阅读说明：本技术 抗程序性死亡配体-1(pd-l1)抗体的抗肿瘤用途 (Anti-tumor use of anti-programmed death ligand-1 (PD-L1) antibodies ) 是由 刘平 王军 肖亮 薛彤彤 罗毅 王利春 王晶翼 于 2019-09-19 设计创作，主要内容包括：本发明提供了抗程序性死亡配体-1(PD-L1)抗体用于制备治疗肿瘤(例如淋巴瘤或实体瘤)药物的用途。(The invention provides the use of an anti-programmed death ligand-1 (PD-L1) antibody for the manufacture of a medicament for the treatment of a tumour (e.g. lymphoma or solid tumour).)

Use of an anti-PD-L1 antibody or an antigen-binding portion thereof, or a composition comprising the antibody or an antigen-binding portion thereof, in the manufacture of a medicament for treating a tumor in an individual,

the antibody, or antigen-binding portion thereof, comprises: a heavy chain variable region (VH) comprising HCDR1 having the sequence SEQ ID NO. 15, HCDR2 having the sequence SEQ ID NO. 16, HCDR3 having the sequence SEQ ID NO. 17; and a light chain variable region (VL) comprising LCDR1 of SEQ ID NO. 18, LCDR2 of SEQ ID NO. 19, and LCDR3 of SEQ ID NO. 20;

the tumor is selected from a solid tumor or lymphoma, wherein the solid tumor is selected from one or more of squamous cell lung carcinoma, Merkel cell carcinoma, nasopharyngeal carcinoma, and cholangiocarcinoma;

preferably, the lymphoma is hodgkin's lymphoma or non-hodgkin's lymphoma; preferably, the non-hodgkin's lymphoma is one or more of peripheral T cell lymphoma, angioimmunoblastic T cell lymphoma, NK/T cell lymphoma and B cell non-hodgkin's lymphoma;

preferably, the anti-PD-L1 antibody is a humanized or chimeric antibody.

The use of claim 1, wherein the VH of the antibody, or antigen-binding portion thereof, comprises a sequence selected from: SEQ ID NOs: 2. 6, 10 or a sequence substantially identical to any one of SEQ ID NOs: 2. 6, 10, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity; and/or the presence of a gas in the gas,

the VL of the antibody, or antigen-binding portion thereof, comprises a sequence selected from the group consisting of: SEQ ID NOs: 4. 8, 12, or a sequence substantially identical to any one of SEQ ID NOs: 4. 8, 12, