254; No. 4,362,663; and No. 4,371,533.

類美登素藥物部分係抗體-藥物偶聯物中之有吸引力的藥物部分，因為其：(i)相對容易藉由發酵或對發酵産物進行化學修飾或衍生化來製備；(ii)適於用適合經由非二硫化物連接子與抗體結合之官能基衍生化；(iii)在血漿中穩定；及(iv)對多種腫瘤細胞株有效。The maytansinoid drug moiety is an attractive drug moiety in antibody-drug conjugates because it is: (i) relatively easy to prepare by fermentation or chemical modification or derivatization of fermentation products; (ii) suitable For derivatization with functional groups suitable for binding to antibodies via non-disulfide linkers; (iii) stable in plasma; and (iv) effective against a variety of tumor cell lines.

適用作類美登素藥物部分之某些類美登素係此項技術中已知的且可根據已知方法自天然來源分離或使用基因工程改造技術製備(參見例如 Yu等人，(2002) PNAS 99:7968-7973)。類美登素亦可根據已知方法合成製備。Certain maytansinoids suitable for use as part of maytansinoids are known in the art and can be isolated from natural sources according to known methods or prepared using genetic engineering techniques ( see, for example, Yu et al., (2002) PNAS 99:7968-7973). Maytansinoids can also be prepared synthetically according to known methods.

示例性類美登素藥物部分包括但不限於具有諸如以下之經修飾芳族環的類美登素藥物部分：C-19-脫氯(美國專利第4256746號)(例如藉由用氫化鋰鋁還原安絲菌素(ansamytocin) P2來製備)；C-20-羥基(或C-20-脫甲基)+/-C-19-脫氯(美國專利第4361650號及第4307016號)(例如藉由使用鏈黴菌(Streptomyces )或放線菌(Actinomyces )脫甲基或使用LAH脫氯來製備)；及C-20-脫甲氧基、C-20-醯氧基(-OCOR)、+/-脫氯(美國專利第4,294,757號)(例如藉由使用醯基氯進行醯化來製備)；以及在芳族環之其他位置處具有修飾者。Exemplary maytansinoid drug moieties include, but are not limited to, maytansinoid drug moieties with modified aromatic rings such as: C-19-dechlorination (U.S. Patent No. 4,256,746) (for example, by using lithium aluminum hydride Reduction of ansamytocin P2); C-20-hydroxy (or C-20-demethylation) +/-C-19-dechlorination (U.S. Patent Nos. 4,361,650 and 4,307,016) (e.g. Prepared by demethylation using Streptomyces or Actinomyces or dechlorination using LAH); and C-20-demethoxy, C-20-oxyl (-OCOR), +/ -Dechlorination (US Patent No. 4,294,757) (for example, prepared by acylation with acetoxychloride); and those with modifications in other positions of the aromatic ring.

示例性類美登素藥物部分亦包括具有諸如以下修飾者：C-9-SH (美國專利第4424219號)(例如藉由使美登醇與H2 S或P2 S5 反應來製備)；C-14-烷氧基甲基(脫甲氧基/CH2 OR)(US 4331598)；C-14-羥甲基或醯氧基甲基(CH2 OH或CH2 OAc)(美國專利第4450254號)(例如自諾卡氏菌(Nocardia)製備)；C-15-羥基/醯氧基(US 4364866)(例如藉由用鏈黴菌轉化美登醇製備)；C-15-甲氧基(美國專利第4313946號及第4315929號)(例如自滑桃樹(Trewia nudlflora)分離)；C-18-N-脫甲基(美國專利第4362663號及第4322348號)(例如藉由用鏈黴菌使美登醇脫甲基來製備)；及4,5-脫氧(US 4371533)(例如藉由用三氯化鈦/LAH還原美登醇製備)。Exemplary maytansinoid drug moieties also include those with modifications such as: C-9-SH (US Patent No. 4424219) (for example, prepared by reacting maytansinol with H 2 S or P 2 S 5 ); C-14-alkoxymethyl (demethoxy/CH 2 OR) (US 4331598); C-14-hydroxymethyl or oxymethyl (CH 2 OH or CH 2 OAc) (US Patent No. No. 4450254) (for example, prepared from Nocardia); C-15-hydroxy/oxyl (US 4364866) (for example, prepared by transforming maytansinol with Streptomyces); C-15-methoxy (U.S. Patent Nos. 4313946 and 4315929) (e.g. isolated from Trewia nudlflora); C-18-N-demethylation (U.S. Patent Nos. 4362663 and 4322348) (e.g. by using chain Prepared by mold demethylation of maytansinol); and 4,5-deoxy (US 4371533) (for example, prepared by reducing maytansinol with titanium trichloride/LAH).

類美登素化合物上之許多位置可用作鍵聯位置。舉例而言，可使用習知偶合技術，藉由與羥基反應來形成酯鍵聯。在一些實施例中，反應可在具有羥基之C-3位置、經羥甲基修飾之C-14位置、經羥基修飾之C-15位置及具有羥基之C-20位置處發生。在一些實施例中，該鍵聯係在美登醇或美登醇類似物之C-3位置處形成。Many positions on the maytansinoid compound can be used as linkage positions. For example, conventional coupling techniques can be used to form ester linkages by reacting with hydroxyl groups. In some embodiments, the reaction can occur at the C-3 position having a hydroxyl group, the C-14 position modified with hydroxymethyl, the C-15 position modified with a hydroxyl group, and the C-20 position having a hydroxyl group. In some embodiments, the linkage is formed at the C-3 position of maytansinol or a maytansinol analog.

類美登素藥物部分包括具有以下結構者：

Figure 02_image046
其中波形線指示類美登素藥物部分之硫原子與抗CD79b免疫偶聯物之連接子的共價連接。各R可獨立地為H或C1 -C6 烷基。將醯胺基團連接至硫原子之伸烷基鏈可為甲烷基、乙烷基或丙基，亦即 ，m係1、2或3 (US 633410；US 5208020；Chari等人(1992)Cancer Res. 52:127-131；Liu等人(1996)Proc. Natl. Acad. Sci USA 93:8618-8623)。The part of maytansinoids includes those with the following structure:
Figure 02_image046
The wavy line indicates the covalent connection between the sulfur atom of the maytansinoid drug moiety and the linker of the anti-CD79b immunoconjugate. Each R may independently be H or C 1 -C 6 alkyl. The alkylene chain connecting the amide group to the sulfur atom can be a methyl group, an ethyl group or a propyl group, that is , m is 1, 2 or 3 (US 633410; US 5208020; Chari et al. (1992) Cancer Res. 52:127-131; Liu et al. (1996) Proc. Natl. Acad. Sci USA 93:8618-8623).

預期類美登素藥物部分之所有立體異構體皆用於本文所提供之方法中所用之抗CD79b免疫偶聯物，亦即 ，在對掌性碳處R 及S 構型之任何組合(US 7276497；US 6913748；US 6441163；US 633410(RE39151)；US 5208020；Widdison等人，(2006) J. Med. Chem. 49:4392-4408，其以全文引用的方式併入本文中)。在一些實施例中，類美登素藥物部分具有以下立體化學：

Figure 02_image048
。It is expected that all stereoisomers of the maytansinoid drug portion are used in the anti-CD79b immunoconjugates used in the methods provided herein, that is , any combination of R and S configurations at the opposing carbon (US 7276497; US 6913748; US 6441163; US 633410 (RE39151); US 5208020; Widdison et al. (2006) J. Med. Chem. 49:4392-4408, which is incorporated herein by reference in its entirety). In some embodiments, the maytansinoid drug moiety has the following stereochemistry:
Figure 02_image048
.

類美登素藥物部分之示例性實施例包括但不限於具有以下結構之DM1；DM3；及DM4：

Figure 02_image049
Figure 02_image051
Figure 02_image053
其中波形線指示藥物之硫原子與抗CD79b免疫偶聯物之連接子(L)的共價連接。Exemplary examples of the maytansinoid drug portion include, but are not limited to, DM1; DM3; and DM4 having the following structures:
Figure 02_image049
Figure 02_image051
Figure 02_image053
The wavy line indicates the covalent connection between the sulfur atom of the drug and the linker (L) of the anti-CD79b immunoconjugate.

其他示例性類美登素抗CD79b免疫偶聯物具有以下結構及縮寫(其中Ab係抗CD79b抗體且p係1至約20。在一些實施例中，p係1至10，p係1至7，p係1至5，或p係1至4)：

Figure 02_image055
Ab -SPP-DM1
Figure 02_image057
Ab-SMCC-DM1Other exemplary maytansinoid anti-CD79b immunoconjugates have the following structures and abbreviations (wherein Ab is an anti-CD79b antibody and p is 1 to about 20. In some embodiments, p is 1 to 10, and p is 1 to 7 , P is 1 to 5, or p is 1 to 4):
Figure 02_image055
Ab -SPP-DM1
Figure 02_image057
Ab-SMCC-DM1

DM1經由BMPEO連接子連接至抗體之硫醇基的示例性抗體-藥物偶聯物具有以下結構及縮寫：

Figure 02_image059
其中Ab係抗CD79b抗體；n係0、1或2；且p係1至約20。在一些實施例中，p係1至10，p係1至7，p係1至5，或p係1至4。An exemplary antibody-drug conjugate in which DM1 is connected to the thiol group of an antibody via a BMPEO linker has the following structure and abbreviations:
Figure 02_image059
Wherein Ab is an anti-CD79b antibody; n is 0, 1, or 2; and p is 1 to about 20. In some embodiments, p ranges from 1 to 10, p ranges from 1 to 7, p ranges from 1 to 5, or p ranges from 1 to 4.

含有類美登素之免疫偶聯物、其製備方法及其治療用途揭示於例如美國專利第5,208,020號及第5,416,064號中；US 2005/0276812 A1；及歐洲專利EP 0 425 235 B1中，其揭示內容以引用的方式明確地併入本文中。另參見 Liu等人，Proc. Natl. Acad. Sci. USA 93:8618-8623 (1996)；及Chari等人，Cancer Research 52:127-131 (1992)。The immunoconjugates containing maytansinoids, their preparation methods and their therapeutic uses are disclosed in, for example, US Patent Nos. 5,208,020 and 5,416,064; US 2005/0276812 A1; and European Patent EP 0 425 235 B1, which disclose The content is expressly incorporated herein by reference. See also Liu et al., Proc. Natl. Acad. Sci. USA 93:8618-8623 (1996); and Chari et al., Cancer Research 52:127-131 (1992).

在一些實施例中，抗CD79b抗體-類美登素偶聯物可藉由將抗CD79b抗體以化學方式連接至類美登素分子，同時不顯著削弱抗體或類美登素分子之生物活性來製備。參見例如 美國專利第5,208,020號(其揭示內容以引用的方式明確地併入本文)。在一些實施例中，每個抗體分子結合平均3-4個類美登素分子之抗CD79b免疫偶聯物在增強目標細胞之細胞毒性方面顯示出功效，不會負面地影響抗體之功能或溶解性。在一些情況下，相對於使用裸抗CD79b抗體，甚至一分子之毒素/抗體亦有望增強細胞毒性。In some embodiments, the anti-CD79b antibody-maytansinoid conjugate can be achieved by chemically linking the anti-CD79b antibody to the maytansinoid molecule without significantly impairing the biological activity of the antibody or maytansinoid molecule. preparation. See, for example, U.S. Patent No. 5,208,020 (the disclosure of which is expressly incorporated herein by reference). In some embodiments, the anti-CD79b immunoconjugate that binds an average of 3-4 maytansinoid molecules per antibody molecule shows efficacy in enhancing the cytotoxicity of target cells without negatively affecting the function or lysis of the antibody Sex. In some cases, compared to the use of naked anti-CD79b antibodies, even a molecule of toxin/antibody is expected to enhance cytotoxicity.

用於製備抗體-類美登素偶聯物之示例性連接基團包括例如本文所述之連接基團及美國專利第5208020號；英国專利0 425 235 B1；Chari等人，Cancer Research 52:127-131 (1992)；US 2005/0276812 A1；及US 2005/016993 A1中揭示之連接基團，該等文獻之揭示內容以引用的方式明確地併入本文中。(2) 奧瑞他汀及海兔毒素 Exemplary linking groups for preparing antibody-maytansinoid conjugates include, for example, the linking groups described herein and U.S. Patent No. 5,208,020; British Patent 0 425 235 B1; Chari et al., Cancer Research 52:127 -131 (1992); US 2005/0276812 A1; and US 2005/016993 A1. The disclosures of these documents are expressly incorporated herein by reference. (2) Auristatin and dolphin

藥物部分包括海兔毒素、奧瑞他汀、以及其類似物及衍生物(US 5635483；US 5780588；US 5767237；US 6124431)。奧瑞他汀係海洋軟體動物化合物海兔毒素-10之衍生物。儘管不意欲受任何特定理論束縛，但經顯示，海兔毒素及奧瑞他汀可干擾微管動力學、GTP水解、以及細胞核及細胞分裂(Woyke等人(2001)Antimicrob. Agents and Chemother . 45(12):3580-3584)且具有抗癌(US 5663149)及抗真菌活性(Pettit等人(1998)Antimicrob. Agents Chemother . 42:2961-2965)。海兔毒素/奧瑞他汀藥物部分可經由肽藥物部分之N (胺基)末端或C (羧基)末端連接至抗體(WO 02/088172；Doronina等人(2003)Nature Biotechnology 21(7):778-784；Francisco等人(2003)Blood 102(4):1458-1465)。The drug part includes dolphin, auristatin, and its analogs and derivatives (US 5635483; US 5780588; US 5767237; US 6124431). Auristatin is a derivative of the marine mollusk compound dorastoxin-10. Although not intending to be bound by any particular theory, it has been shown that dolastatin and auristatin can interfere with microtubule dynamics, GTP hydrolysis, and nuclear and cell division (Woyke et al. (2001) Antimicrob. Agents and Chemother . 45() 12):3580-3584) and has anticancer (US 5663149) and antifungal activities (Pettit et al. (1998) Antimicrob. Agents Chemother . 42:2961-2965). The dopetoxin/austatin drug moiety can be connected to the antibody via the N (amino) end or C (carboxy) end of the peptide drug moiety (WO 02/088172; Doronina et al. (2003) Nature Biotechnology 21(7):778 -784; Francisco et al. (2003) Blood 102(4):1458-1465).

示例性奧瑞他汀實施例包括US 7498298及US 7659241中揭示之N末端連接型單甲基奧瑞他汀藥物部分DE 及DF ，該等專利之揭示內容以全文引用的方式明確併入本文中：

Figure 02_image061
D E
Figure 02_image063
D F 其中DE 及DF 之波形線指示與抗體或抗體-連接子組分之共價連接位點，且在各位置處獨立地： R2 選自H及C1 -C8 烷基； R3 選自H、C1 -C8 烷基、C3 -C8 碳環、芳基、C1 -C8 烷基-芳基、C1 -C8 烷基-(C3 -C8 碳環)、C3 -C8 雜環及C1 -C8 烷基-(C3 -C8 雜環)； R4 選自H、C1 -C8 烷基、C3 -C8 碳環、芳基、C1 -C8 烷基-芳基、C1 -C8 烷基-(C3 -C8 碳環)、C3 -C8 雜環及C1 -C8 烷基-(C3 -C8 雜環)； R5 選自H及甲基； 或R4 及R5 共同形成碳環並具有式-(CRa Rb )n -，其中Ra 及Rb 獨立地選自H、C1 -C8 烷基及C3 -C8 碳環且n選自2、3、4、5及6； R6 選自H及C1 -C8 烷基； R7 選自H、C1 -C8 烷基、C3 -C8 碳環、芳基、C1 -C8 烷基-芳基、C1 -C8 烷基-(C3 -C8 碳環)、C3 -C8 雜環及C1 -C8 烷基-(C3 -C8 雜環)； 各R8 獨立地選自H、OH、C1 -C8 烷基、C3 -C8 碳環及O-(C1 -C8 烷基)； R9 選自H及C1 -C8 烷基； R10 選自芳基或C3 -C8 雜環； Z係O、S、NH或NR12 ，其中R12 係C1 -C8 烷基； R11 選自H、C1 -C20 烷基、芳基、C3 -C8 雜環、-(R13 O)m -R14 或-(R13 O)m -CH(R15 )2 ； m係範圍自1至1000之整數； R13 係C2 -C8 烷基； R14 係H或C1 -C8 烷基； R15 在每次出現時獨立地為H、COOH、-(CH2 )n -N(R16 )2 、-(CH2 )n -SO3 H或-(CH2 )n -SO3 -C1 -C8 烷基； R16 在每次出現時獨立地為H、C1 -C8 烷基或-(CH2 )n -COOH； R18 選自-C(R8 )2 -C(R8 )2 -芳基、-C(R8 )2 -C(R8 )2 -(C3 -C8 雜環)及-C(R8 )2 -C(R8 )2 -(C3 -C8 碳環)；且 n係範圍自0至6之整數。Exemplary auristatin embodiments include the disclosed in US 7498298 and US 7659241 N-terminus single auristatin drug moiety D E and D F, to the disclosure of such patent is expressly incorporated by reference in its entirety herein by :
Figure 02_image061
D E
Figure 02_image063
Wherein the waveform D E D F D F and the line indicates the antibody or antibody - covalently subcomponents of connection sites, and independently at each location: R 2 is selected from H and C 1 -C 8 alkyl; R 3 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbocyclic, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 Carbocyclic), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle); R 4 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbon Ring, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocyclic ring), C 3 -C 8 heterocycle and C 1 -C 8 alkyl- (C 3 -C 8 heterocycle); R 5 is selected from H and methyl; or R 4 and R 5 together form a carbocyclic ring and have the formula -(CR a R b ) n -, wherein R a and R b are independently Is selected from H, C 1 -C 8 alkyl and C 3 -C 8 carbocyclic ring and n is selected from 2, 3, 4, 5 and 6; R 6 is selected from H and C 1 -C 8 alkyl; R 7 is selected From H, C 1 -C 8 alkyl, C 3 -C 8 carbocyclic, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocyclic) , C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle); each R 8 is independently selected from H, OH, C 1 -C 8 alkyl, C 3 -C 8- carbocyclic ring and O-(C 1 -C 8 alkyl); R 9 is selected from H and C 1 -C 8 alkyl; R 10 is selected from aryl or C 3 -C 8 heterocycle; Z is O, S , NH or NR 12 , wherein R 12 is C 1 -C 8 alkyl; R 11 is selected from H, C 1 -C 20 alkyl, aryl, C 3 -C 8 heterocycle, -(R 13 O) m -R 14 or -(R 13 O) m -CH(R 15 ) 2 ; m is an integer ranging from 1 to 1000; R 13 is C 2 -C 8 alkyl; R 14 is H or C 1 -C 8 Alkyl; R 15 is independently H, COOH, -(CH 2 ) n -N(R 16 ) 2 , -(CH 2 ) n -SO 3 H or -(CH 2 ) n -SO at each occurrence 3- C 1 -C 8 alkyl; each occurrence of R 16 is independently H, C 1 -C 8 alkyl or -(CH 2 ) n -COOH; R 18 is selected from -C(R 8 ) 2 -C(R 8 ) 2 -Aryl, -C(R 8 ) 2 -C(R 8 ) 2 -(C 3 -C 8 heterocycle) and -C(R 8 ) 2 -C(R 8 ) 2 -(C 3 -C 8 Carbocyclic); and n is an integer ranging from 0 to 6.

在一個實施例中，R3 、R4 及R7 獨立地為異丙基或第二丁基，且R5 係-H或甲基。在一個示例性實施例中，R3 及R4 各自為異丙基，R5 係-H，且R7 係第二丁基。In one embodiment, R 3 , R 4 and R 7 are independently isopropyl or sec-butyl, and R 5 is -H or methyl. In an exemplary embodiment, R 3 and R 4 are each an isopropyl group, R 5 is -H, and R 7 is a second butyl group.

在另一個實施例中，R2 及R6 各自為甲基，且R9 係-H。In another embodiment, R 2 and R 6 are each methyl, and R 9 is -H.

在另一個實施例中，R8 在每次出現時為-OCH3 。In another embodiment, each occurrence of R 8 is -OCH 3 .

在一個示例性實施例中，R3 及R4 各自為異丙基，R2 及R6 各自為甲基，R5 係-H，R7 係第二丁基，R8 在每次出現時為-OCH3 ，且R9 為-H。In an exemplary embodiment, R 3 and R 4 are each isopropyl, R 2 and R 6 are each methyl, R 5 is -H, R 7 is sec-butyl, and R 8 is each occurrence Is -OCH 3 and R 9 is -H.

在一個實施例中，Z係-O-或-NH-。In one embodiment, Z is -O- or -NH-.

在一個實施例中，R10 係芳基。In one embodiment, R 10 is an aryl group.

在一個示例性實施例中，R10 係-苯基。In an exemplary embodiment, R 10 is -phenyl.

在一個示例性實施例中，當Z為-O-時，R11 係-H、甲基或第三丁基。In an exemplary embodiment, when Z is -O-, R 11 is -H, methyl, or tertiary butyl.

在一個實施例中，當Z為-NH時，R11 係-CH(R15 )2 ，其中R15 係-(CH2 )n -N(R16 )2 ，且R16 為-C1 -C8 烷基或-(CH2 )n -COOH。In one embodiment, when Z is -NH, R 11 is -CH(R 15 ) 2 , wherein R 15 is -(CH 2 ) n -N(R 16 ) 2 , and R 16 is -C 1- C 8 alkyl or -(CH 2 ) n -COOH.

在另一個實施例中，當Z為-NH時，R11 係-CH(R15 )2 其中R15 係-(CH2 )n -SO3 H。In another embodiment, when Z is -NH, R 11 is -CH(R 15 )2, wherein R 15 is -(CH 2 ) n -SO 3 H.

具有式DE 之示例性奧瑞他汀實施例係MMAE，其中波形線指示與抗CD79b免疫偶聯物之連接子(L)之共價連接：

Figure 02_image065
MMAEExample MMAE system having an exemplary auristatin embodiment of formula D E, wherein the wavy line indicates the anti-CD79b immunoconjugate of linker (L) of covalently linked:
Figure 02_image065
MMAE

具有式DF 之一示範性澳瑞他汀實施例為MMAF，其中波形線指示與抗CD79b免疫偶聯物之連接子(L)之共價連接：

Figure 02_image067
MMAFAn exemplary auristatin example of formula DF is MMAF, where the wavy line indicates the covalent attachment to the linker (L) of the anti-CD79b immunoconjugate:
Figure 02_image067
MMAF

其他示例性實施例包括在五肽奧瑞他汀藥物部分之C末端處具有苯丙胺酸羧基修飾之單甲基纈胺酸化合物(WO 2007/008848)及在五肽奧瑞他汀藥物部分之C末端處具有苯丙胺酸側鏈修飾之單甲基纈胺酸化合物(WO 2007/008603)。Other exemplary embodiments include a monomethylvaline compound (WO 2007/008848) with a phenylalanine carboxyl modification at the C-terminus of the pentapeptide auristatin drug moiety and at the C-terminus of the pentapeptide auristatin drug moiety Monomethylvaline compound with modified side chain of phenylalanine (WO 2007/008603).

包含MMAE或MMAF及各種連接子組分的式I之抗CD79b免疫偶聯物的非限制性示例性實施例具有以下結構及縮寫(其中「Ab」係抗CD79b抗體；p係1至約8，「Val-Cit」係纈胺酸-瓜胺酸二肽；且「S」係硫原子)：

Figure 02_image069
Ab-MC-vc-PAB-MMAF
Figure 02_image001
Ab-MC-vc-PAB-MMAE
Figure 02_image072
Ab-MC-MMAE
Figure 02_image074
Ab-MC-MMAFNon-limiting exemplary embodiments of the anti-CD79b immunoconjugate of Formula I comprising MMAE or MMAF and various linker components have the following structure and abbreviations (wherein "Ab" is an anti-CD79b antibody; p is 1 to about 8, "Val-Cit" is a dipeptide of valine-citrulline; and "S" is a sulfur atom):
Figure 02_image069
Ab-MC-vc-PAB-MMAF
Figure 02_image001
Ab-MC-vc-PAB-MMAE
Figure 02_image072
Ab-MC-MMAE
Figure 02_image074
Ab-MC-MMAF

在某些實施例中，抗CD79b免疫偶聯物包含Ab-MC-vc-PAB-MMAE的結構，其中p係例如 約1至約8；約2至約7；約3至約5；約3至約4；或約3.5。在一些實施例中，抗CD79b免疫偶聯物係huMA79bv28-MC-vc-PAB-MMAE，例如 包含Ab-MC-vc-PAB-MMAE之結構的抗CD79b免疫偶聯物，其中p係例如 約1至約8；約2至約7；約3至約5；約3至約4；或約3.5，其中該抗CD79抗體(Ab)包括含SEQ ID NO:36之胺基酸序列的重鏈及含SEQ ID NO:35之胺基酸序列的輕鏈。在一些實施例中，抗CD79b免疫偶聯物係帕妥珠單抗維多汀-piiq。帕妥珠單抗維多汀-piiq之IUPHAR/BPS編號為8404，KEGG編號為D10761，且亦可稱為「DCDS4501A」或「RG7596」。In certain embodiments, the anti-CD79b immunoconjugate comprises the structure of Ab-MC-vc-PAB-MMAE, where p is, for example, about 1 to about 8; about 2 to about 7; about 3 to about 5; about 3 To about 4; or about 3.5. In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE, such as an anti-CD79b immunoconjugate containing the structure of Ab-MC-vc-PAB-MMAE, where p is, for example, about 1 To about 8; about 2 to about 7; about 3 to about 5; about 3 to about 4; or about 3.5, wherein the anti-CD79 antibody (Ab) includes a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and A light chain containing the amino acid sequence of SEQ ID NO:35. In some embodiments, the anti-CD79b immunoconjugate is Pertuzumab Vidotin-piiq. Pertuzumab Vidotin-piiq's IUPhar/BPS number is 8404, KEGG number is D10761, and it can also be called "DCDS4501A" or "RG7596".

包含MMAF及各種連接子組分的式I之抗CD79b免疫偶聯物之非限制性示例性實施例進一步包括Ab-MC-PAB-MMAF及Ab-PAB-MMAF。經顯示，包含藉由不可蛋白水解裂解之連接子連接至抗體之MMAF的免疫偶聯物具有與包含藉由可蛋白水解裂解之連接子連接至抗體之MMAF的免疫偶聯物相當的活性(Doronina等人，(2006)Bioconjugate Chem. 17:114-124)。在一些此類實施例中，咸信藥物釋放受細胞中抗體降解影響。Non-limiting exemplary embodiments of the anti-CD79b immunoconjugate of Formula I comprising MMAF and various linker components further include Ab-MC-PAB-MMAF and Ab-PAB-MMAF. It has been shown that immunoconjugates containing MMAF linked to an antibody by a non-proteolytically cleavable linker have comparable activity to immunoconjugates containing MMAF linked to an antibody by a proteolytically cleavable linker (Doronina Et al. (2006) Bioconjugate Chem. 17:114-124). In some such embodiments, it is believed that the drug release is affected by the degradation of the antibody in the cell.

包含MMAE及各種連接子組分的式I之抗CD79b免疫偶聯物之非限制性示例性實施例進一步包括Ab-MC-PAB-MMAE及Ab-PAB-MMAE。Non-limiting exemplary embodiments of the anti-CD79b immunoconjugate of Formula I comprising MMAE and various linker components further include Ab-MC-PAB-MMAE and Ab-PAB-MMAE.

典型地，基於肽之藥物部分可藉由在兩個或更多個胺基酸及/或肽片段之間形成肽鍵來製備。此等肽鍵可例如根據液相合成方法製備(參見例如 E. Schröder及K. Lübke，「The Peptides」，第1卷，第76-136頁，1965，Academic Press)。在一些實施例中，奧瑞他汀/海兔毒素藥物部分可根據以下方法製備：US 7498298；US 5635483；US 5780588；Pettit等人(1989)J. Am. Chem. Soc. 111:5463-5465；Pettit等人(1998)Anti-Cancer Drug Design 13:243-277；Pettit，G.R.等人Synthesis ，1996，719-725；Pettit等人(1996)J. Chem. Soc. Perkin Trans . 1 5:859-863；及Doronina (2003)Nat. Biotechnol. 21(7):778-784。Typically, peptide-based drug moieties can be prepared by forming peptide bonds between two or more amino acids and/or peptide fragments. These peptide bonds can be prepared, for example, according to a liquid phase synthesis method ( see, for example, E. Schröder and K. Lübke, "The Peptides", Vol. 1, pp. 76-136, 1965, Academic Press). In some embodiments, the auristatin/delatoxin drug portion can be prepared according to the following methods: US 7498298; US 5635483; US 5780588; Pettit et al. (1989) J. Am. Chem. Soc. 111:5463-5465; Pettit et al. (1998) Anti-Cancer Drug Design 13:243-277; Pettit, GR et al. Synthesis , 1996, 719-725; Pettit et al. (1996) J. Chem. Soc. Perkin Trans . 1 5:859- 863; and Doronina (2003) Nat. Biotechnol. 21(7):778-784.

在一些實施例中，式DE 諸如MMAE，及DF 諸如MMAF的奧瑞他汀/海兔毒素藥物部分，以及藥物-連接子中間物及其衍生物，諸如MC-MMAF、MC-MMAE、MC-vc-PAB-MMAF及MC-vc-PAB-MMAE，可使用US 7498298；Doronina等人(2006)Bioconjugate  Chem. 17:114-124；及Doronina等人(2003)Nat. Biotech. 21:778-784中描述之方法製備，且接著與所關注抗體結合。(3) 卡奇黴素 In some embodiments of formula D E, such as MMAE, and D F is MMAF, such as auristatin / dolastatin drug moieties, and drug - linker intermediate and derivatives thereof, such as MC-MMAF, MC-MMAE, MC -vc-PAB-MMAF and MC-vc-PAB-MMAE, US 7498298 can be used; Doronina et al. (2006) Bioconjugate Chem. 17:114-124; and Doronina et al. (2003) Nat. Biotech. 21:778- Prepared by the method described in 784, and then combined with the antibody of interest. (3) calicheamicin

在一些實施例中，抗CD79b免疫偶聯物包含結合於一或多個卡奇黴素分子之抗CD79b抗體。抗生素卡奇黴素家族及其類似物能夠在低於皮莫耳濃度下引起雙股DNA斷裂(Hinman等人，(1993)Cancer Research 53:3336-3342；Lode等人，(1998)Cancer Research 58:2925-2928)。卡奇黴素具有細胞內作用位點，但在某些情況下不易於跨越質膜。因此，在一些實施例中，此等藥劑經由抗體介導之內化達成之細胞吸收可大幅增強其細胞毒性作用。製備具有卡奇黴素藥物部分之抗CD79b抗體免疫偶聯物之非限制性示例性方法例如描述於US 5712374；US 5714586；US 5739116；及US 5767285中。(4) 其他藥物部分 In some embodiments, the anti-CD79b immunoconjugate comprises an anti-CD79b antibody bound to one or more calicheamicin molecules. The calicheamicin family of antibiotics and their analogs can cause double-stranded DNA breaks at concentrations below picomoles (Hinman et al. (1993) Cancer Research 53: 3336-3342; Lode et al. (1998) Cancer Research 58 :2925-2928). The calicheamicin has intracellular sites of action, but in some cases it is not easy to cross the plasma membrane. Therefore, in some embodiments, the cellular uptake of these agents through antibody-mediated internalization can greatly enhance their cytotoxic effects. Non-limiting exemplary methods for preparing anti-CD79b antibody immunoconjugates with a calicheamicin drug moiety are described in, for example, US 5712374; US 5714586; US 5739116; and US 5767285. (4) Other drugs

在一些實施例中，抗CD79b免疫偶聯物包含格爾德黴素(Mandler等人(2000)J. Nat. Cancer Inst. 92(19):1573-1581；Mandler等人(2000)Bioorganic & Med. Chem. Letters 10:1025-1028；Mandler等人(2002)Bioconjugate Chem. 13:786-791)；及/或酶活性毒素及其片段，包括但不限於白喉A鏈、白喉毒素之非結合活性片段、外毒素A鏈(來自綠膿桿菌(Pseudomonas aeruginosa))、蓖麻毒素A鏈、相思豆毒素A鏈、蒴蓮根毒素A鏈、α-帚麴菌素、油桐(Aleurites fordii)蛋白、石竹素(dianthin)蛋白、美洲商陸(Phytolaca americana)蛋白(PAPI、PAPII及PAP-S)、苦瓜(momordica charantia)抑制劑、瀉果素、巴豆毒素、肥皂草(sapaonaria officinalis)抑制劑、白樹毒素(gelonin)、絲裂吉菌素(mitogellin)、局限麯菌素(restrictocin)、酚黴素(phenomycin)、伊諾黴素(enomycin)及新月毒素(tricothecene)。參見例如 WO 93/21232。In some embodiments, the anti-CD79b immunoconjugate comprises geldanamycin (Mandler et al. (2000) J. Nat. Cancer Inst. 92(19): 1573-1581; Mandler et al. (2000) Bioorganic & Med . Chem. Letters 10:1025-1028; Mandler et al. (2002) Bioconjugate Chem. 13:786-791); and/or enzyme-active toxins and fragments thereof, including but not limited to diphtheria A chain, non-binding activity of diphtheria toxin Fragment, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, acacia toxin A chain, capsula root toxin A chain, α-cosmophyllin, Aleurites fordii protein, Dianthin protein, Phytolaca americana protein (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, keratin, crotonin, sapaonaria officinalis inhibitor, white Gelonin, mitogellin, restrictocin, phenomycin, enomycin and tricothecene. See, for example, WO 93/21232.

藥物部分亦包括具有核溶解活性之化合物(例如 核糖核酸酶或DNA核酸內切酶)。The drug portion also includes compounds with nucleolytic activity (for example, ribonuclease or DNA endonuclease).

在某些實施例中，抗CD79b免疫偶聯物包含高放射性原子。多種放射性同位素可用於製造放射性結合之抗體。實例包括At211 、I131 、I125 、Y90 、Re186 、Re188 、Sm153 、Bi212 、P32 、Pb212 、及Lu之放射性同位素。在一些實施例中，當使用抗CD79b免疫偶聯物進行偵測時，其可包含用於閃爍攝影研究之放射性原子，例如Tc99 或I123 ；或用於核磁共振(NMR)成像(又稱為磁共振成像、MRI)之自旋標記，諸如鋯-89、碘-123、碘-131、銦-111、氟-19、碳-13、氮-15、氧-17、釓、錳或鐵。鋯-89可與各種金屬螯合劑錯合且與抗體偶聯物，例如 用於PET成像(WO 2011/056983)。In certain embodiments, the anti-CD79b immunoconjugate contains highly radioactive atoms. A variety of radioisotopes can be used to make radioactively conjugated antibodies. Examples include At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioisotopes of Lu. In some embodiments, when the anti-CD79b immunoconjugate is used for detection, it may contain radioactive atoms used in scintigraphic research, such as Tc 99 or I 123 ; or used in nuclear magnetic resonance (NMR) imaging (also known as Spin labels for magnetic resonance imaging and MRI, such as zirconium-89, iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gamma, manganese or iron . Zirconium-89 can be complexed with various metal chelating agents and conjugated with antibodies, for example for PET imaging (WO 2011/056983).

放射性標記或其他標記可藉由已知方式併入抗CD79b免疫偶聯物中。舉例而言，肽可經生物合成或使用包含例如一或多個氟-19原子替代一或多個氫之適合胺基酸前驅物進行化學合成。在一些實施例中，標記，諸如Tc99 、I123 、Re186 、Re188 及In111 可經由抗CD79b抗體中之半胱胺酸殘基連接。在一些實施例中，釔90可經由抗CD79b抗體之離胺酸殘基連接。在一些實施例中，可使用IODOGEN方法(Fraker等人(1978)Biochem. Biophys. Res. Commun. 80: 49-57併入碘-123。「Monoclonal Antibodies in Immunoscintigraphy」(Chatal，CRC Press 1989)描述某些其他方法。Radioactive labels or other labels can be incorporated into the anti-CD79b immunoconjugate by known means. For example, peptides can be biosynthesized or chemically synthesized using suitable amino acid precursors containing, for example, one or more fluorine-19 atoms instead of one or more hydrogens. In some embodiments, labels such as Tc 99 , I 123 , Re 186 , Re 188 and In 111 can be linked via cysteine residues in the anti-CD79b antibody. In some embodiments, yttrium 90 can be linked via a lysine residue of an anti-CD79b antibody. In some embodiments, the IODOGEN method can be used (Fraker et al. (1978) Biochem. Biophys. Res. Commun. 80: 49-57 incorporates iodine-123. "Monoclonal Antibodies in Immunoscintigraphy" (Chatal, CRC Press 1989) describes Some other methods.

在某些實施例中，抗CD79b免疫偶聯物可包含與前藥活化酶結合之抗CD79b抗體。在一些此類實施例中，前藥活化酶將前藥(例如 肽基化學治療劑，參見 WO 81/01145)轉化成活性藥物，諸如抗癌藥物。在一些實施例中，此類免疫偶聯物可用於抗體依賴性酶介導之前藥療法(「ADEPT」)中。可與抗CD79b抗體結合之酶包括但不限於鹼性磷酸酶，其可用於將含磷酸之前藥轉化成遊離藥物；芳基硫酸酯酶，其可用於將含硫酸之前藥轉化成遊離藥物；胞嘧啶脫胺酶，其可用於將無毒5-氟胞嘧啶轉化成抗癌藥物5-氟尿嘧啶；蛋白酶，諸如沙雷氏菌(serratia)蛋白酶、嗜熱菌蛋白酶(thermolysin)、枯草桿菌蛋白酶(subtilisin)、羧基肽酶及組織蛋白酶(諸如組織蛋白酶B及L)，其可用於將含肽前藥轉化成遊離藥物；D-丙胺醯基羧基肽酶，其可用於轉化含有D-胺基酸取代基之前藥；碳水化合物裂解酶，諸如β-半乳糖苷酶(galactosidase)及神經胺糖酸苷酶，其可用於將糖基化前藥轉化成遊離藥物；β-內醯胺酶(lactamase)，其可用於將用β-內醯胺衍生化之藥物轉化成遊離藥物；及青黴素醯胺酶，諸如青黴素V醯胺酶及青黴素G醯胺酶，其可用於將在胺氮處分別用苯氧基乙醯基或苯基乙醯基衍生化之藥物轉化成遊離藥物。在一些實施例中，酶可藉由此項技術熟知之重組DNA技術與抗體共價結合。參見例如 Neuberger等人，Nature 312:604-608 (1984)。D. 藥物裝載量 In certain embodiments, the anti-CD79b immunoconjugate may comprise an anti-CD79b antibody that binds to a prodrug activating enzyme. In some such embodiments, prodrug activating enzymes convert prodrugs ( e.g., peptidyl chemotherapeutics, see WO 81/01145) into active drugs, such as anticancer drugs. In some embodiments, such immunoconjugates can be used in antibody-dependent enzyme-mediated anterior drug therapy ("ADEPT"). Enzymes that can bind to anti-CD79b antibodies include but are not limited to alkaline phosphatase, which can be used to convert phosphate-containing prodrugs into free drugs; arylsulfatase, which can be used to convert sulfuric acid-containing prodrugs into free drugs; Pyrimidine deaminase, which can be used to convert non-toxic 5-fluorocytosine into anti-cancer drug 5-fluorouracil; proteases, such as serratia protease, thermolysin, subtilisin , Carboxypeptidase and cathepsin (such as cathepsin B and L), which can be used to convert peptide-containing prodrugs into free drugs; D-alanine carboxypeptidase, which can be used to convert D-amino acid substituents Prodrug; carbohydrate lyase, such as β-galactosidase (galactosidase) and neuraminidase, which can be used to convert glycosylation prodrugs into free drugs; β-lactamase, It can be used to convert drugs derivatized with β-lactam into free drugs; and penicillin amidase, such as penicillin V amidase and penicillin G amidase, which can be used to separate phenoxy at the amine nitrogen. Drugs derivatized with phenylacetyl or phenylacetyl are converted into free drugs. In some embodiments, the enzyme can be covalently bound to the antibody by recombinant DNA technology well known in the art. See, for example, Neuberger et al., Nature 312:604-608 (1984). D. Drug loading

藥物裝載量係由p表示，為由式I分子中每個抗CD79b抗體之藥物部分之平均數量。藥物裝載量之範圍可為每個抗體1至20個藥物部分(D)。式I之抗CD79b免疫偶聯物包括與一系列，即1至20個藥物部分結合之抗CD79b抗體的集合。由結合反應製備的抗CD79b免疫偶聯物中每個抗CD79b抗體之藥物部分的平均數量可藉由習知方式，諸如質譜法、ELISA檢定及HPLC表徵。亦可確定用p表示的抗CD79b免疫偶聯物之定量分佈。在一些情況下，自具有其他藥物裝載量之抗CD79b免疫偶聯物分離、純化及表徵p為某一值之均質抗CD79b免疫偶聯物可藉由諸如逆相HPLC或電泳之類方式達成。The drug loading is represented by p, which is the average amount of the drug portion of each anti-CD79b antibody in the formula I molecule. The drug loading can range from 1 to 20 drug fractions per antibody (D). The anti-CD79b immunoconjugate of formula I includes a collection of anti-CD79b antibodies bound to a series of 1 to 20 drug moieties. The average amount of the drug portion of each anti-CD79b antibody in the anti-CD79b immunoconjugate prepared by the binding reaction can be characterized by conventional methods, such as mass spectrometry, ELISA assay, and HPLC. The quantitative distribution of the anti-CD79b immunoconjugate denoted by p can also be determined. In some cases, the separation, purification, and characterization of homogeneous anti-CD79b immunoconjugates with p to a certain value from anti-CD79b immunoconjugates with other drug loadings can be achieved by means such as reverse phase HPLC or electrophoresis.

對於一些抗CD79b免疫偶聯物，p可受抗CD79b抗體上連接位點之數量限制。舉例而言，當連接係如上文某些示例性實施例中之半胱胺酸硫醇時，抗CD79b抗體可僅具有一個或若干個半胱胺酸硫醇基，或可僅具有能連接連接子之一個或若干個具有足夠反應性之硫醇基。在某些實施例中，較高藥物裝載量，例如 p ＞ 5，可引起某些抗CD79b免疫偶聯物之聚集、不溶、毒性或細胞滲透性降低。在某些實施例中，抗CD79b免疫偶聯物之平均藥物裝載量範圍為1至約8；約2至約6；約3至約5；或約3至約4。實際上，經顯示，對於某些抗體-藥物偶聯物，藥物部分/抗體之最佳比率可小於8，且可為約2至約5 (US 7498298)。在某些實施例中，藥物部分/抗體之最佳比率為約3至約4。在某些實施例中，藥物部分/抗體之最佳比率為約3.5。For some anti-CD79b immunoconjugates, p can be limited by the number of attachment sites on the anti-CD79b antibody. For example, when the linking system is the cysteine thiol in some exemplary embodiments above, the anti-CD79b antibody may only have one or several cysteine thiol groups, or may only have the linking link One or several thiol groups with sufficient reactivity. In some embodiments, higher drug loading, such as p>5, can cause aggregation, insolubility, toxicity, or decreased cell permeability of certain anti-CD79b immunoconjugates. In certain embodiments, the average drug loading of the anti-CD79b immunoconjugate ranges from 1 to about 8; from about 2 to about 6; from about 3 to about 5; or from about 3 to about 4. In fact, it has been shown that for certain antibody-drug conjugates, the optimal drug moiety/antibody ratio can be less than 8, and can be about 2 to about 5 (US 7498298). In certain embodiments, the optimal ratio of drug moiety/antibody is about 3 to about 4. In certain embodiments, the optimal ratio of drug moiety/antibody is about 3.5.

在某些實施例中，少於理論最大值之藥物部分在結合反應期間與抗CD79b抗體結合。抗體可含有例如不與藥物-連接子中間物或連接子藥劑反應之離胺酸殘基，如下文所論述。一般而言，抗體並不含有許多可連接至藥物部分之遊離反應性半胱胺酸硫醇基；實際上，抗體中之大多數半胱胺酸硫醇殘基以二硫橋形式存在。在某些實施例中，可在部分或完全還原條件下，用諸如二硫蘇糖醇(DTT)或三羰基乙基膦(TCEP)之類還原劑還原抗CD79b抗體，以産生反應性半胱胺酸硫醇基。在某些實施例中，使抗CD79b抗體經歷變性條件以顯露反應性親核基團，諸如離胺酸或半胱胺酸。In certain embodiments, the portion of the drug that is less than the theoretical maximum is bound to the anti-CD79b antibody during the binding reaction. Antibodies may contain, for example, lysine residues that do not react with drug-linker intermediates or linker agents, as discussed below. Generally speaking, antibodies do not contain many free reactive cysteine thiol groups that can be linked to the drug moiety; in fact, most of the cysteine thiol residues in antibodies exist as disulfide bridges. In certain embodiments, the anti-CD79b antibody can be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonyl ethyl phosphine (TCEP) under partial or complete reduction conditions to produce reactive cysteine Amino acid thiol group. In certain embodiments, the anti-CD79b antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups, such as lysine or cysteine.

抗CD79b免疫偶聯物之裝載量(藥物/抗體比率)可以不同方式且例如藉由以下控制：(i)限制藥物-連接子中間物或連接子藥劑相對於抗體之莫耳過量；(ii)限制結合反應時間或溫度；及(iii)用於半胱胺酸硫醇修飾之部分或限制性還原性條件。The loading of anti-CD79b immunoconjugates (drug/antibody ratio) can be controlled in different ways and, for example, by: (i) limiting the molar excess of the drug-linker intermediate or linker agent relative to the antibody; (ii) Limit the binding reaction time or temperature; and (iii) partial or limited reducing conditions for cysteine thiol modification.

應瞭解，當多個親核性基團與藥物-連接子中間物或連接子藥劑反應時，則所得產物係具有連接至抗CD79b抗體之一或多個藥物部分之分佈的抗CD79b免疫偶聯物化合物之混合物。每個抗體之藥物的平均數量可藉由對抗體具有特異性且對藥物具有特異性之雙重ELISA抗體檢定，自該混合物計算。個別抗CD79b免疫偶聯物分子可藉由質譜法在混合物中鑑別，並藉由HPLC，例如 疏水相互作用層析法分離(參見例如 McDonagh等人(2006) Prot. Engr. Design & Selection 19(7):299-307；Hamblett等人(2004) Clin. Cancer Res. 10:7063-7070；Hamblett，K.J.等人「Effect of drug loading on the pharmacology，pharmacokinetics，and toxicity of an anti-CD30 antibody-drug conjugate,」 文摘號624，American Association for Cancer Research，2004 Annual Meeting，2004年3月27-31日，Proceedings of the AACR，第45卷，2004年3月；Alley，S.C.等人「Controlling the location of drug attachment in antibody-drug conjugates,」 文摘號627，American Association for Cancer Research，2004 Annual Meeting，2004年3月27-31日，Proceedings of the AACR，第45卷，2004年3月)。在某些實施例中，具有單一裝載量值之均質抗CD79b免疫偶聯物可藉由電泳或層析法自結合混合物分離。E. 製備抗 CD79b 免疫偶聯物之方法 It should be understood that when multiple nucleophilic groups react with a drug-linker intermediate or a linker agent, the resulting product is an anti-CD79b immunoconjugate with a distribution of one or more drug moieties attached to the anti-CD79b antibody A mixture of substances and compounds. The average number of drugs per antibody can be calculated from the mixture by double ELISA antibody assays that are specific for the antibody and specific for the drug. Individual anti-CD79b immunoconjugate molecules can be identified in the mixture by mass spectrometry and separated by HPLC, such as hydrophobic interaction chromatography ( see, for example, McDonagh et al. (2006) Prot. Engr. Design & Selection 19(7) ):299-307; Hamblett et al. (2004) Clin. Cancer Res. 10:7063-7070; Hamblett, KJ et al. "Effect of drug loading on the pharmacology, pharmacokinetics, and toxicity of an anti-CD30 antibody-drug conjugate ," Abstract No. 624, American Association for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, Proceedings of the AACR, Volume 45, March 2004; Alley, SC et al. "Controlling the location of drug attachment in antibody-drug conjugates," Abstract No. 627, American Association for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, Proceedings of the AACR, Volume 45, March 2004). In certain embodiments, homogeneous anti-CD79b immunoconjugates with a single loading value can be separated from the binding mixture by electrophoresis or chromatography. E. Method for preparing anti- CD79b immunoconjugate

式I之抗CD79b免疫偶聯物可採用熟習此項技術者已知之有機化學反應、條件及藥劑，藉由若干途徑製備，包括但不限於例如 ：(1)使抗CD79b抗體之親核性基團與二價連接子藥劑反應，經由共價鍵形成Ab-L，隨後與藥物部分D反應；及(2)使藥物部分之親核性基團與二價連接子藥劑反應，經由共價鍵形成D-L，隨後與抗CD79b抗體之親核性基團反應。經由後一途徑製備式I之抗CD79b免疫偶聯物的示例性方法描述於US 7498298中，該專利以引用的方式明確併入本文中。Of formula I of the anti-CD79b immunoconjugate can be known to those skilled in the art of organic chemistry reactions, conditions and agent, prepared by a number of routes, including but not limited to, for example: (1) reacting a nucleophilic group of the anti-CD79b antibody The group reacts with the divalent linker agent to form Ab-L via a covalent bond, and then reacts with the drug moiety D; and (2) the nucleophilic group of the drug moiety reacts with the divalent linker agent via the covalent bond DL is formed, which then reacts with the nucleophilic group of the anti-CD79b antibody. An exemplary method for preparing the anti-CD79b immunoconjugate of Formula I via the latter route is described in US 7498298, which is expressly incorporated herein by reference.

抗體上之親核性基團包括但不限於：(i) N末端胺基；(ii)側鏈胺基，例如 離胺酸；(iii)側鏈硫醇基，例如 半胱胺酸；及(iv)糖羥基或胺基，其中抗體經糖基化。胺基、硫醇基及羥基係親核性基團且能夠與包括以下之連接子部分及連接子藥劑上之親電子基團反應形成共價鍵：(i)活性酯，諸如NHS酯、HOBt酯、鹵代甲酸酯及酸鹵化物；(ii)烷基及苯甲基鹵化物，諸如鹵代乙醯胺；及(iii)醛、酮、羧基及順丁烯二醯亞胺基團。某些抗體具有可還原之鏈間二硫化物，亦即 ，半胱胺酸橋。可藉由用諸如DTT(二硫蘇糖醇)或三羰基乙基膦(TCEP)之類還原劑處理，使得抗CD79b抗體完全或部分還原來使抗CD79b抗體具有反應性以與連接子藥劑結合。因此，各半胱胺酸橋將在理論上形成兩個反應性硫醇親核藥劑。其他親核性基團可經由修飾離胺酸殘基，例如 藉由使離胺酸殘基與2-亞胺基硫雑環戊烷(特勞特氏藥劑(Traut’s reagent))反應，由此將胺轉化成硫醇而引入抗CD79b抗體中。反應性硫醇基亦可藉由引入一個、兩個、三個、四個或更多個半胱胺酸殘基(例如 藉由製備包含一或多個非天然半胱胺酸胺基酸殘基之變異抗體)而引入抗CD79b抗體中。The nucleophilic groups on the antibody include but are not limited to: (i) N-terminal amine group; (ii) side chain amine group, such as lysine; (iii) side chain thiol group, such as cysteine; and (iv) Sugar hydroxyl or amino group, where the antibody is glycosylated. Amine, thiol and hydroxyl are nucleophilic groups and can react with the linker part and the electrophilic group on the linker medicament including the following to form a covalent bond: (i) Active ester, such as NHS ester, HOBt Esters, haloformates and acid halides; (ii) alkyl and benzyl halides, such as haloacetamide; and (iii) aldehyde, ketone, carboxyl and maleimide groups . Certain antibodies have reducible interchain disulfides, that is , cysteine bridges. The anti-CD79b antibody can be fully or partially reduced by treatment with a reducing agent such as DTT (dithiothreitol) or tricarbonyl ethyl phosphine (TCEP) to make the anti-CD79b antibody reactive to bind to the linker agent . Therefore, each cysteine bridge will theoretically form two reactive thiol nucleophiles. Other nucleophilic groups can be modified by modifying lysine residues, for example, by reacting lysine residues with 2-iminothiocyclopentane (Traut's reagent), thereby The amine is converted to thiol and introduced into the anti-CD79b antibody. Reactive thiol groups can also be introduced by introducing one, two, three, four or more cysteine residues ( e.g., by preparing one or more non-natural cysteine amino acid residues). Base variant antibody) and introduced into the anti-CD79b antibody.

本文所描述之抗CD79b免疫偶聯物亦可藉由使抗CD79b抗體上之親電子基團(諸如醛或酮羰基)與連接子藥劑或藥物上之親核性基團之間反應來製造。連接子藥劑上之有用親核性基團包括但不限於醯肼、肟、胺基、肼、硫縮胺基脲、肼羧酸酯及芳基醯肼。在一個實施例中，修飾抗CD79b抗體以引入能夠與連接子藥劑或藥物上之親核性取代基反應之親電子部分。在另一個實施例中，可例如 用高碘酸鹽氧化劑將糖基化之抗CD79b抗體的糖氧化，以形成可與连接子藥劑或藥物部分之胺基反應的醛基或酮基。所得亞胺希夫鹼(Schiff base)基團可形成穩定鍵聯，或可例如 由硼氫化物藥劑還原以形成穩定胺鍵聯。在一個實施例中，使糖基化抗CD79b抗體之碳水化合物部分與半乳糖氧化酶或偏過碘酸鈉反應，可在抗CD79b抗體中產生可與藥物上之適當基團反應之羰基(醛及酮)(Hermanson，Bioconjugate Techniques)。在另一個實施例中，含有N末端絲胺酸或酥胺酸殘基之抗CD79b抗體可與偏過碘酸鈉反應，由此使得醛替代第一個胺基酸(Geoghegan及Stroh，(1992)Bioconjugate Chem. 3:138-146；US 5362852)。此類醛可與藥物部分或連接子親核藥劑反應。The anti-CD79b immunoconjugates described herein can also be produced by reacting the electrophilic group (such as aldehyde or ketone carbonyl) on the anti-CD79b antibody with the nucleophilic group on the linker agent or drug. Useful nucleophilic groups on the linker agent include, but are not limited to, hydrazine, oxime, amine, hydrazine, thiosemicarbazide, hydrazine carboxylate, and arylhydrazine. In one embodiment, the anti-CD79b antibody is modified to introduce an electrophilic moiety capable of reacting with a nucleophilic substituent on the linker agent or drug. In another embodiment, the sugar of the glycosylated anti-CD79b antibody can be oxidized, for example, with a periodate oxidizing agent, to form an aldehyde group or a ketone group that can react with the amine group of the linker agent or the drug moiety. The resulting Schiff base group of the imine may form a stable linkage, or may be reduced, for example, by a borohydride agent, to form a stable amine linkage. In one embodiment, reacting the carbohydrate portion of the glycosylated anti-CD79b antibody with galactose oxidase or sodium metaperiodate can produce a carbonyl (aldehyde group) in the anti-CD79b antibody that can react with the appropriate group on the drug. And ketones) (Hermanson, Bioconjugate Techniques). In another embodiment, an anti-CD79b antibody containing N-terminal serine or threonine residues can be reacted with sodium metaperiodate, thereby allowing aldehydes to replace the first amino acid (Geoghegan and Stroh, (1992) ) Bioconjugate Chem. 3:138-146; US 5362852). Such aldehydes can react with drug moieties or linker nucleophiles.

藥物部分上之示例性親核性基團包括但不限於：胺、硫醇、羥基、醯肼、肟、肼、硫縮胺基脲、肼羧酸酯及芳基醯肼基團，其能夠與包括以下之連接子部分及連接子藥劑上之親電子基團反應形成共價鍵：(i)活性酯，諸如NHS酯、HOBt酯、鹵代甲酸酯及酸鹵化物；(ii)烷基及苯甲基鹵化物，諸如鹵代乙醯胺；(iii)醛、酮、羧基及順丁烯二醯亞胺基團。Exemplary nucleophilic groups on the drug moiety include but are not limited to: amine, thiol, hydroxyl, hydrazine, oxime, hydrazine, thiosemicarbazone, hydrazine carboxylate and aryl hydrazine groups, which can It reacts with the linker part and the electrophilic group on the linker medicament including the following to form a covalent bond: (i) active esters, such as NHS esters, HOBt esters, haloformates and acid halides; (ii) alkane Groups and benzyl halides, such as halogenated acetamide; (iii) aldehyde, ketone, carboxyl and maleimide groups.

可用於製備抗CD79b免疫偶聯物之非限制性示例性交聯藥劑在本文中題為「示例性連接子」之部分中有描述。使用此類交聯藥劑連接包括蛋白質部分及化學部分在內之兩個部分的方法係此項技術中已知的。在一些實施例中，包含抗-CD79b抗體及細胞毒性劑之融合蛋白可例如 藉由重組技術或肽合成來製備。重組DNA分子可包含編碼偶聯物之抗體及細胞毒性部分之區域，該等區域彼此相鄰或由編碼不會破壞偶聯物之所需性質之連接子肽的區域分開。在又另一個實施例中，抗CD79b抗體可與「受體」(諸如抗生蛋白鏈菌素(streptavidin))結合以用於腫瘤預靶向，其中向患者投與抗體-受體偶聯物，隨後使用清除劑自循環中移除未結合之偶聯物且接著投與結合於細胞毒性劑(例如 藥物或放射性核苷酸)之「配體」(例如 抗生物素蛋白(avidin))。關於抗CD79b免疫綴合物的其他細節提供於美國專利第8545850號及第WO/2016/049214號，其內容以引用的方式明確地整體併入本文。V. 抗 CD20 劑 Non-limiting exemplary cross-linking agents that can be used to prepare anti-CD79b immunoconjugates are described in the section entitled "Exemplary Linkers" herein. The method of using such a cross-linking agent to connect two parts including a protein part and a chemical part is known in the art. In some embodiments, a fusion protein comprising an anti-CD79b antibody and a cytotoxic agent can be prepared, for example, by recombinant technology or peptide synthesis. Recombinant DNA molecules may include regions encoding the antibody and cytotoxic portion of the conjugate, which regions are adjacent to each other or separated by regions encoding linker peptides that do not destroy the desired properties of the conjugate. In yet another embodiment, an anti-CD79b antibody can bind to a "receptor" (such as streptavidin) for tumor pre-targeting, where the antibody-receptor conjugate is administered to the patient, The scavenger is then used to remove the unbound conjugate from the circulation and then a "ligand" (e.g. , avidin) that binds to the cytotoxic agent (e.g., drug or radionucleotide) is administered. Additional details on anti-CD79b immunoconjugates are provided in US Patent Nos. 8545850 and WO/2016/049214, the contents of which are expressly incorporated herein by reference in their entirety. V. Anti- CD20 agents

取決於抗CD20抗體與CD20抗原之結合性質及生物活性，可根據Cragg，M.S.等人，Blood 103 (2004) 2738-2743；及Cragg，M.S.等人，Blood 101 (2003) 1045-1052來區分兩種類型之抗CD20抗體(I型及II型抗CD20抗體)，參見 表 C 。 表C：I型及II型抗CD20抗體之性質 I 型抗 CD20 抗體 II 型抗 CD20 抗體 I型CD20抗原決定基 II型CD20抗原決定基 將CD20定位至脂膜筏 不將CD20定位至脂膜筏 增加CDC (若為IgG1同型) 減少CDC (若IgG1同型) ADCC活性(若為IgG1同型) ADCC活性(若為IgG1同型) 完全結合能力 結合能力降低 同型聚集 較強同型聚集 交聯後誘導細胞凋亡 在無交聯情況下誘導強烈細胞死亡 Depending on the binding properties and biological activity of the anti-CD20 antibody to the CD20 antigen, the two can be distinguished according to Cragg, MS et al., Blood 103 (2004) 2738-2743; and Cragg, MS et al., Blood 101 (2003) 1045-1052 the types of anti-CD20 antibodies (type I and type II anti-CD20 antibody), see table C. Table C: Properties of Type I and Type II Anti-CD20 Antibodies Type I anti- CD20 antibody Type II anti- CD20 antibody Type I CD20 epitope Type II CD20 epitope Localization of CD20 to lipid rafts Does not localize CD20 to lipid rafts Increase CDC (if IgG1 isotype) Reduce CDC (if IgG1 isotype) ADCC activity (if IgG1 isotype) ADCC activity (if IgG1 isotype) Fully binding ability Reduced binding capacity Homotype aggregation Strong homogenous aggregation Induces apoptosis after cross-linking Induces strong cell death without cross-linking

I型抗CD20抗體之實例包括例如 利妥昔單抗、HI47 IgG3 (ECACC，融合瘤)、2C6 IgG1 (如WO 2005/103081中所揭示)、2F2 IgG1 (如WO 2004/035607及WO 2005/103081所揭示)及2H7 IgG1 (如WO 2004/056312中所揭示)。Examples of type I anti-CD20 antibodies include, for example , rituximab, HI47 IgG3 (ECACC, fusion tumor), 2C6 IgG1 (as disclosed in WO 2005/103081), 2F2 IgG1 (such as WO 2004/035607 and WO 2005/103081) Disclosed) and 2H7 IgG1 (as disclosed in WO 2004/056312).

在一些實施例中，本文所提供之治療方法中使用的抗CD20抗體係利妥昔單抗。在一些實施例中，利妥昔單抗(參考抗體；I型抗CD20抗體之實例)係含有人類γ1鼠類恆定域且針對人類CD20抗原的經基因工程改造之嵌合單株抗體。然而，該抗體未經糖基化改造，亦未經非岩藻糖基化的，並因此具有至少85%之岩藻糖量。該嵌合抗體包含人類γ1恆定域，並在1998年4月17日發布且讓渡於IDEC Pharmaceuticals Corporation之US 5,736,137(Andersen等人 )中以名稱「C2B8」標識。利妥昔單抗被批準用於治療患有彌漫性大B細胞淋巴瘤(DLBCL)、復發性或難冶性低度惡性或濾泡性CD20陽性B細胞非霍奇金淋巴瘤之患者。活體外 作用機制研究顯示，利妥昔單抗展現人類補體依賴性細胞毒性(CDC) (Reff，M.E.等人，Blood 83(2) (1994) 435-445)。此外，它亦在量測抗體依賴性細胞之細胞毒性(ADCC)的檢定中展現出活性。In some embodiments, the anti-CD20 antibody system rituximab used in the treatment methods provided herein. In some embodiments, rituximab (reference antibody; an example of type I anti-CD20 antibody) is a genetically engineered chimeric monoclonal antibody that contains a human γ1 murine constant domain and is directed against the human CD20 antigen. However, the antibody has not been glycosylated, nor is it non-fucosylated, and therefore has a fucose content of at least 85%. The chimeric antibody contains the human γ1 constant domain, and was released on April 17, 1998 and assigned to IDEC Pharmaceuticals Corporation in US 5,736,137 (Andersen et al. ) under the name "C2B8". Rituximab is approved for the treatment of patients with diffuse large B-cell lymphoma (DLBCL), relapsed or refractory low-grade or follicular CD20-positive B-cell non-Hodgkin lymphoma. In vitro studies of the mechanism of action have shown that rituximab exhibits human complement-dependent cytotoxicity (CDC) (Reff, ME et al., Blood 83(2) (1994) 435-445). In addition, it also exhibits activity in the assay to measure antibody-dependent cellular cytotoxicity (ADCC).

在一些實施例中，根據Kabat等人之編號，本文所提供之治療方法中使用的抗CD20抗體包含利妥昔單抗之CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3。在一些實施例中，本文所提供之治療方法中使用的抗CD20抗體包含利妥昔單抗之VH及VL。在一些實施例中，本文所提供之治療方法中使用的抗CD20抗體包含利妥昔單抗之重鏈及輕鏈。如本文所使用，術語「利妥昔單抗」係指具有CAS登記號174722-31-7之抗CD20抗體。In some embodiments, according to the numbering of Kabat et al., the anti-CD20 antibodies used in the treatment methods provided herein comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2 and CDR-L3. In some embodiments, the anti-CD20 antibodies used in the treatment methods provided herein include the VH and VL of rituximab. In some embodiments, the anti-CD20 antibodies used in the treatment methods provided herein comprise the heavy and light chains of rituximab. As used herein, the term "rituximab" refers to an anti-CD20 antibody with CAS registry number 174722-31-7.

在一些實施例中，本文所提供之治療方法中使用的抗CD20抗體係非岩藻糖基化之抗CD20抗體。In some embodiments, the anti-CD20 antibodies used in the treatment methods provided herein are non-fucosylated anti-CD20 antibodies.

II型抗CD20抗體之實例包括例如 人類化B-Ly1抗體IgG1 (如WO 2005/044859中所揭示之嵌合人類化IgG1抗體)、11B8 IgG1 (如WO 2004/035607中所揭示)及AT80 IgG1。典型地，IgG1同型之II型抗CD20抗體顯示出特有的CDC性質。與IgG1同型之I型抗體相比，II型抗CD20抗體具有降低之CDC (若為IgG1同型)。在一些實施例中，II型抗CD20抗體，例如 GA101抗體，具有增加的抗體依賴性細胞之細胞毒性(ADCC)。在一些實施例中，II型抗CD20抗體，更佳地如WO 2005/044859及WO 2007/031875中所述之非岩藻糖基化人類化B-Ly1抗體。Examples of type II anti-CD20 antibodies include, for example, humanized B-Ly1 antibody IgG1 (as the chimeric humanized IgG1 antibody disclosed in WO 2005/044859), 11B8 IgG1 (as disclosed in WO 2004/035607), and AT80 IgG1. Typically, type II anti-CD20 antibodies of the IgG1 isotype show unique CDC properties. Compared with type I antibodies of IgG1 isotype, type II anti-CD20 antibodies have a reduced CDC (if IgG1 isotype). In some embodiments, type II anti-CD20 antibodies, such as GA101 antibodies, have increased antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, the type II anti-CD20 antibody is more preferably the non-fucosylated humanized B-Ly1 antibody described in WO 2005/044859 and WO 2007/031875.

在一些實施例中，本文所提供之治療方法中使用的抗CD20抗體係GA101抗體。在一些實施例中，如本文所使用，GA101抗體係指結合人類CD20的以下抗體中之任一種：(1)包括含SEQ ID NO:5之胺基酸序列的HVR-H1、含SEQ ID NO:6之胺基酸序列的HVR-H2、含SEQ ID NO:7之胺基酸序列的HVR-H3、含SEQ ID NO:8之胺基酸序列的HVR-L1、含SEQ ID NO:9之胺基酸序列的HVR-L2及含SEQ ID NO:10之胺基酸序列的HVR-L3之抗體；(2)包括含SEQ ID NO:11之胺基酸序列的VH域及含SEQ ID NO:12之胺基酸序列的VL域之抗體；(3)包含SEQ ID NO:13之胺基酸序列及SEQ ID NO:14之胺基酸序列的抗體；(4)稱為奧妥珠單抗之抗體；或(5)包含與SEQ ID NO:13之胺基酸序列具有至少95%、96%、97%、98%或99%序列一致性之胺基酸序列及包含與SEQ ID NO:14之胺基酸序列具有至少95%、96%、97%、98%或99%序列一致性之胺基酸序列的抗體。在一個實施例中，GA101抗體係IgG1同型抗體。In some embodiments, the anti-CD20 anti-GA101 antibody used in the treatment methods provided herein. In some embodiments, as used herein, the GA101 antibody system refers to any one of the following antibodies that bind to human CD20: (1) HVR-H1 containing the amino acid sequence of SEQ ID NO: 5, containing SEQ ID NO HVR-H2 with the amino acid sequence of 6: HVR-H2, HVR-H3 with the amino acid sequence of SEQ ID NO: 7, HVR-L1 with the amino acid sequence of SEQ ID NO: 8 and SEQ ID NO: 9 The amino acid sequence of HVR-L2 and the antibody of HVR-L3 containing the amino acid sequence of SEQ ID NO: 10; (2) including the VH domain containing the amino acid sequence of SEQ ID NO: 11 and the antibody containing SEQ ID An antibody against the VL domain of the amino acid sequence of NO: 12; (3) An antibody comprising the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 14; (4) It is called Ottozu Monoclonal antibody; or (5) comprising an amino acid sequence with at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 13 and comprising the amino acid sequence with SEQ ID NO: 13 An antibody whose amino acid sequence of NO:14 has at least 95%, 96%, 97%, 98% or 99% sequence identity. In one example, the GA101 anti-system IgG1 isotype antibody.

在一些實施例中，本文所提供之治療方法中使用的抗CD20抗體係人類化B-Ly1抗體。在一些實施例中，人類化B-Ly1抗體係指如WO 2005/044859及WO 2007/031875中所揭示之人類化B-Ly1抗體，其藉由與來自IgG1之人類恆定域嵌合且隨後人類化，自鼠類單株抗CD20抗體B-Ly1 (鼠類重鏈之可變區(VH)：SEQ ID NO:3；鼠類輕鏈之可變區(VL)：SEQ ID NO:4；參見 Poppema，S. 及Visser，L.，Biotest Bulletin 3 (1987) 131-139)獲得(參見WO 2005/044859及WO 2007/031875)。人類化B-Ly1抗體詳細揭示於WO 2005/ 044859及WO 2007/031875中。In some embodiments, the anti-CD20 antibody system used in the treatment methods provided herein is a humanized B-Ly1 antibody. In some embodiments, the humanized B-Ly1 antibody system refers to the humanized B-Ly1 antibody as disclosed in WO 2005/044859 and WO 2007/031875 by chimerizing with the human constant domain from IgG1 and then human化, from a murine monoclonal anti-CD20 antibody B-Ly1 (variable region of murine heavy chain (VH): SEQ ID NO: 3; variable region of murine light chain (VL): SEQ ID NO: 4; See Poppema, S. and Visser, L., Biotest Bulletin 3 (1987) 131-139) for obtaining (see WO 2005/044859 and WO 2007/031875). The humanized B-Ly1 antibody is disclosed in detail in WO 2005/ 044859 and WO 2007/031875.

在一些實施例中，人類化B-Ly1抗體具有選自SEQ ID NO:15-16及40-55之群的重鏈可變區(VH)(對應於WO 2005/044859及WO 2007/031875之B-HH2至B-HH9及B-HL8至B-HL17)。在一些實施例中，可變域選自由SEQ ID NO: 15、16、42、44、46、48及50組成之群(對應於WO 2005/044859及WO 2007/031875之B-HH2、BHH-3、B-HH6、B-HH8、B-HL8、B-HL11及B-HL13)。在一些實施例中，人類化B-Ly1抗體具有SEQ ID NO: 55之輕鏈可變區(VL)(對應於WO 2005/044859及WO 2007/031875之B-KV1)。在一些實施例中，人類化B-Ly1抗體具有SEQ ID NO:42之重鏈可變區(VH)(對應於WO 2005/044859及WO 2007/031875之B-HH6)及SEQ ID NO:55之輕鏈可變區(VL)(對應於WO 2005/044859及WO 2007/031875之B-KV1)。在一些實施例中，人類化B-Ly1抗體係IgG1抗體。根據WO 2005/044859；WO 2004/065540；WO 2007/031875；Umana，P.等人 ，Nature Biotechnol. 17 (1999) 176-180；及WO 99/154342中所描述之程序，此類非岩藻糖基化之人類化B-Ly1抗體在Fc區中經糖基化改造(GE)。在一些實施例中，非岩藻糖基化的經糖基化改造之人類化B-Ly1係B-HH6-B-KV1 GE。在一些實施例中，抗CD20抗體係奧妥珠單抗(INN，WHO Drug Information，第26卷，第4期，2012，第453頁推薦)。如本文所使用，奧妥珠單抗係GA101或RO5072759之同義詞。其可以商品名稱GAZYVA®購得以用於治療用途，且以1000 mg/40 mL(25 mg/mL)單劑量小瓶形式提供。此替換所有先前型式(例如 第25卷，第1卷，2011，第75-76頁)，且以前稱為阿富珠單抗(afutuzumab)(INN，WHO Drug Information，第23卷，第2期，2009，第176頁；第22卷，第2期，2008，第124頁推薦)。在一些實施例中，人類化B-Ly1抗體係包括含SEQ ID NO:17之胺基酸序列的重鏈及含SEQ ID NO:18之胺基酸序列的輕鏈之抗體，或此抗體之抗原結合片段。在一些實施例中，人類化B-Ly1抗體包括含SEQ ID NO:17之三個重鏈CDR的重鏈可變區及含SEQ ID NO:18之三個輕鏈CDR的輕鏈可變區。In some embodiments, the humanized B-Ly1 antibody has a heavy chain variable region (VH) selected from the group of SEQ ID NOs: 15-16 and 40-55 (corresponding to WO 2005/044859 and WO 2007/031875 B-HH2 to B-HH9 and B-HL8 to B-HL17). In some embodiments, the variable domain is selected from the group consisting of SEQ ID NO: 15, 16, 42, 44, 46, 48, and 50 (corresponding to B-HH2, BHH- 3. B-HH6, B-HH8, B-HL8, B-HL11 and B-HL13). In some embodiments, the humanized B-Ly1 antibody has a light chain variable region (VL) of SEQ ID NO: 55 (corresponding to B-KV1 of WO 2005/044859 and WO 2007/031875). In some embodiments, the humanized B-Ly1 antibody has a heavy chain variable region (VH) of SEQ ID NO: 42 (corresponding to B-HH6 of WO 2005/044859 and WO 2007/031875) and SEQ ID NO: 55 The light chain variable region (VL) (corresponding to B-KV1 of WO 2005/044859 and WO 2007/031875). In some embodiments, the humanized B-Ly1 anti-system IgG1 antibody. According to the procedures described in WO 2005/044859; WO 2004/065540; WO 2007/031875; Umana, P. et al ., Nature Biotechnol. 17 (1999) 176-180; and WO 99/154342, this type of non-fucoal The glycosylated humanized B-Ly1 antibody is glycosylated (GE) in the Fc region. In some embodiments, the non-fucosylated humanized glycosylated B-Ly1 is B-HH6-B-KV1 GE. In some embodiments, the anti-CD20 antibody system otuzumab (INN, WHO Drug Information, Vol. 26, No. 4, 2012, page 453 recommendation). As used herein, otuzumab is a synonym for GA101 or RO5072759. It is commercially available for therapeutic use under the trade name GAZYVA® and is provided in a single-dose vial of 1000 mg/40 mL (25 mg/mL). This replaces all previous versions ( for example, Volume 25, Volume 1, 2011, Pages 75-76), and was formerly known as afutuzumab (INN, WHO Drug Information, Volume 23, Issue 2) , 2009, page 176; Volume 22, Issue 2, 2008, page 124 recommended). In some embodiments, the humanized B-Ly1 antibody system includes a heavy chain containing the amino acid sequence of SEQ ID NO: 17 and an antibody containing the light chain of the amino acid sequence of SEQ ID NO: 18, or an antibody of this antibody Antigen-binding fragments. In some embodiments, the humanized B-Ly1 antibody includes a heavy chain variable region containing the three heavy chain CDRs of SEQ ID NO: 17 and a light chain variable region containing the three light chain CDRs of SEQ ID NO: 18 .

在一些實施例中，根據Kabat等人之編號，本文所提供之治療方法中使用的抗CD20抗體包含奧妥珠單抗之CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3。在一些實施例中，本文所提供之治療方法中使用的抗CD20抗體包含奧妥珠單抗之VH及VL。在一些實施例中，本文所提供之治療方法中使用的抗CD20抗體包含奧妥珠單抗之重鏈及輕鏈。In some embodiments, according to the numbering of Kabat et al., the anti-CD20 antibodies used in the treatment methods provided herein include CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2 and CDR-L3. In some embodiments, the anti-CD20 antibodies used in the treatment methods provided herein include the VH and VL of otuzumab. In some embodiments, the anti-CD20 antibodies used in the treatment methods provided herein comprise the heavy and light chains of otuzumab.

在一些實施例中，人類化B-Ly1抗體係非岩藻糖基化的經糖基化改造之人類化B-Ly1。此類經糖基化改造之人類化B-Ly1抗體在Fc區中具有改變之糖基化模式，較佳具有降低之岩藻糖殘基量。在一些實施例中，岩藻糖之量係Asn297處寡糖總量的約60%或更少(在一個實施例中，岩藻糖之量在約40%至約60%之間，在另一個實施例中，岩藻糖之量係約50%或更少，而在又一個實施例中，岩藻糖之量係約30%或更少)。在一些實施例中，Fc區之寡糖被平分。此等糖基化改造之人類化B-Ly1抗體具有增加之ADCC。In some embodiments, the humanized B-Ly1 antibody system is non-fucosylated and glycosylated humanized B-Ly1. Such a glycosylated humanized B-Ly1 antibody has an altered glycosylation pattern in the Fc region, and preferably has a reduced amount of fucose residues. In some embodiments, the amount of fucose is about 60% or less of the total amount of oligosaccharides at Asn297 (in one embodiment, the amount of fucose is between about 40% to about 60%, and in another In one embodiment, the amount of fucose is about 50% or less, and in another embodiment, the amount of fucose is about 30% or less). In some embodiments, the oligosaccharides in the Fc region are divided equally. These glycosylated humanized B-Ly1 antibodies have increased ADCC.

如實例2中所述，在使用Raji細胞(ATCC編號CCL-86)之FACSArray (Becton Dickinson)中，使用與Cy5結合的該抗CD20抗體及與Cy5結合之利妥昔單抗，藉由直接免疫螢光量測(量測平均螢光強度(MFI))來測定「與利妥昔單抗相比，抗CD20抗體與Raji細胞(ATCC編號CCL-86)上之CD20結合能力之比率」，並如下計算： 與Raji細胞(ATCC編號CCL-86)上之CD20結合能力之比率=

Figure 02_image076
As described in Example 2, in FACSArray (Becton Dickinson) using Raji cells (ATCC number CCL-86), the anti-CD20 antibody bound to Cy5 and rituximab bound to Cy5 were used by direct immunization Fluorescence measurement (measuring the mean fluorescence intensity (MFI)) is used to determine the ratio of anti-CD20 antibody to CD20 binding capacity on Raji cells (ATCC number CCL-86) compared with rituximab, and Calculate as follows: Ratio of binding capacity to CD20 on Raji cells (ATCC number CCL-86) =
Figure 02_image076

MFI係平均螢光強度。如本文所使用，「Cy5標記比率」係指每分子抗體的Cy5標記分子之數目。MFI is the average fluorescence intensity. As used herein, "Cy5 labeling ratio" refers to the number of Cy5 labeling molecules per molecule of antibody.

典型地，該II型抗CD20抗體具有該第二抗CD20抗體與Raji細胞(ATCC編號CCL-86)上之CD20之結合能力相較於利妥昔單抗的比率為0.3至0.6，且在一個實施例中為0.35至0.55，且在另一個實施例中為0.4至0.5。Typically, the type II anti-CD20 antibody has a binding capacity of the second anti-CD20 antibody to CD20 on Raji cells (ATCC number CCL-86) compared to rituximab at a ratio of 0.3 to 0.6, and in a It is 0.35 to 0.55 in an embodiment, and 0.4 to 0.5 in another embodiment.

「具有增加之抗體依賴性細胞之細胞毒性(ADCC)之抗體」意謂如藉由普通熟習此項技術者已知之任何適合方法所測定，本文所定義之術語抗體具有增加之ADCC。"Antibody with increased antibody-dependent cellular cytotoxicity (ADCC)" means that the term antibody as defined herein has increased ADCC as determined by any suitable method known to those skilled in the art.

以下描述示例性可接受之活體外 ADCC檢定： 1)   該檢定使用已知表現由抗體之抗原結合區識別之目標抗原的目標細胞； 2)   該檢定使用自隨機選擇之健康供體血液分離之人類外周血單核細胞(PBMC)作為效應細胞； 3)   該檢定係根據以下方案進行： i)    PBMC係使用標準密度離心程序分離，並以5×106 個細胞/毫升懸浮於RPMI細胞培養基中； ii)   藉由標準組織培養方法使目標細胞生長，自活力高於90%之指數生長期收集，在RPMI細胞培養基中洗滌，用100微居裏之51 Cr標記，用細胞培養基洗滌兩次，並將其以105 個細胞/毫升之密度再懸浮於細胞培養基中； iii)  將100 μl上述最終目標細胞懸浮液轉移至96孔微量滴定盤之每個孔中； iv)  將抗體在細胞培養基中自4000 ng/ml連續稀釋至0.04 ng/ml，並將50 μl所得抗體溶液添加至96孔微量滴定盤中之目標細胞中，一式三份測試覆蓋以上全濃度範圍之各種抗體濃度； v)   對於最大釋放(MR)對照，含有經標記目標細胞之盤中的額外3個孔接受50 μl 2% (VN)非離子清潔劑水溶液(Nonidet，Sigma，St. Louis)，而非抗體溶液(上述第iv點)； vi)  對於自發釋放(SR)對照，含有經標記目標細胞之盤中的額外3個孔接受50 μl RPMI細胞培養基，而非抗體溶液(上述第iv點)； vii) 接著，將96孔微量滴定盤以50×g離心1分鐘，並在4℃下培育1小時； viii) 將50 μl PBMC懸浮液(上述第i點)添加至各孔中以產生25:1之效應物:目標細胞比率，並將盤置放於恆溫箱中，在5% CO2 氛圍及37℃下保持4小時; ix)   收集來自各孔之無細胞上清液，並使用γ計數器定量實驗釋放之放射性(ER)； x)    根據公式(ER-MR)/(MR-SR) x 100計算各抗體濃度之特異性溶解百分比，其中ER係針對該抗體濃度定量之平均放射性(參見上述第ix點)，MR係針對MR對照(參見上述第V點)定量之平均放射性(參見上述第ix點)，且SR係針對SR對照(參見上述第vi點)定量之平均放射性(參見上述第ix點)； 4)   「增加之ADCC」定義為在以上測試之抗體濃度範圍內觀察到的特異性溶解之最大百分比的增加，及/或達成以上測試之抗體濃度範圍內觀察到的特異性溶解之最大百分比之一半所需的抗體濃度之降低。在一個實施例中，ADCC之增加係相對於使用熟習此項技術者已知之相同標準製造、純化、調配及儲存方法，由相同類型之宿主細胞產生之相同抗體介導的藉由上述檢定量測之ADCC，不過比較抗體(缺乏增加之ADCC)並非由經工程改造成過表現GnTIII及/或經工程改造具有減少的岩藻糖基轉移酶8 (FUT8)基因表現(例如 包括經工程改造以進行FUT8基因剔除)的宿主細胞產生。The following describes exemplary acceptable in vitro ADCC assays: 1) The assay uses target cells known to express the target antigen recognized by the antigen binding region of the antibody; 2) The assay uses human blood isolated from a randomly selected healthy donor Peripheral blood mononuclear cells (PBMC) are used as effector cells; 3) The assay is performed according to the following protocol: i) PBMC is separated using standard density centrifugation procedures and suspended in RPMI cell culture medium at 5×10 6 cells/ml; ii) Use standard tissue culture methods to grow target cells, collect them from the exponential growth phase with viability higher than 90%, wash in RPMI cell culture medium, label with 100 microcuries of 51 Cr, wash twice with cell culture medium, and which at 10 5 cells / ml were resuspended to a density of a cell culture medium; iii) above the 100 μl final target cell suspension was transferred to each well of the microtiter plate wells 96; IV) antibodies in cell culture medium Serially dilute from 4000 ng/ml to 0.04 ng/ml, and add 50 μl of the obtained antibody solution to the target cells in a 96-well microtiter plate, and test in triplicate to cover various antibody concentrations in the above full concentration range; v) For Maximum release (MR) control, 3 additional wells in the dish containing the labeled target cells received 50 μl of 2% (VN) non-ionic detergent aqueous solution (Nonidet, Sigma, St. Louis) instead of antibody solution (the above section iv point); vi) For the spontaneous release (SR) control, the additional 3 wells in the plate containing the labeled target cells received 50 μl of RPMI cell culture medium instead of the antibody solution (point iv above); vii) Next, The 96-well microtiter plate was centrifuged at 50×g for 1 minute and incubated at 4°C for 1 hour; viii) 50 μl of PBMC suspension (point i above) was added to each well to produce a 25:1 effector: Target cell ratio, and place the plate in an incubator for 4 hours at 5% CO 2 and 37°C; ix) Collect the cell-free supernatant from each well, and use a gamma counter to quantify the radioactivity released in the experiment (ER); x) Calculate the specific dissolution percentage of each antibody concentration according to the formula (ER-MR)/(MR-SR) x 100, where ER is the average radioactivity quantified for the antibody concentration (see point ix above), MR is the average radioactivity quantified against the MR control (see point V above) (see point ix above), and SR is the average radioactivity quantified against the SR control (see point vi above) (see point ix above); 4 ) "Increase ADCC" is defined as the increase in the maximum percentage of specific solubilization observed within the antibody concentration range tested above, and/or half of the maximum percentage of specific solubilization observed within the antibody concentration range tested above Required The reduction of the antibody concentration. In one embodiment, the increase in ADCC is mediated by the same antibody produced by the same type of host cell using the same standard manufacturing, purification, preparation and storage methods known to those skilled in the art by the above-mentioned assay. ADCC, but the comparative antibody (lack of increased ADCC) is not engineered to express GnTIII and/or engineered to have reduced fucosyltransferase 8 (FUT8) gene expression ( e.g. including engineered to perform FUT8 gene knockout) produced by host cells.

在一些實施例中，「增加之ADCC」可藉由例如該等抗體之突變及/或糖基化改造來獲得。在一些實施例中，抗CD20抗體經糖基化改造成具有與抗體Fc區連接之雙觸角寡糖，該寡糖被GlcNAc平分。在一些實施例中，藉由在缺乏蛋白質岩藻糖基化之宿主細胞(例如 Lec13 CHO細胞或α-1,6-岩藻糖基轉移酶基因(FUT8)缺失或FUT基因表現敲減之細胞)中表現抗體，將抗CD20抗體糖基化改造成在與Fc區連接之碳水化合物上缺少岩藻糖。在一些實施例中，抗CD20抗體序列已在其Fc區中經工程改造以增強ADCC。在一些實施例中，此類經工程改造之抗CD20抗體變異體包含在Fc區之298位、333位及/或334位具有一或多個胺基酸取代(殘基之EU編號)的Fc區。In some embodiments, "increased ADCC" can be obtained, for example, by mutation and/or glycosylation of the antibodies. In some embodiments, the anti-CD20 antibody is glycosylated to have a biantennary oligosaccharide linked to the Fc region of the antibody, and the oligosaccharide is equally divided by GlcNAc. In some embodiments, by using a host cell that lacks protein fucosylation ( such as Lec13 CHO cells or cells with α-1,6-fucosyltransferase gene (FUT8) deletion or FUT gene expression knockdown ), the anti-CD20 antibody is glycosylated to lack fucose on the carbohydrates linked to the Fc region. In some embodiments, the anti-CD20 antibody sequence has been engineered in its Fc region to enhance ADCC. In some embodiments, such engineered anti-CD20 antibody variants comprise an Fc with one or more amino acid substitutions (EU numbering of residues) at positions 298, 333, and/or 334 of the Fc region Area.

在一些實施例中，術語「補體依賴性細胞毒性(CDC)」係指在補體存在下由根據本發明之抗體溶解人類癌症目標細胞。CDC可藉由在補體存在下，用根據本發明之抗CD20抗體處理表現CD20之細胞製劑來量測。若抗體在100 nM濃度下在4小時後誘導20%或更多腫瘤細胞溶解(細胞死亡)，則發現CDC。在一些實施例中，檢定係用51 Cr或Eu標記之腫瘤細胞執行並量測釋放之51 Cr或Eu。對照包括與補體一起但不與抗體一起培育腫瘤目標細胞。In some embodiments, the term "complement-dependent cytotoxicity (CDC)" refers to the lysis of human cancer target cells by the antibody according to the present invention in the presence of complement. CDC can be measured by treating a cell preparation expressing CD20 with an anti-CD20 antibody according to the present invention in the presence of complement. If the antibody induces 20% or more tumor cell lysis (cell death) after 4 hours at a concentration of 100 nM, CDC is found. In some embodiments, the assay is performed with tumor cells labeled with 51 Cr or Eu and the released 51 Cr or Eu is measured. Controls include growing tumor target cells with complement but not with antibodies.

在一些實施例中，抗CD20抗體係單株抗體，例如 人類抗體。在一個實施例中，抗CD20抗體係抗體片段，例 如Fv、Fab、Fab’、scFv、雙功能抗體或F(ab’)2 片段。在一些實施例中，抗CD20抗體係基本上全長抗體，例如 IgG1抗體、IgG2a抗體或如本文所定義之其他抗體類別或同型。In some embodiments, the anti-CD20 antibody system monoclonal antibody, such as a human antibody. In one embodiment, the anti-CD20 antibody is an antibody fragment, such as Fv, Fab, Fab ', scFv , diabody, or F (ab') 2 fragments. In some embodiments, the anti-CD20 antibody system is substantially full-length antibodies, such as IgG1 antibodies, IgG2a antibodies, or other antibody classes or isotypes as defined herein.

在一些實施例中，抗CD20抗體係ABP 798(美國的Amgen)、Zytux (伊朗的AryoGen Pharmed)、AcellBia/Usmal (俄羅斯的Biocad)、BI 695500 (德國的Boehringer Ingelheim)、Truxima (韓國的Celltrion)、Blitzima (韓國的Celltrion)、Ritemvia(韓國的Celltrion)、Rituzena/Tuxella (韓國的Cellcellon)、CT-P10 (韓國的Celltrion)、Reditux (印度的Dr Reddy’s Laboratories)、Maball (印度的Hetero Group)、MabTas (印度的Intas Biopharmaceuticals)、JHL1101 (台灣的JHL Biotech)、Novex (RTXM83) (西班牙/阿根廷的mAbxience/Laboratorio Elea)、Mabion CD20 (波蘭的Mabion；印度的Mylan)、PF-05280586 (美國的Pfizer)、Kikuzubam (墨西哥的Probiomed)、利妥昔單抗(Zenotech Laboratories)、RituxiRel (印度的Reliance Life Sciences)、SAIT101 (韓國的Samsung BioLogics)、Rixathon/Riximyo (GP2013)(瑞士的Sandoz)、HLX01 (中國的Shanghai Henlius Biotech)、TL011 (以色列的Teva Pharmaceutical Industries；瑞士的Lonza)或Redditux (土耳其的TRPharma)。VI. 抗體 In some embodiments, the anti-CD20 antibody system ABP 798 (Amgen in the United States), Zytux (AryoGen Pharmed in Iran), AcellBia/Usmal (Biocad in Russia), BI 695500 (Boehringer Ingelheim in Germany), Truxima (Celltrion in South Korea) , Blitzima (Celltrion in South Korea), Ritemvia (Celltrion in South Korea), Rituzena/Tuxella (Cellcellon in South Korea), CT-P10 (Celltrion in South Korea), Reditux (Dr Reddy's Laboratories in India), Maball (Hetero Group in India), MabTas (Intas Biopharmaceuticals in India), JHL1101 (JHL Biotech in Taiwan), Novex (RTXM83) (mAbxience/Laboratorio Elea in Spain/Argentina), Mabion CD20 (Mabion in Poland; Mylan in India), PF-05280586 (Pfizer in the United States) ), Kikuzubam (Probiomed in Mexico), Rituximab (Zenotech Laboratories), RituxiRel (Reliance Life Sciences in India), SAIT101 (Samsung BioLogics in South Korea), Rixathon/Riximyo (GP2013) (Sandoz in Switzerland), HLX01 ( Shanghai Henlius Biotech in China), TL011 (Teva Pharmaceutical Industries in Israel; Lonza in Switzerland) or Redditux (TRPharma in Turkey). VI. Antibodies

在一些實施例中，本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)可單獨或組合地併入如下所述之特徵中之任一種。A. 抗體親和力 In some embodiments, the antibodies used in the treatment methods provided herein ( e.g., anti-CD79b antibodies or anti-CD20 antibodies) may incorporate any of the features described below, alone or in combination. A. Antibody affinity

在某些實施例中，本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)之解離常數(Kd) ≤ 1μM、≤ 100 nM、≤ 50 nM、≤ 10 nM、≤ 5 nM、≤ 1 nM、≤ 0.1 nM、≤ 0.01 nM、或≤ 0.001 nM，且視情況≥ 10-13 M (例如 10-8 M或更低，例如 10-8 M至10-13 M，例如 10-9 M至10-13 M)。In certain embodiments, the dissociation constant (Kd) of the antibody used in the treatment methods provided herein ( for example, anti-CD79b antibody or anti-CD20 antibody) is ≤ 1 μM, ≤ 100 nM, ≤ 50 nM, ≤ 10 nM, ≤ 5 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM, and as appropriate ≥ 10 -13 M ( for example, 10 -8 M or lower, such as 10 -8 M to 10 -13 M, such as 10 -9 M to 10 -13 M).

在一個實施例中，Kd係如以下檢定所述，藉由用所關注抗體之Fab型式及其抗原執行的放射性標記之抗原結合檢定(RIA)來量測。Fab對抗原之溶液結合親和力係藉由在滴定系列之未標記抗原存在下，使Fab與最低濃度(125 I)標記之抗原平衡，接著用經抗Fab抗體塗佈之盤捕獲經結合抗原來量測(參見例如 Chen等人，J. Mol. Biol. 293:865-881(1999))。為了確定檢定條件，將MICROTITER® 多孔盤(Thermo Scientific)用含5 μg/ml捕獲抗Fab抗體(Cappel Labs)之50 mM碳酸鈉(pH 9.6)塗佈隔夜，且隨後在室溫(約23℃)下，用含2% (w/v)牛血清白蛋白之PBS阻斷二至五小時。在一個非吸附盤(Nunc #269620)中，將100 pM或26 pM [125 I]-抗原與所關注Fab之連續稀釋液混合(例如 與Presta等人，Cancer Res. 57:4593-4599 (1997)中關於抗VEGF抗體Fab-12之評估一致)。接著，將所關注Fab培育隔夜；然而，培育可持續較長時間(例如 約65小時)以確保達到平衡。之後，將混合物轉移至捕獲盤中，在室溫下培育(例如 一小時)。接著，移除溶液，並將盤用含0.1%聚山梨醇酯20 (TWEEN-20® )之PBS洗滌八次。當盤乾燥時，添加150 μl/孔之閃爍液(MICROSCINT-20TM ；Packard)，並在TOPCOUNTTM γ計數器(Packard)上對盤計數十分鐘。選擇提供小於或等於20%最大結合的各Fab之濃度用於競爭性結合檢定。In one embodiment, Kd is measured by a radiolabeled antigen binding assay (RIA) performed using the Fab type of the antibody of interest and its antigen as described in the following assay. The solution binding affinity of Fab to antigen is measured by balancing the Fab with the lowest concentration (125 I) labeled antigen in the presence of unlabeled antigen in the titration series, and then capturing the bound antigen with a dish coated with anti-Fab antibody. Test ( see, for example, Chen et al., J. Mol. Biol. 293:865-881 (1999)). To determine the assay conditions, the perforated disk MICROTITER ® (Thermo Scientific) containing 5 μg / ml capturing anti-Fab antibody (Cappel Labs) of 50 mM sodium carbonate (pH 9.6) is applied overnight, and then at room temperature (about 23 ℃ ), block with PBS containing 2% (w/v) bovine serum albumin for two to five hours. In a non-adsorbent plate (Nunc #269620), mix 100 pM or 26 pM [ 125 I]-antigen with serial dilutions of the Fab of interest ( e.g., with Presta et al., Cancer Res. 57:4593-4599 (1997) The evaluation of anti-VEGF antibody Fab-12 in) is the same). Next, the Fab of interest is incubated overnight; however, the incubation can continue for a longer time ( e.g., about 65 hours) to ensure that equilibrium is reached. After that, the mixture is transferred to a capture tray and incubated at room temperature ( for example, one hour). Next, the solution was removed, and the disk was washed eight times with PBS containing 0.1% polysorbate 20 (TWEEN-20 ® ). When the disc is dry, add 150 μl/well of scintillation fluid (MICROSCINT-20 ™ ; Packard), and count the disc on a TOPCOUNT™ gamma counter (Packard) for ten minutes. The concentration of each Fab that provides less than or equal to 20% of the maximum binding is selected for the competitive binding assay.

根據另一個實施例，使用BIACORE® -2000或BIACORE® -3000 (BIAcore，Inc.，Piscataway，NJ)，在25℃下使用在約10個反應單位(RU)之經固定抗原CM5晶片，使用表面電漿子共振檢定來量測Kd。簡言之，根據供應商的說明書，用N -乙基-N' -(3-二甲基胺基丙基)-碳化二亞胺鹽酸鹽(EDC)及N -羥基琥珀醯亞胺(NHS)活化羧甲基化葡聚糖生物感測器晶片(CM5，BIACORE，Inc.)。用pH 4.8的10 mM乙酸鈉將抗原稀釋至5 μg/ml (約0.2 μM)，隨後以5 μl/min流速注入，以獲得約10個反應單位(RU)之偶合蛋白。注射抗原後，注射1 M乙醇胺以阻斷未反應之基團。對於動力學量測，在25℃下，以約25 μl/min流速將Fab之兩倍連續稀釋液(0.78 nM至500 nM)注入含0.05%聚山梨醇酯20 (TWEEN-20TM )界面活性劑之PBS (PBST)中。締合速率(kon )及解離速率(koff )係使用簡單的一對一郎謬爾結合模型(one-to-one Langmuir binding model)(BIACORE® Evaluation Software 3.2版)，藉由同時擬合締合及解離感測圖計算。平衡解離常數(Kd)係以比率koff /kon 計算。參見例如 Chen等人，J. Mol. Biol. 293:865-881 (1999)。若藉由以上表面電漿子共振檢定測定締合速率超過106 M-1 s-1 ，則可藉由使用螢光淬滅技術測定締合速率，該螢光淬滅技術量測在遞增濃度之抗原存在下，在25℃下於pH 7.2的含20 nM抗-抗原抗體(Fab形式)之PBS中，如在分光計，諸如具有攪拌比色皿之停流配備分光光度計(Aviv Instruments)或8000系列SLM-AMINCOTM 分光光度計(ThermoSpectronic)中所量測的螢光發射強度(激發= 295 nm；發射= 340 nm，16 nm帶通)的增加或降低。B. 抗體片段 According to another embodiment, BIACORE ® -2000 or BIACORE ® -3000 (BIAcore, Inc., Piscataway, NJ) is used, using a fixed antigen CM5 chip at about 10 reaction units (RU) at 25°C, using a surface Kd is measured by plasmon resonance verification. In short, according to the supplier’s instructions, use N -ethyl- N' -(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N -hydroxysuccinimide ( NHS) activated carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.). The antigen was diluted to 5 μg/ml (about 0.2 μM) with 10 mM sodium acetate pH 4.8, and then injected at a flow rate of 5 μl/min to obtain about 10 reaction units (RU) of coupled protein. After injection of antigen, 1 M ethanolamine was injected to block unreacted groups. For kinetic measurement, at 25°C, two-fold serial dilutions (0.78 nM to 500 nM) of Fab were injected into the interface activity of 0.05% polysorbate 20 (TWEEN-20 TM) at a flow rate of about 25 μl/min. PBS (PBST) of the agent. The association rate (k on ) and dissociation rate (k off ) are based on a simple one-to-one Langmuir binding model (BIACORE ® Evaluation Software version 3.2). Combination and dissociation sensing map calculation. The equilibrium dissociation constant (Kd) based in a ratio k off / k on calculation. See, for example, Chen et al., J. Mol. Biol. 293:865-881 (1999). If the association rate determined by the above surface plasmon resonance test exceeds 10 6 M -1 s -1 , the association rate can be determined by using the fluorescence quenching technique, which measures the increasing concentration In the presence of the antigen, in PBS containing 20 nM anti-antigen antibody (Fab format) at pH 7.2 at 25°C, such as in a spectrometer, such as a stopped-flow spectrophotometer with stirring cuvette (Aviv Instruments) Or increase or decrease the fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm bandpass) measured in the 8000 series SLM-AMINCO TM spectrophotometer (ThermoSpectronic). B. Antibody fragments

在某些實施例中，本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)係抗體片段。抗體片段包括但不限於Fab、Fab'、Fab'-SH、F(ab')2 、Fv及scFv片段，以及下文所描述之其他片段。關於某些抗體片段之評述，參見 Hudson等人，Nat. Med. 9:129-134 (2003)。關於scFv片段之評述，參見例如 Pluckthün，The Pharmacology of Monoclonal Antibodies ，第113卷，Rosenburg及Moore編，(Springer-Verlag，New York)，第269-315頁(1994)；亦參見 WO 93/16185；以及美國專利第5,571,894號及第5,587,458號。關於包含補救受體結合抗原決定基殘基且具有延長之活體內半衰期的Fab及F(ab')2 片段的論述，參見 美國專利第5,869,046號。 In certain embodiments, the antibody (e.g., anti-CD79b antibody or anti-CD20 antibody) used in the treatment methods provided herein is an antibody fragment. Antibody fragments include but are not limited to Fab, Fab', Fab'-SH, F(ab') 2 , Fv and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al., Nat. Med. 9:129-134 (2003). For reviews of scFv fragments, see, for example, Pluckthün, The Pharmacology of Monoclonal Antibodies , Volume 113, Rosenburg and Moore eds, (Springer-Verlag, New York), pages 269-315 (1994); see also WO 93/16185; And US Patent Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab') 2 fragments containing salvage receptor binding epitope residues and having an extended half-life in vivo , see U.S. Patent No. 5,869,046.

雙功能抗體係具有兩個抗原結合位點之抗體片段，其可為二價或雙特異性抗體片段。參見 例如EP 404,097；WO 1993/01161；Hudson等人，Nat. Med. 9:129-134 (2003)；及Hollinger等人，Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)。三功能抗體及四功能抗體亦描述於Hudson等人，Nat. Med. 9:129-134 (2003)中。The bifunctional antibody system has an antibody fragment with two antigen binding sites, which can be a bivalent or bispecific antibody fragment. See, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Trifunctional antibodies and tetrafunctional antibodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

單域抗體係包含抗體重鏈可變域之全部或一部分或輕鏈可變域之全部或一部分的抗體片段。在某些實施例中，單域抗體係人類單域抗體(Domantis，Inc.，Waltham，MA；參見例如 美國專利第6,248,516 B1號)。The single domain antibody system comprises antibody fragments of all or part of the variable domain of the heavy chain of an antibody or all or part of the variable domain of the light chain. In certain embodiments, the single domain antibody system is a human single domain antibody (Domantis, Inc., Waltham, MA; see, for example, U.S. Patent No. 6,248,516 B1).

抗體片段可藉由各種技術製備，包括但不限於蛋白水解消化完整抗體以及由重組宿主細胞(例如大腸桿菌(E. coli )或噬菌體)產生，如本文所述。C. 嵌合及人類化抗體 Antibody fragments can be prepared by various techniques, including but not limited to proteolytic digestion of intact antibodies and production from recombinant host cells such as E. coli or phage, as described herein. C. Chimeric and humanized antibodies

在某些實施例中，本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)係嵌合抗體。某些嵌合抗體描述於例如 美國專利第4,816,567號；及Morrison等人，Proc. Natl. Acad. Sci. USA ，81:6851-6855 (1984)中。在一個實例中，嵌合抗體包含非人類可變區(例如 來源於小鼠、大鼠、倉鼠、兔、或非人靈長類諸如猴的可變區)及人類恆定區。在另一個實例中，嵌合抗體係「類別轉換」抗體，其中類別或子類別已自親本抗體之類別或子類別改變。嵌合抗體包括其抗原結合片段。 In certain embodiments, the antibody (e.g., anti-CD79b antibody or anti-CD20 antibody) used in the treatment methods provided herein is a chimeric antibody. Certain chimeric antibodies are described in, for example, U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA , 81:6851-6855 (1984). In one example, a chimeric antibody includes a non-human variable region ( e.g. , a variable region derived from a mouse, rat, hamster, rabbit, or a non-human primate such as a monkey) and a human constant region. In another example, a chimeric antibody system "class switch" antibody, where the class or subclass has been changed from the class or subclass of the parent antibody. Chimeric antibodies include their antigen-binding fragments.

在某些實施例中，嵌合抗體係人類化抗體。典型地，非人類抗體經歷人類化以降低對人類之免疫原性，同時保留親本非人類抗體之特異性及親和力。一般而言，人類化抗體包含一或多個可變域，其中HVR，例如 CDR (或其部分)來源於非人類抗體，且FR (或其部分)來源於人類抗體序列。人類化抗體視情況亦包含人類恆定區之至少一部分。在一些實施例中，人類化抗體中之一些FR殘基經來自非人類抗體(例如 作為HVR殘基來源之抗體)之相應殘基取代，以例如 恢復或改善抗體特異性或親和力。In certain embodiments, the chimeric antibody is a humanized antibody. Typically, non-human antibodies undergo humanization to reduce immunogenicity to humans while retaining the specificity and affinity of the parental non-human antibody. Generally, humanized antibodies comprise one or more variable domains, where HVR, such as CDR (or part thereof) is derived from a non-human antibody, and FR (or part thereof) is derived from a human antibody sequence. The humanized antibody optionally also contains at least a part of the human constant region. In some embodiments, some FR residues in the humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., an antibody that is the source of HVR residues), for example , to restore or improve antibody specificity or affinity.

人類化抗體及其製備方法評述於例如 Almagro及Fransson，Front. Biosci. 13:1619-1633 (2008)中，且在例如 以下中進一步描述：Riechmann等人，Nature 332:323-329 (1988)；Queen等人，Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989)；美國專利第5，821,337號、第7,527,791號、第6,982,321號及第7,087,409號；Kashmiri等人 ，Methods 36:25-34 (2005) (描述SDR (a-CDR)移植)；Padlan，Mol. Immunol. 28:489-498 (1991) (描述「表面重塑」)；Dall’Acqua等人，Methods 36:43-60 (2005) (描述「FR改組」)；及Osbourn等人，Methods 36:61-68 (2005)；及Klimka等人，Br. J. Cancer ，83:252-260 (2000) (描述FR改組之「引導選擇」方法)。Humanized antibodies and their preparation methods are reviewed in, for example, Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described in, for example , Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86: 10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al ., Methods 36: 25-34 (2005) (description of SDR (a-CDR) transplantation); Padlan, Mol. Immunol. 28:489-498 (1991) (description of "surface remodeling");Dall'Acqua et al., Methods 36:43 -60 (2005) (description "FR reorganization"); and Osbourn et al., Methods 36:61-68 (2005); and Klimka et al., Br. J. Cancer , 83:252-260 (2000) (description FR Reorganized "guided selection" method).

可用於人類化之人類框架區包括但不限於：使用「最佳擬合」方法選擇之框架區(參見例如 Sims等人，J. Immunol. 151:2296 (1993))；來源於具有輕鏈或重鏈可變區之特定子組之人類抗體的共同序列之框架區(參見例如 Carter等人，Proc. Natl. Acad. Sci. USA ，89:4285 (1992)；及Presta等人，J. Immunol. ，151:2623 (1993))；人類成熟(體細胞突變)框架區或人類生殖系框架區(參見例如 Almagro及Fransson，Front. Biosci. 13:1619-1633 (2008))；以及由篩選FR文庫得到的框架區(參見例如 Baca等人，J. Biol. Chem. 272:10678-10684 (1997)；及Rosok等人，J. Biol. Chem. 271:22611-22618 (1996))。D. 人類抗體 Human framework regions that can be used for humanization include, but are not limited to: framework regions selected using the "best fit" method ( see, for example, Sims et al., J. Immunol. 151:2296 (1993)); derived from light chains or The framework region of the common sequence of human antibodies of a specific subset of the heavy chain variable region ( see, for example, Carter et al., Proc. Natl. Acad. Sci. USA , 89:4285 (1992); and Presta et al., J. Immunol . , 151:2623 (1993)); human maturation (somatic mutation) framework region or human germline framework region ( see, for example, Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and by screening FR Framework regions obtained from the library ( see, for example, Baca et al., J. Biol. Chem. 272:10678-10684 (1997); and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)). D. Human antibodies

在某些實施例中，本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)係人類抗體。人類抗體可使用此項技術中已知之各種技術產生。人類抗體大體上描述於van Dijk及van de Winkel，Curr. Opin. Pharmacol. 5: 368-74 (2001)；及Lonberg，Curr. Opin. Immunol. 20:450-459 (2008)。In certain embodiments, the antibodies used in the treatment methods provided herein ( e.g., anti-CD79b antibodies or anti-CD20 antibodies) are human antibodies. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001); and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

人類抗體可藉由向經修飾成響應於抗原攻擊而產生完整人類抗體或具有人類可變區之完整抗體的轉殖基因動物投與免疫原來製備。此類動物典型地含有人類免疫球蛋白基因座之全部或一部分，其置換內源性免疫球蛋白基因座，或存在於染色體外或隨機整合至動物染色體中。在此類轉殖基因小鼠中，內源性免疫球蛋白基因座一般已失活。關於自轉殖基因動物獲得人類抗體之方法的評述，參見 Lonberg，Nat. Biotech. 23:1117-1125 (2005)。亦參見 例如 描述XENOMOUSETM 技術之美國專利第6,075,181號及第6,150,584號；描述HuMab®技術之美國專利第5,770,429號；描述K-M MOUSE®技術之美國專利第7,041,870號；及描述VelociMouse®技術之美國專利申請公開案第US 2007/0061900號。由此類動物產生之完整抗體中的人類可變區可進一步修飾，例如 藉由與不同的人類恆定區組合進行修飾。Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to an antigen challenge. Such animals typically contain all or part of the human immunoglobulin locus, which replaces the endogenous immunoglobulin locus, or is present extrachromosomally or randomly integrated into the animal chromosome. In such transgenic mice, the endogenous immunoglobulin locus is generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example , U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE ™ technology; U.S. Patent No. 5,770,429 describing HuMab® technology; U.S. Patent No. 7,041,870 describing KM MOUSE® technology; and U.S. Patent Application describing VelociMouse® technology Publication No. US 2007/0061900. The human variable regions in intact antibodies produced by such animals can be further modified, for example, by combining with different human constant regions.

人類抗體亦可藉由基於融合瘤之方法製備。用於產生人類單株抗體之人類骨髓瘤及小鼠-人類雜骨髓瘤細胞株已有描述。(參見例如 KozborJ. Immunol. ，133: 3001 (1984)；Brodeur等人，Monoclonal Antibody Production Techniques and Applications ，第51-63頁 (Marcel Dekker，Inc.，New York，1987)；及Boerner等人，J. Immunol. ，147: 86 (1991)。)經由人類B細胞融合瘤技術產生之人類抗體亦描述於Li等人，Proc. Natl. Acad. Sci. USA ，103:3557-3562 (2006)中。額外方法包括例如美國專利第7,189,826號(描述由融合瘤細胞株產生單株人類IgM抗體)及Ni，Xiandai Mianyixue ，26(4):265-268 (2006)(描述人類-人類融合瘤)。人類融合瘤技術(三源融合瘤技術)亦描述於Vollmers及Brandlein，Histology and Histopathology ，20(3):927-937 (2005)及Vollmers及Brandlein，Methods and Findings in Experimental and Clinical Pharmacology ，27(3):185-91 (2005)中。Human antibodies can also be prepared by methods based on fusion tumors. Human myeloma and mouse-human hybrid myeloma cell lines for the production of human monoclonal antibodies have been described. ( See, for example, Kozbor J. Immunol. , 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications , pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol. , 147: 86 (1991).) Human antibodies produced by human B-cell fusion tumor technology are also described in Li et al., Proc. Natl. Acad. Sci. USA , 103:3557-3562 (2006) . Additional methods include, for example, US Patent No. 7,189,826 (describes the production of a single human IgM antibody from a fusion tumor cell line) and Ni, Xiandai Mianyixue , 26(4):265-268 (2006) (describes a human-human fusion tumor). Human fusion tumor technology (triple fusion tumor technology) is also described in Vollmers and Brandlein, Histology and Histopathology , 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology , 27(3 ): 185-91 (2005).

亦可藉由分離選自人類源性噬菌體展示文庫之Fv純系可變域序列來產生人類抗體。接著，可將此類可變域序列與所需人類恆定域組合。用於自抗體文庫選擇人類抗體之技術描述於下文中。E. 文庫源性抗體 Human antibodies can also be produced by isolating Fv cloned variable domain sequences selected from human-derived phage display libraries. Then, such variable domain sequences can be combined with the desired human constant domains. The techniques used to select human antibodies from antibody libraries are described below. E. Library-derived antibodies

在一些實施例中，本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)可藉由篩選組合文庫中具有一或多種所需活性之抗體來分離。舉例而言，此項技術中已知用於產生噬菌體展示文庫且篩選此類文庫值具有所需結合特徵之抗體的多種方法。此類方法評述於例如 Hoogenboom等人，Methods in Molecular Biology 178:1-37 (O’Brien等人編，Human Press，Totowa，NJ，2001)，且進一步描述於例如 McCafferty等人，Nature 348:552-554；Clackson等人，Nature 352: 624-628 (1991)；Marks等人，J. Mol. Biol. 222: 581-597 (1992)；Marks及Bradbury，Methods in Molecular Biology 248:161-175 (Lo編，Human Press，Totowa，NJ，2003)；Sidhu等人，J. Mol. Biol. 338(2): 299-310 (2004)；Lee等人，J. Mol. Biol. 340(5): 1073-1093 (2004)；Fellouse，Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004)；及Lee等人，J. Immunol. Methods 284(1-2): 119-132(2004)。In some embodiments, antibodies used in the treatment methods provided herein ( e.g., anti-CD79b antibodies or anti-CD20 antibodies) can be isolated by screening combinatorial libraries for antibodies with one or more desired activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies with desired binding characteristics. Such methods are reviewed in, for example, Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., eds., Human Press, Totowa, NJ, 2001), and further described in, for example, McCafferty et al., Nature 348:552 -554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, Methods in Molecular Biology 248:161-175 ( Lo eds., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132 (2004).

在某些噬菌體展示方法中，藉由聚合酶鏈反應(PCR)單獨選殖VH及VL基因之譜系且隨機重組於噬菌體文庫中，接著可篩選該等文庫中之抗原結合噬菌體，如Winter等人，Ann. Rev. Immunol. ，12: 433-455 (1994)中所述。噬菌體典型地展示呈單鏈Fv (scFv)片段或Fab片段形式的抗體片段。來自免疫來源之文庫提供抗免疫原之高親和力抗體，而無需構築融合瘤。或者，可在不進行任何免疫之情況下，選殖天然譜系(例如 來自人類)以提供針對多種非自身抗原以及自身抗原之抗體的單一來源，如Griffiths等人，EMBO J ，12: 725-734 (1993)所描述。最後，天然文庫亦可藉由自幹細胞選殖未經重排之V基因區段，且使用含有隨機序列之PCR引子編碼高度可變之CDR3區並實現活體外 重排，以合成方式製得，如Hoogenboom及Winter，J. Mol. Biol. ，227: 381-388 (1992)所描述。描述人類抗體噬菌體文庫之專利公開案包括例如：美國專利第5,750,373號、以及美國專利公開案第2005/0079574號、第2005/0119455號、第2005/0266000號、第2007/0117126號、第2007/0160598號、第2007/0237764號、第2007/0292936號、及第2009/0002360號。In some phage display methods, the lineages of VH and VL genes are separately selected by polymerase chain reaction (PCR) and randomly recombined in a phage library, and then the antigen-binding phages in these libraries can be screened, such as Winter et al. , Ann. Rev. Immunol. , 12: 433-455 (1994). Phages typically display antibody fragments in the form of single chain Fv (scFv) fragments or Fab fragments. Libraries from immune sources provide high-affinity antibodies against immunogens without the need to construct fusion tumors. Alternatively, the natural lineage ( for example, from humans) can be selected without any immunization to provide a single source of antibodies against multiple non-self antigens and self-antigens, such as Griffiths et al., EMBO J , 12: 725-734 (1993). Finally, natural libraries can also be prepared synthetically by selecting unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode highly variable CDR3 regions and realizing in vitro rearrangement. As described by Hoogenboom and Winter, J. Mol. Biol. , 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Patent No. 5,750,373, and U.S. Patent Publication No. 2005/0079574, No. 2005/0119455, No. 2005/0266000, No. 2007/0117126, No. 2007/ No. 0160598, No. 2007/0237764, No. 2007/0292936, and No. 2009/0002360.

自人類抗體文庫分離之抗體或抗體片段在本文中被視為人類抗體或人類抗體片段。F. 多特異性抗體 Antibodies or antibody fragments isolated from human antibody libraries are referred to herein as human antibodies or human antibody fragments. F. Multispecific antibodies

在某些實施例中，本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)係多特異性抗體，例如 雙特異性抗體。多特異性抗體係對至少兩個不同位點具有結合特異性的單株抗體。在某些實施例中，結合特異性之一係針對一種抗原(例如 CD79b或CD20)，且另一個結合特異性係針對任何其他抗原。在某些實施例中，結合特異性之一係針對一種抗原(例如 CD79b或CD20)且另一種結合特異性係針對CD3。參見例如 美國專利第5,821,337號。在某些實施例中，雙特異性抗體可結合至單一抗原(例如 CD79b或CD20)之兩個不同抗原決定基。雙特異性抗體亦可用於使細胞毒性劑定位於表現抗原(例如 CD79b或CD20)之細胞。可製備呈全長抗體或抗體片段形式之雙特異性抗體。 In certain embodiments, the antibodies (e.g., anti-CD79b antibodies or anti-CD20 antibodies) used in the treatment methods provided herein are multispecific antibodies, e.g. bispecific antibodies. The multispecific antibody system has monoclonal antibodies with binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is for one antigen ( eg, CD79b or CD20), and the other binding specificity is for any other antigen. In certain embodiments, one of the binding specificities is for one antigen ( eg, CD79b or CD20) and the other binding specificity is for CD3. See, for example, U.S. Patent No. 5,821,337. In certain embodiments, bispecific antibodies can bind to two different epitopes of a single antigen (eg, CD79b or CD20). Bispecific antibodies can also be used to localize cytotoxic agents to cells expressing antigens, such as CD79b or CD20. Bispecific antibodies can be prepared in the form of full-length antibodies or antibody fragments.

用於製備多特異性抗體之技術包括但不限於重組共表現具有不同特異性之兩個免疫球蛋白重鏈-輕鏈對(參見 Milstein及Cuello，Nature 305: 537 (1983))、WO 93/08829及Traunecker等人EMBO J. 10: 3655 (1991))及「孔中結(knob-in-hole)」工程改造(參見例如 美國專利第5,731,168號)。多特異性抗體亦可藉由以下方法製備：工程改造靜電轉向效應以製備抗體Fc-異二聚分子(WO 2009/089004A1)；使兩種或更多種抗體或片段交聯(參見例如 美國專利第4,676,980號，及Brennan等人，Science ，229: 81 (1985))；使用白胺酸拉煉産生雙特異性抗體(參見例如 Kostelny等人，J. Immunol. ，148(5):1547-1553 (1992))；使用「雙功能抗體」技術製備雙特異性抗體片段(參見例如 Hollinger等人，Proc. Natl. Acad. Sci.  USA ，90:6444-6448 (1993))；及使用單鏈Fv(sFv)二聚體(參見 例如 Gruber等人，J. Immunol. ，152:5368 (1994))；及如例如 Tutt等人J. Immunol. 147: 60 (1991)中所描述來製備三特異性抗體。Techniques for preparing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities ( see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/ 08829 and Traunecker et al. EMBO J. 10: 3655 (1991)) and "knob-in-hole" engineering ( see, for example, U.S. Patent No. 5,731,168). Multispecific antibodies can also be prepared by the following methods: engineering the electrostatic steering effect to prepare antibody Fc-heterodimeric molecules (WO 2009/089004A1); cross-linking two or more antibodies or fragments ( see, for example, U.S. Patent No. 4,676,980, and Brennan et al., Science , 229: 81 (1985); use leucine zip to generate bispecific antibodies (see, for example, Kostelny et al., J. Immunol. , 148(5):1547-1553 (1992)); using "bifunctional antibody" technology to prepare bispecific antibody fragments ( see, for example, Hollinger et al., Proc. Natl. Acad. Sci. USA , 90: 6444-6448 (1993)); and using single-chain Fv (sFv) dimer ( see, for example, Gruber et al., J. Immunol. , 152:5368 (1994)); and, for example, Tutt et al ., J. Immunol. 147: 60 (1991) to prepare trispecific Antibody.

本文亦包括具有三個或更多個功能性抗原結合位點的經工程改造之抗體，包括「章魚抗體(Octopus antibody)」 (參見例如 US 2006/0025576A1)。Also included herein are engineered antibodies with three or more functional antigen binding sites, including "Octopus antibodies" ( see, for example, US 2006/0025576A1).

本文之抗體或片段亦包括「雙重作用FAb」或「DAF」，其包含結合至CD79b以及另一個不同抗原之抗原結合位點(參見 例如US 2008/0069820)。G. 抗體變異體 The antibodies or fragments herein also include "dual acting FAb" or "DAF", which comprise an antigen binding site that binds to CD79b and another different antigen ( see, for example, US 2008/0069820). G. Antibody variants

在某些實施例中，涵蓋本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)之胺基酸序列變異體。舉例而言，可能期望改善抗CD79b抗體或抗CD20抗體之結合親和力及/或其他生物性質。抗體之胺基酸序列變異體可藉由將適當修飾引入編碼該抗體之核苷酸序列中或藉由肽合成來製備。此類修飾包括例如抗體胺基酸序列內殘基之缺失及/或插入及/或取代。可進行缺失、插入及取代之任何組合來獲得最終構築體，只要最終構築體具有所需特徵，例如 抗原結合。(i) 取代、插入及缺失變異體 In certain embodiments, amino acid sequence variants of the antibodies (e.g., anti-CD79b antibody or anti-CD20 antibody) used in the treatment methods provided herein are covered. For example, it may be desirable to improve the binding affinity and/or other biological properties of an anti-CD79b antibody or an anti-CD20 antibody. The amino acid sequence variants of the antibody can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the amino acid sequence of the antibody. Any combination of deletion, insertion, and substitution can be performed to obtain the final construct, as long as the final construct has the desired characteristics, such as antigen binding. (i) Substitution, insertion and deletion variants

在某些實施例中，提供具有一或多個胺基酸取代之抗體變異體。用於取代突變誘發之所關注位點包括HVR及FR。保守取代顯示於 表 D 中之標題「較佳取代」下。更多實質性改變提供於 表 D 之標題「示例性取代」下且如下文中參考胺基酸側鏈類別進一步描述。可將胺基酸取代引入所關注抗體中，且針對如下所需活性篩選產物，例如 保留/改善之抗原結合、降低之免疫原性、或改善之ADCC或CDC。 表 D 原始殘基 示例性取代 較佳取代 Ala (A) Val；Leu；Ile Val Arg (R) Lys；Gln；Asn Lys Asn (N) Gln；His；Asp，Lys；Arg Gln Asp (D) Glu；Asn Glu Cys (C) Ser；Ala Ser Gln (Q) Asn；Glu Asn Glu (E) Asp；Gln Asp Gly (G) Ala Ala His (H) Asn；Gln；Lys；Arg Arg Ile (I) Leu；Val；Met；Ala；Phe；正白胺酸 Leu Leu (L) 正白胺酸；Ile；Val；Met；Ala；Phe Ile Lys (K) Arg；Gln；Asn Arg Met (M) Leu；Phe；Ile Leu Phe (F) Trp；Leu；Val；Ile；Ala；Tyr Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Val；Ser Ser Trp (W) Tyr；Phe Tyr Tyr (Y) Trp；Phe；Thr；Ser Phe Val (V) Ile；Leu；Met；Phe；Ala；正白胺酸 Leu In certain embodiments, antibody variants with one or more amino acid substitutions are provided. The sites of interest for substitution mutagenesis include HVR and FR. Conservative substitutions are shown in Table D under the heading "preferred substitutions". More substantial changes are provided under the heading "Exemplary Substitutions" of Table D and are described further below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest, and the product screened for desired activities such as retained/improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. Table D Original residue Exemplary substitution Better replace Ala (A) Val; Leu; Ile Val Arg (R) Lys; Gln; Asn Lys Asn (N) Gln; His; Asp, Lys; Arg Gln Asp (D) Glu; Asn Glu Cys (C) Ser; Ala Ser Gln (Q) Asn; Glu Asn Glu (E) Asp; Gln Asp Gly (G) Ala Ala His (H) Asn; Gln; Lys; Arg Arg Ile (I) Leu; Val; Met; Ala; Phe; Leucine Leu Leu (L) Leucine; Ile; Val; Met; Ala; Phe Ile Lys (K) Arg; Gln; Asn Arg Met (M) Leu; Phe; Ile Leu Phe (F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Val; Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser Phe Val (V) Ile; Leu; Met; Phe; Ala; Leucine Leu

胺基酸可根據共有側鏈性質分組： (1)  疏水性：正白胺酸、Met、Ala、Val、Leu、Ile； (2)  中性親水性：Cys、Ser、Thr、Asn、Gln； (3)  酸性：Asp、Glu； (4)  鹼性：His、Lys、Arg； (5)  影響鏈取向之殘基：Gly、Pro； (6)  芳族：Trp、Tyr、Phe。Amino acids can be grouped according to shared side chain properties: (1) Hydrophobicity: Leucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln; (3) Acidity: Asp, Glu; (4) Alkaline: His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; (6) Aromatics: Trp, Tyr, Phe.

非保守取代將需要將此等類別之一的成員換成另一類別。Non-conservative substitutions will require replacing a member of one of these categories with another category.

一種類型之取代變異體涉及取代親本抗體(例如 人類化或人類抗體)之一或多個高變區殘基。一般而言，所得選擇用於進一步研究之變異體相對於親本抗體將具有某些生物性質之改變(例如 改善) (例如 增加之親和力、減少之免疫原性)，及/或將具有基本上保留的親本抗體之某些生物性質。示例性取代變異體係親和力成熟抗體，該抗體可例如 使用基於噬菌體展示之親和力成熟技術，諸如本文所述之技術便利地產生。簡言之，一或多個HVR殘基發生突變，且該等變異體抗體展示於噬菌體上並針對特定生物活性(例如 結合親和力)進行篩選。One type of substitution variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally speaking, the resulting variants selected for further research will have certain biological changes ( e.g. improvement) ( e.g. increased affinity, decreased immunogenicity) relative to the parent antibody, and/or will have substantially Certain biological properties of the retained parent antibody. Exemplary instead of variant system affinity mature antibodies, the antibodies can be conveniently produced, for example, using phage display-based affinity maturation techniques such as those described herein. In short, one or more HVR residues are mutated, and these variant antibodies are displayed on phage and screened for specific biological activity (e.g., binding affinity).

可在HVR中進行改變(例如 取代)，例如 以改善抗體親和力。可在HVR「熱點」，亦即 由在體細胞成熟過程期間經歷高頻率突變之密碼子編碼的殘基，及/或SDR (a-CDR)中進行此等改變(參見例如 Chowdhury，Methods Mol.Biol. 207:179-196，2008)，並測試所得變異體VH或VL之結合親和力。藉由構築次級文庫且自該等文庫中再選擇所進行的親和力成熟描述於例如 Hoogenboom等人，Methods in Molecular Biology 178:1-37 (O’Brien等人編，Human Press，Totowa，NJ，(2001)。)在親和力成熟之一些實施例中，藉由多種方法(例如 易錯PCR、鏈改組或寡核苷酸定點突變誘發)中之任一種將多樣性引入選擇用於實現成熟之可變基因中。接著，產生次級文庫。接著，篩選該文庫以鑒別具有所需親和力之任何抗體變異體。另一種引入多樣性之方法涉及HVR引導之方法，其中使數個HVR殘基(例如 每次4-6個殘基)隨機化。參與抗原結合之HVR殘基可例如 使用丙胺酸掃描突變誘發或模型化特別地鑑別。具體言之，通常靶向CDR-H3及CDR-L3。 Changes (e.g. substitutions) can be made in the HVR, for example to improve antibody affinity. These changes can be made in HVR "hot spots", that is , residues encoded by codons that undergo high-frequency mutations during the somatic cell maturation process, and/or SDR (a-CDR) ( see, for example, Chowdhury, Methods Mol. Biol. 207:179-196, 2008), and tested the binding affinity of the obtained variant VH or VL. Affinity maturation by constructing secondary libraries and selecting from these libraries is described in, for example, Hoogenboom et al., Methods in Molecular Biology 178:1-37 (eds by O'Brien et al., Human Press, Totowa, NJ, (2001).) In some embodiments of affinity maturation, diversity is introduced into selection by any of a variety of methods (such as error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis) to achieve maturation. Changing genes. Next, a secondary library is generated. Next, the library is screened to identify any antibody variants with the desired affinity. Another method of introducing diversity involves HVR-guided methods, in which several HVR residues ( e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. Specifically, CDR-H3 and CDR-L3 are usually targeted.

在某些實施例中，取代、插入或缺失可出現於一或多個HVR內，只要此類改變基本上不會降低該抗體結合抗原之能力。舉例而言，可在HVR中進行基本上不會降低結合親和力之保守性改變(例如 ，如本文所提供之保守取代)。此等改變可在HVR「熱點」或SDR之外。在上文所提供之變異體VH及VL序列的某些實施例中，各HVR未改變，或含有僅一個、兩個或三個胺基酸取代。In certain embodiments, substitutions, insertions, or deletions may occur in one or more HVRs, as long as such changes do not substantially reduce the ability of the antibody to bind antigen. For example, conservative changes (e.g. , conservative substitutions as provided herein) can be made in HVR that do not substantially reduce binding affinity. These changes can be outside the HVR "hot spot" or SDR. In certain embodiments of the variant VH and VL sequences provided above, each HVR is unchanged or contains only one, two or three amino acid substitutions.

用於鑑別抗體中可作為突變誘發之目標之殘基或區域的有用方法稱爲「丙胺酸掃描突變誘發」，如Cunningham及Wells (1989)Science ，244:1081-1085所述。在此方法中，鑑別一個殘基或一組目標殘基(例如 帶電殘基，諸如Arg、Asp、His、Lys及Glu)並將其置換為中性或帶負電胺基酸(例如 丙胺酸或聚丙胺酸)以確定抗體與抗原之相互作用是否受影響。進一步取代可在對初始取代展示功能敏感性的胺基酸位置處引入。替代地或另外，使用抗原-抗體複合物之晶體結構來鑑別抗體與抗原之間的接觸點。該等接觸殘基及相鄰殘基可作為取代之候選物而被靶向或消除。可篩選變異體以確定其是否含有所需性質。A useful method for identifying residues or regions in antibodies that can be targeted for mutagenesis is called "alanine scanning mutagenesis", as described by Cunningham and Wells (1989) Science , 244:1081-1085. In this method, a residue or a set of target residues ( e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced with neutral or negatively charged amino acids ( e.g., alanine or Polyalanine) to determine whether the interaction between the antibody and the antigen is affected. Further substitutions can be introduced at amino acid positions that exhibit functional sensitivity to the initial substitution. Alternatively or in addition, the crystal structure of the antigen-antibody complex is used to identify contact points between the antibody and the antigen. These contact residues and neighboring residues can be targeted or eliminated as candidates for substitution. The variants can be screened to determine whether they contain the desired properties.

胺基酸序列插入包括長度在一個殘基至含有一百個或更多個殘基之多肽之範圍內的胺基末端及/或羧基末端融合，以及單個或多個胺基酸殘基之序列內插入。末端插入序列之實例包括具有N末端甲硫胺醯基殘基之抗體。該抗體分子之其他插入變異體包括該抗體之N末端或C末端與酶(例如 針對ADEPT)或增加該抗體之血清半衰期之多肽的融合物。(ii) 糖基化變異體 Amino acid sequence insertions include amino-terminal and/or carboxy-terminal fusions ranging from one residue to polypeptides containing one hundred or more residues, and sequences of single or multiple amino acid residues内 Insert. Examples of terminal insertion sequences include antibodies with N-terminal methionine residues. Other insertion variants of the antibody molecule include fusions of the N-terminus or C-terminus of the antibody with an enzyme ( for example, for ADEPT) or a polypeptide that increases the serum half-life of the antibody. (ii) Glycosylation variants

在某些實施例中，改變本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)以增加或降低抗體糖基化之程度。抗體中糖基化位點之添加或缺失可藉由改變胺基酸序列以便產生或移除一或多個糖基化位點而便利地實現。In certain embodiments, the antibodies used in the treatment methods provided herein ( e.g., anti-CD79b antibodies or anti-CD20 antibodies) are changed to increase or decrease the degree of antibody glycosylation. The addition or deletion of glycosylation sites in an antibody can be conveniently achieved by changing the amino acid sequence to create or remove one or more glycosylation sites.

在抗體包含Fc區時，可改變與其連接之碳水化合物。由哺乳動物細胞產生之天然抗體典型地包含分支、雙觸角寡糖，該寡糖一般藉由N-鍵聯連接至該Fc區之CH2域的Asn297。參見例如 Wright等人，TIBTECH 15:26-32 (1997)。該寡糖可包括各種碳水化合物，例如 甘露糖、N-乙醯基葡糖胺(GlcNAc)、半乳糖及唾液酸，以及連接至雙觸角寡糖結構之「主幹」中之GlcNAc的岩藻糖。在一些實施例中，可對本發明抗體中之寡糖進行修飾以便產生具有某些改善之性質的抗體變異體。When the antibody contains an Fc region, the carbohydrate linked to it can be changed. Natural antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides, which are generally linked to Asn297 in the CH2 domain of the Fc region by N-linking. See, for example, Wright et al., TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, and fucose linked to GlcNAc in the "stem" of the biantennary oligosaccharide structure . In some embodiments, the oligosaccharides in the antibodies of the invention can be modified to produce antibody variants with certain improved properties.

在一個實施例中，提供具有缺乏(直接或間接地)連接至Fc區之岩藻糖之碳水化合物結構的抗體變異體。舉例而言，該抗體中岩藻糖之量可為1%至80%、1%至65%、5%至65%、或20%至40%。岩藻糖之量係藉由計算糖鏈內Asn297處之岩藻糖相對於如藉由MALDI-TOF質譜法所量測的連接至Asn 297之所有糖結構(例如 複合物、雜交體及高甘露糖結構)之總和的平均量來確定，如例如WO 2008/077546中所述。Asn297係指位於Fc區中大致297位處之天冬醯胺殘基(Fc區殘基之Eu編號)；然而，由於抗體中存在微小序列變化，Asn297亦可位於297位上游或下游約±3個胺基酸處，亦即 ，在294位與300位之間。該等岩藻糖基化變異體可具有改善之ADCC功能。參見例如 美國專利公開案第US 2003/0157108號(Presta，L.)；第US 2004/0093621號(Kyowa Hakko Kogyo Co.，Ltd)。關於「去岩藻糖基化」或「缺乏岩藻糖」抗體變異體之公開案之實例包括：US 2003/0157108；WO 2000/61739；WO 2001/29246；US 2003/0115614；US 2002/0164328；US 2004/0093621；US 2004/0132140；US 2004/0110704；US 2004/0110282；US 2004/0109865；WO 2003/085119；WO 2003/084570；WO 2005/035586；WO 2005/035778；WO2005/053742；WO2002/031140；Okazaki等人，J. Mol. Biol. 336:1239-1249 (2004)；Yamane-Ohnuki等人，Biotech. Bioeng. 87: 614 (2004)。能夠產生去岩藻糖基化抗體之細胞株的實例包括缺乏蛋白質岩藻糖基化作用之Lec13 CHO細胞(Ripka等人，Arch. Biochem. Biophys. 249:533-545 (1986)；美國專利申請案第US 2003/0157108 A1號，Presta，L；及WO 2004/056312 A1，Adams等人 ，尤其是見於實例11)及基因剔除之細胞株，諸如α-1,6-岩藻糖基轉移酶基因FUT8 基因剔除之CHO細胞(參見例如 Yamane-Ohnuki等人，Biotech. Bioeng. 87: 614 (2004)；Kanda，Y. 等人， Biotechnol. Bioeng .，94(4):680-688 (2006)；及WO2003/085107)。In one embodiment, antibody variants having a carbohydrate structure lacking (directly or indirectly) fucose linked to the Fc region are provided. For example, the amount of fucose in the antibody can be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is calculated by calculating the fucose at Asn297 in the sugar chain relative to all sugar structures connected to Asn 297 as measured by MALDI-TOF mass spectrometry ( such as complexes, hybrids, and high mannose The average amount of the sum of the sugar structure) is determined, as described in, for example, WO 2008/077546. Asn297 refers to the asparagine residue located at approximately position 297 in the Fc region (Eu numbering of residues in the Fc region); however, due to minor sequence changes in the antibody, Asn297 can also be located approximately ±3 upstream or downstream of position 297 One amino acid location, that is , between 294 and 300. These fucosylation variants may have improved ADCC function. See, for example, U.S. Patent Publication No. US 2003/0157108 (Presta, L.); No. US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications regarding "defucosylation" or "deficient fucose" antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328 ; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al., J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application Case No. US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al ., especially seen in Example 11) and gene knock-out cell lines, such as α-1,6-fucosyltransferase Gene FUT8 gene knock-out CHO cells ( see, for example, Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al ., Biotechnol. Bioeng ., 94(4): 680-688 (2006) ; And WO2003/085107).

抗體變異體進一步具有平分寡糖，例如 其中連接至抗體Fc區之雙觸角寡糖經GlcNAc平分。此類抗體變異體可具有降低之岩藻糖基化及/或改善之ADCC功能。此類抗體變異體之實例描述於例如 WO 2003/011878 (Jean-Mairet等人)；美國專利第6,602,684號(Umana等人)；及US 2005/0123546 (Umana等人 )中。亦提供在連接至Fc區之寡糖中具有至少一個半乳糖殘基之抗體變異體。該等抗體變異體可具有改善之CDC功能。此類抗體變異體描述於例如 WO 1997/30087 (Patel等人)；WO 1998/58964 (Raju，S.)；及WO 1999/22764 (Raju，S.)中。(iii) Fc 變異體 The antibody variants further have bisected oligosaccharides, for example, in which the biantennary oligosaccharides linked to the Fc region of the antibody are bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described in, for example, WO 2003/011878 (Jean-Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al. ). An antibody variant having at least one galactose residue in the oligosaccharide linked to the Fc region is also provided. These antibody variants may have improved CDC function. Such antibody variants are described in, for example, WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.). (iii) Fc variant

在某些實施例中，可將一或多個胺基酸修飾引入本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)之Fc區中，由此產生Fc區變異體。Fc區變異體可包含在一或多個胺基酸位置處包含胺基酸修飾(例如 取代)之人類Fc區序列(例如 人類IgG1、IgG2、IgG3或IgG4 Fc區)。In certain embodiments, one or more amino acid modifications can be introduced into the Fc region of an antibody (for example, an anti-CD79b antibody or an anti-CD20 antibody) used in the treatment methods provided herein, thereby generating Fc region variants . The Fc region variant may comprise a human Fc region sequence ( e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) that includes an amino acid modification (e.g., substitution) at one or more amino acid positions.

在某些實施例中，本發明涵蓋具有一些而非全部效應功能之抗體變異體，該等效應功能使該抗體變異體成為抗體之活體內 半衰期極為重要但某些效應子功能(諸如補體及ADCC)不必要或有害之應用的理想候選物。可進行活體外 及/或活體內 細胞毒性檢定以確定CDC及/或ADCC活性之降低/耗盡。舉例而言，可進行Fc受體(FcR)結合檢定以確保抗體缺乏FcγR結合(因此有可能缺乏ADCC活性)，但保留FcRn結合能力。用於介導ADCC之原代細胞NK細胞僅表現Fc(RIII，而單核細胞表現Fc(RI、Fc(RII及Fc(RIII。造血細胞上之FcR表現概述於Ravetch及Kinet，Annu. Rev. Immunol. 9:457-492 (1991)第464頁之表3中。用於評估所關注分子之ADCC活性之活體外 檢定的非限制性實例描述於美國專利第5,500,362號中(參見例如 Hellstrom，I. 等人，Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986))及Hellstrom，I 等人，Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985)；5,821,337 (參見 Bruggemann，M. 等人，J. Exp. Med. 166:1351-1361 (1987))。替代地，可採用非放射性檢定方法(參見 例如用於流動式細胞量測術之ACTI™ 非放射性細胞毒性檢定(CellTechnology，Inc. Mountain View，CA)；及CytoTox 96® 非放射性細胞毒性檢定(Promega，Madison，WI))。可用於此類檢定之效應細胞包括外周血單核細胞(PBMC)及自然殺手(NK)細胞。替代地或另外，所關注分子之ADCC活性可例如 在動物模型中，諸如Clynes等人，Proc. Nat'l Acad. Sci. USA 95:652-656 (1998)中所揭示之動物模型進行活體內 評估。亦可進行C1q結合檢定以確定該抗體不能結合C1q且因此缺乏CDC活性。參見例如 WO 2006/029879及WO 2005/100402中的C1q及C3c結合ELISA。為評估補體活化，可進行CDC檢定(參見 例如Gazzano-Santoro等人 ，J. Immunol. Methods 202:163 (1996)；Cragg，M.S.等人，Blood 101:1045-1052 (2003)；以及Cragg，M.S.及M.J. Glennie，Blood 103:2738-2743 (2004))。FcRn結合及活體內 清除率/半衰期測定亦可使用此項技術中已知之方法執行(參見例如 Petkova，S.B. 等人，Int’l. Immunol. 18(12):1759-1769 (2006))。In certain embodiments, the present invention encompasses antibody variants with some but not all effector functions. These effector functions make the antibody variant become an antibody whose in vivo half-life is extremely important but certain effector functions (such as complement and ADCC ) Ideal candidate for unnecessary or harmful applications. In vitro and/or in vivo cytotoxicity assays can be performed to determine the reduction/depletion of CDC and/or ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to ensure that the antibody lacks FcγR binding (and therefore may lack ADCC activity), but retains FcRn binding ability. The primary cells used to mediate ADCC NK cells only express Fc(RIII, while monocytes express Fc(RI, Fc(RII and Fc(RIII). The expression of FcR on hematopoietic cells is summarized in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991) page 464 in Table 3. A non-limiting example of an in vitro assay for assessing the ADCC activity of the molecule of interest is described in U.S. Patent No. 5,500,362 (see, for example, Hellstrom, I . Et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 ( See Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, a non-radioactive assay method can be used ( see, for example, ACTI™ non-radioactive for flow cytometry Cytotoxicity test (CellTechnology, Inc. Mountain View, CA); and CytoTox 96 ® non-radioactive cytotoxicity test (Promega, Madison, WI). Effector cells that can be used in this type of test include peripheral blood mononuclear cells (PBMC) and Natural killer (NK) cells. Alternatively or in addition, the ADCC activity of the molecule of interest can be, for example, in an animal model such as Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). The disclosed animal model is evaluated in vivo . C1q binding assays can also be performed to determine that the antibody cannot bind to C1q and therefore lacks CDC activity. See, for example , the C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. For evaluation of complement Activation, CDC assay can be performed ( see, for example, Gazzano-Santoro et al ., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie , Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life determination can also be performed using methods known in the art ( see, for example, Petkova, SB et al., Int'l. Immunol. 18 ( 12):1759-1769 (2006) ).

效應功能減弱之抗體包括在Fc區殘基238、265、269、270、297、327及329中之一或多個中具有取代的抗體(美國專利第6,737,056號)。此類Fc突變體包括在胺基酸位置265、269、270、297及327中之兩個或更多個處具有取代的Fc突變體，包括殘基265及297取代為丙胺酸的所謂「DANA」Fc突變體(美國專利第7,332,581號)。Antibodies with reduced effector functions include antibodies with substitutions in one or more of residues 238, 265, 269, 270, 297, 327, and 329 in the Fc region (US Patent No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of the amino acid positions 265, 269, 270, 297, and 327, including the so-called “DANA” in which residues 265 and 297 are substituted with alanine. "Fc mutant (US Patent No. 7,332,581).

已描述具有改善或減少的與FcR之結合的某些抗體變異體(參見例如 美國專利第6,737,056號；WO 2004/056312；及Shields等人，J. Biol. Chem. 9(2):6591-6604，2001))。Certain antibody variants with improved or reduced binding to FcR have been described ( see, e.g., U.S. Patent No. 6,737,056; WO 2004/056312; and Shields et al., J. Biol. Chem. 9(2): 6591-6604 , 2001)).

在某些實施例中，抗體變異體包含具有改善ADCC之一或多個胺基酸取代的Fc區，該等取代例如 在Fc區中位置298、333及/或334 (殘基之EU編號)處之取代。In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, such as at positions 298, 333, and/or 334 in the Fc region (EU numbering of residues) Place it instead.

在一些實施例中，在Fc區中進行改變(亦即 ，改善或減少) C1q結合及/或補體依賴性細胞毒性(CDC)之改變，例如 ，如美國專利第6,194,551號；WO 99/51642；及Idusogie等人，J. Immunol. 164:4178-4184 (2000)中所述。 In some embodiments, changes (ie , improvement or reduction) of C1q binding and/or complement dependent cytotoxicity (CDC) are made in the Fc region, for example , as in US Patent No. 6,194,551; WO 99/51642; And Idusogie et al., J. Immunol. 164:4178-4184 (2000).

具有增加之半衰期及改善之與新生兒Fc受體(FcRn)之結合的抗體描述於US2005/0014934A1 (Hinton等人)中，該FcRn負責將母體IgG轉移至胎兒(Guyer等人，J. Immunol. 117:587 (1976)及Kim等人，J. Immunol. 24:249 (1994))。該等抗體包含具有一或多個改善Fc區與FcRn之結合之取代的Fc區。此類Fc變異體包括在以下Fc區殘基中之一或多個處具有取代之變異體：238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434，例如 Fc區殘基434處之取代(美國專利第7,371,826號)。Antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn) are described in US2005/0014934A1 (Hinton et al.). The FcRn is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)). The antibodies comprise an Fc region with one or more substitutions that improve the binding of the Fc region to FcRn. Such Fc variants include variants with substitutions in one or more of the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356 , 360, 362, 376, 378, 380, 382, 413, 424, or 434, such as the substitution of residue 434 in the Fc region (U.S. Patent No. 7,371,826).

亦參見 Duncan及Winter，Nature 322:738-40 (1988)；美國專利第5,648,260號；美國專利第5,624,821號；及WO 94/29351，其涉及Fc區變異體之其他實例。(iv) 經半胱胺酸工程改造之抗體變異體 See also Duncan and Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94/29351, which relates to other examples of Fc region variants. (iv) Antibody variants engineered by cysteine

在某些實施例中，可能需要産生經半胱胺酸工程改造之抗體，例如 「thioMAb」，其中本文所提供之治療方法中使用的抗CD79b抗體或抗CD20抗體之一或多個殘基經半胱胺酸殘基取代。在特定實施例中，經取代殘基出現於抗體之可及位點處。藉由用半胱胺酸取代該等殘基，由此使反應性硫醇基定位於抗體之可及位點處且可用於使抗體與其他部分，諸如藥物部分或連接子-藥物部分結合，以產生如本文中進一步描述之免疫偶聯物。在某些實施例中，以下殘基中之任一個或多個可經半胱胺酸取代：輕鏈之V205 (Kabat編號)；重鏈之A118 (EU編號)；及重鏈Fc區之S400 (EU編號)。參見例如 WO 2009/012268，用於本文所述之方法中的示例性經半胱胺酸工程改造之抗CD79b抗體。經半胱胺酸工程改造之抗體可如例如 美國專利第7,521,541號中所描述産生。(v) 抗體衍生物 In certain embodiments, it may be necessary to produce cysteine engineered antibodies, such as "thioMAb", in which one or more residues of the anti-CD79b antibody or anti-CD20 antibody used in the treatment methods provided herein are Cysteine residues are substituted. In a specific embodiment, the substituted residue is present at an accessible site of the antibody. By substituting cysteine for these residues, the reactive thiol group is positioned at the accessible site of the antibody and can be used to bind the antibody to other parts, such as the drug moiety or the linker-drug moiety, To produce immunoconjugates as described further herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) for the light chain; A118 (EU numbering) for the heavy chain; and S400 for the Fc region of the heavy chain (EU number). See , for example, WO 2009/012268, an exemplary cysteine engineered anti-CD79b antibody used in the methods described herein. Cysteine-engineered antibodies can be produced as described in, for example, U.S. Patent No. 7,521,541. (v) Antibody derivatives

在某些實施例中，本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)可進一步修飾成包含此項技術中已知且容易獲得的額外非蛋白質部分。適於使抗體衍生化之部分包括但不限於水溶性聚合物。水溶性聚合物之非限制性實例包括但不限於聚乙二醇(PEG)、乙二醇/丙二醇共聚物、羧甲基纖維素、葡聚糖、聚乙烯醇、聚乙烯吡咯啶酮、聚-1,3-二氧雜環戊烷、聚-1,3,6-三噁烷、乙烯/順丁烯二酸酐共聚物、聚胺基酸(均聚物或無規共聚物)、及葡聚糖或聚(n-乙烯基吡咯啶酮)聚乙二醇、聚丙二醇(propropylene glycol)均聚物、聚氧化丙烯/氧化乙烯共聚物、聚氧乙基化多元醇(例如 甘油)、聚乙烯醇及其混合物。聚乙二醇丙醛可因其在水中之穩定性而在製造方面具有優勢。該聚合物可具有任何分子量，且可為分支或無分支的。連接至抗體的聚合物之數量可以變化，且若連接的聚合物多於一種，則該等聚合物可為相同或不同的分子。一般而言，用於衍生化之聚合物的數量及/或類型可基於多種考慮因素確定，該等考慮因素包括但不限於欲改善之抗體之特定性質或功能、抗體衍生物是否將在限定條件下用於療法等。In certain embodiments, the antibodies used in the treatment methods provided herein ( e.g., anti-CD79b antibodies or anti-CD20 antibodies) can be further modified to include additional non-protein moieties known and readily available in the art. Suitable moieties for derivatizing antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymer, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly -1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acid (homopolymer or random copolymer), and Dextran or poly(n-vinylpyrrolidone) polyethylene glycol, polypropylene glycol (propropylene glycol) homopolymer, polyoxypropylene/ethylene oxide copolymer, polyoxyethylated polyol ( e.g. glycerol), Polyvinyl alcohol and its mixtures. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer can have any molecular weight and can be branched or unbranched. The number of polymers attached to the antibody can vary, and if more than one polymer is attached, the polymers can be the same or different molecules. Generally speaking, the quantity and/or type of polymer used for derivatization can be determined based on a variety of considerations, including but not limited to the specific properties or functions of the antibody to be improved, and whether the antibody derivative will be under limited conditions It is used for therapy and so on.

在另一個實施例中，提供抗體與非蛋白質部分的偶聯物，該非蛋白質部分可藉由曝露於輻射進行選擇性加熱。在一個實施例中，非蛋白質部分係碳奈米管(Kam等人，Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005))。輻射可具有任何波長，且包括但不限於不損害普通細胞但將非蛋白部分加熱至殺死抗體-非蛋白部分附近之細胞之溫度的波長。H. 重組方法及組成物 In another embodiment, conjugates of antibodies and non-protein moieties are provided, which can be selectively heated by exposure to radiation. In one example, the non-protein portion is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation can have any wavelength, and includes, but is not limited to, wavelengths that do not damage normal cells but heat the non-protein part to a temperature that kills cells near the antibody-non-protein part. H. Recombination method and composition

可使用例如 美國專利第4,816,567號中所描述之重組法及組成物製造抗體。在一個實施例中，提供編碼本文所述之抗體的經分離核酸。此類核酸可編碼構成抗體VL之胺基酸序列及/或構成抗體VH之胺基酸序列(例如 抗體之輕鏈及/或重鏈)。在另一個實施例中，提供一或多種包含此類核酸之載體(例如 表現載體)。在又一實施例中，提供包含此類核酸之宿主細胞。在一個此類實施例中，宿主細胞包含(例如 經以下轉型)：(1)含核酸之載體，該核酸編碼構成抗體VL之胺基酸序列及構成抗體VH之胺基酸序列；或(2)第一載體，其包含編碼構成抗體VL之胺基酸序列的核酸，以及第二載體，其包含編碼構成抗體VH之胺基酸序列的核酸。在一個實施例中，宿主細胞係真核細胞，例如 中國倉鼠卵巢(CHO)細胞或淋巴系細胞(例如 Y0、NS0、Sp20細胞)。在一個實施例中，提供一種製備抗體之方法，其中該方法包括在適於表現該抗體之條件下培養如上文所提供的包含編碼該抗體之核酸的宿主細胞，及視情況自該宿主細胞(或宿主細胞培養基)回收該抗體。Antibodies can be produced using, for example , the recombinant methods and compositions described in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an antibody described herein is provided. Such nucleic acid may encode the amino acid sequence constituting the antibody VL and/or the amino acid sequence constituting the antibody VH ( e.g., the light chain and/or heavy chain of an antibody). In another embodiment, one or more vectors ( e.g., expression vectors) containing such nucleic acids are provided. In yet another embodiment, a host cell containing such nucleic acid is provided. In one such embodiment, the host cell contains ( e.g., transformed): (1) a vector containing a nucleic acid encoding the amino acid sequence constituting the antibody VL and the amino acid sequence constituting the antibody VH; or (2 ) The first vector contains the nucleic acid encoding the amino acid sequence constituting the antibody VL, and the second vector contains the nucleic acid encoding the amino acid sequence constituting the antibody VH. In one embodiment, the host cell line is a eukaryotic cell, such as a Chinese Hamster Ovary (CHO) cell or a lymphoid line cell ( e.g., Y0, NS0, Sp20 cells). In one embodiment, there is provided a method of preparing an antibody, wherein the method comprises culturing a host cell containing the nucleic acid encoding the antibody as provided above under conditions suitable for expressing the antibody, and optionally from the host cell ( Or host cell culture medium) to recover the antibody.

對於重組産生抗體，將編碼抗體，例如 上文所述之抗體的核酸分離，並插入一或多種載體中以用於在宿主細胞中進一步選殖及/或表現此類核酸可易於使用習知程序(例如 藉由使用能夠特異性結合至編碼抗體重鏈及輕鏈之基因的寡核苷酸探針)分離及定序。For recombinant production of antibodies, nucleic acids encoding antibodies, such as the antibodies described above, are isolated and inserted into one or more vectors for further selection and/or expression of such nucleic acids in host cells. Conventional procedures can be easily used. ( E.g., by using oligonucleotide probes capable of specifically binding to genes encoding antibody heavy and light chains) separation and sequencing.

適於選殖或表現編碼抗體之載體的宿主細胞包括本文所述之原核或真核細胞。舉例而言，抗體可在細菌中產生，特別是在不需要糖基化及Fc效應功能時更是如此。對於在細菌中表現抗體片段及多肽，參見例如 美國專利第5,648,237號、第5,789,199號及第5,840,523號。(亦參見 Charlton，Methods in Molecular Biology ，第 248 卷 (B.K.C. Lo編，Humana Press，Totowa，NJ，2003)，第245-254頁，其描述抗體片段在大腸桿菌 中之表現。)在表現之後，可自細菌細胞糊狀物之可溶性部分中分離抗體且可將其進一步純化。Host cells suitable for selection or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies can be produced in bacteria, especially when glycosylation and Fc effector functions are not required. For the expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo ed, Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli of.) After the performance, The antibody can be separated from the soluble portion of the bacterial cell paste and can be further purified.

除原核生物外，真核微生物諸如絲狀真菌或酵母係適用於編碼抗體之載體的選殖或表現宿主，包括糖基化路徑已經「人類化」，使得産生具有部分或完全人類糖基化模式之抗體的真菌及酵母菌株。參見 Gerngross，Nat. Biotech. 22:1409-1414 (2004)及Li等人，Nat. Biotech. 24:210-215 (2006)。In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeasts are suitable for the selection or expression of antibody-encoding vectors, including glycosylation pathways that have been "humanized", resulting in partial or complete human glycosylation patterns. The antibodies against fungal and yeast strains. See Gerngross, Nat. Biotech. 22:1409-1414 (2004) and Li et al., Nat. Biotech. 24:210-215 (2006).

適用於表現糖基化抗體之宿主細胞亦來源於多細胞生物體(無脊椎動物及脊椎動物)。無脊椎動物細胞之實例包括植物及昆蟲細胞。已鑑別出可與昆蟲細胞聯合使用，尤其用於轉染草地黏蟲(Spodoptera frugiperda )細胞之衆多桿狀病毒株。Suitable host cells for expressing glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Many baculovirus strains have been identified that can be used in combination with insect cells, especially for the transfection of Spodoptera frugiperda cells.

植物細胞培養物亦可用作宿主。參見例如 美國專利第5,959,177號、第6,040,498號、第6,420,548號、第7,125,978號及第6,417,429號(描述用於在轉殖基因植物中產生抗體之PLANTIBODIESTM 技術)。Plant cell cultures can also be used as hosts. See, for example, U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (description of PLANTIBODIES ™ technology for producing antibodies in transgenic plants).

脊椎動物細胞亦可用作宿主。舉例而言，適於在懸浮液中生長之哺乳動物細胞株可為有用的。有用哺乳動物宿主細胞株之其他實例係經SV40(COS-7)轉型之猴腎CV1細胞株；人類胚胎腎細胞株(293或293細胞，如例如 Graham等人，J. Gen Virol. 36:59 (1977)所描述)；幼倉鼠腎細胞(BHK)；小鼠塞爾托利細胞(mouse sertoli cell)(TM4細胞，如例如 Mather，Biol. Reprod. 23:243-251 (1980)所描述)；猴腎細胞(CV1)；非洲綠猴腎細胞(VERO-76)；人類子宮頸癌細胞(HELA)；犬腎細胞(MDCK；布法羅大鼠肝細胞(buffalo rat liver cell；BRL 3A)；人類肺細胞(W138)；人類肝細胞(Hep G2)；小鼠乳腺腫瘤(MMT 060562)；TRI細胞，如例如 Mather等人，Annals N.Y. Acad. Sci. 383:44-68 (1982)所描述；MRC 5細胞；及FS4細胞。其他有用的哺乳動物宿主細胞株包括中國倉鼠卵巢(CHO)細胞，包括DHFR- CHO細胞(Urlaub等人，Proc. Natl. Acad. Sci.  USA 77:4216 (1980))；及骨髓瘤細胞株，諸如Y0、NS0及Sp2/0。關於適於產生抗體之某些哺乳動物宿主細胞株的評述，參見例如 Yazaki及Wu，Methods in Molecular Biology ，第 248 卷 (B.K.C. Lo編，Humana Press，Totowa，NJ)，第255-268頁 (2003)。I. 檢定 Vertebrate cells can also be used as hosts. For example, mammalian cell lines suitable for growth in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 cell lines transformed by SV40 (COS-7); human embryonic kidney cell lines (293 or 293 cells, such as, for example, Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells, as described in, for example, Mather, Biol. Reprod. 23:243-251 (1980)) ; Monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); Human cervical cancer cells (HELA); Canine kidney cells (MDCK; buffalo rat liver cells; BRL 3A) ; Human lung cells (W138); Human hepatocytes (Hep G2); Mouse breast tumors (MMT 060562); TRI cells, as described in, for example, Mather et al., Annals NY Acad. Sci. 383:44-68 (1982) ; MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese Hamster Ovary (CHO) cells, including DHFR - CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980) )); and myeloma cell lines, such as Y0, NS0 and Sp2 / 0 Commenting adapted to generate certain mammalian host cell lines of the antibody, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKC. Lo eds, Humana Press, Totowa, NJ), pages 255-268 (2003). I. Verification

本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)可藉由此項技術中已知之各種檢定針對其物理/化學性質及/或生物活性進行鑑別、篩選或表徵。Antibodies used in the treatment methods provided herein ( for example, anti-CD79b antibodies or anti-CD20 antibodies) can be identified, screened or characterized by various assays known in the art for their physical/chemical properties and/or biological activities.

在一個態樣中，測試本文所提供之治療方法中使用的抗體(例如 抗CD79b抗體或抗CD20抗體)之抗原結合活性，例如 藉由已知方法，諸如ELISA、BIACore® 、FACS或西方墨點法(Western blot)。In one aspect, the antigen binding activity of antibodies used in the treatment methods provided herein ( for example, anti-CD79b antibody or anti-CD20 antibody) is tested, for example, by known methods such as ELISA, BIACore ® , FACS or Western blot Method (Western blot).

在另一個態樣中，可使用競爭檢定鑒別與本文所述之任何抗體競爭結合至目標抗原的抗體。在某些實施例中，此類競爭性抗體結合至與本文所述之抗體所結合相同之抗原決定基(例如 線性或構形抗原決定基)。用於定位抗體所結合之抗原決定基的詳細示例性方法提供於Morris (1996) 「Epitope Mapping Protocols」，Methods in Molecular Biology ，第66卷 (Humana Press，Totowa，NJ)中。In another aspect, a competition assay can be used to identify antibodies that compete with any of the antibodies described herein for binding to the target antigen. In certain embodiments, such competitive antibodies bind to the same epitope ( e.g., linear or conformational epitope) that the antibodies described herein bind. A detailed exemplary method for locating the epitope bound by the antibody is provided in Morris (1996) "Epitope Mapping Protocols", Methods in Molecular Biology , Vol. 66 (Humana Press, Totowa, NJ).

在一個示例性競爭檢定中，在包含結合至抗原之第一經標記抗體(例如 本文所述之任何抗體)及第二未標記抗體的溶液中培育經固定抗原，該第二未標記抗體與該第一抗體競爭結合至抗原之能力經測試。第二抗體可存在於融合瘤上清液中。作為對照，在包含第一標記抗體但無第二未標記抗體之溶液中培育經固定抗原。在允許第一抗體結合至抗原之條件下培育後，移除過量未結合之抗體，並量測與經固定抗原締合之標記的量。若相對於對照樣品，測試樣品中與經固定抗原締合之標記的量基本上降低，則此指示第二抗體與第一抗體競爭結合至抗原。參見 Harlow及Lane (1988)Antibodies: A Laboratory Manual 第14章 (Cold Spring Harbor Laboratory，Cold Spring Harbor，NY)。 VII. 化學治療劑 In an exemplary competition assay, the immobilized antigen is incubated in a solution containing a first labeled antibody that binds to the antigen ( such as any antibody described herein) and a second unlabeled antibody, the second unlabeled antibody and the The ability of the primary antibody to compete for binding to the antigen was tested. The second antibody may be present in the supernatant of the fusion tumor. As a control, the immobilized antigen was incubated in a solution containing the first labeled antibody but no second unlabeled antibody. After incubation under conditions that allow the first antibody to bind to the antigen, the excess unbound antibody is removed, and the amount of label associated with the immobilized antigen is measured. If the amount of label associated with the immobilized antigen in the test sample is substantially reduced relative to the control sample, this indicates that the second antibody competes with the first antibody for binding to the antigen. See Harlow and Lane (1988) Antibodies: A Laboratory Manual Chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). VII. Chemotherapeutics

在一些實施例中，一或多種化學治療劑包含可用於治療癌症之化合物。化學治療劑之實例包括厄洛替尼(TARCEVA® ，Genentech/OSI Pharm.)；硼替佐米(VELCADE® ，Millennium Pharm.)；二硫龍；表沒食子兒茶素沒食子酸酯；鹽孢菌素A；卡非佐米；17-AAG (格爾德黴素)；根赤殼菌素；乳酸脫氫酶A (LDH-A)；氟維司群(FASLODEX® ，AstraZeneca)；舒尼替尼(SUTENT® ，Pfizer/Sugen)；來曲唑(FEMARA® ，Novartis)；甲磺酸伊馬替尼(GLEEVEC® ，Novartis)；菲那舒那(VATALANIB® ，Novartis)；奧沙利鉑(益樂鉑® ，Sanofi)；5-FU (5-氟尿嘧啶)；甲醯四氫葉酸；雷帕黴素(西羅莫司，RAPAMUNE® ，Wyeth)；拉帕替尼(TYKERB® ，GSK572016，Glaxo Smith Kline)；洛那法尼(SCH 66336)；索拉非尼(NEXAVAR® ，Bayer Labs)；吉非替尼(IRESSA® ，AstraZeneca)；AG1478；烷基化劑，諸如噻替派及CYTOXAN® 環磷醯胺；烷基磺酸酯，諸如白消安、英丙舒凡及哌泊舒凡；氮丙啶，諸如苯并多巴、卡巴醌、美妥多巴及脲多巴；伸乙亞胺及甲基密胺，包括六甲密胺、三伸乙基密胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三羥甲基密胺；番荔枝內酯(尤其是布拉它辛及布拉它辛酮)；喜樹鹼(包括拓撲替康及伊立替康)；苔蘚蟲素；卡利他汀；CC-1065 (包括其阿多來新、卡折來新及比折來新合成類似物)；念珠藻素(尤其是念珠藻素1及念珠藻素8)；腎上腺皮質類固醇(包括潑尼松及潑尼松龍)；乙酸環丙孕酮；5α-還原酶，包括非那雄胺及度他雄胺)；伏立諾他；羅米地辛；帕比司他；丙戊酸；莫西司他；海兔毒素；阿地介白素；滑石；倍癌黴素(包括合成類似物KW-2189及CB1-TM1)；艾榴塞洛素；水鬼蕉鹼；匍枝珊瑚醇；海綿抑素；氮芥，諸如苯丁酸氮芥、氯瑪法辛、氯磷醯胺、雌氮芥、異環磷醯胺、甲氮芥、甲氮芥氧化物鹽酸鹽、美法蘭、新恩比興、膽固醇苯乙酸氮芥、潑尼莫斯汀、曲磷胺、尿嘧啶氮芥；亞硝基脲，諸如卡莫司汀、氯脲黴素、福莫司汀、洛莫司汀、尼莫司汀及雷莫司汀；抗生素，諸如烯二炔抗生素(例如 卡奇黴素，尤其是卡奇黴素γ1I及卡奇黴素ω1I (Angew Chem.Intl. Ed. Engl. 1994 33:183-186)；達內黴素，包括達內黴素A；雙膦酸鹽，諸如氯膦酸二鈉；埃斯培拉黴素；以及新製癌菌素發色團及相關色蛋白烯二炔抗生素發色團)、阿克拉黴素、放線菌素、安曲黴素、氮雜絲胺酸、博萊黴素、放線菌素C、卡拉比星、洋紅黴素、嗜癌菌素、色黴素、放線菌素D、柔紅黴素、地托比星、6-重氮-5-側氧基-L-正白胺酸、ADRIAMYCIN® (小紅莓)、(N-嗎啉基)-小紅莓、氰基(N-嗎啉基)-小紅莓、2-吡咯啉基-小紅莓及去氧小紅莓)、表柔比星、依索比星、依維莫斯、索曲托林、伊達比星、麻西羅黴素、絲裂黴素，諸如絲裂黴素C、黴酚酸、諾拉黴素、橄欖黴素、培洛黴素、泊非黴素、嘌呤黴素、三鐵阿黴素、羅多比星、鏈黑菌素、鏈脲佐菌素、殺結核菌素、烏本美司)、淨司他汀、佐柔比星；抗代謝物，諸如甲胺喋呤及5-氟尿嘧啶(5-FU)；葉酸類似物，諸如二甲葉酸、甲胺喋呤、蝶羅呤、三甲曲沙；嘌呤類似物，諸如氟達拉濱、6-巰基嘌呤、硫咪嘌呤、硫鳥嘌呤；嘧啶類似物，諸如安西他滨、氮雜胞苷、6-氮雜尿苷、卡莫氟、阿糖胞苷、雙脫氧尿苷、脫氧氟尿苷、依诺他滨、氟脫氧尿苷；雄激素，諸如卡魯睾酮、丙酸屈他雄酮、環硫雄醇、美雄烷、睾內酯；抗腎上腺素，諸如胺格魯米特、米托坦、曲洛司坦；葉酸補充劑，諸如亞葉酸；醋葡醛内酯；醛磷醯胺糖苷；胺基乙醯丙酸；恩尿嘧啶；胺苯吖啶；比曲比新；比生群；伊達曲沙；地磷醯胺；地美可辛；地吖醌；艾弗米新；依利醋铵；埃坡霉素；依托格鲁；硝酸鎵；羥基脲；香菇多糖；氯尼达明；類美登素，諸如美登素及安丝菌素；米托胍腙；米托蒽醌；莫哌达醇；二胺硝吖啶；喷司他丁；蛋胺氮芥；吡柔比星；洛索蒽醌；足叶草酸；2-乙基醯肼；丙卡巴嗪；PSK® 多糖複合物(JHS Natural Products，Eugene，Oreg.)；雷佐生；根瘤菌素；西佐喃；锗螺胺；细交链孢菌酮酸；三亚胺醌；2,2',2''-三氯三乙胺；单端孢霉烯(尤其是T-2毒素，疣孢菌素A；漆斑菌素A 及蛇形菌素)；烏瑞沙；長春地辛；達卡巴嗪；甘露莫司汀；二溴甘露醇；二溴卫矛醇；哌泊溴烷；加胞嘧啶；阿拉伯糖苷(「Ara-C」)；環磷醯胺；噻替哌；紫杉醇，例如 TAXOL (太平洋紫杉醇)；Bristol-Myers Squibb Oncology，Princeton，N.J.)，ABRAXANE® (無克列莫佛)、白蛋白工程改造的太平洋紫杉醇奈米粒子調配物(American Pharmaceutical Partners，Schaumberg，Ill.)及TAXOTERE® (多克他賽、多西他賽；Sanofi-Aventis)；苯丁酸氮芥；健擇(GEMZAR)® (吉西他濱)；6-硫鳥嘌呤；巰基嘌呤；甲胺喋呤；鉑類似物，諸如順鉑及卡鉑；长春碱；依托泊苷(VP-16)；異環磷醯胺；米托蒽醌；長春新鹼；NAVELBINE® (長春瑞賓)；诺消灵；替尼泊苷；伊達曲沙；道諾黴素；胺基喋呤；卡培他濱(XELODA® )；依班膦酸鹽；CPT-11；拓撲異構酶抑製劑RFS 2000；二氟甲基鳥胺酸(DMFO)；類視黃醇，諸如視黃酸；及上述任一種之醫藥學上可接受之鹽、酸及衍生物；以及上述兩種或更多種之組合，諸如CHOP(環磷醯胺、小紅莓、長春新鹼及潑尼松龍之組合療法的縮寫)及FOLFOX (利用奧沙利鉑(益樂鉑TM )與5-FU及亞葉酸之治療方案的縮寫)。化學治療劑之額外實例包括苯達莫司汀(或鹽酸苯達莫司汀) (TREANDA®)、依魯替尼、來那度胺及/或艾代拉裡斯(GS-1101)。In some embodiments, the one or more chemotherapeutic agents comprise compounds that can be used to treat cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA ® , Genentech/OSI Pharm.); bortezomib (VELCADE ® , Millennium Pharm.); disulfide; epigallocatechin gallate; Halosporin A; Carfilzomib; 17-AAG (geldanamycin); Radicicol; Lactate dehydrogenase A (LDH-A); Fulvestrant (FASLODEX ® , AstraZeneca); Sunitinib (SUTENT ® , Pfizer/Sugen); Letrozole (FEMARA ® , Novartis); Imatinib mesylate (GLEEVEC ® , Novartis); Fenasuna (VATALANIB ® , Novartis); Osali platinum (Yi lobaplatin ®, Sanofi); 5-FU (5- fluorouracil); A-tetrahydrofolic acid acyl; rapamycin (sirolimus, RAPAMUNE ®, Wyeth); lapatinib (TYKERB ®, GSK572016 , Glaxo Smith Kline); Lonafani (SCH 66336); Sorafenib (NEXAVAR ® , Bayer Labs); Gefitinib (IRESSA ® , AstraZeneca); AG1478; Alkylating agents such as thiotepa and CYTOXAN ® Cyclophosphamide; Alkyl Sulfonates, such as Busulfan, Inprosufane, and Peposufan; Aziridines, such as Benzodopa, Carbachol, Metophamine and Uretopa; Ethylene imine and methyl melamine, including hexamethylmelamine, triethylene melamine, triethylene phosphatidamide, triethylene thiophosphatidamide and trimethylol melamine; in annona Esters (especially blatacine and blataxinone); camptothecin (including topotecan and irinotecan); bryophyllin; calstatin; CC-1065 (including its adolaxine, carbamide); Zorexin and Zorexin synthetic analogues); Nostocin (especially Nostocin 1 and Nostocin 8); Adrenal corticosteroids (including prednisone and prednisolone); Cyproterone acetate ; 5α-reductase, including finasteride and dutasteride); Vorinostat; Romidepsin; Pabirestat; Valproic acid; Moxistat; Aplytoxin; Aldesin Talc; becarcinomycin (including synthetic analogues KW-2189 and CB1-TM1); eductolol; hydrocoprine; clitoris; spongostatin; nitrogen mustards, such as nitrophenylbutyrate Mustard, chlormafaxine, chlorphosphamide, estramustine, ifosfamide, chlorambucil, chlorambucil oxide hydrochloride, Melphalan, New Enbixion, cholesterol phenylacetate nitrogen mustard, Prednistine, trifosamine, uracil mustard; nitrosoureas such as carmustine, chlordiacin, formustine, lomustine, nimustine, and ramustine ; Antibiotics, such as enediyne antibiotics (such as calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I ( Ange w Chem.Intl. Ed. Engl. 1994 33:183-186); danomycin, including danemycin A; bisphosphonates, such as clodronate disodium; esperamicin; and new Carcinogen chromophore and related chromoprotein enediyne antibiotic chromophore), aclarithromycin, actinomycin, antoxin, azaserine, bleomycin, actinomycin C, Calabicin, carmine, carcinophilin, chromomycin, actinomycin D, daunorubicin, ditorubicin, 6-diazo-5-oxo-L-ortho-leucine, ADRIAMYCIN ® (Cranberry), (N-morpholinyl)-Cranberry, Cyano (N-morpholinyl)-Cranberry, 2-Pyrololinyl-Cranberry and Deoxycranberry) , Epirubicin, esorubicin, everimos, sotratorin, idarubicin, methiromycin, mitomycin, such as mitomycin C, mycophenolic acid, norlamycin Oleuromycin, pelomycin, pofilomycin, puromycin, tri-iron adriamycin, rhodoubicin, streptozotocin, streptozotocin, tuberculin, Ubenmei Division), netstatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folate analogs, such as dimethicone, methotrexate, pterorin, trimethoprim Trixa; purine analogs such as fludarabine, 6-mercaptopurine, thiomipurine, thioguanine; pyrimidine analogs such as ancitabine, azacytidine, 6-azauridine, carmofur , Cytarabine, dideoxyuridine, deoxyfluridine, enoxabine, fluorodeoxyuridine; androgens, such as carlutestosterone, drotasterone propionate, thiosterol, methandrolidine, testosterone Lactone; antiadrenaline, such as migluminide, mitotane, and tripostane; folic acid supplements, such as leucovorin; acetoglucurolide; aldophosphamide glycoside; aminoacetin; Enuracil; Acridine; Bitributer; Bisantrene; Idatrioxa; Desfasamide; Dimexine; Diacrquinone; Efmixin; Elimate; Epothilone; Etoglu; gallium nitrate; hydroxyurea; lentinan; clonidamin; maytansinoids, such as maytansine and ansamicin; mitogen hydrazone; mitoxantrone; moperidol; diamine Nitracridine; Pentastatin; Methamine mustard; Pirubicin; Loxoxantrone; Podoxalic acid; 2-Ethylhydrazine; Procarbazine; PSK ® Polysaccharide Complex (JHS Natural Products, Eugene , Oreg.); Razosan; Rhizobium; Cizonan; Germanium; Alternaria tenuinic acid; Triimine quinone; 2,2',2''-Trichlorotriethylamine; Trichothecene Mycosene (especially T-2 toxin, verrucosporin A; myrophyllin A and osmandin); Uressa; Vindesine; Dacarbazine; Mannomustine; Dibromomannitol; Dibromodulcitol; Pipebromidine; Cytosine; Arabinoside ("Ara-C");Cyclophosphamide;Thiotepa; Paclitaxel, such as TAXOL (paclitaxel); Bristol-Myers Squibb Oncology, Princeton , NJ), ABR AXANE ® (without Cremophor), albumin engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, Ill.) and TAXOTERE ® (docetaxel, docetaxel; Sanofi-Aventis) Chlorambucil; Gemzar (GEMZAR) ® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; etoposide (VP -16); Ifosfamide; Mitoxantrone; Vincristine; NAVELBINE ® (vinorelbine); Nuoxaline; Teniposide; Idatrioxa; Daunorubicin; Aminopterin; Capecitabine (XELODA ® ); Ibandronate; CPT-11; Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoids, such as retinoic acid; and Pharmaceutically acceptable salts, acids and derivatives of any of the above; and combinations of two or more of the above, such as CHOP (a combination of cyclophosphamide, cranberry, vincristine and prednisolone) abbreviations therapy) and FOLFOX (oxaliplatin using (Yi lobaplatin (TM)) with a treatment regimen abbreviations 5-FU and the leucovorin). Additional examples of chemotherapeutic agents include bendamustine (or bendamustine hydrochloride) (TREANDA®), ibrutinib, lenalidomide, and/or aidelaris (GS-1101).

在一些實施例中，該一或多種化學治療劑包含用於調控、減少、阻斷或抑制可促進癌症生長之激素之作用的抗激素劑，且通常呈全身(systemic或whole-body)治療之形式。其本身可能為激素。實例包括抗雌激素及選擇性雌激素受體調節劑(SERM)，包括例如他莫昔芬(包括NOLVADEX®他莫昔芬)、雷洛昔芬、屈落昔芬、4-羥基他莫昔芬、曲沃昔芬、凱奧昔芬、LY117018、奥那司酮及托瑞米芬(FARESTON®)；抗孕激素；雌激素受體下調劑(ERD)；雌激素受體拮抗劑，諸如氟維司群(FASLODEX®)；用於抑製或關閉卵巢功能之藥劑，例如促黃體激素釋放激素(LHRH)促效劑，諸如醋酸亮丙瑞林(LUPRON®及ELIGARD®)、醋酸戈舍瑞林、醋酸布塞林及雷公藤甲素；抗雄激素，諸如氟他胺、尼魯米特及比卡魯胺；以及抑制可調節腎上腺雌激素生成之酶芳香化酶的芳香化酶抑製劑，例如4(5)-咪唑、胺格魯米特、醋酸甲地孕酮(MEGASE®)、依西美坦(AROMASIN®)、甲芬斯坦、法卓唑、伏洛唑(RIVISOR®)、來曲唑(FEMARA®)及阿那曲唑(ARIMIDEX®)。另外，此類化學治療劑之定義包括雙膦酸鹽，諸如氯膦酸二鈉(例如BONEFOS®或OSTAC®)、依替膦酸鹽(DIDROCAL®)、NE-58095、唑來膦酸/唑來膦酸鹽(ZOMETA®)、阿崙膦酸鹽(FOSAMAX®)、帕米膦酸鹽(AREDIA®)、替洛膦酸鹽(SKELID®)或利塞膦酸鹽(ACTONEL®)；以及曲沙他滨(1,3-二氧雜環己烷核苷胞嘧啶類似物)；反義寡核苷酸，特別是抑制與異常細胞增殖有關之信號傳導途徑中之基因表現的寡核苷酸，例如PKC-α、Raf、H-Ras及表皮生長因子受體(EGF-R)；疫苗，諸如THERATOPE®疫苗及基因治療疫苗，例如ALLOVECTIN®疫苗、LEUVECTIN®疫苗及VAXID®疫苗。In some embodiments, the one or more chemotherapeutic agents include antihormonal agents for regulating, reducing, blocking, or inhibiting the effects of hormones that can promote cancer growth, and are usually in the form of systemic or whole-body therapy. form. It may be a hormone by itself. Examples include anti-estrogen and selective estrogen receptor modulators (SERM), including, for example, tamoxifen (including NOLVADEX® tamoxifen), raloxifene, droloxifene, 4-hydroxy tamoxifen Fen, trovoxifen, keoxifene, LY117018, onlastone, and toremifene (FARESTON®); antiprogestins; estrogen receptor downregulators (ERD); estrogen receptor antagonists, such as Fulvestrant (FASLODEX®); an agent used to inhibit or shut down ovarian function, such as luteinizing hormone releasing hormone (LHRH) agonists, such as leuprolide acetate (LUPRON® and ELIGARD®), goseray acetate Lin, buserin acetate, and triptolide; antiandrogens such as flutamide, nilutamide, and bicalutamide; and aromatase inhibitors that inhibit aromatase, an enzyme that regulates adrenal estrogen production , Such as 4(5)-imidazole, aminegluminide, megestrol acetate (MEGASE®), exemestane (AROMASIN®), mefenstein, fazrozole, volazole (RIVISOR®), Letrozole (FEMARA®) and Anastrozole (ARIMIDEX®). In addition, the definition of such chemotherapeutic agents includes bisphosphonates, such as clodronate disodium (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/azole Ledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tilodronate (SKELID®) or risedronate (ACTONEL®); and Traxatabine (1,3-dioxane nucleoside cytosine analogue); antisense oligonucleotides, especially oligonucleotides that inhibit gene expression in signal transduction pathways related to abnormal cell proliferation Acids, such as PKC-α, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines, such as THERATOPE® vaccines and gene therapy vaccines, such as ALLOVECTIN® vaccines, LEUVECTIN® vaccines and VAXID® vaccines.

在一些實施例中，該一或多種化學治療劑包含拓撲異構酶1抑製劑(例如 LURTOTECAN®)；抗雌激素，諸如氟維司群；Kit抑製劑，諸如伊馬替尼或EXEL-0862(酪胺酸激酶抑製劑)；EGFR抑製劑，諸如厄洛替尼或西妥昔單抗；抗VEGF抑製劑，諸如貝伐單抗；阿立替康；rmRH (例如 ABARELIX®)；拉帕替尼及二甲苯磺酸拉帕替尼(一種ErbB-2及EGFR雙重酪胺酸激酶小分子抑製劑，又稱為GW572016)；17AAG (作為熱休克蛋白(Hsp) 90毒素之格爾德黴素衍生物)，以及上述任一種之醫藥學上可接受之鹽，酸或衍生物。In some embodiments, the one or more chemotherapeutic agents comprise a topoisomerase 1 inhibitor ( e.g. LURTOTECAN®); an antiestrogens, such as fulvestrant; a Kit inhibitor, such as imatinib or EXEL-0862 ( Tyrosine kinase inhibitors); EGFR inhibitors, such as erlotinib or cetuximab; anti-VEGF inhibitors, such as bevacizumab; arinotecan; rmRH ( for example, ABARELIX®); lapatinib And lapatinib ditosylate (a small molecule inhibitor of ErbB-2 and EGFR dual tyrosine kinase, also known as GW572016); 17AAG (as a heat shock protein (Hsp) 90 toxin derived from geldanamycin物), and any of the above-mentioned pharmaceutically acceptable salts, acids or derivatives.

在一些實施例中，該一或多種化學治療劑包含抗體，諸如阿崙單抗(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)、乌妥昔单抗、奧法木單抗、替伊莫單抗、帕妥珠单抗(OMNITARG®，2C4，Genentech)、曲妥珠單抗(HERCEPTIN®，Genentech)、托西莫單抗(Bexxar，Corixia)及抗體藥物偶聯物吉妥珠單抗奧唑米星。與該等化合物組合的作為藥劑具有治療潛力之額外人類化單株抗體包括：阿泊珠单抗、阿塞珠单抗、阿特利单抗、巴匹珠单抗、比伐单抗美登素、莫坎妥珠单抗美登素、西地珠单抗、聚乙二醇结合赛妥珠单抗、西斯妥珠單抗、西妥珠單抗、達西珠單抗、依库珠单抗、艾法珠單抗、依帕珠单抗、艾利珠單抗、非维珠单抗、弗妥利珠單抗、吉妥珠單抗奧佐米星、奥英妥珠单抗奧佐米星、伊匹单抗、拉贝珠单抗、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、諾維珠單抗、努維珠單抗、奧瑞珠單抗、奧馬珠單抗、帕利珠單抗、帕考珠單抗、培斯妥珠單抗、培妥珠單抗、培克珠單抗、拉維珠單抗、蘭尼單抗、瑞維珠單抗、瑞替珠单抗、瑞賽珠單抗、洛維珠單抗、魯匹單抗、西罗珠单抗、西匹珠單抗、索妥珠單抗、他珠单抗四氢西泮、他度珠單抗、他利珠單抗、替巴珠單抗、托利珠單抗、妥拉珠單抗、圖克珠單抗西莫白介素、圖西妥單抗、奧馬珠單抗、優妥珠單抗、乌司奴单抗、维西珠单抗、及抗介白素-12 (ABT-874/J695，Wyeth Research and Abbott Laboratories)，其係一種經基因修飾成識別介白素-12 p40蛋白質的重組僅人類序列之全長IgG1λ抗體。In some embodiments, the one or more chemotherapeutic agents comprise antibodies, such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), Panyl Monoclonal antibodies (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), Utuximab, Ofatumumab, Titumomab, Pertuzumab (OMNITARG® , 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Colixia) and the antibody-drug conjugate gemtuzumab ozogamicin. Additional humanized monoclonal antibodies that have therapeutic potential as medicaments in combination with these compounds include: apolizumab, atezolizumab, atlizumab, bapiizumab, bivacizumab maytan Cetuzumab, Mocantuzumab, Maytansine, Cidizumab, Polyethylene Glycol Combination Certuzumab, Cistuzumab, Cetuzumab, Daclizumab, Ecuador Lizumab, ifazizumab, ipalizumab, elizumab, felizumab, fltolizumab, gemtuzumab ozogamicin, otuzumab Anti-Ozomicin, Ipilimumab, Rabelizumab, Lintuzumab, Matuzumab, Mepolizumab, Movizumab, Motuzumab, Natalizumab Mab, Nituzumab, Novizumab, Nuvizumab, Orrelizumab, Omalizumab, Palivizumab, Pascolizumab, Perstuzumab , Pertuzumab, pexelizumab, lavelizumab, ranibizumab, revizumab, retilizumab, reseizumab, lovizumab, lupi Mab, Sirolizumab, Cipilizumab, Sotuzumab, Talizumab, Tetrahydrozepam, Taduzumab, Taclizumab, Tibazizumab, Tolizumab Ruzumab, tolatuzumab, tuctilizumab, simo interleukin, tucetuzumab, omalizumab, eutumuzumab, usnuzumab, vesizizumab, and anti Interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories), which is a recombinant human-only full-length IgG1λ antibody genetically modified to recognize the interleukin-12 p40 protein.

在一些實施例中，該一或多種化學治療劑包含烷基化劑。烷基化劑係藉由抑制DNA轉錄成RNA並由此停止蛋白質合成起作用的一類抗腫瘤藥或抗癌藥。烷基化劑用烷基(Cn H2n+1 )取代DNA上之氫原子，使得DNA鏈內形成交聯，由此導致DNA股斷裂，導致異常鹼基配對、細胞分裂抑制，並最終導致細胞死亡。此作用出現在所有細胞中，但快速分裂的細胞，諸如癌細胞，典型地對烷基化劑之作用最敏感。In some embodiments, the one or more chemotherapeutic agents comprise an alkylating agent. Alkylating agents are a class of anti-tumor drugs or anti-cancer drugs that inhibit the transcription of DNA into RNA and thereby stop protein synthesis. The alkylating agent replaces the hydrogen atoms on the DNA with alkyl groups (C n H 2n+1 ), causing cross-links to form in the DNA strands, thereby causing DNA strands to break, resulting in abnormal base pairing, cell division inhibition, and ultimately Cell death. This effect occurs in all cells, but rapidly dividing cells, such as cancer cells, are typically the most sensitive to the effects of alkylating agents.

烷基化劑一般分為六類：(1)氮芥類，包括但不限於例如 甲氮芥、環磷醯胺、異環磷醯胺、苯達莫司汀、美法蘭及苯丁酸氮芥；(2)伸乙基胺及亞甲基胺衍生物，其包括但不限於例如 六甲密胺及噻替哌；(3)烷基磺酸酯，其包括但不限於例如 白消安；(4)亞硝基脲，其包括但不限於例如 卡莫司汀及洛莫司汀；(5)三氮烯，其包括但不限於例如 達卡巴嗪及丙卡巴嗪、替莫唑胺；及(6)含鉑抗腫瘤劑，其包括但不限於例如 順鉑、卡鉑及奧沙利鉑。任何已知的烷基化劑(包括但不限於以上列出之烷基化劑)可用於本文所提供之治療方法中。苯達莫司汀係本文所述方法中使用的示例性烷基化劑。苯達莫司汀的化學名稱為 4-(5-(雙(2-氯乙基)胺基)-1-甲基-1H-苯并[d]咪唑-2-基)丁酸，且其分子式為C16 H21 Cl2 N3 O2 且分子量為358.263 g/mol。苯達莫司汀(CAS註冊處#16506-27-7)係含有嘌呤樣苯并咪唑環的雙官能甲氮芥衍生物。苯達莫司汀可以粉末形式用於溶液及溶液劑型。在一些實施例中，本文所述之方法中使用的烷基化劑係苯達莫司汀之鹽或溶劑合物。在一些實施例中，苯達莫司汀鹽係鹽酸苯達莫司汀(CAS # 3543-75-7)，其分子式為C16 H21 Cl2 N3 O2 .HCl且其分子量為394.72 g/mol。鹽酸苯達莫司汀可以BENDEKA、TREANDA、TREAKISYM、RIBOMUSTIN、LEVACT、MUSTIN及其他市售。Alkylating agents are generally divided into six categories: (1) Nitrogen mustards, including, but not limited to, for example , chlorambucil, cyclophosphamide, ifosfamide, bendamustine, meflan and phenylbutyric acid Nitrogen mustard; (2) Ethyleneamine and methyleneamine derivatives, which include, but are not limited to, for example, hexamethylmelamine and thiotepa; (3) Alkyl sulfonates, which include, but are not limited to, for example, busulfan (4) Nitrosoureas, which include, but are not limited to, for example, carmustine and lomustine; (5) Triazene, which includes, but is not limited to, for example, dacarbazine and procarbazine, temozolomide; and ( 6) Platinum-containing antitumor agents, which include, but are not limited to, for example , cisplatin, carboplatin, and oxaliplatin. Any known alkylating agent (including but not limited to the alkylating agents listed above) can be used in the treatment methods provided herein. Bendamustine is an exemplary alkylating agent used in the methods described herein. The chemical name of bendamustine is 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, and its The molecular formula is C 16 H 21 Cl 2 N 3 O 2 and the molecular weight is 358.263 g/mol. Bendamustine (CAS Registry #16506-27-7) is a bifunctional methamine derivative containing a purine-like benzimidazole ring. Bendamustine can be used in powder form in solution and solution dosage forms. In some embodiments, the alkylating agent used in the methods described herein is a salt or solvate of bendamustine. In some embodiments, the bendamustine salt is bendamustine hydrochloride (CAS # 3543-75-7), its molecular formula is C 16 H 21 Cl 2 N 3 O 2 .HCl and its molecular weight is 394.72 g /mol. Bendamustine hydrochloride is commercially available as BENDEKA, TREANDA, TREAKISYM, RIBOMUSTIN, LEVACT, MUSTIN and others.

在一些實施例中，該一或多種化學治療劑包含吉西他濱(例如 健擇® )。吉西他濱係一種抗代謝物核苷類似物(2',2'-二氟脫氧胞苷)。由於僅其二磷酸酯及三磷酸酯形式具有細胞毒性活性，故在藉由脫氧胞苷激酶進行細胞內磷酸化後，其變得具有活性。具體言之，三磷酸酯形式與脫氧胞苷三磷酸酯競爭以無活性鹼基形式併入DNA中，而二磷酸酯形式抑制核糖核苷酸還原酶，核糖核苷酸還原酶係正常DNA合成必不可少的酶。根據IUPAC命名法，吉西他濱亦可稱為「2'-脫氧-2',2'-二氟胞苷單鹽酸鹽」(β-異構體)，並具有以下結構：

Figure 02_image078
In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine (e.g. gemzar ®). Gemcitabine is an antimetabolite nucleoside analog (2',2'-difluorodeoxycytidine). Since only its diphosphate and triphosphate forms have cytotoxic activity, it becomes active after intracellular phosphorylation by deoxycytidine kinase. Specifically, the triphosphate form competes with deoxycytidine triphosphate to be incorporated into DNA in the form of inactive bases, while the diphosphate form inhibits ribonucleotide reductase, which is responsible for normal DNA synthesis Essential enzymes. According to IUPAC nomenclature, gemcitabine can also be called "2'-deoxy-2',2'-difluorocytidine monohydrochloride" (β-isomer), and has the following structure:
Figure 02_image078

術語「2'-脫氧-2',2'-二氟胞苷單鹽酸鹽(β-異構體)」或「吉西他濱」之使用(除非另外說明)包含醫藥學上可接受之溶劑合物(包括水合物)及多晶型形式或其醫藥學上可接受之鹽。2'-脫氧-2',2'-二氟胞苷單鹽酸鹽(β-異構體)之醫藥組成物可包含一或多種稀釋劑、媒劑及/或賦形劑。包含2'-脫氧-2',2'-二氟胞苷單鹽酸鹽(β-異構體)之醫藥組成物的一個實例係健擇® (鹽酸吉西他濱)。健擇®包含作為活性成分之2'-脫氧-2',2'-二氟胞苷單鹽酸鹽(β-異構體)及其他無活性成分，其呈無菌形式，僅供靜脈內使用。健擇®小瓶含有與甘露醇(分別為200 mg或1 g)及乙酸鈉(分別為12.5 mg或62.5 mg)一起調配為無菌凍乾粉形式的200 mg或1 g鹽酸吉西他濱(以游離鹼表示)。可添加鹽酸及/或氫氧化鈉以調整pH值。The use of the term "2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer)" or "gemcitabine" (unless otherwise specified) includes pharmaceutically acceptable solvates (Including hydrates) and polymorphic forms or pharmaceutically acceptable salts thereof. The pharmaceutical composition of 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer) may contain one or more diluents, vehicles and/or excipients. An example of a pharmaceutical composition containing 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer) is Gemcitabine® (gemcitabine hydrochloride). Gemze® contains 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer) as the active ingredient and other inactive ingredients, which are in sterile form and are for intravenous use only . Gemcitabine® vials contain 200 mg or 1 g gemcitabine hydrochloride (expressed as free base) formulated as a sterile lyophilized powder with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) ). Hydrochloric acid and/or sodium hydroxide can be added to adjust the pH.

在一些實施例中，該一或多種化學治療劑包含奧沙利鉑(例如 益樂鉑® )。奧沙利鉑係一種化學治療劑，其分子式為C8 H14 N2 O4 Pt且化學名稱為順-[(1R,2R)-1,2-環己烷二胺-N,N][草酸根合(2-)-O,O]鉑。其化學結構顯示如下：

Figure 02_image080
In some embodiments, the one or more chemotherapeutic agents including oxaliplatin (e.g. Yi lobaplatin ®). Oxaliplatin is a chemotherapeutic agent with a molecular formula of C 8 H 14 N 2 O 4 Pt and a chemical name of cis-[(1R,2R)-1,2-cyclohexanediamine-N,N][ Oxalate and (2-)-O,O]platinum. Its chemical structure is shown as follows:
Figure 02_image080

術語「順-[(1R,2R)-1,2-環己烷二胺-N,N][草酸根合(2-)-O,O] 鉑」或「奧沙利鉑」之使用(除非另外說明)包含醫藥學上可接受之溶劑合物(包括水合物)及多晶型形式或其醫藥學上可接受之鹽。奧沙利鉑之鉑原子在兩個相鄰鳥苷殘基之間形成1,2-股內交聯，使雙螺旋向大溝彎曲約30度。奧沙利鉑具有不可水解的二胺基環己烷(DACH)載體配體，該配體保留在藥物之最終細胞毒性代謝物中。它與DNA及其他大分子之反應係藉由草酸酯中之一個或兩個羧基酯基團水解，留下DACH鉑單加合物或雙官能DACH-鉑交聯而進行。DACH-鉑加合物的內在化學及位阻特性看來會導致缺乏與順鉑之交叉耐藥性(如Di Francesco等人 (2002) Cell Mol Life Sci，59(11):1914-27中所評述)。奧沙利鉑之鹼水解以兩個連續步驟得到草酸根合單齒錯合物(pKa 7.23)及二水合奧沙利鉑錯合物。假定單齒中間物可與內源性化合物迅速反應(Jerremalm等人 ，(2003) J Pharm Sci，92(2):436-438)。已報導與序列5′-d(CCTCTGGTCTCC)形成雙鏈體的結合至DNA十二聚體之奧沙利鉑的晶體結構；鉑原子在兩個相鄰鳥苷殘基之間形成1,2-股內交聯，使雙螺旋向大溝彎曲約30度。結晶學提供關於對掌性在介導奧沙利鉑與雙鏈體DNA之間相互作用中之重要性的結構性證據(Spingler等人 ，(2001) Inorg Chem，40(22):5596-602)。因此，奧沙利鉑之成功在於其誘導由龐大加合物以及股內及股間交聯引起之DNA損傷的能力(Takahara等人 ，(1995) Nature，377(6550):649-52)，以及其誘導細胞凋亡的能力(Boulikas及Vougiouka，(2003) Oncol Rep，10(6):1663-82)。Use of the term "cis-[(1R,2R)-1,2-cyclohexanediamine-N,N][oxalato(2-)-O,O]platinum" or "oxaliplatin" ( Unless otherwise specified) includes pharmaceutically acceptable solvates (including hydrates) and polymorphic forms or pharmaceutically acceptable salts thereof. The platinum atom of oxaliplatin forms a 1,2-strand internal crosslink between two adjacent guanosine residues, which makes the double helix bend about 30 degrees toward the major groove. Oxaliplatin has a non-hydrolyzable diaminocyclohexane (DACH) carrier ligand, which remains in the final cytotoxic metabolite of the drug. It reacts with DNA and other macromolecules by hydrolyzing one or two carboxyl ester groups in oxalate, leaving DACH platinum monoadduct or bifunctional DACH-platinum cross-linking. The inherent chemical and steric hindrance properties of DACH-platinum adducts appear to lead to the lack of cross-resistance with cisplatin (as described in Di Francesco et al. (2002) Cell Mol Life Sci, 59(11): 1914-27). Comment). The alkali hydrolysis of oxaliplatin yields the oxaliplatin monodentate complex (pKa 7.23) and the oxaliplatin dihydrate complex in two consecutive steps. It is assumed that the monodentate intermediate can react rapidly with endogenous compounds (Jerremalm et al ., (2003) J Pharm Sci, 92(2):436-438). It has been reported that the crystal structure of oxaliplatin bound to DNA dodecamer that forms a duplex with the sequence 5'-d (CCTCTGGTCTCC); the platinum atom forms 1,2- between two adjacent guanosine residues The intra-strand cross-links make the double helix bend about 30 degrees toward the big groove. Crystallography provides structural evidence on the importance of opposability in mediating the interaction between oxaliplatin and duplex DNA (Spingler et al ., (2001) Inorg Chem, 40(22): 5596-602 ). Therefore, the success of oxaliplatin lies in its ability to induce DNA damage caused by bulky adducts and intra-strand and inter-strand cross-links (Takahara et al ., (1995) Nature, 377(6550):649-52), and Its ability to induce apoptosis (Boulikas and Vougiouka, (2003) Oncol Rep, 10(6):1663-82).

在一些實施例中，該一或多種化學治療劑包含吉西他濱及奧沙利鉑(例如 健擇® 及益樂鉑® )。在一些實施例中，該一或多種化學治療劑係吉西他濱及奧沙利鉑(例如 健擇® 及益樂鉑® )。VIII. 醫藥調配物 In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine and oxaliplatin (e.g. Gemzar ® and benefits lobaplatin ®). In some embodiments, the one or more chemotherapeutic agents based gemcitabine and oxaliplatin (e.g. Gemzar ® and benefits lobaplatin ®). VIII. Pharmaceutical formulations

用於本文所述之任何方法中的本文所述之任何藥劑(例如 抗CD79b免疫偶聯物、抗CD20劑及免疫調節劑)之醫藥調配物係藉由將具有所需純度之該等藥劑與一或多種可選醫藥學上可接受之載劑(Remington's Pharmaceutical Sciences 第16版，Osol，A. 編 (1980))混合而製備成凍乾調配物或水溶液形式。醫藥學上可接受之載劑在所用劑量及濃度下對接受者無毒，且包括但不限於：緩衝劑，諸如磷酸鹽、檸檬酸鹽及其他有機酸；抗氧化劑，包括抗壞血酸及甲硫胺酸；防腐劑(諸如氯化十八烷基二甲基苯甲基銨；氯化六甲雙銨(hexamethonium chloride)；苯紮氯銨(benzalkonium chloride)；苄索氯銨(benzethonium chloride)；苯酚、丁醇或苯甲醇；對羥基苯甲酸烷基酯，諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯；兒茶酚；間苯二酚；環己醇；3-戊醇；及間-甲酚)；低分子量(小於約10個殘基)多肽；蛋白質，諸如血清白蛋白、明膠或免疫球蛋白；親水性聚合物，諸如聚乙烯吡咯啶酮；胺基酸，諸如甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸或離胺酸；單糖、二糖及其他碳水化合物，包括葡萄糖、甘露糖或糊精；螯合劑，諸如EDTA；糖，諸如蔗糖、甘露糖醇、海藻糖或山梨糖醇；成鹽相對離子，諸如鈉；金屬錯合物(例如 Zn-蛋白質錯合物)；及/或非離子性界面活性劑，諸如聚乙二醇(PEG)。本文中之示例性醫藥學上可接受之載劑進一步包括間質藥物分散劑，諸如可溶性中性活性玻尿酸酶醣蛋白(sHASEGP)，例如人類可溶性PH-20玻尿酸酶糖蛋白，諸如rHuPH20 (HYLENEX® ，Baxter International，Inc.)。某些示例性sHASEGP (包括rHuPH20)及使用方法描述於美國專利公開案第2005/0260186號及第2006/0104968號中。在一個態樣中，sHASEGP與一或多種額外糖胺聚糖酶，諸如軟骨素酶組合。The pharmaceutical formulations of any of the agents described herein ( e.g., anti-CD79b immunoconjugates, anti-CD20 agents, and immunomodulators) used in any of the methods described herein are obtained by combining these agents with the required purity with One or more optional pharmaceutically acceptable carriers ( Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)) are mixed to prepare lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are non-toxic to recipients at the dose and concentration used, and include but are not limited to: buffers, such as phosphate, citrate and other organic acids; antioxidants, including ascorbic acid and methionine ; Preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride); benzethonium chloride; phenol, butyl Alcohol or benzyl alcohol; Alkyl parabens, such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-methyl Phenol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulin; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, bran Glucamic acid, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose , Mannitol, trehalose or sorbitol; salt-forming relative ions, such as sodium; metal complexes ( such as Zn-protein complexes); and/or nonionic surfactants, such as polyethylene glycol ( PEG). On the example used herein pharmaceutically acceptable carrier further comprises interstitial drug dispersion agents such as soluble neutral-active enzyme hyaluronic acid glycoprotein (a sHASEGP), such as a human soluble PH-20 enzyme hyaluronic acid glycoproteins, such as rHuPH20 (HYLENEX ® , Baxter International, Inc.). Certain exemplary sHASEGP (including rHuPH20) and methods of use are described in U.S. Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, sHASEGP is combined with one or more additional glycosaminoglycanase, such as chondroitinase.

示例性凍乾抗體或免疫偶聯物調配物描述於美國專利第6,267,958號中。水性抗體或免疫偶聯物調配物包括美國專利第6,171,586號及WO2006/044908中所述者，後一調配物包括組胺酸-乙酸鹽緩衝劑。Exemplary lyophilized antibody or immunoconjugate formulations are described in US Patent No. 6,267,958. Aqueous antibody or immunoconjugate formulations include those described in U.S. Patent No. 6,171,586 and WO2006/044908. The latter formulation includes histidine-acetate buffer.

本文之調配物亦可含有所治療之特定適應症所必需之多種活性成分，較佳為具有不會對彼此産生不利影響之互補活性的活性成分。The formulation herein may also contain multiple active ingredients necessary for the specific indication being treated, preferably active ingredients with complementary activities that do not adversely affect each other.

活性成分可包埋於例如藉由凝聚技術或藉由界面聚合製備之微膠囊中，例如分別用於膠態藥物遞送系統中(例如脂質體、白蛋白微球、微乳液、奈米粒子及奈米膠囊)或在巨乳液中之羥甲基纖維素或明膠-微膠囊及聚(甲基丙烯酸甲酯)微膠囊。此類技術揭示於Remington's Pharmaceutical Sciences ，第16版，Osol，A. 編(1980)中。The active ingredient can be embedded in microcapsules prepared by coacervation technology or by interfacial polymerization, for example, respectively used in colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticle and nanoparticle). Rice capsules) or hydroxymethyl cellulose or gelatin-microcapsules and poly(methyl methacrylate) microcapsules in macroemulsion. Such techniques are disclosed in Remington's Pharmaceutical Sciences , 16th edition, Osol, A. Ed. (1980).

可準備持續釋放製劑。持續釋放製劑之適合實例包括含有抗體或免疫偶聯物之固體疏水性聚合物之半透性基質，該等基質呈成形物品，例如 薄膜或微膠囊形式。Sustained release formulations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing antibodies or immunoconjugates, which matrices are in the form of shaped articles, such as films or microcapsules.

打算供活體內 投與之調配物一般為無菌的。無菌性可易於例如 藉由經無菌過濾膜過濾來實現。The formulations intended for in vivo administration are generally sterile. Sterility can be easily achieved, for example, by filtration through a sterile filter membrane.

關於包含抗CD79免疫偶聯物之醫藥調配物的其他細節提供於WO 2009/099728中，該專利之內容以全文引用的方式明確併入本文中。 IX. 套組及製品 Additional details about the pharmaceutical formulations containing anti-CD79 immunoconjugates are provided in WO 2009/099728, the content of which is expressly incorporated herein by reference in its entirety. IX. Sets and products

在另一個實施例中，提供一種製品或套組，其包含抗CD79b免疫偶聯物(諸如本文所述)及至少一種額外藥劑。在一些實施例中，該至少一種額外藥劑係抗CD20抗體(諸如利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)。在一些實施例中，該製品或套組進一步包含包裝插頁，該包裝插頁包含有關使用抗CD79b免疫偶聯物與至少一種額外藥劑，諸如抗CD20抗體(例如 利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)之組合治療或延遲個體之B細胞增殖性疾病(例如 DLBCL，諸如復發性/難治性DLBCL)的說明書。此項技術中已知的任何抗CD79b免疫偶聯物及抗癌劑可包括在該製品或套組中。在一些實施例中，該套組包括含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係與抗CD20抗體(諸如利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)組合使用以治療患有彌漫性大B細胞淋巴瘤(DLBCL)的有需要之人類個體。在一些實施例中，該套組係根據本文所提供之任何方法使用。In another embodiment, there is provided an article or kit comprising an anti-CD79b immunoconjugate (such as described herein) and at least one additional agent. In some embodiments, the at least one additional agent is an anti-CD20 antibody (such as rituximab) and one or more chemotherapeutic agents ( such as gemcitabine and oxaliplatin). In some embodiments, the product or kit further comprises a package insert, the package insert contains information related to the use of an anti-CD79b immunoconjugate and at least one additional agent, such as an anti-CD20 antibody ( for example , rituximab) and a Or a combination of multiple chemotherapeutics ( e.g. gemcitabine and oxaliplatin) to treat or delay a B cell proliferative disease ( e.g. DLBCL, such as relapsed/refractory DLBCL) in an individual. Any anti-CD79b immunoconjugate and anti-cancer agent known in the art can be included in the product or kit. In some embodiments, the kit includes an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is linked to an anti-CD20 antibody (such as ritux Cixiimab) and one or more chemotherapeutic agents ( e.g., gemcitabine and oxaliplatin) are used in combination to treat human individuals in need with diffuse large B-cell lymphoma (DLBCL). In some embodiments, the kit is used according to any of the methods provided herein.

在一些實施例中，該套組包括含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且其中p在1與8之間，該免疫偶聯物係與利妥昔單抗、吉西他濱及奧沙利鉑組合使用以治療患有彌漫性大B細胞淋巴瘤(DLBCL)的有需要之人類個體。在一些實施例中，該套組係根據本文所提供之任何方法使用。In some embodiments, the kit includes an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is combined with rituximab and gemcitabine It is used in combination with oxaliplatin to treat human individuals in need with diffuse large B-cell lymphoma (DLBCL). In some embodiments, the kit is used according to any of the methods provided herein.

在一些實施例中，該套組包括含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO:19之胺基酸序列之VH的重鏈，及(ii)含SEQ ID NO:20之胺基酸序列之VL的輕鏈，且其中p在2與5之間。在一些實施例中，p在3與4之間，例如 3.5。在一些實施例中，該免疫偶聯物包含抗CD79抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在某些實施例中，抗CD79b免疫偶聯物包含Ab-MC-vc-PAB-MMAE之結構。在一些實施例中，抗CD79b免疫偶聯物係帕妥珠單抗維多汀-piiq。在一些實施例中，該至少一種額外藥劑係抗CD20抗體(諸如利妥昔單抗)及一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)。在一些實施例中，該套組係用於根據本文提供之方法治療個體(例如 具有本文所述之一或多種特徵之個體)之DLBCL。In some embodiments, the kit includes an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) the heavy chain of VH containing the amino acid sequence of SEQ ID NO: 19, and (ii) the light chain of VL containing the amino acid sequence of SEQ ID NO: 20 Chain, and where p is between 2 and 5. In some embodiments, p is between 3 and 4, such as 3.5. In some embodiments, the immunoconjugate comprises an anti-CD79 antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In certain embodiments, the anti-CD79b immunoconjugate comprises the structure of Ab-MC-vc-PAB-MMAE. In some embodiments, the anti-CD79b immunoconjugate is Pertuzumab Vidotin-piiq. In some embodiments, the at least one additional agent is an anti-CD20 antibody (such as rituximab) and one or more chemotherapeutic agents ( such as gemcitabine and oxaliplatin). In some embodiments, the kit is used to treat DLBCL in an individual (e.g., an individual having one or more of the characteristics described herein) according to the methods provided herein.

在一些實施例中，該套組包括含下式之免疫偶聯物：

Figure 02_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO:19之胺基酸序列之VH的重鏈，及(ii)含SEQ ID NO:20之胺基酸序列之VL的輕鏈，且其中p在2與5之間。在一些實施例中，p在3與4之間，例如 3.5。在一些實施例中，該免疫偶聯物包含抗CD79抗體，該抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。在某些實施例中，抗CD79b免疫偶聯物包含Ab-MC-vc-PAB-MMAE之結構。在一些實施例中，抗CD79b免疫偶聯物係帕妥珠單抗維多汀-piiq。在一些實施例中，該至少一種額外藥劑係利妥昔單抗、吉西他濱及奧沙利鉑。在一些實施例中，該套組係用於根據本文提供之方法治療個體(例如 具有本文所述之一或多種特徵之個體)之DLBCL。In some embodiments, the kit includes an immunoconjugate comprising the following formula:
Figure 02_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) the heavy chain of VH containing the amino acid sequence of SEQ ID NO: 19, and (ii) the light chain of VL containing the amino acid sequence of SEQ ID NO: 20 Chain, and where p is between 2 and 5. In some embodiments, p is between 3 and 4, such as 3.5. In some embodiments, the immunoconjugate comprises an anti-CD79 antibody, the antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a light chain containing the amino acid sequence of SEQ ID NO: 35. In certain embodiments, the anti-CD79b immunoconjugate comprises the structure of Ab-MC-vc-PAB-MMAE. In some embodiments, the anti-CD79b immunoconjugate is Pertuzumab Vidotin-piiq. In some embodiments, the at least one additional agent is rituximab, gemcitabine, and oxaliplatin. In some embodiments, the kit is used to treat DLBCL in an individual (e.g., an individual having one or more of the characteristics described herein) according to the methods provided herein.

在一些實施例中，抗CD79b免疫偶聯物、抗CD20抗體(諸如利妥昔單抗)及該一或多種化學治療劑(例如 吉西他濱及奧沙利鉑)係在同一容器或獨立容器中。適合容器包括例如瓶、小瓶、袋子及注射器。該容器可由多種材料形成，諸如玻璃、塑料(諸如聚氯乙烯或聚烯烴)或金屬合金(諸如不銹鋼或哈氏合金(hastelloy))。在一些實施例中，該容器容納調配物，且在該容器上或與容器相聯之標籤可指示使用指導。製品或套組可進一步包括自商業及使用者觀點看合乎需要之其他材料，包括其他緩衝劑、稀釋劑、過濾器、針、注射器及帶有使用說明書之包裝插頁。在一些實施例中，該製品進一步包括一或多種其他藥劑(例如 化學治療劑及抗腫瘤劑)。該一或多種藥劑之適合容器包括例如瓶、小瓶、袋子及注射器。表 E ：胺基酸序列 。 名稱 序列 SEQ ID NO 人類CD79b前體；登錄號NP_000617.1；信號序列 = 胺基酸1至28 RFIARKRGFT VKMHCYMNSA SGNVSWLWKQ EMDENPQQLK LEKGRMEESQ NESLATLTIQ GIRFEDNGIY FCQQKCNNTS EVYQGCGTEL RVMGFSTLAQ LKQRNTLKDG IIMIQTLLII LFIIVPIFLL LDKDDSKAGM EEDHTYEGLD IDQTATYEDI VTLRTGEVKW SVGEHPGQE 1 人類成熟CD79b，無信號序列；胺基酸29至229 AR SEDRYRNPKG SACSRIWQSP RFIARKRGFT VKMHCYMNSA SGNVSWLWKQ EMDENPQQLK LEKGRMEESQ NESLATLTIQ GIRFEDNGIY FCQQKCNNTS EVYQGCGTEL RVMGFSTLAQ LKQRNTLKDG IIMIQTLLII LFIIVPIFLL LDKDDSKAGM EEDHTYEGLD IDQTATYEDI VTLRTGEVKW SVGEHPGQE 2 mMAb抗CD20抗體B-Ly1之VH Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Lys Leu Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr Met Gln Leu Thr Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Leu Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 3 mMAb抗CD20抗體B-Ly1之VL Asn Pro Val Thr Leu Gly Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 4 GA101 HVR-H1 Gly Tyr Ala Phe Ser Tyr 5 GA101 HVR-H2 Phe Pro Gly Asp Gly Asp Thr Asp 6 GA101 HVR-H3 Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr 7 GA101 HVR-L1 Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr 8 GA101 HVR-L2 Gln Met Ser Asn Leu Val Ser 9 GA101 HVR-L3 Ala Gln Asn Leu Glu Leu Pro Tyr Thr 10 GA101 VH Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 11 GA101 VL Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val 12 GA101重鏈 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 13 GA101輕鏈 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 14 人類化B-Ly1抗體之VH (B-HH2) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 15 人類化B-Ly1抗體之VH (B-HH3) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 16 人類化B-Ly1重鏈 QVQLVQSGAE VKKPGSSVKV SCKASGYAFS YSWINWVRQA PGQGLEWMGR IFPGDGDTDY NGKFKGRVTI TADKSTSTAY MELSSLRSED TAVYYCARNV FDGYWLVYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPG 17 人類化B-Ly1輕鏈 DIVMTQTPLS LPVTPGEPAS ISCRSSKSLL HSNGITYLYW YLQKPGQSPQ LLIYQMSNLV SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCAQNLELP YTFGGGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC 18 huMA79bv28重鏈可變區 EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSS 19 huMA79bv28輕鏈可變區 DIQLTQSPSS LSASVGDRVT ITCKASQSVD YEGDSFLNWY QQKPGKAPKL LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPL TFGQGTKVEI KR 20 huMA79bv28 HVR H1 GYTFSSYWIE 21 huMA79bv28 HVR H2 GEILPGGGDTNYNEIFKG 22 huMA79bv28 HVR H3 TRRVPIRLDY 23 huMA79bv28 HVR L1 KASQSVDYEGDSFLN 24 huMA79bv28 HVR L2 AASNLES 25 huMA79bv28 HVR L3 QQSNEDPLT 26 huMA79bv28重鏈(HC)框架區(FR)1 EVQLVESGGGLVQPGGSLRLSCAAS 27 huMA79bv28 HC FR2 WVRQAPGKGLEWI 28 huMA79bv28 HC FR3 RATFSADTSKNTAYLQMNSLRAEDTAVYYC 29 huMA79bv28 HC FR4 WGQGTLVTVSS 30 huMA79bv28輕鏈(LC)FR1 DIQLTQSPSSLSASVGDRVTITC 31 huMA79bv28 LC FR2 WYQQKPGKAPKLLIY 32 huMA79bv28 LC FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC 33 huMA79bv28 LC FR4 FGQGTKVEIKR 34 huMA79bv28輕鏈(Igκ) DIQLTQSPSS LSASVGDRVT ITCKASQSVD YEGDSFLNWY QQKPGKAPKL LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPL TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC 35 huMA79bv28重鏈(IgG1) EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG 36 huMA79bv28 A118C半胱胺酸工程改造之重鏈(IgG1) EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSSCST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG 37 huMA79bv28 V205C半胱胺酸工程改造之輕鏈(Igκ) DIQLTQSPSS LSASVGDRVT ITCKASQSVD YEGDSFLNWY QQKPGKAPKL LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPL TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV THQGLSSPCT KSFNRGEC 38 huMA79bv28 S400C半胱胺酸工程改造之重鏈(IgG1) EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDC DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK 39 人類化B-Ly1抗體之VH (B-HH4) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 40 人類化B-Ly1抗體之VH (B-HH5) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 41 人類化B-Ly1抗體之VH (B-HH6) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 42 人類化B-Ly1抗體之VH (B-HH7) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 43 人類化B-Ly1抗體之VH (B-HH8) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 44 人類化B-Ly1抗體之VH (B-HH9) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 45 人類化B-Ly1抗體之VH (B-HL8) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 46 人類化B-Ly1抗體之VH (B-HL10) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 47 人類化B-Ly1抗體之VH (B-HL11) Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 48 人類化B-Ly1抗體之VH (B-HL12) Glu Val Gln Leu Val Glu Ser Gly Ala Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 49 人類化B-Ly1抗體之VH (B-HL13) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 50 人類化B-Ly1抗體之VH (B-HL14) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Lys Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 51 人類化B-Ly1抗體之VH (B-HL15) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ser Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 52 人類化B-Ly1抗體之VH (B-HL16) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 53 人類化B-Ly1抗體之VH (B-HL17) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 54 人類化B-Ly1抗體之VL (B-KVI) Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val 55 In some embodiments, the anti-CD79b immunoconjugate, anti-CD20 antibody (such as rituximab), and the one or more chemotherapeutic agents ( such as gemcitabine and oxaliplatin) are in the same container or separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. The container may be formed of a variety of materials, such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloy (such as stainless steel or Hastelloy). In some embodiments, the container contains the formulation, and a label on or associated with the container may indicate instructions for use. The product or kit may further include other materials that are desirable from a commercial and user point of view, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some embodiments, the preparation further includes one or more other agents ( e.g., chemotherapeutic agents and antitumor agents). Suitable containers for the one or more medicaments include, for example, bottles, vials, bags, and syringes. Table E : Amino acid sequence . name sequence SEQ ID NO Human CD79b precursor; accession number NP_000617.1; signal sequence = amino acid 1 to 28 RFIARKRGFT VKMHCYMNSA SGNVSWLWKQ EMDENPQQLK LEKGRMEESQ NESLATLTIQ GIRFEDNGIY FCQQKCNNTS EVYQGCGTEL RVMGFSTLAQ LKQRNTLKDG IIMIQTLLII LFIIVPIFLL LDKDDSKAGM EEDHTY EGLD SVG IDQTAGEV IDQTAGEV 1 Human mature CD79b, no signal sequence; amino acids 29 to 229 AR SEDRYRNPKG SACSRIWQSP RFIARKRGFT VKMHCYMNSA SGNVSWLWKQ EMDENPQQLK LEKGRMEESQ NESLATLTIQ GIRFEDNGIY FCQQKCNNTS EVYQGCGTEL RVMGFSTLAQ LKQRNTLKDG IIMIQTLLGE KWEDKDG IIMIQTLLII LFTYVPIFGM LDKEDSVG LDKEDKAV LDKEDKAV EETYQ EETYQE 2 VH of mMAb anti-CD20 antibody B-Ly1 Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Lys Leu Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr Met Gln Leu Thr Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Leu Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 3 mMAb anti-CD20 antibody B-Ly1 VL Asn Pro Val Thr Leu Gly Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 4 GA101 HVR-H1 Gly Tyr Ala Phe Ser Tyr 5 GA101 HVR-H2 Phe Pro Gly Asp Gly Asp Thr Asp 6 GA101 HVR-H3 Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr 7 GA101 HVR-L1 Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr 8 GA101 HVR-L2 Gln Met Ser Asn Leu Val Ser 9 GA101 HVR-L3 Ala Gln Asn Leu Glu Leu Pro Tyr Thr 10 GA101 VH Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 11 GA101 VL Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val 12 GA101 heavy chain Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 13 GA101 light chain Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 14 VH of humanized B-Ly1 antibody (B-HH2) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 15 VH of humanized B-Ly1 antibody (B-HH3) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 16 Humanized B-Ly1 heavy chain QVQLVQSGAE VKKPGSSVKV SCKASGYAFS YSWINWVRQA PGQGLEWMGR IFPGDGDTDY NGKFKGRVTI TADKSTSTAY MELSSLRSED TAVYYCARNV FDGYWLVYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPG 17 Humanized B-Ly1 light chain DIVMTQTPLS LPVTPGEPAS ISCRSSKSLL HSNGITYLYW YLQKPGQSPQ LLIYQMSNLV SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCAQNLELP YTFGGGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LQSSFNKSLQSLQSSGVKSGSLQSLQSSGPTEKSL QNNWDSKPREAKVTEKSL QNNWDSKTYTLSEKSL VTNSEKSL QNNFYKPREAKVTEKSL 18 huMA79bv28 heavy chain variable region EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSS 19 huMA79bv28 light chain variable region DIQLTQSPSS LSASVGDRVT ITCKASQSVD YEGDSFLNWY QQKPGKAPKL LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPL TFGQGTKVEI KR 20 huMA79bv28 HVR H1 GYTFSSYWIE twenty one huMA79bv28 HVR H2 GEILPGGGDTNYNEIFKG twenty two huMA79bv28 HVR H3 TRRVPIRLDY twenty three huMA79bv28 HVR L1 KASQSVDYEGDSFLN twenty four huMA79bv28 HVR L2 AASNLES 25 huMA79bv28 HVR L3 QQSNEDPLT 26 huMA79bv28 heavy chain (HC) framework region (FR) 1 EVQLVESGGGLVQPGGSLRLSCAAS 27 huMA79bv28 HC FR2 WVRQAPGKGLEWI 28 huMA79bv28 HC FR3 RATFSADTSKNTAYLQMNSLRAEDTAVYYC 29 huMA79bv28 HC FR4 WGQGTLVTVSS 30 huMA79bv28 light chain (LC) FR1 DIQLTQSPSSLSASVGDRVTITC 31 huMA79bv28 LC FR2 WYQQKPGKAPKLLIY 32 huMA79bv28 LC FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC 33 huMA79bv28 LC FR4 FGQGTKVEIKR 34 huMA79bv28 light chain (Igκ) DIQLTQSPSS LSASVGDRVT ITCKASQSVD YEGDSFLNWY QQKPGKAPKL LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPL TFGQGTKVEI KRTVAAPSVF IFPPSDEQSVD YEGDSFLNWY QQKPGKAPKL LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPL TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL TL DYFNKACEQLK SGTASVVCLS DNFKACEQSKAVTSVTSVKS DNFKACEQLSKATSV 35 huMA79bv28 heavy chain (IgG1) EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG 36 huMA79bv28 A118C Cysteine Engineered Heavy Chain (IgG1) EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSSCST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG 37 huMA79bv28 V205C Cysteine Engineered Light Chain (Igκ) DIQLTQSPSS LSASVGDRVT ITCKASQSVD YEGDSFLNWY QQKPGKAPKL LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPL TFGQGTKVEI KRTVAAPSVF ITCKASQSVD YEGDSFLNWY QQKPGKAPKLA 38 huMA79bv28 S400C Cysteine Engineered Heavy Chain (IgG1) EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDC DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK 39 VH of humanized B-Ly1 antibody (B-HH4) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 40 VH of humanized B-Ly1 antibody (B-HH5) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 41 VH of humanized B-Ly1 antibody (B-HH6) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 42 VH of humanized B-Ly1 antibody (B-HH7) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 43 VH of humanized B-Ly1 antibody (B-HH8) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 44 VH of humanized B-Ly1 antibody (B-HH9) Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 45 VH of humanized B-Ly1 antibody (B-HL8) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 46 VH of humanized B-Ly1 antibody (B-HL10) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 47 VH of humanized B-Ly1 antibody (B-HL11) Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 48 VH of humanized B-Ly1 antibody (B-HL12) Glu Val Gln Leu Val Glu Ser Gly Ala Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 49 VH of humanized B-Ly1 antibody (B-HL13) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Gly Val Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 50 VH of humanized B-Ly1 antibody (B-HL14) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Lys Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 51 VH of humanized B-Ly1 antibody (B-HL15) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ser Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 52 VH of humanized B-Ly1 antibody (B-HL16) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 53 VH of humanized B-Ly1 antibody (B-HL17) Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 54 Humanized B-Ly1 antibody VL (B-KVI) Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val 55

本說明書被認為足以使熟習此項技術者能夠實踐本發明。熟習此項技術者自前述描述將對除本文所顯示且描述之內容外的本發明之各種修改顯而易知，且該等修改在隨附申請專利範圍之範圍內。本文所引用之所有出版物、專利、專利申請案特此以全文引用之方式併入用於所有目的。 實例This description is considered sufficient to enable those skilled in the art to practice the present invention. Those who are familiar with the art will clearly know various modifications of the present invention in addition to the content shown and described herein from the foregoing description, and these modifications are within the scope of the attached patent application. All publications, patents, and patent applications cited in this article are hereby incorporated by reference in their entirety for all purposes. Instance

以下係本發明之方法及組成物的實例。應瞭解，鑑於上文所提供之一般描述，可實踐各種其他實施例。實例 1 ：一項 III 期、開放標記、多中心之隨機化研究，用於評價帕妥珠單抗維多汀組合利妥昔單抗加吉西他濱加奧沙利鉑 (Pola-R-GemOx) 與單獨使用 R-GemOx 對於患有復發性 / 難治性彌漫性大 B 細胞淋巴瘤之患者的安全性及功效。 The following are examples of the method and composition of the present invention. It should be appreciated that, given the general description provided above, various other embodiments may be practiced. Example 1 : A Phase III , open-label, multi-center randomized study to evaluate the combination of Pertuzumab, Vidotine, Rituximab, Gemcitabine, and Oxaliplatin (Pola-R-GemOx) and R-GemOx alone for patients with relapsed / refractory patients with diffuse large B-cell lymphoma of safety and efficacy.

本實例描述一項III期、開放標記、多中心之隨機化研究，用於評價帕妥珠單抗維多汀組合利妥昔單抗加吉西他濱加奧沙利鉑(Pola-R-GemOx)與單獨使用R-GemOx對於患有復發性/難治性(R/R)彌漫性大B細胞淋巴瘤(DLBCL)之患者之安全性及功效的比較。在本研究中，治療分為兩個階段：1)評估Pola-R-GemOx組合之安全性的初步安全性磨合期(第1階段)；及2)比較Pola-R-GemOx與R-GemOx之安全性及功效的隨機對照試驗(RCT)期(第2階段)。I. 研究目標 A. 第 1 階段：安全性磨合期 安全性目標及終點 主要安全性目標 This example describes a Phase III, open-label, multi-center randomized study to evaluate the combination of Pertuzumab, Vidotine, Rituximab, Gemcitabine, and Oxaliplatin (Pola-R-GemOx) and Comparison of the safety and efficacy of R-GemOx alone for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). In this study, the treatment was divided into two stages: 1) the initial safety run-in period to assess the safety of the Pola-R-GemOx combination (stage 1); and 2) the comparison between Pola-R-GemOx and R-GemOx Safety and Efficacy Randomized Controlled Trial (RCT) Phase (Phase 2). I. Research goals A. Phase 1 : Safety goals and main safety goals of the end point during the safety run-in period

本研究第1階段之主要安全性目標係評價作為組合療法之Pola-R-GemOx的安全性及耐受性。主要安全性終點 The main safety goal of the first phase of this study is to evaluate the safety and tolerability of Pola-R-GemOx as a combination therapy. Primary safety endpoint

根據國家癌症研究院常見不良事件評價準則第5版(NCI CTCAE v5.0)，本研究第1階段之主要安全性終點係身體檢查結果及不良事件(AE)之發生率、性質及嚴重程度，其中特別關注周圍神經病變。次要安全性目標 According to the 5th edition of the National Cancer Institute Common Adverse Events Evaluation Guidelines (NCI CTCAE v5.0), the main safety endpoints of the first stage of this study are the results of physical examination and the incidence, nature and severity of adverse events (AE). Particular attention is paid to peripheral neuropathy. Secondary security goal

本研究第1階段之次要安全性目標係評價作為組合療法之Pola-R-GemOx之安全性及耐受性及評估帕妥珠單抗維多汀之免疫原性。次要安全性終點 The secondary safety goal of the first phase of this study is to evaluate the safety and tolerability of Pola-R-GemOx as a combination therapy and to evaluate the immunogenicity of Pertuzumab vedotine. Secondary safety endpoint

本研究第1階段之次要安全性終點係周圍神經病變之發生率及評估，此係藉由癌症療法功能評估/婦科腫瘤學組-神經毒性12項量表(FACT/GOG-Ntx12)量測；Pola-R-GemOx之耐受性，此係藉由劑量中止、劑量減少及劑量強度量測；及基線時抗藥物抗體(ADA)之流行率及研究期間ADA之發生率。功效目標及終點 次要功效目標 The secondary safety endpoint of the first stage of this study is the incidence and assessment of peripheral neuropathy, which is measured by the Cancer Therapy Functional Assessment/Gynecological Oncology Group-Neurotoxicity 12-item Scale (FACT/GOG-Ntx12) ; Tolerability of Pola-R-GemOx, which is measured by dose discontinuation, dose reduction, and dose intensity; and the prevalence of anti-drug antibodies (ADA) at baseline and the incidence of ADA during the study period. Efficacy goals and endpoint secondary efficacy goals

本研究第1階段之次要功效目標係評價Pola-R-GemOx之功效。次要功效終點 The secondary efficacy goal of the first stage of this study is to evaluate the efficacy of Pola-R-GemOx. Secondary efficacy endpoint

本研究第1階段之次要功效終點如下： ●    完全反應(CR)，定義為根據Lugano 2014反應標準(Cheson等人 ，(2014) J Clin Oncol 32:3059-3068)，在治療結束時基於PET-CT實現完全代謝反應之患者的比例。 ●    客觀反應率(ORR)，定義為根據Lugano 2014反應標准，在治療結束時實現完全或部分代謝反應(基於包括PET CT資料在內之反應)之患者的比例。 ●    最佳總體反應(BOR)，定義為根據Lugano 2014反應標準，所記錄的自治療開始直至治療結束時的最佳反應。 ●    無進展存活期(PFS)，定義為自首次給與研究治療至根據Lugano 2014反應標準確定首次出現疾病進展(基於包括PET CT資料或不包括任何PET資料之反應)，或由任何原因引起之死亡的時間。 ●    總體存活期(OS)，定義為自首次給與研究治療至由任何原因引起之死亡的時間。 ●    無事件存活期(EFSeff )，定義為自首次給與研究治療至最早出現以下任一種的時間： ○    疾病進展或復發(基於包括PET CT資料或不包括任何PET資料之反應)。 ○    由任何原因引起之死亡。 ○    起始任何非方案指定之抗淋巴瘤治療(NALT)。藥物動力學目標及終點 藥物動力學目標 The secondary efficacy endpoints of the first phase of this study are as follows: ● Complete response (CR), defined as based on the Lugano 2014 response criteria (Cheson et al ., (2014) J Clin Oncol 32:3059-3068), based on PET at the end of treatment -The proportion of patients with a complete metabolic response on CT. ● The objective response rate (ORR) is defined as the proportion of patients who achieve a complete or partial metabolic response (based on the response including PET CT data) at the end of treatment according to the Lugano 2014 response criteria. ● The best overall response (BOR) is defined as the best response recorded from the beginning of treatment to the end of treatment according to the Lugano 2014 response standard. ● Progression-free survival (PFS) is defined as the time from the first administration of study treatment to the first occurrence of disease progression (based on the response including PET CT data or excluding any PET data) according to the Lugano 2014 response criteria, or caused by any reason Time of death. ● Overall survival (OS) is defined as the time from the first administration of study treatment to death from any cause. ● Event-free survival (EFS eff ) is defined as the time from the first administration of study treatment to the earliest appearance of any of the following: ○ Disease progression or recurrence (based on the response including PET CT data or not including any PET data). ○ Death caused by any cause. ○ Initiate any non-planned anti-lymphoma treatment (NALT). Pharmacokinetic goals and end-point pharmacokinetic goals

本研究第1階段之藥物動力學目標係評價帕妥珠單抗維多汀之藥物動力學(PK)譜。藥物動力學終點 The pharmacokinetic goal of the first phase of this study is to evaluate the pharmacokinetic (PK) profile of Pertuzumab vedotine. Pharmacokinetic endpoint

本研究第1階段之藥物動力學終點係在復發性或難治性DLBCL患者中帕妥珠單抗維多汀組合R-GemOx之PK譜以及帕妥珠單抗維多汀與R-GemOx之間之潛在PK相互作用。 B. 第 2 階段：隨機對照試驗 (RCT) 功效目標及終點 主要及次要功效目標 The pharmacokinetic endpoint of the first phase of this study is between the PK profile of Pertuzumab and R-GemOx in patients with relapsed or refractory DLBCL and between Pertuzumab and R-GemOx. The potential PK interaction. B. Phase 2 : Randomized Controlled Trial (RCT) efficacy targets and endpoints primary and secondary efficacy targets

本研究第2階段之主要及次要功效目標係評價Pola-R-GemOx與單獨-GemOx之功效比較。主要功效終點 The primary and secondary efficacy goals of the second stage of this study are to evaluate the efficacy of Pola-R-GemOx and GemOx alone. Primary efficacy endpoint

本研究第2階段之主要功效終點係總體存活期(OS)，OS定義為自隨機分組至由任何原因引起之死亡的時間。次要功效終點 The main efficacy endpoint of the second phase of this study is overall survival (OS), which is defined as the time from randomization to death from any cause. Secondary efficacy endpoint

本研究第2階段之次要功效終點如下： ●    分層測試程序中包括的關鍵次要重點(參見 以下第V節)： ○    PFS，定義為自隨機分組至根據Lugano 2014反應標準確定首次出現疾病進展，或由任何原因引起之死亡的時間。 ○    CRR，定義為根據Lugano 2014反應標準，在治療結束時基於PET-CT實現完全代謝反應之患者的比例。 ○    ORR，定義為根據Lugano 2014反應標準，在治療結束時實現完全或部分代謝反應之患者的比例。 ● 未針對測試多重性程序調整之次要終點 ○    BOR，定義為根據Lugano 2014反應標準，所記錄的自隨機分組直至治療結束時的最佳反應。 ○    CRR，定義為根據Lugano 2014反應標準，在治療結束時基於PET-CT實現完全代謝反應之患者的比例。 ○    ORR，定義為根據Lugano 2014反應標准，在治療結束時實現完全或部分代謝反應(基於包括PET CT資料在內之反應)之患者的比例。 ○    客觀反應(DoR)之持續時間，定義為根據Lugano 2014反應標準，自首次出現記錄之客觀反應(基於包括PET CT資料在內之反應)至疾病進展(基於包括PET CT資料或不包括任何PET資料之反應)，或由任何原因引起之死亡的時間，以先到者為準。 ○    EFSeff，定義為自隨機分組至最早出現以下任一種的時間： ●    疾病進展或復發(基於包括PET CT資料或不包括任何PET資料之反應)。 ●    由任何原因引起之死亡。 ●    起始任何NALT。患者報告結果 (PRO) 目標及終點 次要及探索性 PRO 目標 The secondary efficacy endpoints of the second phase of this study are as follows: ● The key secondary points included in the stratified testing program ( see section V below): ○ PFS, defined as from randomization to the first occurrence of disease based on the Lugano 2014 response criteria Time to progress, or death from any cause. ○ CRR is defined as the proportion of patients who achieve a complete metabolic response based on PET-CT at the end of treatment according to the Lugano 2014 response criteria. ○ ORR is defined as the proportion of patients who achieve a complete or partial metabolic response at the end of treatment according to the Lugano 2014 response criteria. ● Secondary endpoint not adjusted for the test multiplicity program ○ BOR is defined as the best response recorded from randomization to the end of treatment based on the Lugano 2014 response standard. ○ CRR is defined as the proportion of patients who achieve a complete metabolic response based on PET-CT at the end of treatment according to the Lugano 2014 response criteria. ○ ORR is defined as the proportion of patients who achieve a complete or partial metabolic response (based on the response including PET CT data) at the end of treatment according to the Lugano 2014 response criteria. ○ The duration of an objective response (DoR) is defined as the time from the first recorded objective response (based on the response including PET CT data) to disease progression (based on the PET CT data or not including any PET) according to the Lugano 2014 response criteria Data response), or the time of death caused by any cause, whichever comes first. ○ EFSeff, defined as the time from randomization to the earliest appearance of any of the following: ● Disease progression or recurrence (based on the response including PET CT data or not including any PET data). ● Death caused by any cause. ● Start any NALT. Patient Report Outcome (PRO) goals and endpoints, secondary and exploratory PRO goals

本研究第2階段之次要PRO目標係評價治療及疾病對健康相關生活品質之影響。次要 PRO 終點 The secondary PRO goal of the second stage of this study is to evaluate the impact of treatment and disease on health-related quality of life. Secondary PRO endpoint

本研究第2階段之次要PRO終點如下： ● 如藉由歐洲癌症研究及治療組織生活品質核心問卷表30 (European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire，Core 30，EORTC QLQ-C30)量測的身體機能及疲勞之惡化時間。 ● 如藉由癌症治療功能評估-淋巴瘤(FACT-Lym)分量表量測的淋巴瘤症狀進展的時間。 ● 如由 FACT/GOG-NTX-12分量表分數量測的周圍神經病變自基線之變化。探索性 PRO 終點 ● 本研究第2階段之探索性PRO終點係描述性匯總統計，以及EORTC QLQ-C30、FACT-Lym分量表、FACT/GOG-NTX-12及EQ-5D-5L所有量表自基線之變化。安全性目標及終點 安全性目標 The secondary PRO endpoints of the second stage of this study are as follows: ● For example, according to the European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire, Core 30, EORTC QLQ -C30) Measured physical function and deterioration time of fatigue. ● For example, the time to the progression of lymphoma symptoms measured by the functional assessment of cancer treatment-lymphoma (FACT-Lym) subscale. ● The change from baseline in peripheral neuropathy as measured by the FACT/GOG-NTX-12 subscale. Exploratory PRO endpoints ● The exploratory PRO endpoints in the second stage of this study are descriptive summary statistics, and all scales of EORTC QLQ-C30, FACT-Lym, FACT/GOG-NTX-12 and EQ-5D-5L Changes from the baseline. Safety goals and end-point safety goals

本研究第2階段之安全性目標係評價Pola-R-GemOx與R-GemOx之安全性及耐受性的比較以及評估帕妥珠單抗維多汀之免疫原性。安全性終點 The safety goal of the second phase of this study is to evaluate the safety and tolerability of Pola-R-GemOx and R-GemOx, and to evaluate the immunogenicity of Pertuzumab vedotine. Safety endpoint

本研究第2階段之安全性終點如下： ● 根據NCI CTCAE v5.0及身體檢查結果，AE(包括周圍神經病變)之發生率、性質及嚴重程度。 ● 如由劑量中止、劑量減少及劑量強度評估之耐受性。 ● 如由FACT-GOG/Ntx12量測的周圍神經病變之發生率及評估。 ● 基線時抗藥物抗體(ADA)之流行率及在研究期間ADA之發生率。生物標記物目標及終點 探索性生物標記物目標 The safety endpoints of the second phase of this study are as follows: ● According to NCI CTCAE v5.0 and physical examination results, the incidence, nature and severity of AEs (including peripheral neuropathy). ● If tolerability is assessed by dose discontinuation, dose reduction, and dose intensity. ● The incidence and evaluation of peripheral neuropathy as measured by FACT-GOG/Ntx12. ● The prevalence of anti-drug antibodies (ADA) at baseline and the incidence of ADA during the study period. Biomarker targets and endpointsExploratory biomarker targets

本研究第2階段之探索性生物標記物終點係鑑別滿足以下標準之生物標記物： ● 對帕妥珠單抗維多汀(亦即 ，預測性生物標記物)之反應的預示。 ● 與進展成更嚴重之疾病(亦即 ，預後生物標記物)有關。 ● 提供帕妥珠單抗維多汀活性之證據，或增加對疾病生物學之知識及了解。探索性生物標記物終點 The exploratory biomarker endpoint of the second phase of this study is to identify biomarkers that meet the following criteria: ● Predictions of response to Pertuzumab vedotine (ie , predictive biomarker). ● Related to progression to more serious diseases ( ie , prognostic biomarkers). ● Provide evidence of Pertuzumab Vidotin activity, or increase knowledge and understanding of disease biology. Exploratory biomarker endpoint

本研究第2階段之探索性生物標記物目標係，該等功效終點包括總體存活期(OS)、無進展存活期(PFS)及完全反應(CR)率在內之功效終點與探索性生物標記物，諸如起源亞型之分子DLBCL預後細胞、BCL2及MYC雙表現因子以及關鍵淋巴瘤突變之間的關聯。藥物動力學目標及終點 藥物動力學目標 The exploratory biomarker targets for the second phase of this study are the efficacy endpoints including overall survival (OS), progression-free survival (PFS), and complete response (CR) rates, including efficacy endpoints and exploratory biomarkers The relationship between DLBCL prognostic cells, BCL2 and MYC dual expression factors, and key lymphoma mutations. Pharmacokinetic goals and end-point pharmacokinetic goals

本研究第2階段之藥物動力學目標係評價帕妥珠單抗維多汀之藥物動力學(PK)譜。藥物動力學終點 The pharmacokinetic goal of the second phase of this study is to evaluate the pharmacokinetic (PK) profile of Pertuzumab vedotine. Pharmacokinetic endpoint

本研究第2階段之藥物動力學終點如下： ● 復發性或難治性DLBCL患者中帕妥珠單抗維多汀結合R-GemOx之PK譜。 ● 帕妥珠單抗維多汀與R-GemOx之間之潛在PK相互作用。II. 患者 The pharmacokinetic endpoints of the second phase of this study are as follows: ● The PK profile of Pertuzumab vedotine combined with R-GemOx in patients with relapsed or refractory DLBCL. ● Potential PK interaction between Pertuzumab Vidotin and R-GemOx. II. Patients

在安全性磨合期(第1階段)中招募約10名患者，且在隨機分組部分(第2階段)中招募約206名患者，總計約216名患者。 A. 納入標準 Approximately 10 patients were recruited in the safety run-in period (stage 1), and approximately 206 patients were recruited in the randomization part (stage 2), for a total of approximately 216 patients. A. Inclusion criteria

若患者滿足以下標準，則將其納入本研究中： ● 年齡≥18歲。 ● 經組織學確定的非特指型(NOS)彌漫性大B細胞淋巴瘤，或有惰性疾病轉化為DLBCL之病史。 ● 至少一線(≥1線)之先前全身性療法。 ○    允許先前自體造血幹細胞移植(HSCT)；化學療法之後進行鞏固性自體HSCT計為一線療法。 ○    允許先前同種異體HSCT，只要患者停用所有免疫抑制療法且沒有活動性移植物抗宿主病(GVHD)；化學療法之後進行同種異體HSCT計為一線療法。 ○    局部療法(例如 放射療法)不被視為治療方法。 ● 復發性或難治性疾病，定義如下： ○    復發性：自完成最後一線療法開始持續≥6個月之反應後復發的疾病。 ○    難治性：在治療期間進展或在先前療法之6個月內(＜ 6個月)進展的疾病。 ● 至少一個二維可量測之病灶，定義為如由CT或MRI所量測，最長尺寸＞ 1.5 cm。 ● 美國東岸癌症臨床研究合作組織(ECOG)體能狀態為0、1或2。 ○    ECOG體能狀態為3的患者被認為納入RCT階段(第2階段)，但前提是該狀態與DLBCL相關，且在篩查期間的7天類固醇治療前期(例如 1 mg/kg潑尼松)之後。必須觀察到ECOG體能狀態隨後改善成2或更低，才有資格招募至研究中。 ● 如藉由以下所定義的適當血液功能： ○    血紅蛋白≥ 8 g/dL。 ○    嗜中性白血球絕對計數(ANC)≥1.5 × 109 個/公升或當嗜中性白血球減少症係由基礎疾病引起時且在投與類固醇之前，則≥ 0.5 × 109 個。 ○    血小板計數≥ 75 × 109 個/公升或當血小板減少症係由基礎疾病引起時，則≥ 50 × 109 個。 ● 對於有生育能力的婦女：同意戒酒或使用避孕措施，並同意不捐獻卵子。 ● 對於男性：同意戒酒或使用避孕措施，並同意不捐獻精子。 B. 排除標準 Patients will be included in this study if they meet the following criteria: ● Age ≥18 years. ● Histologically determined non-specific type (NOS) diffuse large B-cell lymphoma, or a history of indolent disease transformed into DLBCL. ● At least one line (≥1 line) of previous systemic therapy. ○ Prior autologous hematopoietic stem cell transplantation (HSCT) is allowed; consolidation autologous HSCT after chemotherapy is counted as first-line therapy. ○ Prior allogeneic HSCT is allowed, as long as the patient stops all immunosuppressive therapies and does not have active graft-versus-host disease (GVHD); allogeneic HSCT after chemotherapy is counted as first-line therapy. ○ Local therapy ( such as radiation therapy) is not considered a treatment method. ● Relapsed or refractory diseases are defined as follows: ○ Relapsed: Diseases that relapse after a response that lasts ≥ 6 months since the completion of the last-line therapy. ○ Refractory: diseases that progress during treatment or within 6 months (<6 months) of previous therapy. ● At least one two-dimensional measurable lesion is defined as the longest dimension> 1.5 cm as measured by CT or MRI. ●East Coast Cancer Clinical Research Cooperative (ECOG) physical status is 0, 1, or 2. ○ Patients with an ECOG performance status of 3 are considered to be included in the RCT stage (stage 2), provided that the status is related to DLBCL and after the 7-day pre-steroid treatment ( for example, 1 mg/kg prednisone) during the screening period . It must be observed that the ECOG performance status subsequently improves to 2 or lower to be eligible for enrollment in the study. ● Appropriate blood function as defined by the following: ○ Hemoglobin ≥ 8 g/dL. ○ absolute neutrophil count (ANC) ≥1.5 × 10 9 cells / liter or when a disease based neutropenia caused by underlying diseases and before administration of the steroid, the ≥ 0.5 × 10 9 th. ○ Platelet count ≥ 75 × 10 9 /L or when thrombocytopenia is caused by an underlying disease, then ≥ 50 × 109 . ● For women of fertility: agree to abstain from alcohol or use contraceptive measures, and agree not to donate eggs. ● For men: agree to abstain from alcohol or use contraceptive measures, and agree not to donate sperm. B. Exclusion criteria

若患者滿足以下標準，則將其納入本研究中： ● 對人類化或鼠類單株抗體(或重組抗體相關融合蛋白)有嚴重過敏或過敏性反應史，或已知對鼠類產品敏感或過敏史。 ● 禁忌使用利妥昔單抗、吉西他濱或奧沙利鉑。 ● 在招募時，根據NCI CTCAE v5.0評估為 ＞1級之周圍神經病變。 ● 先前使用帕妥珠單抗維多汀或吉西他濱加鉑基藥劑之組合。 ● 參與任何先前或正在進行之帕妥珠單抗維多汀試驗。 ● 在第1週期第1天之前的2週內，採用放射療法、化學療法、免疫療法、免疫抑制療法或用於癌症治療目的之任何研究藥劑進行之治療。 ○    除脫髮外，由先前療法引起的所有急性、臨床上顯著之治療相關毒性必須在第1週期第1天之前消退成≤2級。 ● 徵募時計劃進行的自體或同種異體幹細胞移植。 ○    本試驗排除適於幹細胞移植的僅接受一種先前療法之患者。不適合移植之原因包括年齡、體能狀態、共病、移植失敗或手術失敗、對挽救療法之反應不足、患者拒絕或後勤原因。 ● 徵募時原發性或繼發性中樞神經系統(CNS)淋巴瘤。 ● 里希特氏轉化或先前毛細管滲漏症候群(CLL)。 ● 以下任何實驗室異常值，除非實驗室異常值係由於潛在淋巴瘤引起： ○    肌酐 ＞ 1.5 ×正常值上限(ULN)或測得的肌酐清除率＜ 30 mL/min。 ○    天冬胺酸轉胺酶(AST)或丙胺酸轉胺酶(ALT) ＞ 2.5 × ULN。 ○    總膽紅素≥1.5 × ULN；若總膽紅素≤3 × ULN，則招募患有吉爾伯特氏病(Gilbert disease)之患者。 ○    在無治療性抗凝存在下，國際標準化比值(INR)或凝血酶原時間(PT) ＞ 1.5 × ULN。 ○    在無狼瘡抗凝物存在下，部分凝血酶原時間(PTT)或活化的部分凝血酶原時間(aPTT) ＞ 1.5 × ULN。 ● 可能會影響與方案或結果解釋之順應性的其他惡性疾病史。例外包括： ○    在研究之前的任何時間患有積極治療之皮膚基底或鱗狀細胞癌或子宮頸原位癌 病史的患者均符合條件。 ○    患有出於根治意圖適當治療之任何其他惡性疾病的患者(且在招募之前惡性疾病未經治療≥2年即緩解)係符合條件的。 ○    患有在研究前任何時間均不需要治療的低度惡性早期前列腺癌(格里森評分(Gleason score)為6分或更低，第1期或第2期)的患者係符合條件的。 ● 可能會影響與方案或結果解釋之順應性的不受控制之重大伴隨疾病的跡象，包括重大心血管疾病(諸如紐約心臟協會[NYHA] 第III級或第IV級心髒病、近6個月內發生心肌梗塞、不穩定型心律失常或不穩定型心絞痛)或重大肺部疾病(包括阻塞性肺病及支氣管痙攣史)。 ● 在研究招募時已知的活動性細菌、病毒、真菌、分枝桿菌、寄生蟲或其他感染(不包括甲床之真菌感染)，或在第1週期第1天之前4週內發生的任何主要感染事件。 ● 疑似或潛伏性肺結核患者；潛伏性結核病係藉由陽性乾擾素-γ釋放檢定確定。 ● 針對慢性B型肝炎病毒(HBV)感染之陽性測試結果(定義為陽性B型肝炎表面抗原[HBsAg]血清學)。 ○    若未偵測到HBV DNA，則納入患有隱匿性或先前HBV感染之患者(定義為陰性HBsAg及陽性B型肝炎核心抗體[HBcAb])，但前提是該等患者在每個週期之第1天以及在最後一個研究治療週期後至少12個月內的每個月經歷DNA測試。 ● 針對C型肝炎病毒(HCV)抗體之陽性測試結果。 ○    針對HCV抗體呈陽性之患者只有在聚合酶鏈反應(PCR)針對HCV RNA呈陰性之情況下才有資格。 ● 已知呈人類免疫缺陷病毒(HIV)血清反應陽性狀態之病史。對於HIV狀態不明之患者，若當地法規要求，則在篩查中執行HIV測試。 ● 治療前4週內接種活疫苗。 ● 近期接受除診斷外的重大手術(在第1週期第1天開始前的6週內)。 ● 任何其他疾病、代謝功能異常、身體檢查發現或臨床實驗室發現提供關於某種疾病或病況之合理懷疑，該疾病或病況禁忌使用研究藥物或可能會影響結果解釋或使患者處於治療併發症高風險中。 ● 懷孕或哺乳，或打算在研究期間或在最後一劑研究藥物後之12個月內懷孕。III. 研究設計 Patients will be included in this study if they meet the following criteria: ● Have a history of severe allergies or allergic reactions to humanized or murine monoclonal antibodies (or recombinant antibody-related fusion proteins), or are known to be sensitive to murine products or allergies. ● The use of rituximab, gemcitabine or oxaliplatin is contraindicated. ● At the time of recruitment, according to NCI CTCAE v5.0, it was assessed as> Grade 1 peripheral neuropathy. ● Previous use of Pertuzumab vedotine or gemcitabine plus platinum-based agents. ● Participate in any previous or ongoing Pertuzumab Verdotin trial. ● Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy or any research drug used for cancer treatment within 2 weeks before the first day of the first cycle. ○ Except for alopecia, all acute and clinically significant treatment-related toxicities caused by previous therapies must subside to grade ≤2 before the first day of the first cycle. ● Autologous or allogeneic stem cell transplantation planned during recruitment. ○ This trial excludes patients who are eligible for stem cell transplantation and receive only one previous therapy. Reasons that are not suitable for transplantation include age, physical status, comorbidities, transplantation failure or surgical failure, insufficient response to salvage therapy, patient rejection, or logistical reasons. ● Primary or secondary central nervous system (CNS) lymphoma at the time of recruitment. ● Richter's transformation or previous capillary leak syndrome (CLL). ● Any of the following laboratory abnormal values, unless the laboratory abnormal values are caused by underlying lymphoma: ○ Creatinine> 1.5 × upper limit of normal (ULN) or measured creatinine clearance rate <30 mL/min. ○ Aspartate aminotransferase (AST) or alanine aminotransferase (ALT)> 2.5 × ULN. ○ Total bilirubin ≥ 1.5 × ULN; if total bilirubin ≤ 3 × ULN, recruit patients with Gilbert disease. ○ In the absence of therapeutic anticoagulation, the international normalized ratio (INR) or prothrombin time (PT)> 1.5 × ULN. ○ In the absence of lupus anticoagulant, partial prothrombin time (PTT) or activated partial prothrombin time (aPTT)> 1.5 × ULN. ● History of other malignant diseases that may affect the compliance with the protocol or interpretation of the results. Exceptions include: ○ Patients with a history of actively treated skin basal or squamous cell carcinoma or cervical carcinoma in situ at any time before the study are eligible. ○Patients with any other malignant diseases that are appropriately treated with the intent of radical cure (and the malignant diseases are remission without treatment for ≥ 2 years before recruitment) are eligible. ○ Patients with low-grade early-stage prostate cancer (Gleason score of 6 or lower, stage 1 or stage 2) that do not require treatment at any time before the study are eligible. ● Signs of uncontrolled major concomitant diseases that may affect compliance with the protocol or interpretation of the results, including major cardiovascular diseases (such as New York Heart Association [NYHA] grade III or IV heart disease, recent 6 months Myocardial infarction, unstable arrhythmia or unstable angina pectoris) or major lung disease (including obstructive lung disease and history of bronchospasm). ● Active bacteria, viruses, fungi, mycobacteria, parasites, or other infections (excluding fungal infections of the nail bed) known at the time of research recruitment, or any that occurred within 4 weeks before the first day of the first cycle Major infection events. ● Patients with suspected or latent tuberculosis; latent tuberculosis is confirmed by positive interferon-γ release test. ● Positive test result for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen [HBsAg] serology). ○ If HBV DNA is not detected, include patients with occult or previous HBV infection (defined as negative HBsAg and positive hepatitis B core antibody [HBcAb]), provided that these patients are in the first period of each cycle Go through DNA testing for 1 day and every month for at least 12 months after the last study treatment cycle. ● Positive test result against hepatitis C virus (HCV) antibody. ○ Patients who are positive for HCV antibodies are only eligible if they are negative for HCV RNA by polymerase chain reaction (PCR). ● Known medical history of human immunodeficiency virus (HIV) seropositive status. For patients with unknown HIV status, if required by local regulations, HIV testing will be performed during the screening. ● Inoculate live vaccines within 4 weeks before treatment. ●Recently undergoing major surgery other than diagnosis (within 6 weeks before the start of day 1 of cycle 1). ● Any other diseases, abnormal metabolic function, physical examination findings or clinical laboratory findings provide reasonable suspicion about a certain disease or condition that is contraindicated in the use of study drugs or may affect the interpretation of the results or put the patient at high complications At risk. ● Are pregnant or breastfeeding, or intend to become pregnant during the study period or within 12 months after the last dose of study drug. III. Research Design

本研究係針對患有復發性或難治性DLBCL之患者進行的一項III期、多中心、開放標記之隨機化研究。本研究由篩選期、治療期(第1階段及第2階段)及治療後期組成。治療後期包括在最後一劑研究治療後28天發生的治療結束訪視及隨訪期。報告不良事件、嚴重不良事件及特別關注之不良事件，直至最後一劑研究藥物後90天或直至起始非方案指定之抗淋巴瘤治療(NALT)為止。This study is a phase III, multicenter, open-label randomized study for patients with relapsed or refractory DLBCL. This study consists of a screening period, a treatment period (phase 1 and phase 2), and a later treatment period. The post-treatment period includes the end-of-treatment visit and follow-up period that occurred 28 days after the last dose of study treatment. Report adverse events, serious adverse events, and adverse events of special concern until 90 days after the last dose of study drug or until the initiation of non-planned anti-lymphoma therapy (NALT).

本研究之總體設計呈現於圖 1 中。 A. 篩選期 The overall design of this study is presented in Figure 1 . A. Screening period

為了符合本研究的條件，患者必須患有經組織學確認的復發性或難治性DLBCL。In order to qualify for this study, patients must have histologically confirmed relapsed or refractory DLBCL.

患者可在徵募前經歷自體造血幹細胞移植(HSCT)；化學療法之後進行鞏固性自體HSCT計為一線療法 。先前經歷同種異體HSCT之患者亦招募，只要患者停用所有免疫抑制療法且未患活動性移植物抗宿主病(GVHD)；化學療法之後進行同種異體HSCT計為一線療法。局部療法(例如 放射療法)不被視為治療線。招募時排除患有根據NCI CTCAE v5.0評估為超過1級之周圍神經病變的患者。其他納入及排除標准提供於以上第 II 節 中。 B. 治療期 Patients can undergo autologous hematopoietic stem cell transplantation (HSCT) before recruitment; consolidation autologous HSCT after chemotherapy is counted as first-line therapy. Patients who have previously undergone allogeneic HSCT are also recruited, as long as the patient stops all immunosuppressive therapies and does not suffer from active graft-versus-host disease (GVHD); allogeneic HSCT after chemotherapy is counted as first-line therapy. Local therapy ( e.g. radiation therapy) is not considered a treatment line. Patients with peripheral neuropathy that was assessed as more than grade 1 according to NCI CTCAE v5.0 were excluded at the time of recruitment. Other inclusion and exclusion criteria provided in section II above. B. Treatment period

治療期分為兩個階段，即安全性磨合階段(第1階段)及隨機化對照試驗(第2階段)。The treatment period is divided into two stages, namely the safety run-in stage (stage 1) and randomized controlled trials (stage 2).

在第1階段的安全性磨合中，有10名患者接受用Pola-R-GemOx進行的實驗性研究治療。In the first phase of the safety run-in, 10 patients received experimental treatment with Pola-R-GemOx.

在第2階段的隨機化對照試驗(RCT)中，患者以1:1比率隨機分配至接受用Pola-R-GemOx進行的實驗性研究治療或用R-GemOx進行的對照研究治療。In the Phase 2 Randomized Controlled Trial (RCT), patients were randomly assigned to receive experimental study treatment with Pola-R-GemOx or controlled study treatment with R-GemOx at a ratio of 1:1.

本研究之隨機化部分(第2階段)的主要目標係評價如由OS量測的Pola-R-GemOx與R-GemOx在復發性或難治性DLBCL患者中之功效的比較。假設R-GemOx組之中值OS為9.5個月(Mounier等人 ，(2013) Haematologica，98:1726-1731)且隨機分組比率為 1:1，需要進行121次事件才能偵測到6.3個月之中值OS組間差異(危險比[HR] = 0.60)且機率為80%且雙向α為0.05。基於上述統計假設，並預期在最後一名患者隨機分組後約11個月之招募期(每個月18名患者)及14個月之隨訪，本研究第2階段總計納入約206名患者，其中考慮到10%之估計退出率。患者按1:1比率隨機分入Pola-R-GemOx及R-GemOx治療。The main goal of the randomization part (phase 2) of this study is to evaluate the comparison of the efficacy of Pola-R-GemOx and R-GemOx in patients with relapsed or refractory DLBCL as measured by OS. Assuming that the median OS in the R-GemOx group is 9.5 months (Mounier et al . (2013) Haematologica, 98:1726-1731) and the randomization ratio is 1:1, 121 events are required to detect 6.3 months The median OS difference between groups (hazard ratio [HR] = 0.60) and the probability was 80% and the two-way α was 0.05. Based on the above statistical assumptions, and the enrollment period of about 11 months (18 patients per month) and a follow-up period of 14 months after the randomization of the last patient, a total of about 206 patients will be included in the second phase of this study. Taking into account the estimated exit rate of 10%. Patients were randomly divided into Pola-R-GemOx and R-GemOx treatments at a ratio of 1:1.

在治療期之兩個階段中，患者接受至多8個週期的Pola-R-GemOx或8個週期的R-GemOx，每個週期為21天。第 1 階段：安全性磨合期 In the two phases of the treatment period, patients receive up to 8 cycles of Pola-R-GemOx or 8 cycles of R-GemOx, each cycle for 21 days. Phase 1 : Safety run-in period

總計10名患者接受Pola-R-GemOx治療。該10名患者在三個組中錯開接受治療： ● 第1組：前3名患者。 ● 第2組：其次3名患者。 ● 第3組：最後4名患者。A total of 10 patients received Pola-R-GemOx treatment. The 10 patients received treatment in three groups staggered: ● Group 1: The first 3 patients. ● Group 2: 3 patients next. ● Group 3: The last 4 patients.

在每個組內，在所有受試者之第四個週期結束時評價安全性，且關注點為急性周圍神經病變毒性。在一組內進行所有安全性評價並明晰進一步受試者招募計劃後，即開始下一組之招募。繼續進行此程序，直至全部三個組均已完全徵募為止。Within each group, safety was evaluated at the end of the fourth cycle of all subjects, and the focus was on acute peripheral neuropathy toxicity. After performing all safety evaluations in one group and clarifying the further subject recruitment plan, the recruitment of the next group will be started. Continue this procedure until all three groups have been fully recruited.

在分別完成第1組及第2組之所有安全性評價並批准徵募下一組之前，不招募第2組及第3組。若一組內的患者在第4個週期之治療前因疾病進展、死亡或不直接歸因於周圍神經病變之任何其他原因而中止治療，則該患者將被替換。The second and third groups will not be recruited until all the safety evaluations of the first and second groups are completed and the recruitment of the next group is approved. If a patient in a group discontinues treatment due to disease progression, death, or any other reason not directly attributable to peripheral neuropathy before the fourth cycle of treatment, the patient will be replaced.

一旦一組所有人群均完成至少四個週期，即評價Pola-R-GemOx之總體安全性特徵，且特別關注周圍神經病變，並就是否開啟下一個組提供建議 (推進/不推進決策)。阻止進一步招募至下一組的潛在理由係一組內＞ 33.33%的患者患有≥3級之周圍神經病變的情形，該疾病不能在14天內消退為≤1級。劑量調整之潛在有益作用、周圍神經病變事件消退之時程等被認為在推進/不推進決策中。此外，在第2組及第3組之安全性評價時，對先前組中進行超過第四個治療週期之所有患者再評價，以評估利用Pola-R-GemOx之累積神經毒性的可能性以及周圍神經病變消退之過程。Once all groups in a group have completed at least four cycles, evaluate the overall safety characteristics of Pola-R-GemOx, pay special attention to peripheral neuropathy, and provide advice on whether to open the next group (advance/non-advance decision). The underlying reason for preventing further recruitment to the next group is that> 33.33% of the patients in the group have peripheral neuropathy ≥ grade 3, which cannot resolve to grade ≤ 1 within 14 days. The potential beneficial effects of dose adjustment, the time course of the resolution of peripheral neuropathy events, etc. are considered to be in the decision to advance/not advance. In addition, in the safety evaluation of the second and third groups, all patients in the previous group who had undergone more than the fourth treatment cycle were re-evaluated to assess the possibility of cumulative neurotoxicity using Pola-R-GemOx and the surrounding The process of neuropathy subsiding.

第1階段還評估了帕妥珠單抗維多汀與R-GemOx之組合的ADA及稀疏PK譜。Phase 1 also evaluated the ADA and sparse PK profile of the combination of Pertuzumab Vidotin and R-GemOx.

本研究安全磨合期(第1階段)之概述提供於圖 2 中。An overview of the safe running-in period (phase 1) of this study is provided in Figure 2 .

在第十名受試者完成整個治療期(圖 2 )後，評估Pola-R-GemOx方案之安全性及耐受性，並作出關於在第十名患者之治療結束時是否繼續進入研究第2階段(RCT階段)之決策(推進/不推進決策)(圖 2 )。在第1階段結束時的形式推進/不推進決策係如下確定： ● 當在第1階段治療期中剩餘的最後一名患者接受了最後一劑Pola-R-GemOx時，對第1階段研究人群的整體安全性進行評述，特別關注級別≥3級之周圍神經病變事件之頻率、病程及可逆性： ○    若第1階段(n = 10)中有3名或更少患者在治療期內患有≥3級之周圍神經病變，該疾病不能在14天內消退為≤1級，則研究繼續進行至第2階段，即隨機化對照試驗(RCT)階段。 ○    若第1階段(n = 10)中有4名或更少患者在治療期內患有≥3級之周圍神經病變，該疾病不能在14天內消退為≤1級，則研究暫時擱置。 ○    評估在劑量調整後在原始研究治療劑量下周圍神經病變之風險是否能令人滿意地減輕。After the tenth subject has completed the entire treatment period ( Figure 2 ), evaluate the safety and tolerability of the Pola-R-GemOx regimen, and make a decision on whether to continue to enter the second study at the end of the tenth patient’s treatment Stage (RCT stage) decision (advance/non-advance decision) ( Figure 2 ). The decision-making system for form advance/non-advance at the end of phase 1 is determined as follows: ● When the last patient remaining in the treatment period of phase 1 received the last dose of Pola-R-GemOx, the effect of the phase 1 study population The overall safety is reviewed, with special attention to the frequency, course and reversibility of peripheral neuropathy events of grade ≥3: ○ If 3 or less patients in stage 1 (n = 10) have ≥ For grade 3 peripheral neuropathy, if the disease does not resolve within 14 days to ≤ grade 1, the study will continue to the second stage, which is the randomized controlled trial (RCT) stage. ○ If 4 or fewer patients in stage 1 (n = 10) have peripheral neuropathy of grade ≥3 during the treatment period, and the disease cannot resolve to grade ≤1 within 14 days, the study will be temporarily shelved. ○ Assess whether the risk of peripheral neuropathy can be satisfactorily reduced at the original research dose after the dose adjustment.

根據前面的資訊，提供關於是否繼續進入第2階段(RCT階段)之建議。第 2 階段：隨機化對照試驗 Based on the previous information, provide advice on whether to proceed to the second stage (RCT stage). Phase 2 : Randomized Controlled Trials

若在安全性磨合期(第1階段)中Pola-R-GemOx組合療法被認為可耐受的，則開始進入RCT階段之招募。總計206名合格患者以1:1 比率隨機分配至接受Pola-R-GemOx (實驗性治療)或R-GemOx (對照)。If the Pola-R-GemOx combination therapy is considered tolerable during the safety run-in period (phase 1), then the recruitment into the RCT phase begins. A total of 206 eligible patients were randomly assigned to receive Pola-R-GemOx (experimental treatment) or R-GemOx (control) at a ratio of 1:1.

隨機分組係藉由IxRS，使用分層排列區組(stratified permuted block)執行。分層因素包括：1)先前的多線全身治療或療法數(1對比≥2)；2)最後一次全身治療或療法之結果(復發性對比難治性)；及3)年齡(≤70歲對比＞ 70歲)。對於根據先前的多線全身治療或療法數分層：化學療法之後進行鞏固性自體HSCT計為一線療法；化學療法之後進行同種異體HSCT計為一線療法；局部療法(例如 放射療法)不被視為治療方法。對於根據最後一次全身性療法或治療之結果分層：復發性疾病定義為在最後一線治療完成後≥6個月復發的疾病；難治性疾病定義為在治療期間進展或在先前療法之6個月內(＜ 6個月)進展之疾病。Random grouping is performed by IxRS using a stratified permuted block. Stratification factors include: 1) the number of previous multi-line systemic treatments or therapies (1 vs. ≥ 2); 2) the results of the last systemic treatment or therapy (relapse vs. refractory); and 3) age (≤70 years vs. > 70 years old). For stratification according to the number of previous multi-line systemic treatments or therapies: consolidation autologous HSCT after chemotherapy is counted as first-line therapy; allogeneic HSCT after chemotherapy is counted as first-line therapy; local therapy ( such as radiotherapy) is not considered For the treatment method. For stratification based on the results of the last systemic therapy or treatment: recurrent disease is defined as disease that relapses ≥ 6 months after the completion of the last-line treatment; refractory disease is defined as progression during treatment or 6 months of previous treatment Disease that progressed within (< 6 months).

分層產生的治療組在疾病進展及疾病狀態方面大致相同，由此確保實驗組(Pola-R-GemOx)與對照組(R-GemOx)之間的可比性。The treatment groups generated by stratification are roughly the same in terms of disease progression and disease state, thereby ensuring the comparability between the experimental group (Pola-R-GemOx) and the control group (R-GemOx).

在RCT階段執行中期安全性分析。在將前10名及20名患者分別隨機分配至各組中並完成至少2個治療週期後，執行第一次及第二次安全性中期分析。此後，中期安全性評估之頻率取決於在第二次安全性中期評估期間所觀察到的≥3級之周圍神經病變事件的數量。在14天內恢復至≤1級的≥3級之周圍神經病變不被考慮在停止規則中。Perform mid-term safety analysis during the RCT phase. After the top 10 and 20 patients were randomly assigned to each group and completed at least 2 treatment cycles, the first and second safety interim analysis were performed. Thereafter, the frequency of the interim safety assessment depends on the number of peripheral neuropathy events ≥ Grade 3 observed during the second interim safety assessment. Peripheral neuropathy of grade ≥3 that recovers to grade ≤1 within 14 days is not considered in the stopping rule.

藉由根據NCI CTCAE v5.0之不良事件、FACT/GOG-Ntx12得分、臨床實驗室測試結果、心電圖(ECG)及生命體徵評估安全性。反應評估係根據Lugano 2014標準，基於治療結束時正電子發射斷層攝影術-電腦斷層攝影(PET-CT)掃描進行。The safety is evaluated by NCI CTCAE v5.0 adverse events, FACT/GOG-Ntx12 score, clinical laboratory test results, electrocardiogram (ECG) and vital signs. The response assessment is based on the Lugano 2014 standard, based on a positron emission tomography-computer tomography (PET-CT) scan at the end of the treatment.

第2階段評估帕妥珠單抗維多汀與R-GemOx之組合的ADA及稀疏PK譜。此外，第2階段亦評估生物標記物及患者報告結果。 C. 研究結束及研究持續時間 In the second stage, the ADA and sparse PK profile of the combination of Pertuzumab Vidotin and R-GemOx were evaluated. In addition, Phase 2 also evaluates biomarkers and patient report results. C. The end of the study and the duration of the study

在初步安全性磨合期後，隨機分組階段之徵募在約11個月內進行。After the initial safety run-in period, the enlistment of the random grouping phase is carried out within about 11 months.

此係一個事件驅動之試驗。當死亡事件達到目標數量(121例死亡)時，即確定最終OS分析之臨床截止日期，預期此係在研究之RCT階段中第一名患者被隨機分組後約25個月(第一名患者登錄日[first patient in，FPI])。This is an event-driven experiment. When the target number of deaths (121 deaths) is reached, the clinical cut-off date for the final OS analysis is determined. It is expected that this will be about 25 months after the first patient is randomized in the RCT phase of the study (the first patient logs in Day [first patient in, FPI]).

研究持續時間及進行最終分析之時間取決於徵募速率及發生的事件數。在整個研究過程中監測死亡事件，並更新研究時間表。IV. 研究用藥品之投與劑量及時間 The duration of the study and the time to conduct the final analysis depend on the rate of recruitment and the number of events that occur. Monitor deaths throughout the study and update the study schedule. IV. Dosage and time of research drugs

本研究之研究用藥品(investigational medicinal product，IMP)係Pola-R-GemOx。對照療法係R-GemOx。The investigational medicinal product (IMP) used in this study is Pola-R-GemOx. The control therapy is R-GemOx.

Pola-R-GemOx實驗治療方案之概述提供於圖 3A 。An overview of the experimental treatment regimen of Pola-R-GemOx is provided in Figure 3A .

R-GemOx對照治療方案之概述提供於圖 3B 。 A. 帕妥珠單抗維多汀 An overview of the R-GemOx control regimen is provided in Figure 3B . A. Pertuzumab Vidotin

僅在實驗治療組(Pola-R-GemOx)中，在每個21天週期之第1天，靜脈內投與1.8 mg/kg帕妥珠單抗維多汀，持續至多8個週期。Only in the experimental treatment group (Pola-R-GemOx), 1.8 mg/kg Pertuzumab vedotine was administered intravenously on the first day of each 21-day cycle for up to 8 cycles.

帕妥珠單抗維多汀係在同一天於投與利妥昔單抗之後投與，或在利妥昔單抗劑量延遲之情況下於次日投與。Pertuzumab vedotine was administered on the same day after rituximab, or on the next day when the dose of rituximab was delayed.

使用在篩選(第-28天至第-1天)期間獲得的患者體重確定所有治療週期之劑量；若在給定治療週期第1天之前的96個小時內患者的體重大於或小於在篩選期間獲得的體重的10%，則使用新體重計算劑量。引起劑量調整之體重被視為將來劑量調整之新參考體重。相應地修改所有後續劑量。若當地護理標準容許，則關於體重變化＜10%之劑量調整亦係可接受的。Use the weight of the patient obtained during the screening (day -28 to day -1) to determine the dose for all treatment cycles; if the patient's weight in the 96 hours prior to day 1 of the given treatment cycle is greater or less than during the screening period 10% of the weight obtained, the new weight is used to calculate the dose. The weight that caused the dose adjustment is regarded as the new reference weight for future dose adjustments. Modify all subsequent doses accordingly. If the local standard of care permits, a dose adjustment with respect to weight change <10% is also acceptable.

將初始劑量投與患者，該等患者應在90±10分鐘內充分補水(根據當地指南)。在開始投與帕妥珠單抗維多汀之前≥30分鐘，可向各個患者投與前驅給藥(例如 按照機構標準實踐，口服500-1000 mg對乙醯胺基酚或撲熱息痛(paracetamol)及50-100 mg苯海拉明(diphenhydramine))。主治醫生可酌情投與皮質類固醇類藥物。若在沒有前驅給藥的情況下，在第一次輸注時觀察到輸注相關反應(IRR)，則在後續給藥之前投與前驅給藥。The initial dose is administered to patients, and these patients should be fully hydrated within 90 ± 10 minutes (according to local guidelines). Before starting the administration of Pertuzumab Verdotin ≥30 minutes, each patient can be administered prodrug ( for example, according to the standard practice of the institution, oral 500-1000 mg of p-acetaminophen or paracetamol (paracetamol) and 50-100 mg diphenhydramine (diphenhydramine)). The attending doctor may administer corticosteroids as appropriate. If an infusion-related reaction (IRR) is observed during the first infusion in the absence of prodrug, the prodrug should be administered before the subsequent dosing.

對於經歷輸注相關症狀之患者，將減慢或中止帕妥珠單抗維多汀那個輸注。在初始劑量後，觀察患者90分鐘，確定是否出現發熱、發冷、寒戰、低血壓、噁心或其他輸注相關症狀。若先前的輸注耐受性良好，則在30±10分鐘內投與後續劑量的帕妥珠單抗維多汀，隨後在輸注後進行30分鐘的觀察期。For patients experiencing infusion-related symptoms, the infusion of Pertuzumab vedotine will be slowed or discontinued. After the initial dose, observe the patient for 90 minutes to determine whether there is fever, chills, chills, hypotension, nausea, or other infusion-related symptoms. If the previous infusion is well tolerated, the subsequent dose of Pertuzumab Verdotin is administered within 30 ± 10 minutes, followed by a 30-minute observation period after the infusion.

在投與帕妥珠單抗維多汀期間，在開始輸注之前、在輸注期間每15±5分鐘、在輸注結束時、在第1週期之給藥完成後每30±10分鐘持續90分鐘、以及在後續週期中完成給藥後30±10分鐘，評估生命體徵。During the administration of Pertuzumab Verdotin, before the start of the infusion, every 15±5 minutes during the infusion, at the end of the infusion, every 30±10 minutes after the completion of the first cycle for 90 minutes, And 30 ± 10 minutes after the completion of the administration in the subsequent cycle, the vital signs are assessed.

帕妥珠單抗維多汀係凍乾調配物 (每個小瓶140 mg)。投藥之前，將凍乾的粉末用無菌注射用水復原至7.2 mL體積。 B. 利妥昔單抗 Pertuzumab Vidotin is a lyophilized formulation (140 mg per vial). Before administration, the lyophilized powder was reconstituted to a volume of 7.2 mL with sterile water for injection. B. Rituximab

在每個21天週期的第1天，靜脈內投與375 mg/m2 利妥昔單抗(Mabthera/Rituxan® )，持續至多8個週期。利妥昔單抗係在同一天於投與帕妥珠單抗維多汀之前投與，或在利妥昔單抗劑量延遲之情況下，於次日投與帕妥珠單抗維多汀。On day 1 of each 21-day cycle, 375 mg/m 2 rituximab (Mabthera/Rituxan ® ) was administered intravenously for up to 8 cycles. Rituximab was administered on the same day before Pertuzumab Verdotin, or in the case of a delay in the dose of Rituximab, Pertuzumab Verdot was administered on the next day .

在第1週期投與利妥昔單抗期間，在輸注前，接著在輸注開始後約每15±5分鐘持續90分鐘、以及在輸注結束後每30±10分鐘直至1小時，獲得生命體徵。在後續週期投與利妥昔單抗期間，在輸注前、在輸注開始後及在輸注結束後約每30±10分鐘直至1小時，記錄下生命體徵。During the first cycle of administration of rituximab, vital signs were obtained before the infusion, then approximately every 15±5 minutes after the start of the infusion for 90 minutes, and every 30±10 minutes to 1 hour after the end of the infusion. During the administration of rituximab in subsequent cycles, the vital signs were recorded before the infusion, after the start of the infusion, and approximately every 30±10 minutes to 1 hour after the end of the infusion.

使用在篩選時計算的患者體表面積(BSA)計算整個研究期間利妥昔單抗的劑量，除非患者體重自篩選時增加或減少＞ 10%，在此情況下，將重新計算BSA並用於後續劑量測定。對於肥胖患者，沒有BSA上限且建議採用實際體重，而非經調整劑量。根據機構指南，對肥胖患者實施經驗性劑量調整(肥胖定義為體重指數≥30，以千克除以平方公尺量度)。Use the patient's body surface area (BSA) calculated at screening to calculate the dose of rituximab throughout the study period, unless the patient's body weight has increased or decreased by> 10% since screening, in which case BSA will be recalculated and used for subsequent doses Determination. For obese patients, there is no upper limit for BSA and it is recommended to use actual body weight instead of adjusted dose. According to institutional guidelines, implement empirical dose adjustments for obese patients (obesity is defined as body mass index ≥ 30, measured by kilograms divided by square meters).

利妥昔單抗之投與係在投與其他研究治療之前至少30分鐘完成。若患者的IRR風險增加(高腫瘤負荷、高外周淋巴細胞計數)，則分兩天輸注利妥昔單抗。必要時，在輸注利妥昔單抗期間經歷不良事件之患者在次日繼續投與利妥昔單抗。若將利妥昔單抗之劑量分兩天投與，則兩次輸注均在適當前驅給藥情況下以第一輸注速率進行。The administration of rituximab was completed at least 30 minutes before the administration of other study treatments. If the patient has an increased risk of IRR (high tumor burden, high peripheral lymphocyte count), rituximab is infused over two days. If necessary, patients who experienced adverse events during rituximab infusion continued to be administered rituximab the next day. If the dose of rituximab is administered in two days, both infusions will be carried out at the first infusion rate under appropriate pre-dose conditions.

所有利妥昔單抗輸注均在開始每次輸注前≥30分鐘，使用口服對乙醯胺基酚(例如 650-1000 mg)及抗組胺藥諸如鹽酸苯海拉明(50-100 mg)之前驅給藥後投與(除非有禁忌)。允許使用額外糖皮質激素(例如 100 mg IV潑尼松或潑尼松龍或等效物)。對於在先前輸注時未經歷輸注相關症狀之患者，可省略後續輸注時的前驅給藥。All rituximab infusions were taken ≥30 minutes before the start of each infusion, using oral acetaminophen ( eg 650-1000 mg) and antihistamines such as diphenhydramine hydrochloride (50-100 mg) Pre-dose after administration (unless contraindicated). Additional glucocorticoids are allowed ( eg 100 mg IV prednisone or prednisolone or equivalent). For patients who have not experienced infusion-related symptoms during the previous infusion, the pre-administration during the subsequent infusion can be omitted.

利妥昔單抗經由專用管線以緩慢IV輸注投與。使用IV輸注泵(諸如Braun Infusomat Space)控制利妥昔單抗之輸注速率。具有聚氯乙烯(PVC)、聚胺酯(PUR)或聚乙烯(PE)作為產品接觸面的投藥套件及具有聚烯烴、聚丙烯(PP)、PVC或PE作為產品接觸面之IV袋係相容的。由於可能存在吸附，故不使用其他串聯過濾器。用於投與帕妥珠單抗維多汀之串聯過濾器不被用於利妥昔單抗之投與。Rituximab is administered as a slow IV infusion via a dedicated pipeline. An IV infusion pump (such as Braun Infusomat Space) is used to control the infusion rate of rituximab. Dosing kits with polyvinyl chloride (PVC), polyurethane (PUR) or polyethylene (PE) as the product contact surface and IV bags with polyolefin, polypropylene (PP), PVC or PE as the product contact surface are compatible . Due to the possibility of adsorption, other in-line filters are not used. The tandem filter used for the administration of Pertuzumab vedotine is not used for the administration of rituximab.

若患者耐受第一個週期之研究治療，而沒有明顯的輸注反應，則根據當地機構指南，以快速輸注方式投與利妥昔單抗。If the patient tolerates the first cycle of study treatment without obvious infusion reaction, rituximab is administered as a bolus infusion according to the guidelines of the local institution.

表 1 提供投與第一次及後續利妥昔單抗輸注液之概述。表 1 ：投與第一次及後續利妥昔單抗輸注液 。 第一次輸注(第1週期第1天) 後續輸注    ●    以50 mg/hr初始速率開始輸注 ●    若沒有發生輸注相關反應或超敏反應，則每30分鐘以50 mg/hr增量增加輸注速率，直至最大400 mg/hr。 ●    若發生反應，則停止或減慢輸注。根據機構指南投與藥物及支持性護理。若反應消退，則以50%降低之速率(亦即 ，在反應發生時所用速率之50%)重新開始輸注。    ●    若患者在先前輸注期間經歷輸注相關反應或超敏反應，則以50 mg/hr初始速率開始輸注並遵循說明書進行第一次輸注。 ●    若患者良好耐受先前的輸注(定義為在最終輸注速率為≥ 100 mg/hr期間無2級反應)，則開始100 mg/hr速率之輸注。 ●    若沒有發生反應，則每30分鐘以100 mg/hr增量增加輸注速率，直至最大400 mg/hr。 ●    若發生反應，則停止或減慢輸注。根據機構指南投與藥物及支持性護理。若反應消退，則以50%降低之速率(亦即 ，在反應發生時所用速率之50%)重新開始輸注。 C. 吉西他濱 Table 1 provides an overview of the first and subsequent rituximab infusions. Table 1 : The first and subsequent rituximab infusions were administered . First infusion (Day 1 of Cycle 1) Follow-up infusion ● Start the infusion at an initial rate of 50 mg/hr. ● If no infusion-related reactions or hypersensitivity reactions occur, increase the infusion rate in increments of 50 mg/hr every 30 minutes to a maximum of 400 mg/hr. ● If a reaction occurs, stop or slow down the infusion. Administer drugs and supportive care according to institutional guidelines. If the reaction subsides, the infusion is restarted at a 50% reduced rate ( that is , 50% of the rate used when the reaction occurs). ● If the patient experiences an infusion-related reaction or hypersensitivity during the previous infusion, start the infusion at an initial rate of 50 mg/hr and follow the instructions for the first infusion. ● If the patient tolerates the previous infusion well (defined as no grade 2 response during the final infusion rate ≥ 100 mg/hr), start the 100 mg/hr infusion. ● If no reaction occurs, increase the infusion rate in 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. ● If a reaction occurs, stop or slow down the infusion. Administer drugs and supportive care according to institutional guidelines. If the reaction subsides, the infusion is restarted at a 50% reduced rate ( that is , 50% of the rate used when the reaction occurs). C. Gemcitabine

在每個21天週期的第2天，靜脈內投與1000 mg/m2 吉西他濱，持續至多8個週期。吉西他濱係在同一天於奧沙利鉑之前投與。若利妥昔單抗給藥分兩天進行，則吉西他濱在第2天(亦即 ，完成利妥昔單抗給藥的當天)或次日投與。On the second day of each 21-day cycle, 1000 mg/m 2 gemcitabine was administered intravenously for up to 8 cycles. Gemcitabine was administered before oxaliplatin on the same day. If the administration of rituximab is divided into two days, gemcitabine is administered on the second day ( that is , the day when the administration of rituximab is completed) or the next day.

若發生血液毒性反應，則應推遲週期。If a blood toxic reaction occurs, the cycle should be postponed.

投與吉西他濱之方法描述於El Gnaoui等人 ，(2007) Ann Oncol，18:1363-1368中。簡言之，以10 mg/m2 /min之固定劑量速率投與1000 mg/m2 吉西他濱(於500 mL生理鹽水中)。經顯示，與標準的30分鐘IV時程相比，此延長之投藥時程可達成優良的細胞內藥物濃度。 D. 奧沙利鉑 The method of administration of gemcitabine is described in El Gnaoui et al . (2007) Ann Oncol, 18: 1363-1368. In short, 1000 mg/m 2 gemcitabine (in 500 mL normal saline) was administered at a fixed dose rate of 10 mg/m 2 /min. It has been shown that compared with the standard 30-minute IV time course, this extended administration time course can achieve excellent intracellular drug concentration. D. Oxaliplatin

在每個21天週期的第2天，靜脈內投與100 mg/m2 奧沙利鉑，持續至多8個週期。奧沙利鉑係在同一天於吉西他濱之後投與。若利妥昔單抗給藥分兩天進行，則奧沙利鉑在第2天(亦即 ，完成利妥昔單抗給藥的當天)或次日投與。On the second day of each 21-day cycle, 100 mg/m 2 of oxaliplatin was administered intravenously for up to 8 cycles. Oxaliplatin was administered after gemcitabine on the same day. If rituximab is administered on two days, oxaliplatin is administered on the second day ( that is , the day when rituximab is administered) or the next day.

投與奧沙利鉑之方法在當地處方資訊中有描述。 E. 劑量調整 The method of administering oxaliplatin is described in the local prescribing information. E. Dose adjustment

如表 2 所示，進行劑量調整或減少。所有不良事件均基於在該週期之第1天輸注之前72小時內獲得的實驗室測試結果。症狀分級係根據NCI-CTCAE v5.0。對於支持性治療，若患者在前4個小時裡未接受支持性治療，則用對乙醯胺基酚/撲熱息痛及抗組胺藥如苯海拉明治療患者。可能需要IV生理食鹽水。對於支氣管痙攣、蕁麻疹或呼吸困難，患者可能需要抗組胺藥、氧氣、皮質類固醇(例如 100 mg IV潑尼松龍或等效物)、及/或支氣管擴張劑。需要降壓藥支持的低血壓患者將持久地停用研究藥物。對於在症狀完全消退後重新開始輸注之後的輸注速率增加，輸注係以達到中止之前速率之50%的速率重新開始。在不存在輸注相關症狀的情況下，每30分鐘，以每小時50 mg之增量增加輸注速率。表 2 ：管理經歷不良事件之患者的指南 。 事件 劑量延遲或修改 3級或4級嗜中性白血球減少症 ● 保持所有治療，直至ANC恢復至 ＞ 1000個/μl。 ● 必要時，投與生長因子(例如 G-CSF)。 ● 若在第7天或之前ANC恢復至 ＞ 1000個/μl，則在無任何額外劑量減少情況下重新開始所有治療。 ● 若在第7天之後，則帕妥珠單抗維多汀之劑量減少至1.4 mg/kg。若先前減少帕妥珠單抗維多汀之劑量，則中止治療。 3級或4級血小板減少症 ● 保持所有治療，直至血小板恢復至 ＞75,000個/μl。 ● 若在第7天或之前血小板恢復至 ＞ 75,000個/μl，則在無任何額外劑量減少情況下重新開始所有治療。 ● 若在第7天之後，血小板恢復至＞ 75,000個/μl，則將帕妥珠單抗維多汀之劑量減少至1.4 mg/kg。若先前減少帕妥珠單抗維多汀之劑量，則中止治療。 2級或3級周圍神經病變 ● 所有研究治療均延遲直至改善至≤1級。 ● 若在≤ 14天內恢復至級別≤ 1級，則用1.4 mg/kg持久減少之劑量的帕妥珠單抗維多汀及75 mg/m2 劑量之奧沙利鉑重新開始研究治療。 ● 若在第14天或之前未恢復至級別≤ 1級、若患者先前患有2級周圍神經病變及/或若先前劑量減少至1.4 mg/kg帕妥珠單抗維多汀或75 mg/m2 奧沙利鉑，則中止單獨帕妥珠單抗維多汀。若患者先前患有3級周圍神經病變，則中止研究治療。 ● 若直至＞ 14天或在下一個週期之時程日期之後才恢復成≤1級，則持久地中止奧沙利鉑及帕妥珠單抗維多汀。 4級周圍神經病變(包括其病徵及症狀) ● 中止所有治療。 咽喉感覺異常 ● 奧沙利鉑輸注延長至6小時。 1-2級IRR ● 輸注減慢或保持。 ● 給予患者支持性治療。 ● 在症狀消退後，重新開始輸注速率增加。 ● 對於1-2級IRR，在下一個週期中經90分鐘輸注帕妥珠單抗維多汀。若未發生輸注相關反應，則在30分鐘內投與後續輸注。在所有週期內均投與前驅給藥。 ● 對於2級喘息或蕁麻疹，若症狀再次出現，則立即停止輸注並持久地中止研究藥物。 3級IRR ● 中止輸注。 ● 給予支持性治療。 ● 在症狀消退後，重新開始輸注速率增加。 ● 若再次發生相同嚴重程度之相同不良事件，則持久地中止治療。 ● 若患者初次出現3級喘息、支氣管痙攣或全身性蕁麻疹，則持久地中止研究藥物。 4級IRR ● 立即中止輸注，積極治療症狀，並持久地中止研究藥物。 總膽紅素 ＞ 3.0 mg/dL ● 治療延遲直至在≤14天內消退至≤1.5 mg/dL。評價因果關係。 ● 在無膽汁鬱積或黃疸或肝功能障礙跡象之類任何發現之情況下且在無其他促成因素(例如 轉移性疾病之惡化或同時暴露於已知肝毒性劑或具有經證明之感染性病源)存在之情況下，涉及肝轉胺酶增加＞3 ×基線及直接膽紅素增加＞2 × ULN的任何病例表明潛在的藥物誘發之肝損傷(DILI)，並中止治療。 3級或4級腫瘤溶解症候群 ● 保持所有研究治療。患者之下一次劑量延遲至多14天。 ● 在TLS完全解決後，結合預防性療法，在下一個時程之輸注期間，重新投與全劑量之研究治療。 以上未具體描述的3級或4級非血液毒性(不包括脫髮、噁心及嘔吐) ● 研究治療延遲最多14天。 ● 若觀察到改善成級別≤1級或基線，則以降低之劑量或以全劑量繼續研究療法。 2級非血液毒性 ● 研究治療延遲最多14天 ● 若觀察到改善成級別≤1級或基線，則投與研究治療之先前劑量。 1級非血液毒性 ● 無劑量減少或延遲。 B型肝炎再活化(如由新偵測到的HBV-DNA量所示) ● 若HBV-DNA量在WHO推薦的29與100 IU/mL範圍之間，則在2週內重新測試HBV-DNA量。若仍呈陽性，則保持所有研究治療，並用適當核苷類似物治療患者。患者被轉診至腸胃病醫師或肝病醫師。 ● 若HBV-DNA量在WHO推薦的＞ 100 IU/mL之臨界值，則保持所有研究治療，並用適當核苷類似物治療患者。患者被轉診至腸胃病醫師或肝病醫師。 ● 若在進行適當抗病毒療法之同時，觀察到HBV-DNA病毒載量升高(超過100 IU/mL)，則中止所有研究治療。 ANC= 嗜中性白血球絕對計數；G-CSF = 粒細胞集落刺激因子；HBV = B型肝炎病毒；IRR = 輸注相關反應；IV = 靜脈內；LMWH= 低分子量肝素；R = 利妥昔單抗；ULN = 正常值上限；WHO = 世界衛生組織。 F. 伴隨療法 As shown in Table 2 , adjust or reduce the dose. All adverse events are based on laboratory test results obtained within 72 hours prior to the infusion on day 1 of the cycle. Symptom classification is based on NCI-CTCAE v5.0. For supportive treatment, if the patient has not received supportive treatment in the first 4 hours, treat the patient with paracetamol/paracetamol and antihistamines such as diphenhydramine. May need IV saline. For bronchospasm, urticaria, or dyspnea, patients may need antihistamines, oxygen, corticosteroids ( eg 100 mg IV prednisolone or equivalent), and/or bronchodilators. Patients with hypotension who need antihypertensive support will permanently discontinue study drugs. For an increase in the infusion rate after the resumption of the infusion after the symptoms have completely subsided, the infusion is restarted at a rate that reaches 50% of the rate before the discontinuation. In the absence of infusion-related symptoms, increase the infusion rate in increments of 50 mg per hour every 30 minutes. Table 2 : Guidelines for the management of patients experiencing adverse events . event Dose delay or modification Grade 3 or 4 neutropenia ● Keep all treatments until ANC returns to> 1000/μl. ● If necessary, administer growth factors ( such as G-CSF). ● If the ANC returns to> 1000 pcs/μl on or before the 7th day, all treatments will be restarted without any additional dose reduction. ● If after the 7th day, the dose of Pertuzumab Verdotin is reduced to 1.4 mg/kg. If the dose of Pertuzumab Verdotin was previously reduced, the treatment was discontinued. Grade 3 or 4 thrombocytopenia ● Keep all the treatments until the platelets recover to> 75,000/μl. ● If platelets recover to> 75,000/μl on or before day 7, all treatments will be restarted without any additional dose reduction. ● If the number of platelets recovered to> 75,000/μl after the 7th day, reduce the dose of Pertuzumab Verdotin to 1.4 mg/kg. If the dose of Pertuzumab Verdotin was previously reduced, the treatment was discontinued. Grade 2 or 3 peripheral neuropathy ● All study treatments were delayed until improvement to ≤1 grade. ● If the recovery to grade ≤ 1 within ≤ 14 days, the study treatment should be restarted with a sustained reduced dose of 1.4 mg/kg of Pertuzumab vedotine and a dose of 75 mg/m 2 of oxaliplatin. ● If it does not return to grade ≤ grade 1 on or before day 14, if the patient has previously had grade 2 peripheral neuropathy and/or if the previous dose is reduced to 1.4 mg/kg pertuzumab vedotine or 75 mg/kg m 2 Oxaliplatin, discontinue Pertuzumab vedotine alone. If the patient had previously had grade 3 peripheral neuropathy, the study treatment was discontinued. ● If the level of ≤1 is not restored until> 14 days or after the schedule date of the next cycle, oxaliplatin and Pertuzumab vedotine should be permanently discontinued. Grade 4 peripheral neuropathy (including its signs and symptoms) ● Discontinue all treatments. Throat paresthesia ● Oxaliplatin infusion was extended to 6 hours. 1-2 level IRR ● The infusion is slowed down or maintained. ● Give patients supportive treatment. ● After the symptoms subsided, restart the infusion rate to increase. ● For grade 1-2 IRR, pertuzumab vedotine is infused over 90 minutes in the next cycle. If no infusion-related reactions occur, follow-up infusions are administered within 30 minutes. Prodrugs were administered in all cycles. ● For grade 2 wheezing or urticaria, if symptoms recur, stop the infusion immediately and discontinue the study drug for a long time. Level 3 IRR ● Discontinue the infusion. ● Give supportive treatment. ● After the symptoms subsided, restart the infusion rate to increase. ● If the same adverse event of the same severity occurs again, the treatment is permanently discontinued. ● If the patient has Grade 3 wheezing, bronchospasm, or systemic urticaria for the first time, discontinue the study drug for a long time. Level 4 IRR ● Immediately stop the infusion, actively treat the symptoms, and permanently discontinue the study drug. Total bilirubin> 3.0 mg/dL ● Treatment is delayed until it resolves to ≤1.5 mg/dL within ≤14 days. Evaluate causality. ● In the absence of any findings such as cholestasis or jaundice or signs of liver dysfunction, and in the absence of other contributing factors ( such as exacerbation of metastatic disease or simultaneous exposure to known hepatotoxic agents or a proven source of infectious disease) Where it exists, any case involving an increase in liver transaminases> 3 × baseline and an increase in direct bilirubin> 2 × ULN indicates potential drug-induced liver injury (DILI), and treatment is discontinued. Grade 3 or 4 tumor lysis syndrome ● Maintain all research treatments. The patient's next dose is delayed up to 14 days. ● After TLS is completely resolved, combined with preventive therapy, during the next time course of infusion, re-administer the full dose of the study treatment. Grade 3 or 4 non-hematological toxicity not specifically described above (excluding hair loss, nausea and vomiting) ● Study treatment is delayed up to 14 days. ● If an improvement to grade ≤ 1 or baseline is observed, continue the study therapy at the reduced dose or at the full dose. Grade 2 non-hematological toxicity ● Study treatment is delayed for up to 14 days ● If improvement to grade ≤ 1 or baseline is observed, the previous dose of study treatment is administered. Grade 1 non-hematological toxicity ● No dose reduction or delay. Hepatitis B reactivation (as shown by the newly detected amount of HBV-DNA) ● If the amount of HBV-DNA is between 29 and 100 IU/mL recommended by the WHO, retest the amount of HBV-DNA within 2 weeks. If it is still positive, keep all study treatments and treat the patient with appropriate nucleoside analogs. The patient was referred to a gastroenterologist or hepatologist. ● If the amount of HBV-DNA is above the cut-off value of 100 IU/mL recommended by the WHO, keep all study treatments and treat patients with appropriate nucleoside analogs. The patient was referred to a gastroenterologist or hepatologist. ● If an increase in HBV-DNA viral load (more than 100 IU/mL) is observed while appropriate antiviral therapy is being administered, all study treatments should be discontinued. ANC = absolute neutrophil count; G-CSF = granulocyte colony stimulating factor; HBV = hepatitis B virus; IRR = infusion-related reaction; IV = intravenous; LMWH = low molecular weight heparin; R = rituximab ; ULN = upper limit of normal; WHO = World Health Organization. F. Concomitant therapy

除方案規定之治療外，自起始研究治療之前7天至研究完成/中止訪視，患者所用伴隨療法由任何藥物(例如 處方藥、非處方藥、疫苗、草藥或順勢療法、營養補充劑)組成。記錄下所有此類藥物。In addition to the treatment specified in the protocol, the concomitant therapy used by the patient consists of any drugs ( such as prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathy, nutritional supplements) from 7 days before the start of the study treatment to the completion of the study/discontinuation of the visit. Record all such drugs.

在研究期間，允許患者使用以下療法：口服避孕藥、激素替代療法及/或其他維持療法。During the study period, patients are allowed to use the following therapies: oral contraceptives, hormone replacement therapy, and/or other maintenance therapies.

一般而言，研究人員根據當地的標準實踐，管理按照臨床指示用支持性療法進行的患者護理。在整個研究過程中，根據機構標準，對於最佳醫療護理提供必要的支持性措施，包括在有臨床指徵時，使用生長因子(例如 促紅細胞生成素)。若有臨床指徵，則對任何患者進行止吐療法。在研究過程中，研究人員可酌情使用並非旨在治療癌症的草藥療法。 G. 前驅給藥 在帕妥珠單抗維多汀之前的前驅給藥 In general, researchers manage patient care with supportive therapy in accordance with clinical instructions in accordance with local standard practices. Throughout the research process, in accordance with institutional standards, provide the necessary supportive measures for the best medical care, including the use of growth factors ( such as erythropoietin) when clinically indicated. If there are clinical indications, antiemetic therapy is given to any patient. During the research process, researchers may use herbal therapies that are not designed to treat cancer at their discretion. G. premedication premedication before pertuzumab of Wei Duoting

帕妥珠單抗維多汀輸注係在利妥昔單抗輸注之後立即進行。因此，由於在所有利妥昔單抗輸注之前皆需要進行前驅給藥(參見下文)，故不需要再針對帕妥珠單抗維多汀進行前驅給藥。Pertuzumab vedotine infusion is performed immediately after rituximab infusion. Therefore, since pro-administration is required before all rituximab infusions (see below), there is no need for pro-administration of Pertuzumab vedotine.

然而，若延遲給與帕妥珠單抗維多汀，則在前驅給藥之後投與帕妥珠單抗維多汀。在開始投與帕妥珠單抗維多汀之前≥30分鐘投與的前驅給藥由500-1000 mg口服對乙醯胺基酚或撲熱息痛及50-100 mg苯海拉明(根據機構標準實踐)組成。主治醫生可酌情投與皮質類固醇類藥物。在利妥昔單抗之前的前驅給藥 However, if the administration of Pertuzumab Verdotin is delayed, Pertuzumab Verdot will be administered after the pre-administration. The pre-dose of ≥30 minutes before the start of the administration of Pertuzumab Verdotin consists of 500-1000 mg oral p-acetaminophen or paracetamol and 50-100 mg diphenhydramine (according to institutional standard practice )composition. The attending doctor may administer corticosteroids as appropriate. Predose before rituximab

所有利妥昔單抗輸注均在前驅給藥之後投與患者。在利妥昔單抗療法之前需要進行以下前驅給藥： ● 在所有輸注開始之前≥30分鐘口服對乙醯胺基酚/撲熱息痛(650–1000 mg)。 ● 在每次輸注開始之前≥30分鐘，抗組胺藥，諸如苯海拉明(25-50 mg)(除非有禁忌)。對腫瘤溶解症候群高危患者之前驅給藥 All rituximab infusions are administered to patients after prodose. Prior to rituximab therapy, the following pre-administration is required: ● Oral p-acetaminophen/paracetamol (650–1000 mg) ≥ 30 minutes before the start of all infusions. ● ≥30 minutes before the start of each infusion, antihistamines such as diphenhydramine (25-50 mg) (unless contraindicated). Pre-administration for high-risk patients with tumor lysis syndrome

具有高腫瘤負荷並被研究人員認為有發生腫瘤溶解風險之患者在起始治療之前亦接受腫瘤溶解預防。Patients with high tumor burden and considered by researchers to be at risk of tumor lysis also receive tumor lysis prevention before starting treatment.

患者經歷充分補水。自第一劑研究治療之前1-2天開始，需維持每天約3 L的流體攝入量。The patient experiences adequate hydration. Starting 1-2 days before the first dose of study treatment, a fluid intake of approximately 3 L per day should be maintained.

此外，自第1週期第1天治療及補水之前48-72小時開始，用每天300 mg口服別嘌呤醇或適合替代性治療(例如 尿酸氧化酶)治療具有高腫瘤負荷並被認為有發生腫瘤溶解風險之患者。若研究人員認為合適，則患者將繼續接受重複的預防，並在隨後的每個治療週期之前進行適當補水。感染之預防 In addition, starting 48-72 hours before treatment and hydration on the first day of the first cycle, treatment with 300 mg oral allopurinol or suitable alternative therapy ( such as urate oxidase) per day has high tumor burden and is considered to have tumor lysis Patients at risk. If the researcher considers it appropriate, the patient will continue to receive repeated prophylaxis and be properly hydrated before each subsequent treatment cycle. Prevention of infection

針對肺囊腫及皰疹病毒感染之抗感染預防係基於各個患者之風險因素，根據機構實踐或研究人員之偏好制定。在針對B型肝炎再活化之預防性抗病毒藥物為護理標準之國家/地區，患者用此類藥物進行治療(Flowers等人，2013；NCCN 2017)。嗜中性白血球減少症之預防及治療 The anti-infection prevention for lung cyst and herpes virus infection is based on the risk factors of each patient, and is formulated according to the practice of the institution or the preference of the researchers. In countries/regions where preventive antiviral drugs for hepatitis B reactivation are the standard of care, patients are treated with such drugs (Flowers et al., 2013; NCCN 2017). Prevention and treatment of neutropenia

根據當地/機構指南，在每個療法週期中投與G-CSF作為主要預防措施。G-CSF之劑量及形式係由研究人員決定。根據研究人員之判斷，允許使用額外G-CSF治療嗜中性白血球減少症。針對 B 型肝炎再活化之監測及治療 According to local/institutional guidelines, G-CSF is administered as the main preventive measure in each therapy cycle. The dosage and form of G-CSF are determined by researchers. According to the judgement of the researchers, the use of additional G-CSF is allowed for the treatment of neutropenia. Monitoring and treatment for hepatitis B reactivation

若未偵測到HBV DNA，則將患有潛伏性或先前HBV感染之患者(定義為HBsAg呈陰性及B型肝炎核心抗體[HBcAb]呈陽性)納入本研究中。此等患者之HBV DNA量係在每個週期之第1天以及在研究治療之最後一個週期之後至少12個月內，藉助於即時PCR，並使用靈敏度為至少10 IU/mL之檢定獲得。If HBV DNA was not detected, patients with latent or previous HBV infection (defined as HBsAg negative and hepatitis B core antibody [HBcAb] positive) were included in this study. The amount of HBV DNA of these patients was obtained on the first day of each cycle and at least 12 months after the last cycle of the study treatment by means of real-time PCR and a test with a sensitivity of at least 10 IU/mL.

若HBV-DNA檢定呈陽性且高於世界衛生組織(WHO)之100 IU/mL的臨界值，則保持研究治療，並用適當核苷類似物治療患者(持續最後一劑利妥昔單抗之後至少1年)，並立即轉診至腸胃病醫生或肝病醫生進行管理。一旦HBV DNA量降至無法偵測之水準，患者立即重新開始研究治療。If the HBV-DNA test is positive and is higher than the World Health Organization (WHO) cut-off value of 100 IU/mL, the study treatment is maintained and the patient is treated with appropriate nucleoside analogs (at least after the last dose of rituximab 1 year), and immediately referred to a gastroenterologist or liver doctor for management. Once the amount of HBV DNA fell to an undetectable level, the patient immediately restarted the study and treatment.

若HBV DNA檢定呈陽性且≤100 IU/mL，則患者將在2週內重新測試。若該檢定仍呈陽性，則保持研究治療，並用適當核苷類似物治療患者(持續最後一劑利妥昔單抗之後至少1年)，且立即轉診至腸胃病醫生或肝病醫生進行管理。一旦HBV DNA量降至無法偵測之水準，患者立即重新開始研究治療。If the HBV DNA test is positive and ≤100 IU/mL, the patient will be retested within 2 weeks. If the test is still positive, the study treatment is maintained, and the patient is treated with appropriate nucleoside analogs (for at least 1 year after the last dose of rituximab), and immediately referred to a gastroenterologist or hepatologist for management. Once the amount of HBV DNA fell to an undetectable level, the patient immediately restarted the study and treatment.

若患者之HBV DNA量超過100 IU/mL，則當患者正在接受抗病毒藥物時，研究治療將持久地中止。If the patient's HBV DNA amount exceeds 100 IU/mL, the study treatment will be permanently discontinued while the patient is receiving antiviral drugs.

在針對B型肝炎再活化之預防性抗病毒藥物為護理標準之國家/地區，患者經歷預防性治療。謹慎療法 (Cautionary Therapy) In countries/regions where preventive antiviral drugs for reactivation of hepatitis B are the standard of care, patients undergo preventive treatment. Cautious therapy (Cautionary Therapy)

對於有QT延長病史或易發生QT延長之患者、正在服用已知可延長QT間隔之藥品的患者以及患有電解質紊亂，諸如低血鉀症、低血鈣症或低鎂血症之患者，投與奧沙利鉑應謹慎。在投與奧沙利鉑之前及之後，定期對QT間隔進行密切監測。在指定時間點，遵照臨床指示獲得心電圖記錄。若出現QT延長，則中止使用奧沙利鉑治療。For patients with a history of QT prolongation or prone to QT prolongation, patients taking drugs known to prolong the QT interval, and patients suffering from electrolyte disorders such as hypokalemia, hypocalcemia or hypomagnesemia, the administration Caution should be taken with oxaliplatin. Before and after the administration of oxaliplatin, the QT interval should be closely monitored on a regular basis. At the designated time point, follow the clinical instructions to obtain the ECG record. If prolonged QT occurs, discontinue treatment with oxaliplatin.

正接受強效CYP3A抑製劑之患者在給與帕妥珠單抗維多汀時應密切監測其不良反應(Han等人 ，(2013) J Clin Pharmacol，53:866-77)。Patients who are receiving strong CYP3A inhibitors should be closely monitored for adverse reactions when administering Pertuzumab Vidot (Han et al ., (2013) J Clin Pharmacol, 53:866-77).

作為P-gp抑製劑之伴隨藥物被認為應謹慎進行，因為該等藥物可能會導致不良反應，需要密切監測。若患者正在服用P-gp抑製劑類別中之任何藥物，則研究人員將評估並記錄已知或懷疑屬於該等類別之藥物的使用。需密切監測同時接受強效P-gp抑製劑與vc-MMAE ADC (例如 帕妥珠單抗維多汀)之患者的不良反應。禁止療法 Concomitant drugs as P-gp inhibitors are considered to be carried out with caution, because these drugs may cause adverse reactions and require close monitoring. If the patient is taking any of the drugs in the P-gp inhibitor category, the researcher will evaluate and record the use of drugs that are known or suspected to belong to these categories. Close monitoring of adverse reactions in patients receiving both a potent P-gp inhibitor and a vc-MMAE ADC ( such as Pertuzumab and Vidotin) is required. Prohibit therapy

用本方案未定義為研究治療之其他伴隨抗腫瘤劑、放射療法或任何類型之其他同時使用之研究用藥劑治療會導致患者退出研究治療。Treatment with other concomitant anti-tumor agents, radiotherapy, or any type of other concurrently used study agents that are not defined as study treatment by this protocol will cause the patient to withdraw from study treatment.

如下所述，禁止使用以下伴隨療法： ● 在起始研究治療之前2週內且在研究治療期間，禁止進行研究療法(方案規定之研究治療除外)。 ● 用於CNS預防的除吉西他濱、奧沙利鉑及鞘內化學療法外之細胞毒性化學療法。 ● 除研究治療外的免疫療法或免疫抑制療法。 ● 放射免疫療法. ● 除避孕藥、穩定的激素替代療法或醋酸甲地孕酮外的激素療法。 ● 用於治療淋巴瘤之生物藥劑。 ○    若有臨床指徵，則允許使用生物藥劑作為支持性療法，諸如造血生長因子。 ● 旨在治療淋巴瘤的任何療法(鞘內CNS預防除外)。 ● 放射療法 。 ● 免疫接種 。 ○    參與本研究之患者在起始利妥昔單抗之前至少28天、在研究治療期間之任何時間或直至B細胞恢復之前可能未接受用活病毒疫苗進行之初次或加強疫苗接種。As described below, the following concomitant therapies are prohibited: ● During the study treatment period and within 2 weeks before the initiation of the study treatment, study treatment is prohibited (except for the study treatment specified in the protocol). ● Cytotoxic chemotherapy except gemcitabine, oxaliplatin and intrathecal chemotherapy for CNS prevention. ● Immunotherapy or immunosuppressive therapy other than research treatment. ● Radioimmunotherapy. ● Hormone therapy other than birth control pills, stable hormone replacement therapy, or megestrol acetate. ● A biological agent for the treatment of lymphoma. ○ If there are clinical indications, the use of biopharmaceuticals as supportive therapies, such as hematopoietic growth factors, is allowed. ● Any therapy designed to treat lymphoma (except intrathecal CNS prevention). ● Radiation Therapy . ● Immunization . ○ Patients participating in this study may not receive the initial or booster vaccination with live virus vaccine at least 28 days before initiation of rituximab, at any time during the study treatment period, or until B-cell recovery.

需要使用此等藥劑中任何一種的患者將中止研究治療。 V. 研究評估 A. 患者及疾病特徵 Patients who need to use any of these agents will discontinue study treatment. V. Research and evaluation A. Patient and disease characteristics

記錄下病史，包括臨床上顯著之疾病、手術、癌症病史(包括先前的癌症療法、不適合移植之原因，2016年WHO分類、當前Ann Arbor分期及程序)、ECOG體能狀態及生殖狀態。此外，亦記錄下在起始研究治療之前7天內患者使用的所有藥物(例如 處方藥、非處方藥、疫苗、草藥或順勢療法、營養補充劑)。Record the medical history, including clinically significant diseases, surgery, cancer history (including previous cancer treatments, reasons for unsuitability for transplantation, 2016 WHO classification, current Ann Arbor staging and procedures), ECOG performance status and reproductive status. In addition, all medications used by the patient in the 7 days prior to the initiation of the study treatment ( for example, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathy, nutritional supplements) are also recorded.

執行全面身體檢查，並記錄下在基線時鑑別的任何異常情況。Perform a comprehensive physical examination and record any abnormalities identified at baseline.

作為腫瘤評估之一部分，身體檢查包括評價淋巴結腫大、肝腫大及脾腫大之存在及程度。As part of tumor assessment, physical examination includes evaluation of the presence and extent of lymphadenopathy, hepatomegaly, and splenomegaly.

在研究過程中，執行有限的以症狀為導向的身體檢查，並將其局限於主要相關系統(亦即，心血管系統、呼吸系統、與症狀相關之系統以及與腫瘤評估相關之系統[淋巴結、肝臟及脾臟])。有限的身體檢查亦監測神經病變之症狀，包括感覺減退、感覺亢進、感覺異常、感覺遲鈍、不適、灼燒感、無力、步態不穩、失去平衡、體位性低血壓、暈厥或神經病變性疼痛。記錄下自基線異常的變化。During the research process, a limited symptom-oriented physical examination was performed and restricted to the main related systems (ie, cardiovascular system, respiratory system, system related to symptoms, and system related to tumor assessment [lymph nodes, Liver and spleen]). Limited physical examinations also monitor the symptoms of neuropathy, including hypoesthesia, hyperesthesia, paresthesias, insensitivity, malaise, burning sensation, weakness, gait instability, loss of balance, orthostatic hypotension, syncope, or neuropathic pain . Record the abnormal changes from the baseline.

記錄下生命體徵、體重、身高及BSA。僅在篩選時需要身高及BSA，除非自最後一次BSA評估起體重變化＞ 10%，在此情況下，將重新計算BSA。獲得ECG記錄。Record vital signs, weight, height and BSA. Height and BSA are only required for screening, unless the weight change> 10% since the last BSA assessment, in which case the BSA will be recalculated. Obtain ECG records.

執行實驗治療組與對照組之比較。按治療組匯總所有隨機分組患者之人口統計變量，諸如年齡、性別、人種/種族及基線特徵(特別是分層變量)。使用均值、標準差、中值、範圍及四分間距匯總連續變量。按比例匯總分類變量。Perform the comparison between the experimental treatment group and the control group. Summarize the demographic variables of all randomized patients by treatment group, such as age, gender, race/ethnicity, and baseline characteristics (especially stratification variables). Use the mean, standard deviation, median, range, and interquartile range to summarize continuous variables. Summarize categorical variables proportionally.

呈現關於累積研究藥物劑量、劑量調整/中斷及暴露持續時間之描述性統計。對ECG進行描述性分析。使用關於連續變量之描述性統計分析生命體徵之變化。Presents descriptive statistics on cumulative study drug dose, dose adjustment/interruption, and exposure duration. Descriptive analysis of ECG. Use descriptive statistics on continuous variables to analyze changes in vital signs.

執行以下評估： ● 國際預後指數(IPI): 一種臨床醫生評估工具，用於對NHL患者之OS進行預後評估(International Non-Hodgkin's Lymphoma Prognostic Factors 1993)。該工具基於對五個臨床因素之量測，包括年齡、血清及乳酸脫氫酶(LDH)量、ECOG體能狀態、癌症分期及結外部位累及情況。 ● 美國東岸癌症臨床研究合作組織表現(ECOG)：一種臨床醫生評估工具，其根據患者之自我護理能力、日常活動及身體能力(步行、工作等)描述患者之功能水準(ECOG ACRIN Cancer Research Group 2018)。Perform the following assessment: ● International Prognostic Index (IPI): A clinician evaluation tool for prognostic evaluation of OS in NHL patients (International Non-Hodgkin's Lymphoma Prognostic Factors 1993). The tool is based on the measurement of five clinical factors, including age, serum and lactate dehydrogenase (LDH) levels, ECOG performance status, cancer stage, and extranodal involvement. ● United States East Coast Cancer Clinical Research Cooperative Organization Performance (ECOG): A clinician assessment tool that describes the functional level of the patient based on the patient's self-care ability, daily activities and physical ability (walking, work, etc.) (ECOG ACRIN Cancer Research Group 2018) .

執行以下實驗室測試： ● 血液學：白血球(WBC)計數、紅血球(RBC)計數、血紅蛋白、血球比容、血小板計數、差異計數(嗜中性白血球、嗜酸性白血球、嗜鹼性白血球、單核球、淋巴細胞)。 ● 血清或血漿化學：鈉、鉀、氯化物、碳酸氫鹽(或CO2 )、葡萄糖、血尿素氮(BUN)或尿素、肌酐、總蛋白質、白蛋白、磷、鈣、總膽紅素及(若可獲得)直接膽紅素、鹼性磷酸酶、丙胺酸轉胺酶(ALT)、天冬胺酸轉胺酶(AST)、尿酸及乳酸脫氫酶(LDH)。 ● 凝血：國際標準化比率(INR)或凝血酶原時間(PT)，以及部分凝血活酶時間(PTT)或活化的部分凝血活酶時間(aPTT)。 ● 病毒血清學：HIV；B型肝炎表面抗體(HBsAb)、HBsAg及總HBcAb；若患者呈HBcAb陽性，則藉由PCR偵測HBV-DNA；HCV抗體；若患者呈HCV抗體陽性，則藉由PCR偵測HCV RNA。Perform the following laboratory tests: ● Hematology: White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit, platelet count, differential count (neutrophil white blood cell, eosinophilic white blood cell, basophilic white blood cell, monocyte) Ball, lymphocyte). ● Serum or plasma chemistry: sodium, potassium, chloride, bicarbonate (or CO 2 ), glucose, blood urea nitrogen (BUN) or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin and (If available) Direct bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), uric acid and lactate dehydrogenase (LDH). ● Coagulation: International normalized ratio (INR) or prothrombin time (PT), and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT). ● Virus serology: HIV; hepatitis B surface antibody (HBsAb), HBsAg and total HBcAb; if the patient is positive for HBcAb, HBV-DNA is detected by PCR; HCV antibody; if the patient is positive for HCV antibody, by PCR detects HCV RNA.

實驗室數據值超出正常範圍。此外，亦匯總所選實驗室數據及生命體徵之變化。 B. 統計評估 The laboratory data value is outside the normal range. In addition, the selected laboratory data and vital signs changes are also summarized. B. Statistical evaluation

分析人群定義如下： ● 意向治療(ITT)人群：所有隨機分組的患者，根據其分配之治療組進行分組，無論是否接受分配之研究治療。 ● 安全性磨合期人群：在安全性磨合期(第1階段)間接受任何量之任何研究藥物的患者。 ● 安全人群：在隨機化對照試驗(第2階段)期間接受任何量之任何研究藥物的患者。 ● PRO可評價人群：PRO可評價人群包括具有基線評估及至少1次基線後評估之所有隨機分組患者。所有PRO分析均基於在隨機分組時分配之治療組執行。 ● 藥物動力學可評價之人群：PK人群包括接受至少一劑研究藥物並具有至少一個給藥後濃度結果的所有患者。The analysis population is defined as follows: ● Intention-to-treat (ITT) population: All randomized patients are grouped according to their assigned treatment group, regardless of whether they receive the assigned study treatment. ● Safety run-in period population: Patients who receive any amount of any study drug during the safety run-in period (stage 1). ● Safe population: Patients who receive any amount of any study drug during the randomized controlled trial (Phase 2). ● PRO evaluable population: PRO evaluable population includes all randomized patients with baseline assessment and at least one post-baseline assessment. All PRO analyses were performed based on the treatment group assigned at the time of randomization. ● Population whose pharmacokinetics can be evaluated: The PK population includes all patients who have received at least one dose of the study drug and have at least one post-dose concentration result.

對於所有功效分析，根據在隨機分組時分配之治療對患者進行分組。對於所有安全性分析，根據實際接受之治療對患者進行分組。For all efficacy analyses, patients were grouped according to the treatments assigned at the time of randomization. For all safety analyses, patients are grouped according to the actual treatment received.

假設檢驗係雙側的，除非另有指示。本研究之I型誤差(α)係0.05 (雙側)。 C. 安全性 Hypothesis testing is two-sided, unless otherwise indicated. The type I error (α) in this study is 0.05 (two-sided). C. Security

藉由根據NCI CTCAE v5.0之不良事件、FACT/GOG-Ntx12得分、臨床實驗室測試結果、心電圖(ECG)及生命體徵評估安全性。The safety is evaluated by NCI CTCAE v5.0 adverse events, FACT/GOG-Ntx12 score, clinical laboratory test results, electrocardiogram (ECG) and vital signs.

安全評估包括監測及記錄不良事件，包括嚴重不良事件及特別值得關注之不良事件、執行安全實驗室評估、量測生命體徵以及進行對研究之安全性評價至關重要的其他測試。在起始研究藥物後，報告所有不良事件，直至90天或在最後一劑研究藥物後起始NALT。Safety assessment includes monitoring and recording of adverse events, including serious adverse events and adverse events of particular concern, performing safety laboratory assessments, measuring vital signs, and conducting other tests that are critical to the safety evaluation of the research. After initiating study drug, report all adverse events until 90 days or initiating NALT after the last dose of study drug.

安全性係經由不良事件匯總及研究治療暴露來評估，並按治療組提供。Safety is assessed through adverse event summary and study treatment exposure, and is provided by treatment group.

不良事件之逐字描述藉由對應術語、適當的分類詞典水準及毒性等級匯總。對於每名患者，若相同不良事件發生多次，則在匯總中使用報告的最大嚴重程度。Verbatim descriptions of adverse events are summarized by corresponding terms, appropriate classification dictionary levels, and toxicity levels. For each patient, if the same adverse event occurs multiple times, the maximum severity reported is used in the summary.

分開地匯總以下治療中出現之不良事件：導致終止研究藥物之不良事件、導致劑量減少或中斷之不良事件、≥3級不良事件、導致死亡之不良事件、嚴重不良事件及特別之關注之不良事件。此外，適當時，亦提供暴露調整之分析以及復發AE之分析。Separately summarize the adverse events that occurred in the following treatments: adverse events leading to the discontinuation of the study drug, adverse events leading to dose reduction or interruption, adverse events ≥ grade 3, adverse events leading to death, serious adverse events, and adverse events of special concern . In addition, when appropriate, analysis of exposure adjustments and analysis of recurrent AEs are also provided.

匯總所有死亡及死亡原因。Summarize all deaths and causes of death.

按時間匯總相關實驗室值，並在適當時，鑑別NCI CTCAE v5.0之3級及4級值。NCI CTCAE級別之變化按治療組列出。Summarize relevant laboratory values by time, and identify NCI CTCAE v5.0 level 3 and 4 values when appropriate. The changes in NCI CTCAE levels are listed by treatment group.

在整個研究過程中，匯總由FACT/GOG-Ntx12得分及NCI CTCAE v5.0量度之周圍神經病變。此外，亦基於AE計算周圍神經病變之比率，包括所有患者均完成第2週期或先前報告此類事件。During the entire study, the peripheral neuropathy measured by FACT/GOG-Ntx12 score and NCI CTCAE v5.0 was collected. In addition, the rate of peripheral neuropathy was also calculated based on AE, including all patients who completed cycle 2 or previously reported such events.

藉由檢查並匯總惡化時間、以及針對不同PRO工具之選定問題自基線之變化，分析患者報告結果。Analyze the results of patient reports by checking and summarizing the time of deterioration and the changes from baseline for the selected problems of different PRO tools.

呈現關於累積研究藥物劑量、劑量調整/中斷及暴露持續時間之描述性統計。對ECG進行描述性分析。使用關於連續變量之描述性統計分析生命體徵之變化。Presents descriptive statistics on cumulative study drug dose, dose adjustment/interruption, and exposure duration. Descriptive analysis of ECG. Use descriptive statistics on continuous variables to analyze changes in vital signs.

本研究特別關注之不良事件如下： ● 周圍神經病變≥ 3級 ● 根據Hy定律所確定的潛在藥物誘發之肝損傷病例，其包括ALT或AST升高以及膽紅素升高或顯性黃疸。報告以下不良事件： ○    治療中出現之ALT或AST＞3×基線值以及總膽紅素＞2×ULN(其中≥35%為直接膽紅素)。 ○    治療中出現之ALT或AST＞3×基線值以及顯性黃疸。 ● 任何級別的腫瘤溶解症候群(與因果關係無關)。 ● 進行性多灶性腦白質病。 ● 如根據桑普森標準所確定，全身性超敏反應/過敏性反應及類過敏性反應。 ● 第二惡性疾病。The adverse events of particular concern in this study are as follows: ● Peripheral neuropathy ≥ Grade 3 ● Potential drug-induced liver injury cases determined by Hy's law include elevated ALT or AST and elevated bilirubin or dominant jaundice. Report the following adverse events: ○ ALT or AST during treatment>3×baseline value and total bilirubin>2×ULN (where ≥35% is direct bilirubin). ○ ALT or AST> 3×baseline value and dominant jaundice during treatment. ● Any grade of tumor lysis syndrome (not related to causality). ● Progressive multifocal leukoencephalopathy. ● As determined by Sampson’s criteria, systemic hypersensitivity/allergic reactions and anaphylaxis-like reactions. ● The second malignant disease.

與預期的基礎疾病進展模式明顯一致的事件不記錄作為不良事件。不良事件報告並非源自於PRO資料。Events that are clearly consistent with the expected underlying disease progression pattern are not recorded as adverse events. Adverse event reports are not derived from PRO data.

研究人員跟踪每例不良事件，直至事件消退成基線等級或更佳，事件被研究人員評估為穩定，患者失訪或患者撤回同意書。The researchers tracked each adverse event until the event resolved to a baseline level or better, the event was assessed as stable by the researcher, the patient was lost to follow-up, or the patient withdrew the consent.

在不良事件報告期結束(定義為在最後一劑研究藥物後90天或起始NALT)後，報告所有死亡原因，無論原因如何，以及咸信與先前暴露於研究藥物有關之嚴重AE。After the end of the adverse event reporting period (defined as 90 days after the last dose of study drug or initiation of NALT), report all causes of death, regardless of the cause, as well as serious AEs believed to be related to previous exposure to study drug.

在中止研究治療後及之後，對經歷周圍神經病變AE之所有患者進行隨訪，以檢查可能發生之惡化(Coasting現象)，直至AE消退或穩定。After and after discontinuation of the study treatment, all patients who experienced peripheral neuropathy AEs were followed up to check for possible deterioration (Coasting phenomenon) until the AE subsided or stabilized.

使用劑量中斷、劑量減少及劑量強度確定耐受性。 D. 功效 主要功效終點 Use dose interruption, dose reduction, and dose intensity to determine tolerability. D. Efficacy The primary efficacy endpoint

本研究之隨機化部分的主要功效目標係基於以下終點評價Pola-R-GemOx與R-GemOx在復發性或難治性DLBCL患者中之功效的比較： ● 總體存活期(OS)，定義為自隨機分組至研究期間由任何原因引起死亡之時間。The main efficacy goal of the randomization part of this study is to evaluate the efficacy of Pola-R-GemOx and R-GemOx in patients with relapsed or refractory DLBCL based on the following endpoints: ● Overall survival (OS) is defined as the time from randomization to death from any cause during the study period.

對ITT人群完成主要功效分析，其中患者係根據在隨機分組時分配之治療進行分組。未死亡患者之資料將在最後得知患者存活之日期進行審查。否則，在隨機分組日 + 1天對資料進行審查。Complete the main efficacy analysis for the ITT population, in which patients are grouped according to the treatment assigned at the time of randomization. The data of the non-dead patients will be reviewed when the patient's survival date is last known. Otherwise, the data will be reviewed on the random grouping day + 1 day.

用Kaplan-Meier方法估算每個治療組之中值OS，並產生Kaplan-Meier曲線。藉由分層對數秩檢驗比較各治療組之間的OS。使用分層Cox比例風險模型估算死亡之風險比(HR)。如上所述，分層因素與藉由IxRS確定之隨機分層因素相同。提供HR之95%信賴區間(CI)。使用Brookmeyer-Crowley方法構築每個治療組之中值OS的95% CI。The Kaplan-Meier method was used to estimate the median OS of each treatment group, and a Kaplan-Meier curve was generated. The stratified log-rank test was used to compare the OS between the treatment groups. A stratified Cox proportional hazard model was used to estimate the hazard ratio (HR) of death. As mentioned above, the stratification factor is the same as the random stratification factor determined by IxRS. Provide 95% confidence interval (CI) for HR. The Brookmeyer-Crowley method was used to construct a 95% CI for the median OS of each treatment group.

本研究之I型誤差(α)係0.05(雙側)。The type I error (α) in this study is 0.05 (two-sided).

若患者有資格接受HSCT並經歷移植(符合其最大利益)，則針對OS及PFS執行敏感性分析，以評估其可能具有的影響。為此，在移植時審查患者資料。次要功效終點 If the patient is eligible for HSCT and undergoes a transplant (in its best interest), perform a sensitivity analysis for OS and PFS to assess its possible impact. For this reason, patient data is reviewed at the time of transplant. Secondary efficacy endpoint

以下各節詳述針對本研究隨機化部分(第2階段)之次要終點的分析。在安全性磨合期(第1階段)執行類似的分析，但僅限於描述性統計。The following sections detail the analysis of the secondary endpoints of the randomization part (phase 2) of this study. A similar analysis is performed during the safety run-in period (phase 1), but only for descriptive statistics.

在篩選時、在治療期間及之後根據臨床指示、在最後一劑研究藥物之後28天且接著在隨訪期間每兩個月(PET-CT)及六個月(CT)至最多兩年，獲得PET-CT及CT掃描。Obtain PET at screening, during and after treatment according to clinical instructions, 28 days after the last dose of study drug, and then every two months (PET-CT) and six months (CT) during follow-up for up to two years -CT and CT scan.

為了將總體I型誤差率控制在顯著性之雙側0.05水準，使用分層測試程序調整主要及關鍵次要功效終點之多項統計測試。關鍵次要終點按以下次序進行測試： ● PFS。 ● 在治療結束時之完全反應率(CRR)(基於包括PET-CT資料在內之反應)。 ● 在治療結束時之客觀反應率(ORR)(基於包括PET-CT資料在內之反應)。In order to control the overall Type I error rate at the significance level of 0.05 on both sides, a stratified test procedure was used to adjust multiple statistical tests for the primary and key secondary efficacy endpoints. The key secondary endpoints are tested in the following order: ● PFS. ● Complete response rate (CRR) at the end of treatment (based on response including PET-CT data). ● Objective response rate (ORR) at the end of treatment (based on response including PET-CT data).

給定的假設只有在所有先前假設均在雙側0.05水準顯著性下被拒絕後才會被拒絕。A given hypothesis will only be rejected after all previous hypotheses have been rejected at the two-sided 0.05 level of significance.

對於其他終點之測試，不執行多重性調整，並謹慎解釋。For other end-point tests, no adjustment for multiplicity is performed, and interpretation should be made with caution.

基於身體檢查評估反應，並在治療結束時使用Lugano 2014反應標准執行PET-CT掃描。在篩選時、治療中期(自第4週期第15天至第5週期第1天)以及在治療結束時進行腫瘤評估。初始及治療結束評估包括PET。在長期隨訪中或在研究結束之前，每6個月進行一次CT掃描，為期2年。收集用於腫瘤評估的所有主要成像資料。The response was evaluated based on a physical examination, and a PET-CT scan was performed using Lugano 2014 response criteria at the end of the treatment. Tumor evaluation was performed at the time of screening, mid-treatment (from day 15 of cycle 4 to day 1 of cycle 5) and at the end of treatment. The initial and end-of-treatment evaluations include PET. During the long-term follow-up or before the end of the study, CT scans were performed every 6 months for 2 years. Collect all major imaging data for tumor evaluation.

PET-CT掃描包括顱底至大腿中部。在臨床上適當時，執行全身PET-CT掃描。不使用圖像增強系統(諸如GE Healthcare之Q.Clear或類似產品)。利用IV造影之CT掃描包括胸部、腹部及骨盆掃描；若有臨床指徵，則亦包括頸部CT掃描。只有在當地監管機構要求時，才將用於反應評估之CT掃描局限於先前累及之區域。根據研究人員之判斷，若懷疑患有進行性疾病，則可隨時重複進行CT掃描。在懷疑疾病進展或復發之任何時間，執行包括放射線攝影評估在內之完整腫瘤評估。在篩選及治療結束評估時必須使用PET-CT。The PET-CT scan covers the base of the skull to the middle of the thigh. When clinically appropriate, perform a whole-body PET-CT scan. No image enhancement system (such as GE Healthcare's Q.Clear or similar products) is used. CT scans using IV imaging include chest, abdomen, and pelvic scans; if there are clinical indications, CT scans of the neck are also included. The CT scan used for response assessment is limited to the previously affected area only when required by the local regulatory agency. According to the judgment of the researcher, if a progressive disease is suspected, the CT scan can be repeated at any time. At any time when disease progression or recurrence is suspected, a complete tumor evaluation including radiographic evaluation is performed. PET-CT must be used for screening and end-of-treatment assessment.

在PET-CT上骨信號呈陰性之患者經歷骨髓活檢。Patients with negative bone signals on PET-CT undergo bone marrow biopsy.

在禁忌使用造影劑之患者(例如 造影劑過敏或腎清除力受損之患者)中，容許在無造影劑情況下進行CT或聯合PET-CT掃描，只要該等掃描允許在研究治療期間一致且精確地量測目標病灶。In patients whose use of contrast agents is contraindicated ( for example, patients with allergy to contrast agents or impaired renal clearance), CT or combined PET-CT scans are allowed without contrast agents, as long as these scans are allowed to be consistent and consistent during the study treatment period. Accurately measure the target lesion.

適用後續療法(例如 CAR-T療法或自體幹細胞移植)的具有PR或CR反應之患者需要進行研究且仍可進行評價。完全反應率 Patients with PR or CR response who are suitable for follow-up therapies ( such as CAR-T therapy or autologous stem cell transplantation) need to be studied and can still be evaluated. Complete response rate

完全反應率(CRR)定義為根據Lugano 2014反應標准，在治療結束時具有完全代謝反應(基於包括PET CT資料在內之反應)之患者的比例。不符合此等標準之患者，包括未經歷任何基線後腫瘤評估之患者，被視為無反應者。The complete response rate (CRR) is defined as the proportion of patients who have a complete metabolic response (based on the response including PET CT data) at the end of treatment according to the Lugano 2014 response criteria. Patients who do not meet these criteria, including those who have not undergone any post-baseline tumor assessment, are considered non-responders.

CRR係使用ITT人群分析。The CRR system uses ITT population analysis.

計算每個治療組之CRR估算值，並使用Clopper-Pearson方法計算其95%信賴區間(CI)。計算各治療組之間的CRR差異，並使用二項式分佈之正態近似值計算其95%CI。使用分層Cochran-Mantel-Haenszel檢驗比較各治療組之間的CRR。分層因素與關於分析主要終點OS所描述的分層因素相同。Calculate the estimated value of CRR for each treatment group, and use the Clopper-Pearson method to calculate its 95% confidence interval (CI). Calculate the CRR difference between the treatment groups, and use the normal approximation of the binomial distribution to calculate its 95% CI. The stratified Cochran-Mantel-Haenszel test was used to compare the CRR between the treatment groups. The stratification factors are the same as those described in the analysis of the primary endpoint OS.

使用不包括PET資料之反應對CRR重複進行所述分析，並因此考慮具有完全反應而非完全代謝反應之患者。客觀反應率 The analysis was repeated for CRR using responses that did not include PET data, and therefore patients with complete responses rather than complete metabolic responses were considered. Objective response rate

客觀反應定義為根據Lugano 2014反應標准，在治療結束時的完全或部分代謝反應(基於包括PET CT資料在內之反應)。不符合此等標準之患者，包括未經歷任何基線後腫瘤評估之患者，被視為無反應者。The objective response is defined as the complete or partial metabolic response (based on the response including PET CT data) at the end of treatment according to the Lugano 2014 response criteria. Patients who do not meet these criteria, including those who have not undergone any post-baseline tumor assessment, are considered non-responders.

ORR定義為具有客觀反應之患者的比例。ORR is defined as the proportion of patients with an objective response.

ORR係使用ITT人群分析。The ORR system uses ITT population analysis.

計算每個治療組之ORR估算值，並使用Clopper-Pearson方法計算其95% CI。計算各治療組之間的ORR差異，並使用二項式分佈之正態近似值計算其95%CI。使用分層Cochran-Mantel-Haenszel檢驗比較各治療組之間的ORR。分層因素與關於分析主要終點OS所描述的分層因素相同。Calculate the estimated ORR of each treatment group, and use the Clopper-Pearson method to calculate its 95% CI. Calculate the ORR difference between the treatment groups, and use the normal approximation of the binomial distribution to calculate its 95% CI. The stratified Cochran-Mantel-Haenszel test was used to compare ORR between treatment groups. The stratification factors are the same as those described in the analysis of the primary endpoint OS.

使用不包括PET資料之反應對ORR重複進行所述分析，客觀反應(基於不包括PET資料之反應)則定義為在治療結束時之完全或部分反應(基於不包括PET資料之反應)。最佳總體反應 The ORR analysis was repeated using the response that did not include PET data, and the objective response (based on the response that did not include the PET data) was defined as the complete or partial response (based on the response that did not include the PET data) at the end of the treatment. Best overall response

最佳總體反應(BOR)定義為根據Lugano 2014反應標准，在研究時代最佳反應(基於包括PET-CT或CT資料在內之反應)。The best overall response (BOR) is defined as the best response in the research era (based on the response including PET-CT or CT data) according to the Lugano 2014 response criteria.

BOR係使用ITT人群分析。The BOR system uses ITT population analysis.

計算每個治療組之BOR估算值，並使用Clopper-Pearson方法計算其95% CI。無進展存活期 Calculate the estimated value of BOR for each treatment group, and use the Clopper-Pearson method to calculate its 95% CI. Progression-free survival

無進展存活期(PFS)定義為自隨機分組至首次發生疾病進展或由任何原因導致之死亡(以先發生者為準)的時間。未報告疾病進展而死亡的患者被視為在死亡之日發生的事件。在分析時(臨床截止值)既未進展亦未死亡的患者以及失訪患者將在最後一次可評價之腫瘤評估日進行審查。未經歷基線後腫瘤評估之患者在隨機分組 +1天時進行審查。提供了Kaplan-Meier估算值以及中值、第25及第75個百分位數之相關95% CI。Kaplan-Meier曲線直觀地描述各治療組之差異。治療效果之估算係使用分層Cox比例風險分析(包括95%信賴限值)，以風險比表示。反應持續時間 Progression-free survival (PFS) is defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first). Patients who died without reporting disease progression are considered events that occurred on the day of death. Patients who have neither progressed nor died at the time of analysis (clinical cut-off value) and patients lost to follow-up will be reviewed on the last evaluable tumor evaluation day. Patients who have not undergone post-baseline tumor assessment will be reviewed on day 1 of randomization. Provides Kaplan-Meier estimates and the associated 95% CIs of the median, 25th and 75th percentiles. The Kaplan-Meier curve visually describes the differences between treatment groups. The treatment effect is estimated using a stratified Cox proportional hazard analysis (including the 95% confidence limit), expressed as a hazard ratio. Duration of response

使用Lugano 2014反應標準評估具有客觀反應之患者的反應持續時間(DOR)。DOR定義為自首次出現完整或部分反應的日期(以先記錄之狀態為準)直至記錄下進行性疾病或死亡之首個日期(以先發生者為準)之間的時間間隔。在分析時未進展且未死亡的患者將在最後一個腫瘤評估日期時進行審查。若在首次出現完全或部分反應之日後未執行腫瘤評估，則在首次出現完全或部分反應之日加1天時對DOR進行審查。DOR係基於一小組未隨機分組之患者(特別是達到客觀反應之患者)，因此，出於描述目的對各治療組進行比較。使用PFS分析之詳細方法進行DOR分析，但該分析未分層。無事件存活期 The Lugano 2014 response standard was used to evaluate the duration of response (DOR) of patients with objective responses. DOR is defined as the time interval from the date of the first occurrence of a complete or partial response (whichever is recorded first) to the first date of recording of a progressive disease or death (whichever occurs first). Patients who did not progress and did not die at the time of analysis will be reviewed on the last tumor evaluation date. If tumor assessment is not performed after the first full or partial response, the DOR will be reviewed on the day of the first full or partial response plus 1 day. DOR is based on a small group of patients who are not randomized (especially those who achieve an objective response). Therefore, the treatment groups are compared for descriptive purposes. The detailed method of PFS analysis was used for DOR analysis, but the analysis was not stratified. Event-free survival

無事件存活期(EFSeff )定義為自隨機分組至最早出現以下病例之時間： ● 疾病進展或復發。 ● 由任何原因引起之死亡。 ● 起始任何NALT。Event-free survival (EFS eff ) is defined as the time from randomization to the earliest appearance of the following cases: ● Disease progression or recurrence. ● Death caused by any cause. ● Start any NALT.

無EFSeff 事件之患者在最後一次可評價之腫瘤評估時進行審查。未經歷基線後腫瘤評估之患者在隨機分組時進行審查。使用PFS分析之詳細方法進行EFSeff 分析。 E. 患者報告結果 Patients without EFS eff events will be reviewed at the last evaluable tumor evaluation. Patients who did not undergo post-baseline tumor assessment were reviewed at randomization. Use the detailed method of PFS analysis to perform EFS eff analysis. E. Patient report results

完成患者報告結果(PRO)工具，以評估治療益處且更全面地表徵帕妥珠單抗維多汀之安全性型態。此外，PRO工具亦能夠捕獲每名患者關於使用帕妥珠單抗維多汀之直接體驗。Complete the patient report results (PRO) tool to assess the benefits of treatment and to more fully characterize the safety profile of Pertuzumab Verdotin. In addition, the PRO tool can also capture each patient's direct experience of using Pertuzumab Verdotin.

除非另外說明，否則使用PRO可評價人群對訪視匯總及自基線之變化、反應者分析以及混合效應模型重複量測(MMRM)建模進行描述性分析。使用ITT人群進行完成分析及惡化時間分析。Unless otherwise specified, use PRO to evaluate populations for descriptive analysis of visit summary and change from baseline, responder analysis, and mixed-effects model repeated measures (MMRM) modeling. Use ITT population for completion analysis and deterioration time analysis.

經由使用以下工具收集PRO資料：FACT/GOG-Ntx12、EQ-5D-5L、EORTC QLQ-C30及FACT/Lym。FACT/GOG-Ntx12 Collect PRO data by using the following tools: FACT/GOG-Ntx12, EQ-5D-5L, EORTC QLQ-C30 and FACT/Lym. FACT/GOG-Ntx12

FACT/GOG-Ntx12係一項12項之患者報告結果工具，其係設計成用於量測化學療法誘發之周圍神經病變(Kopec等人 ，(2006) J Supportive Oncol，4:W1-W8)。FACT/GOG-Ntx得分在整個試驗中，包括在第1階段(安全性磨合期)及第2階段(RCT)期間均有報告。對於FACT/GOG-Ntx-12問卷量表中之每一項，在每次訪視時的描述性統計以及自基線之變化均由治療組報告。對於問卷內缺失之項目，根據開發人員指南計算按比例分配之得分(Calhoun等人 ，(2003) Int J Gynecol Cancer，13:741-748)。在每個時間點按治療組匯總PRO完成率。對於神經毒性分量表，在安全性磨合期人群中報告每次訪視時的描述性統計以及自基線之變化。EQ-5D-5L FACT/GOG-Ntx12 is a 12-item patient reporting tool designed to measure peripheral neuropathy induced by chemotherapy (Kopec et al . (2006) J Supportive Oncol, 4: W1-W8). FACT/GOG-Ntx scores were reported throughout the trial, including during the first phase (safety run-in period) and the second phase (RCT). For each item in the FACT/GOG-Ntx-12 questionnaire, the descriptive statistics at each visit and the change from baseline were reported by the treatment group. For items that are missing in the questionnaire, a prorated score is calculated according to the developer's guide (Calhoun et al ., (2003) Int J Gynecol Cancer, 13:741-748). At each time point, the PRO completion rate was summarized by treatment group. For the neurotoxicity subscale, the descriptive statistics at each visit and the change from baseline are reported in the safety run-in period population. EQ-5D-5L

EuroQol 5維問卷 [5級版(EQ-5D-5L])係經過驗證的自我報告健康狀況問卷，其被用於通過5個維度計算健康狀況效用得分(EuroQol (1990) Health Policy，16:199-208；Brooks (1996) Health Policy，37:53-72；Herdman等人 ，(2011) 20:1727-1736；Janssen等人 ，(2013) Qual Life Res，22:1717-1727)。全部五個維度可組合成一個五位數的數字，以描述患者之健康狀態。藉由使用公佈之權重，將此描述性數字轉換成單個匯總指標效用得分。在本研究中，使用UK crosswalk值集(由EuroQol研究基金會在http://www(dot)euroqol(dot)org/about-eq-5d/valuation-of-eq-5d；Devlin等人， (2017) Health Economics，1-16發布)。此外，在該問卷之第二部分中，當前健康狀況係藉由視覺模擬量表(VAS)量度，其值的範圍自0至100。EuroQol 5-dimensional questionnaire [5 level version (EQ-5D-5L]) is a verified self-reported health status questionnaire, which is used to calculate the health status utility score through 5 dimensions (EuroQol (1990) Health Policy, 16:199 -208; Brooks (1996) Health Policy, 37:53-72; Herdman et al ., (2011) 20:1727-1736; Janssen et al ., (2013) Qual Life Res, 22:1717-1727). All five dimensions can be combined into a five-digit number to describe the health status of the patient. By using the published weights, this descriptive number is converted into a single aggregate indicator utility score. In this study, the UK crosswalk value set was used (by the EuroQol Research Foundation at http://www(dot)euroqol(dot)org/about-eq-5d/valuation-of-eq-5d; Devlin et al., ( 2017) Health Economics, released 1-16). In addition, in the second part of the questionnaire, the current health status is measured by the visual analog scale (VAS), and its value ranges from 0 to 100.

對於隨時間推移進行的每項EQ-5D-5L評估，對每個問題之五個類別中每個類別之每個問題中患者之數量及百分比執行評價。治療組提供在每次訪視時EQ-5D-5L指標效用得分之匯總以及自基線之相關變化。對EuroQoL視覺模擬量表(EQ-VAS)執行類似分析。For each EQ-5D-5L assessment performed over time, the number and percentage of patients in each question in each of the five categories of each question are evaluated. The treatment group provides a summary of the EQ-5D-5L index utility scores and related changes from baseline at each visit. A similar analysis was performed on the EuroQoL visual analog scale (EQ-VAS).

藉由混合線性模型分析指標效用得分及VAS。此外，報告EQ-5D-5L指標及EQ-VAS得分超過有臨床意義之臨限值之變化的患者比例亦有報告。有臨床意義之改善臨限值定義為指標效用得分的+0.07分變化及VAS得分的+7分變化。EORTC QLQ-C30 Analyze the indicator utility score and VAS by the mixed linear model. In addition, the proportion of patients who reported changes in EQ-5D-5L indicators and EQ-VAS scores that exceeded clinically significant thresholds was also reported. The clinically significant improvement threshold is defined as a +0.07 point change in the indicator utility score and a +7 point change in the VAS score. EORTC QLQ-C30

EORTC QLQ-C30係經過驗證且可靠的自我報告量表(Aaronson等人 ，(1993) J Natl Cancer Inst，85:365-376；Fitzsimmons等人 ，(1999) 35:939-941)。其由30個問題組成，評估患者功能之五個態樣(身體、情感、地位、認知及社交)、三個症狀量表(疲勞、噁心及嘔吐、疼痛)、總體健康/生活品質、以及六個單項(呼吸困難、失眠、食慾不振、便秘、腹瀉及財務困難)，加上前一周的回憶期。EORTC QLQ-C30 is a validated and reliable self-report scale (Aaronson et al ., (1993) J Natl Cancer Inst, 85:365-376; Fitzsimmons et al ., (1999) 35:939-941). It consists of 30 questions, assessing five aspects of patient function (physical, emotional, status, cognitive and social), three symptom scales (fatigue, nausea and vomiting, pain), overall health/quality of life, and six A single item (dyspnea, insomnia, loss of appetite, constipation, diarrhea, and financial difficulties), plus the recall period of the previous week.

對於EORTC QLQ-C30問卷，將報告所有項目及分量表在每次訪視時之匯總統計以及線性轉換得分自基線之變化。For the EORTC QLQ-C30 questionnaire, the summary statistics of all items and subscales at each visit and the change in linear conversion scores from the baseline will be reported.

惡化時間定義為自隨機分組至首次記錄EORTC QLQ-C30身體功能量表自基線下降10分之時間。對於疲勞，惡化時間定義為自隨機分組至首次記錄自基線增加10分之時間。若在基准後進行評估，則在最後一個未缺失評估日期對在臨床資料截止時未觀察到惡化的患者進行審查；若在基線後未進行評估，則在隨機分組日期+1天進行審查。使用分層Cox比例風險模型估算惡化時間之風險比。提供風險比之95% CI。用Kaplan-Meier方法估算每個治療組之中值惡化時間，並產生Kaplan-Meier曲線。Deterioration time was defined as the time from randomization to the first recording of the EORTC QLQ-C30 body function scale from baseline by 10 minutes. For fatigue, the time to deterioration is defined as the time from randomization to the first recording of a 10 point increase from baseline. If the assessment is performed after the baseline, the patients who have not observed deterioration at the end of the clinical data will be reviewed on the last non-missing assessment date; if the assessment is not performed after the baseline, the review will be conducted on the randomization date+1 day. Use the stratified Cox proportional hazard model to estimate the hazard ratio of the time to deterioration. Provides a 95% CI of the hazard ratio. The Kaplan-Meier method was used to estimate the median deterioration time of each treatment group, and a Kaplan-Meier curve was generated.

EORTC QLQ-C30資料係根據EORTC評分手冊(Fayers等人 ，(2001) European Organisation for Research and Treatment of Cancer，Brussels)進行評分。缺失的資料將根據時間點進行評估及報告。在資料不完整的情況下，對於所有問卷分量表，若完成超過50%的構成項目，則按照評分手冊及公佈之驗證報告計算按比例分配之得分。對於少於50%項目完成的分量表，該分量表被視為缺失。在每個時間點預期完成EORTC QLQ-C30的患者中，完成率係根據患者之數量及比例匯總。FACT-Lym The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers et al . (2001) European Organisation for Research and Treatment of Cancer, Brussels). The missing data will be evaluated and reported based on the time point. In the case of incomplete information, for all questionnaire subscales, if more than 50% of the constituent items are completed, the prorated score will be calculated according to the scoring manual and the published verification report. For subscales that are less than 50% completed, the subscale is considered missing. Among patients who are expected to complete EORTC QLQ-C30 at each time point, the completion rate is based on the number and proportion of patients. FACT-Lym

FACT-Lym係經過驗證的健康相關生活品質(HRQoL)工具，專用於淋巴瘤患者。其由FACT通用問卷 (FACT-G)加上淋巴瘤專用分量表(FACT-Lym LYMS；範圍0-60)組成(Cella等人 ，(1993) J Clin ONcol，11:570-579；Cella等人 ，(2005) Blood，106:750)。計算三個匯總量表，即FACT-Lym試驗結果指標、FACT-G及FACT-Lym總得分。較高的分數反映較佳的HRQoL。FACT-Lym is a validated health-related quality of life (HRQoL) tool designed for patients with lymphoma. It consists of the FACT general questionnaire (FACT-G) plus a lymphoma-specific subscale (FACT-Lym LYMS; range 0-60) (Cella et al ., (1993) J Clin ONcol, 11:570-579; Cella et al. , (2005) Blood, 106:750). Calculate three summary scales, namely FACT-Lym test result indicators, FACT-G and FACT-Lym total scores. A higher score reflects a better HRQoL.

對於FACT-Lym問卷量表中之每一項，在每次訪視時的描述性統計以及自基線之變化均由治療組報告。For each item in the FACT-Lym questionnaire, the descriptive statistics at each visit and the change from baseline are reported by the treatment group.

在各個分量表及FACT-Lym TOT層面上有臨床意義的最小重要性差異(亦即，被認為對患者極為重要的最小量變化)已預先指定，並用於定義由於治療而在FACT-Lym LYMS得分(≥ 3分)、FACT-Lym TOI得分(≥ 6分)及FACT-Lym TOT得分(≥ 7分)上報告有意義之變化的患者比例(Carter等人 ，(2008) Blood，112:2376)。The smallest clinically significant difference in importance (ie, the smallest change considered to be extremely important to the patient) at the level of each subscale and FACT-Lym TOT has been pre-specified and used to define the FACT-Lym LYMS score due to treatment The proportion of patients reporting meaningful changes in FACT-Lym TOI score (≥ 6 points), FACT-Lym TOT score (≥ 7 points) (Carter et al ., (2008) Blood, 112:2376).

惡化時間定義為自隨機分組至首次記錄自基線有＞ 3分下降的時間(Carter等人 ，(2008) Blood，112: 2376；Hlubocky等人 ，(2013) Lymphoma，ID147176)。若在基准後進行評估，則在最後一個未缺失評估日期對在臨床資料截止時未觀察到惡化的患者進行審查；若在基線後未進行評估，則在隨機分組日期+1天進行審查。使用分層Cox比例風險模型估算惡化時間之風險比。提供風險比之95% CI。用Kaplan-Meier方法估算每個治療組之中值惡化時間，並產生Kaplan-Meier曲線。使用原始的1點惡化，用FACT-Lym LYMS的各個B症狀項目進行補充項目級分析。對於問卷內缺失之項目，根據開發人員指南計算按比例分配之得分(Webster等人 ，(2003) Health Qual Life Outcomes，1:79)。在每個時間點按治療組匯總PRO完成率。 F. 藥物動力學分析 Deterioration time was defined as the time from randomization to the first recording of> 3 points drop from baseline (Carter et al ., (2008) Blood, 112: 2376; Hlubocky et al ., (2013) Lymphoma, ID147176). If the evaluation is performed after the baseline, the patients who have not seen deterioration at the end of the clinical data will be reviewed on the last non-missing evaluation date; if the evaluation is not performed after the baseline, the review will be conducted on the randomization date+1 day. The hierarchical Cox proportional hazard model is used to estimate the hazard ratio of the time to deterioration. Provides a 95% CI of the hazard ratio. The Kaplan-Meier method was used to estimate the median deterioration time of each treatment group, and a Kaplan-Meier curve was generated. Using the original 1-point deterioration, supplementary item-level analysis was performed with each B symptom item of FACT-Lym LYMS. For items that are missing in the questionnaire, a prorated score is calculated according to the developer’s guide (Webster et al . (2003) Health Qual Life Outcomes, 1:79). At each time point, the PRO completion rate was summarized by treatment group. F. Pharmacokinetic analysis

在第1階段及第2階段期間，對血液樣品執行帕妥珠單抗維多汀之PK分析。使用驗證之方法定量血清帕妥珠單抗維多汀總抗體(包括所有藥物比抗體比率[DAR]物種，包括DAR 0及DAR≥1)、血漿帕妥珠單抗維多汀偶聯物(以acMMAE評價)及血漿未結合MMAE濃度。亦分析樣品中之其他潛在的分解代謝物。During Phase 1 and Phase 2, PK analysis of Pertuzumab Verdotin was performed on blood samples. Use validated methods to quantify the total serum Pertuzumab Vidotin antibody (including all drug-to-antibody ratio [DAR] species, including DAR 0 and DAR≥1), and plasma Pertuzumab Vidotin conjugate ( Evaluated by acMMAE) and plasma unbound MMAE concentration. Other potential catabolic metabolites in the sample are also analyzed.

將帕妥珠單抗維多汀、吉西他濱及奧沙利鉑之個別及平均血清及血漿濃度隨時間變化之資料製成表格並作圖。針對每種分析物之每次採樣計算濃度資料之匯總統計。估算PK參數、最大濃度(Cmax )及低谷濃度(C谷 )(適用於所收集之數據)。將此等參數之估算值製成表格並進行匯總(平均值及SD)。PK參數係基於可用資料，使用適當技術確定。將人群PK分析方法應用於PK參數估算。藉由將當前研究中之PK與歷史資料相比較來評估潛在的藥物相互作用。藉由人群PK分析探索PK變異性與人口統計及病理生理學共變量之間的潛在相關性。藉由探索性圖形分析及PK-藥效學模型探索PK變異性與藥效學、功效及安全性結果之間的潛在相關性。 G. 免疫原性分析 The individual and mean serum and plasma concentrations of Pertuzumab vedotine, gemcitabine and oxaliplatin over time were tabulated and graphed. Calculate summary statistics of concentration data for each sample of each analyte. Estimate PK parameters, maximum concentration (C max ) and trough concentration (C trough ) (applicable to the collected data). The estimated values of these parameters are tabulated and summarized (average value and SD). PK parameters are determined based on available information and using appropriate techniques. The population PK analysis method is applied to the estimation of PK parameters. Evaluate potential drug interactions by comparing the PK in the current study with historical data. The population PK analysis was used to explore the potential correlation between PK variability and demographic and pathophysiological covariates. Explore the potential correlation between PK variability and pharmacodynamics, efficacy and safety results through exploratory graphical analysis and PK-pharmacodynamic models. G. Immunogenicity analysis

在第1階段及第2階段期間，使用經過驗證的抗體橋接ELISA篩选並確定患者血清樣品中抗帕妥珠單抗維多汀抗體之存在，且表徵並測定已確定之ADA陽性樣品之力價。During Phase 1 and Phase 2, a validated antibody bridge ELISA was used to screen and determine the presence of anti-pertuzumab vidotin antibody in patient serum samples, and to characterize and determine the strength of the determined ADA-positive samples price.

免疫原性分析人群由接受至少一劑帕妥珠單抗維多汀且具有至少一種可評價之基線後ADA樣品的所有患者組成。根據所接受的治療將患者分組，或若在研究中止之前未接受治療，則根據分配之治療進行分組。The immunogenicity analysis population consisted of all patients who received at least one dose of Pertuzumab Verdotin and had at least one evaluable post-baseline ADA sample. Patients are grouped according to the treatment they received, or if they have not received treatment before the study is discontinued, they are grouped according to the assigned treatment.

按治療組匯總基線時(基線流行率)及基線之後(基線後流行率)的ADA陽性及ADA陰性患者之數量及比例。在測定基線後發生率時，若患者呈ADA陰性或基線資料缺失但在研究藥物暴露後測試呈ADA陽性(治療誘發之ADA反應)；或若患者在基線時呈ADA陽性且一或多個基線後樣品之力價比基線樣品之力價高至少0.60個力價單位(治療增強之ADA反應)，則將其視為ADA陽性。若患者呈ADA陰性或基線資料缺失且所有基線後樣品均呈陰性；或若患者在基線時呈ADA陽性但沒有力價比基線樣品之力價高至少0.60個力價單位之任何基線後樣品(不受治療影響)，則將其視為ADA陰性。The number and proportion of ADA-positive and ADA-negative patients at baseline (baseline prevalence) and after baseline (post-baseline prevalence) were summarized by treatment group. When determining the incidence after baseline, if the patient is ADA negative or baseline data is missing but tested positive for ADA after study drug exposure (treatment-induced ADA response); or if the patient is ADA positive at baseline and one or more baselines The power price of the latter sample is at least 0.60 power unit higher than the power price of the baseline sample (ADA response for treatment enhancement), then it is considered ADA positive. If the patient is ADA-negative or baseline data is missing and all post-baseline samples are negative; or if the patient is ADA-positive at baseline but does not have any post-baseline sample that is at least 0.60 units higher than that of the baseline sample ( Not affected by treatment), it is considered ADA negative.

使用標準語言及/或術語分析及報告ADA狀態與安全性、功效、PK及生物標記物終點之間的關係。 H. 生物標記物分析 Use standard language and/or terminology to analyze and report the relationship between ADA status and safety, efficacy, PK, and biomarker endpoints. H. Biomarker analysis

在第2階段期間，對腫瘤組織及血漿樣品執行生物標記物測試分析。During the second phase, biomarker test analysis is performed on tumor tissue and plasma samples.

無創、簡單的血漿收集即可評估循環腫瘤DNA (ctDNA)，咸信該DNA係來自腫瘤細胞之凋亡殘留物。對ctDNA定量並評估其基因組突變。除了將此在基線時之資訊與臨床功效相關聯以進行預後及治療效果評價外，此資訊亦允許在分子層面上監測殘留疾病並跟踪純系進化。Non-invasive and simple plasma collection can assess circulating tumor DNA (ctDNA), which is believed to be derived from the apoptotic residue of tumor cells. Quantify ctDNA and evaluate its genome mutations. In addition to correlating this information at baseline with clinical efficacy for prognostic and therapeutic effect evaluation, this information also allows monitoring of residual diseases at the molecular level and tracking of pure lineage evolution.

對與腫瘤生物學有關之生物標記物以及帕妥珠單抗維多汀及利妥昔單抗之作用機制進行分析。The biomarkers related to tumor biology and the mechanism of action of Pertuzumab vedotine and rituximab were analyzed.

分析評估預後及/或候選生物標記物之預測價值。探索候選生物標記物與治療相關及治療不相關之OS、PFS及PET-CT CR率以及其他療效及安全性指標之間的關聯，以分別評估潛在的預測及預後值。使用單變量及/或多元變量統計方法評價基線預後特徵，包括DLBCL亞型(亦即，COO)及突變譜，對功效之影響。Analyze and evaluate the prognosis and/or the predictive value of candidate biomarkers. Explore the correlation between candidate biomarkers and treatment-related and treatment-unrelated OS, PFS, PET-CT CR rates, and other efficacy and safety indicators to evaluate potential predictive and prognostic values, respectively. Use univariate and/or multivariate statistical methods to evaluate baseline prognostic characteristics, including DLBCL subtypes (ie, COO) and mutation profiles, and their effects on efficacy.

迄今為止，最確定的DLBCL生物標記物子集係與B-細胞源性腫瘤之發展階段或起源細胞(COO)一致的以分子確定之型態，亦即，活化之B-細胞樣(ABC)型態、生髮中心B-細胞樣(GCB)或未分類型態、BCL2/MYC雙表現子譜(以MYC及BCL2之高表現為特徵)、以及BCL2/MYC雙重擊中型態(在BCL2及MYC中之易位)。在WHO分類之最新修訂版中，定義了一個新的分子亞組，即伴有MYC以及BCL2及/或BCL6重排之高惡性度B細胞淋巴瘤(HGBL DH/TH) (Swerdlow等人 ，(2016) Blood，127:2375-2390)。最近，已鑑別出超出上述類別之分子亞型，具有獨特的基因型、表觀遺傳特徵及臨床特徵。實例包括Schmitz等人 ，(2018) N Engl J Med，378:1396-1407所述之基因亞型以及Chapuy等人 ，(2018) Nat Med，24:679-690所述之五個DLBCL亞群。So far, the most definite subset of DLBCL biomarkers is consistent with the developmental stage or cell of origin (COO) of B-cell-derived tumors in a molecularly defined form, that is, activated B-cell-like (ABC) Type, germinal center B-cell-like (GCB) or undifferentiated type, BCL2/MYC dual performance subspectrum (characterized by the high performance of MYC and BCL2), and BCL2/MYC double hit type (in BCL2 and Translocation in MYC). In the latest revision of the WHO classification, a new molecular subgroup is defined, namely high-grade B-cell lymphoma (HGBL DH/TH) with MYC and BCL2 and/or BCL6 rearrangement (Swerdlow et al ., ( 2016) Blood, 127: 2375-2390). Recently, molecular subtypes beyond the above categories have been identified, with unique genotypes, epigenetic characteristics and clinical characteristics. Examples include the genotype described in Schmitz et al ., (2018) N Engl J Med, 378:1396-1407, and the five DLBCL subgroups described in Chapuy et al ., (2018) Nat Med, 24:679-690.

本研究之生物標記物包括但不限於以上論述之任何生物標記物、帕妥珠單抗維多汀(CD79b)之目標、藉由新一代定序(NGS)進行之腫瘤突變譜分析以及DLBCL中確定之預後生物標記物(起源細胞、BCL2/MYC雙重表現及BCL2/MYC雙重易位)。表 3 提供示例性探索性生物標記物之匯總。表 3 ：回顧性探索性研究之生物標記物 ( 第 2 階段 ) 。 樣品類型 定時 ( 均為強制性的 ) 提出的生物標記物 腫瘤組織 新鮮或存檔 ●    基於RNA之基因表現譜分析，包括但不限於起源細胞基因標誌分析。 ●    IHC及蛋白質組譜分析，包括BCL2及MYC。 ●    易位譜，包括BCL2及MYC。 ●    藉由NGS進行之突變譜分析，包括但不限於CD79b。 血漿 C1D1(給藥前)、C2D1(給藥前)、C5D1(給藥前)及治療結束(或治療中止，以先到者為準) ●    ctDNA量及純系突變譜。 ●    作為疾病生物學、預後、亞群及治療反應之周圍量度之ctDNA。 ctDNA=循環腫瘤DNA；IHC=免疫組織化學；NGS=新一代定序。 I. 亞組分析 The biomarkers in this study include, but are not limited to, any of the biomarkers discussed above, the target of Pertuzumab Vidotin (CD79b), tumor mutation profile analysis by next-generation sequencing (NGS), and DLBCL Determined prognostic biomarkers (cells of origin, BCL2/MYC dual expression and BCL2/MYC dual translocation). Table 3 provides a summary of exemplary exploratory biomarkers. Table 3: A retrospective study of exploratory biomarkers (Phase 2). Sample type Timing ( all mandatory ) Proposed biomarkers Tumor tissue Fresh or archived ● RNA-based gene expression profile analysis, including but not limited to gene marker analysis of cells of origin. ● IHC and proteomic profile analysis, including BCL2 and MYC. ● Translocation spectrum, including BCL2 and MYC. ● Mutation profile analysis by NGS, including but not limited to CD79b. plasma C1D1 (before administration), C2D1 (before administration), C5D1 (before administration) and end of treatment (or treatment is discontinued, whichever comes first) ● ctDNA amount and pure line mutation spectrum. ● ctDNA as a peripheral measure of disease biology, prognosis, subgroups and treatment response. ctDNA = circulating tumor DNA; IHC = immunohistochemistry; NGS = next-generation sequencing. I. Subgroup analysis

為了評估由人口統計及相關基線特徵所確定之亞組中治療效益研究結果之一致性，對此等亞組中之OS及PFS進行評價。In order to evaluate the consistency of the results of the treatment benefit study in the subgroups determined by demographics and related baseline characteristics, the OS and PFS in these subgroups were evaluated.

使用分層的Cox比例風險模型評估治療效益之一致性，並以95% CI估算風險比。使用森林圖(Forest plot)匯總結果。 J. 中期安全性分析 A stratified Cox proportional hazard model was used to evaluate the consistency of treatment benefit, and the hazard ratio was estimated with 95% CI. Use Forest plot to summarize the results. J. Mid-term safety analysis

進行若干安全性中期分析，包括檢查FACT/GOG-Ntx12。在安全性磨合期(階段1)間，安全性資料要分析至少3次。在RCT階段期間，在每個治療組中將前10名及20名患者隨機分組後，分析安全性資料；在RCT階段期間進行後續中期分析之頻率取決於第二次中期分析中≥3級周圍神經病變事件之數量。必要時，此等中期安全性分析評估所有徵募患者，直至該等患者完成研究治療為止。Conduct several safety interim analyses, including checking FACT/GOG-Ntx12. During the safety run-in period (stage 1), safety data should be analyzed at least 3 times. During the RCT phase, after randomizing the top 10 and 20 patients in each treatment group, analyze the safety data; the frequency of subsequent interim analyses during the RCT phase depends on the level of ≥3 in the second interim analysis The number of neuropathic events. When necessary, these mid-term safety analyses evaluate all recruited patients until these patients have completed the study treatment.

圖 1 係實例1中所描述之研究之總體設計示意圖。Pola= 帕妥珠單抗維多汀；Rand = 隨機化；R-GemOx = 利妥昔單抗加吉西他濱加奧沙利鉑；R/R DLBCL = 復發性或難治性彌漫性大B細胞淋巴瘤。圖 2 係實例1中所描述之研究之第1階段(安全性研究磨合期)的示意圖。EOT= 治療結束；RCT= 隨機對照試驗(第2階段)。圖 3A-3B 顯示實例1中所描述之研究的實驗治療方案及對照治療方案。圖 3A 係實例1中所描述之研究之實驗治療方案(Pola-R-GemOx)的示意圖。菱形表示利妥昔單抗之劑量(375 mg/m2 )；圓形表示帕妥珠單抗維多汀(1.8 mg/kg)；細箭頭表示吉西他濱之劑量(1000 mg/m2 )；寬箭頭表示奧沙利鉑之劑量(100 mg/m2 )；a 利妥昔單抗係在帕妥珠單抗維多汀之前投與；b 吉西他濱係在奧沙利鉑之前投與。圖 3B 顯示實例1中所描述之研究的對照治療方案(R-GemOx)的示意圖。菱形表示利妥昔單抗之劑量(375 mg/m2 )；細箭頭表示吉西他濱之劑量(1000 mg/m2 )；寬箭頭表示奧沙利鉑之劑量(100 mg/m2 )；a 吉西他濱係在奧沙利鉑之前投與。在圖 3A-3B 中，C= 週期(1個週期係21天；D = 天；及IV = 靜脈內。 Figure 1 is a schematic diagram of the overall design of the study described in Example 1. Pola = Pertuzumab vedotine; Rand = randomized; R-GemOx = rituximab plus gemcitabine plus oxaliplatin; R/R DLBCL = relapsed or refractory diffuse large B-cell lymphoma . Figure 2 is a schematic diagram of the first phase (safety study run-in period) of the study described in Example 1. EOT = end of treatment; RCT = randomized controlled trial (phase 2). Figures 3A-3B show the experimental treatment plan and the control treatment plan of the study described in Example 1. Figure 3A is a schematic diagram of the experimental treatment protocol (Pola-R-GemOx) of the study described in Example 1. The diamond indicates the dose of rituximab (375 mg/m 2 ); the circle indicates the dose of Pertuzumab Verdotin (1.8 mg/kg); the thin arrow indicates the dose of gemcitabine (1000 mg/m 2 ); width The arrow indicates the dose of oxaliplatin (100 mg/m 2 ); a rituximab was administered before Pertuzumab vedotine; b gemcitabine was administered before oxaliplatin. FIG. 3B shows a schematic diagram of the control treatment protocol (R-GemOx) of the study described in Example 1. FIG. The diamond represents the dose of rituximab (375 mg/m 2 ); the thin arrow represents the dose of gemcitabine (1000 mg/m 2 ); the wide arrow represents the dose of oxaliplatin (100 mg/m 2 ); a gemcitabine It was administered before oxaliplatin. In Figures 3A-3B , C = cycle (1 cycle is 21 days; D = day; and IV = intravenous.

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Claims (62)

一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a)     包含下式之免疫偶聯物
Figure 03_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且 其中p在1與8之間， (b)     利妥昔單抗， (c)     吉西他濱，及 (d)     奧沙利鉑。A method for treating diffuse large B-cell lymphoma (DLBCL) in a human subject in need, the method comprising administering to the human subject an effective amount of: (a) an immunoconjugate comprising the following formula
Figure 03_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and where p is between 1 and 8, (b) Rituximab, (c) Gemcitabine, And (d) Oxaliplatin. 如請求項1之方法，其中該抗CD79b抗體包括(i)含SEQ ID NO: 19之胺基酸序列的重鏈可變域(VH)及(ii)含SEQ ID NO: 20之胺基酸序列的輕鏈可變域(VL)。The method of claim 1, wherein the anti-CD79b antibody comprises (i) a heavy chain variable domain (VH) containing the amino acid sequence of SEQ ID NO: 19 and (ii) the amino acid containing SEQ ID NO: 20 Sequence of the light chain variable domain (VL). 如請求項1或請求項2之方法，其中該抗CD79b抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈。The method of claim 1 or claim 2, wherein the anti-CD79b antibody comprises (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a heavy chain containing the amino acid sequence of SEQ ID NO: 35 Light chain. 如請求項1至3中任一項之方法，其中p在2與5之間。Such as the method of any one of claims 1 to 3, wherein p is between 2 and 5. 如請求項1至4中任一項之方法，其中p在3與4之間。Such as the method of any one of claims 1 to 4, wherein p is between 3 and 4. 如請求項1至5中任一項之方法，其中該免疫偶聯物係帕妥珠單抗維多汀-piiq。The method according to any one of claims 1 to 5, wherein the immunoconjugate is Pertuzumab Vidotin-piiq. 如請求項1至2或4至5中任一項之方法，其中該抗CD79b抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。The method according to any one of claims 1 to 2 or 4 to 5, wherein the anti-CD79b antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a heavy chain containing the amino acid sequence of SEQ ID NO: 35 Light chain. 如請求項1至2或4至5中任一項之方法，其中該抗CD79b抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。The method according to any one of claims 1 to 2 or 4 to 5, wherein the anti-CD79b antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a heavy chain containing the amino acid sequence of SEQ ID NO: 38 Light chain. 如請求項1至2、4或7中任一項之方法，其中該免疫偶聯物係依拉妥珠單抗維多汀。The method according to any one of claims 1 to 2, 4 or 7, wherein the immunoconjugate is elatuzumab vedotine. 如請求項1至9中任一項之方法，其中該免疫偶聯物係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與且奧沙利鉑係以約100 mg/m2 之劑量投與。The method according to any one of claims 1 to 9, wherein the immunoconjugate is administered at a dose of about 1.8 mg/kg, rituximab is administered at a dose of about 375 mg/m 2, and gemcitabine It is administered at a dose of about 1000 mg/m 2 and oxaliplatin is administered at a dose of about 100 mg/m 2 . 如請求項1至10中任一項之方法，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與一或多個21天週期。The method according to any one of claims 1 to 10, wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for one or more 21-day cycles. 如請求項11之方法，其中該免疫偶聯物在每個週期係以約1.8 mg/kg之劑量投與，利妥昔單抗在每個週期係以約375 mg/m2 之劑量投與，吉西他濱在每個週期係以約1000 mg/m2 之劑量投與，且奧沙利鉑在每個週期係以約100 mg/m2 之劑量投與。The method of claim 11, wherein the immunoconjugate is administered at a dose of about 1.8 mg/kg in each cycle, and rituximab is administered at a dose of about 375 mg/m 2 in each cycle Gemcitabine is administered at a dose of about 1000 mg/m 2 in each cycle, and oxaliplatin is administered at a dose of about 100 mg/m 2 in each cycle. 如請求項11或請求項12之方法，其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。Such as the method of claim 11 or claim 12, wherein the immunoconjugate and rituximab are administered intravenously on the first day of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered in each Administer intravenously on day 2 of a 21-day cycle. 如請求項1至13中任一項之方法，其中利妥昔單抗係在該免疫偶聯物之前投與。The method according to any one of claims 1 to 13, wherein rituximab is administered before the immunoconjugate. 如請求項1至14中任一項之方法，其中吉西他濱係在奧沙利鉑之前投與。Such as the method of any one of claims 1 to 14, wherein gemcitabine is administered before oxaliplatin. 如請求項11至15中任一項之方法，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至多八個21天週期。The method according to any one of claims 11 to 15, wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for at most eight 21-day cycles. 如請求項11至16中任一項之方法，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與八個21天週期。The method according to any one of claims 11 to 16, wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for eight 21-day cycles. 一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：  (a)     包含下式之免疫偶聯物
Figure 03_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈， 且其中p在2與5之間， (b)     利妥昔單抗， (c)     吉西他濱，及 (d)     奧沙利鉑； 其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期間，該免疫偶聯物係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與；且 其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。A method for treating diffuse large B-cell lymphoma (DLBCL) in a human subject in need, the method comprising administering to the human subject an effective amount of: (a) an immunoconjugate comprising the following formula
Figure 03_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein during each week, the immunoconjugate is administered at a dose of about 1.8 mg/kg, and rituximab is administered at a dose of about 375 mg/m 2 . Gemcitabine is administered at a dose of about 1000 mg/m 2 and oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein the immunoconjugate and rituximab are administered at each 21 It was administered intravenously on the first day of the day cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle. 如請求項18之方法，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少兩個、至少三個、至少四個、至少五個、至少六個或至少七個21天週期。The method of claim 18, wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered at least two, at least three, at least four, at least five, at least six or at least Seven 21-day cycles. 如請求項18之方法，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與八個21天週期。The method of claim 18, wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for eight 21-day cycles. 如請求項18至20中任一項之方法，其中利妥昔單抗係在該免疫偶聯物之前投與。The method according to any one of claims 18 to 20, wherein rituximab is administered before the immunoconjugate. 如請求項18至21中任一項之方法，其中吉西他濱係在奧沙利鉑之前投與。Such as the method of any one of claims 18 to 21, wherein gemcitabine is administered before oxaliplatin. 如請求項18至22中任一項之方法，其中該免疫偶聯物係帕妥珠單抗維多汀-piiq。The method according to any one of claims 18 to 22, wherein the immunoconjugate is Pertuzumab Vidotin-piiq. 如請求項1至23中任一項之方法，其中該人類個體已經接受至少一種針對DLBCL之先前療法。The method of any one of claims 1 to 23, wherein the human individual has received at least one previous therapy for DLBCL. 如請求項1至24中任一項之方法，其中該人類個體已接受至少一種針對DLBCL之先前全身性療法。The method of any one of claims 1 to 24, wherein the human individual has received at least one previous systemic therapy for DLBCL. 如請求項1至25中任一項之方法，其中該DLBCL係經組織學確定的非特指型(NOS) DLBCL，或者該人類個體有惰性疾病轉化為DLBCL之病史。The method according to any one of claims 1 to 25, wherein the DLBCL is a histologically determined non-specific (NOS) DLBCL, or the human individual has a history of converting an indolent disease to DLBCL. 如請求項1至26中任一項之方法，其中該DLBCL係復發性或難治性DLBCL。The method according to any one of claims 1 to 26, wherein the DLBCL is relapsed or refractory DLBCL. 如請求項1至27中任一項之方法，其中該人類個體之美國東岸癌症臨床研究合作組織(ECOG)體能狀態為0、1或2。The method according to any one of claims 1 to 27, wherein the East Coast Cancer Clinical Research Collaboration (ECOG) performance status of the human individual is 0, 1, or 2. 如請求項1至28中任一項之方法，其中該人類個體未經歷計劃之自體或同種異體幹細胞移植(SCT)。The method of any one of claims 1 to 28, wherein the human individual has not undergone planned autologous or allogeneic stem cell transplantation (SCT). 如請求項1至29中任一項之方法，其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前，該人類個體並非造血幹細胞移植(HSCT)之候選人。The method according to any one of claims 1 to 29, wherein the human individual is not a candidate for hematopoietic stem cell transplantation (HSCT) before administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin . 如請求項1至30中任一項之方法，其中在投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑之前，該人類個體並非自體造血幹細胞移植(HSCT)之候選人。The method according to any one of claims 1 to 30, wherein the human individual is not an autologous hematopoietic stem cell transplantation (HSCT) before administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin candidate. 如請求項1至31中任一項之方法，其中該人類個體已接受至少兩種針對DLBCL之先前療法。The method of any one of claims 1 to 31, wherein the human individual has received at least two previous therapies for DLBCL. 如請求項1至32中任一項之方法，其中該人類個體未曾接受用吉西他濱及鉑基藥劑之組合進行之先前療法。The method according to any one of claims 1 to 32, wherein the human individual has not received prior therapy with a combination of gemcitabine and platinum-based agents. 如請求項1至33中任一項之方法，其中該人類個體未接受用針對DLBCL之帕妥珠單抗維多汀-piiq進行之先前療法。The method of any one of claims 1 to 33, wherein the human individual has not received previous therapy with Pertuzumab Vidotin-piiq for DLBCL. 如請求項1至34中任一項之方法，其中根據5.0版國家癌症研究院常見不良事件評價準則，該人類個體之周圍神經病變不大於1級。Such as the method of any one of claim items 1 to 34, wherein the peripheral neuropathy of the human individual is not greater than grade 1 according to the evaluation criteria for common adverse events of the National Cancer Institute version 5.0. 如請求項1至35中任一項之方法，其中該人類個體未患原發性或繼發性中樞神經系統淋巴瘤。The method according to any one of claims 1 to 35, wherein the human individual does not suffer from primary or secondary central nervous system lymphoma. 如請求項1至36中任一項之方法，其中該人類個體係成人。Such as the method of any one of claims 1 to 36, wherein the human is an adult. 如請求項37之方法，其中該成人患有非特指型復發性或難治性彌漫性大B細胞淋巴瘤。The method of claim 37, wherein the adult has unspecified relapsed or refractory diffuse large B-cell lymphoma. 如請求項1至38中任一項之方法，其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。The method according to any one of claims 1 to 38, wherein the administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin does not cause peripheral neuropathy of grade 3 or higher, and the disease Cannot subside to grade 1 or lower within 14 days. 如請求項1至38中任一項之方法，其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。The method according to any one of claims 1 to 38, wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered to a plurality of human individuals such that 33% or more of the plurality of human individuals Few human individuals experience grade 3 or higher peripheral neuropathy, which cannot resolve to grade 1 or lower within 14 days. 一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：  (a)     包含下式之免疫偶聯物
Figure 03_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且 其中p在1與8之間， (b)     利妥昔單抗， (c)     吉西他濱，及 (d)     奧沙利鉑； 其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。A method for treating diffuse large B-cell lymphoma (DLBCL) in a human subject in need, the method comprising administering to the human subject an effective amount of: (a) an immunoconjugate comprising the following formula
Figure 03_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and where p is between 1 and 8, (b) Rituximab, (c) Gemcitabine, And (d) Oxaliplatin; wherein the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not cause peripheral neuropathy of grade 3 or higher, and the disease cannot be used within 14 days The internal regression is level 1 or lower. 一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：  (a)     包含下式之免疫偶聯物
Figure 03_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且 其中p在1與8之間， (b)     利妥昔單抗， (c)     吉西他濱，及 (d)     奧沙利鉑； 其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。A method for treating diffuse large B-cell lymphoma (DLBCL) in a human subject in need, the method comprising administering to the human subject an effective amount of: (a) an immunoconjugate comprising the following formula
Figure 03_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and where p is between 1 and 8, (b) Rituximab, (c) Gemcitabine, And (d) Oxaliplatin; wherein the administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin to multiple human individuals makes 33% or less of the human individuals Experienced grade 3 or higher peripheral neuropathy, the disease cannot resolve to grade 1 or lower within 14 days. 一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之： (a)     包含下式之免疫偶聯物
Figure 03_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈， 且其中p在2與5之間， (b)     利妥昔單抗， (c)     吉西他濱，及 (d)     奧沙利鉑； 其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期間，該免疫偶聯物係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與； 其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且 其中投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑不會引起3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。A method for treating diffuse large B-cell lymphoma (DLBCL) in a human subject in need, the method comprising administering to the human subject an effective amount of: (a) an immunoconjugate comprising the following formula
Figure 03_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein during each week, the immunoconjugate is administered at a dose of about 1.8 mg/kg, and rituximab is administered at a dose of about 375 mg/m 2 . Gemcitabine is administered at a dose of about 1000 mg/m 2 and oxaliplatin is administered at a dose of about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are administered every 21 days The first day of the cycle is administered intravenously, and the gemcitabine and oxaliplatin are administered intravenously on the second day of each 21-day cycle; and the immunoconjugate, rituximab, Gemcitabine and oxaliplatin do not cause peripheral neuropathy of grade 3 or higher, and the disease cannot resolve to grade 1 or lower within 14 days. 一種用於治療有需要之人類個體的彌漫性大B細胞淋巴瘤(DLBCL)之方法，該方法包括向該人類個體投與有效量之：  (a)     包含下式之免疫偶聯物
Figure 03_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 36之胺基酸序列的重鏈及(ii)含SEQ ID NO: 35之胺基酸序列的輕鏈， 且其中p在2與5之間， (b)     利妥昔單抗， (c)     吉西他濱，及 (d)     奧沙利鉑； 其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中在每個週期間，該免疫偶聯物係以約1.8 mg/kg之劑量投與，利妥昔單抗係以約375 mg/m2 之劑量投與，吉西他濱係以約1000 mg/m2 之劑量投與，且奧沙利鉑係以約100 mg/m2 之劑量投與； 其中該免疫偶聯物與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與；且 其中向多名人類個體投與該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑使得該多名人類個體中33%或更少的人類個體經歷3級或更高級別的周圍神經病變，該疾病不能在14天內消退為1級或更低級別。A method for treating diffuse large B-cell lymphoma (DLBCL) in a human subject in need, the method comprising administering to the human subject an effective amount of: (a) an immunoconjugate comprising the following formula
Figure 03_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain containing the amino acid sequence of SEQ ID NO: 35, and wherein p Between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are based Administer at least one 21-day cycle, wherein during each week, the immunoconjugate is administered at a dose of about 1.8 mg/kg, and rituximab is administered at a dose of about 375 mg/m 2 . Gemcitabine is administered at a dose of about 1000 mg/m 2 and oxaliplatin is administered at a dose of about 100 mg/m 2 ; wherein the immunoconjugate and rituximab are administered every 21 days It was administered intravenously on the first day of the cycle, and gemcitabine and oxaliplatin were administered intravenously on the second day of each 21-day cycle; and the immunoconjugate, oxaliplatin was administered to multiple human subjects. Tuximab, gemcitabine, and oxaliplatin caused 33% or less of the multiple human individuals to experience grade 3 or higher peripheral neuropathy, and the disease did not subside to grade 1 or higher within 14 days Lower level. 如請求項41至44中任一項之方法，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少兩個、至少三個、至少四個、至少五個、至少六個或至少七個21天週期。The method according to any one of claims 41 to 44, wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered at least two, at least three, at least four, and at least five , At least six or at least seven 21-day cycles. 如請求項41至44中任一項之方法，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑係投與八個21天週期。The method according to any one of claims 41 to 44, wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for eight 21-day cycles. 如請求項41至46中任一項之方法，其中利妥昔單抗係在該免疫偶聯物之前投與。The method according to any one of claims 41 to 46, wherein rituximab is administered before the immunoconjugate. 如請求項41至47中任一項之方法，其中吉西他濱係在奧沙利鉑之前投與。Such as the method of any one of claims 41 to 47, wherein gemcitabine is administered before oxaliplatin. 如請求項41至48中任一項之方法，其中該免疫偶聯物係帕妥珠單抗維多汀-piiq。The method according to any one of claims 41 to 48, wherein the immunoconjugate is Pertuzumab Vidotin-piiq. 如請求項41至42或45至48中任一項之方法，其中該抗CD79b抗體包括含SEQ ID NO: 37之胺基酸序列的重鏈及含SEQ ID NO: 35之胺基酸序列的輕鏈。The method according to any one of claims 41 to 42 or 45 to 48, wherein the anti-CD79b antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a heavy chain containing the amino acid sequence of SEQ ID NO: 35 Light chain. 如請求項41至42或45至48中任一項之方法，其中該抗CD79b抗體包括含SEQ ID NO: 36之胺基酸序列的重鏈及含SEQ ID NO: 38之胺基酸序列的輕鏈。The method according to any one of claims 41 to 42 or 45 to 48, wherein the anti-CD79b antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 36 and a heavy chain containing the amino acid sequence of SEQ ID NO: 38 Light chain. 如請求項41至42、45至48或50中任一項之方法，其中該免疫偶聯物係依拉妥珠單抗維多汀。The method according to any one of claims 41 to 42, 45 to 48, or 50, wherein the immunoconjugate is elatuzumab vedotine. 如請求項39至52中任一項之方法，其中該免疫偶聯物、利妥昔單抗、吉西他濱及奧沙利鉑已投與至少四個21天週期。The method of any one of claims 39 to 52, wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin have been administered for at least four 21-day cycles. 一種套組，其包括含有下式之免疫偶聯物
Figure 03_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且 其中p在1與8之間， 該免疫偶聯物與利妥昔單抗、吉西他濱及奧沙利鉑組合使用以根據請求項1至53中任一項之方法治療患有彌漫性大B細胞淋巴瘤(DLBCL)的有需要之人類個體。A kit comprising an immunoconjugate containing the following formula
Figure 03_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 Sequence HVR-L2; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, the immunoconjugate is combined with rituximab, gemcitabine and Oxaliplatin is used in combination to treat human individuals in need with diffuse large B-cell lymphoma (DLBCL) according to the method of any one of claims 1 to 53. 一種套組，該套組包含帕妥珠單抗維多汀-piiq，其與利妥昔單抗、吉西他濱及奧沙利鉑組合使用以根據請求項1至53中任一項之方法治療患有彌漫性大B細胞淋巴瘤(DLBCL)的有需要之人類個體。A kit comprising Pertuzumab vedotine-piiq, which is used in combination with rituximab, gemcitabine and oxaliplatin to treat patients according to the method of any one of claims 1 to 53 Human individuals in need with diffuse large B-cell lymphoma (DLBCL). 一種免疫偶聯物，其包含下式
Figure 03_image001
， 其中Ab係抗CD79b抗體，該抗體包括(i)含SEQ ID NO: 21之胺基酸序列的HVR-H1；(ii)含SEQ ID NO: 22之胺基酸序列的HVR-H2；(iii)含SEQ ID NO: 23之胺基酸序列的HVR-H3；(iv)含SEQ ID NO: 24之胺基酸序列的HVR-L1；(v)含SEQ ID NO: 25之胺基酸序列的HVR-L2；及(vi)含SEQ ID NO: 26之胺基酸序列的HVR-L3，且 其中p在1與8之間 該免疫偶聯物與利妥昔單抗、吉西他濱及奧沙利鉑組合使用以根據請求項1至53中任一項之方法治療彌漫性大B細胞淋巴瘤(DLBCL)。An immunoconjugate comprising the formula
Figure 03_image001
, Wherein Ab is an anti-CD79b antibody, which includes (i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 containing the amino acid sequence of SEQ ID NO: 22; iii) HVR-H3 containing the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 containing the amino acid sequence of SEQ ID NO: 24; (v) HVR-L1 containing the amino acid sequence of SEQ ID NO: 25 HVR-L2 of the sequence; and (vi) HVR-L3 containing the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8. The immunoconjugate is combined with rituximab, gemcitabine, and Thaliplatin is used in combination to treat diffuse large B-cell lymphoma (DLBCL) according to any one of claims 1 to 53. 一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與1.8 mg/kg劑量之帕妥珠單抗維多汀-piiq、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑。A method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering to the human individual a 1.8 mg/kg dose of Pertuzumab Anti-Vidotin-piiq, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2. 一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與1.8 mg/kg劑量之帕妥珠單抗維多汀-piiq、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑，其中該帕妥珠單抗維多汀-piiq、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中該帕妥珠單抗維多汀-piiq與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。A method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering to the human individual a 1.8 mg/kg dose of Pertuzumab Anti-Vidostin-piiq, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2 in which the Pertuzumab is Piiq, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, wherein the Pertuzumab Vidotin-piiq and rituximab are administered in each 21-day cycle It was administered intravenously on the 1st day, and gemcitabine and oxaliplatin were administered intravenously on the 2nd day of each 21-day cycle. 一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與4.8 mg/kg劑量之依拉妥珠單抗維多汀、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑。A method for the treatment of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering to the human individual a dose of 4.8 mg/kg elatuzu Monoclonal antibody vedotine, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2. 一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與3.6 mg/kg劑量之依拉妥珠單抗維多汀、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑。A method for the treatment of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering to the human individual a 3.6 mg/kg dose of elatuzu Monoclonal antibody vedotine, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2. 一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與4.8 mg/kg劑量之依拉妥珠單抗維多汀、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑，其中該依拉妥珠單抗維多汀、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中該依拉妥珠單抗維多汀與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。A method for the treatment of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering to the human individual a dose of 4.8 mg/kg elatuzu Monoclonal antibody vitotine, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2 , of which the enlatuzumab rituximab Rituximab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein the enlatuzumab vedotine and rituximab are administered at the first of each 21-day cycle It was administered intravenously every day, and gemcitabine and oxaliplatin were administered intravenously on the 2nd day of each 21-day cycle. 一種用於治療有需要之人類個體之復發性或難治性彌漫性大B細胞淋巴瘤(R/R DLBCL)的方法，該方法包括向該人類個體投與3.6 mg/kg劑量之依拉妥珠單抗維多汀、375 mg/m2 劑量之利妥昔單抗、1000 mg/m2 劑量之吉西他濱及100 mg/m2 劑量之奧沙利鉑，其中該依拉妥珠單抗維多汀、利妥昔單抗、吉西他濱及奧沙利鉑係投與至少一個21天週期，其中該依拉妥珠單抗維多汀與利妥昔單抗係在每個21天週期之第1天靜脈內投與，且其中吉西他濱與奧沙利鉑係在每個21天週期之第2天靜脈內投與。A method for the treatment of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human individual in need, the method comprising administering to the human individual a 3.6 mg/kg dose of elatuzu Monoclonal antibody vitotine, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 and oxaliplatin at a dose of 100 mg/m 2 , of which the enlatuzumab rituximab Rituximab, gemcitabine and oxaliplatin are administered for at least one 21-day cycle, wherein the enlatuzumab vedotine and rituximab are administered at the first of each 21-day cycle It was administered intravenously every day, and gemcitabine and oxaliplatin were administered intravenously on the 2nd day of each 21-day cycle.
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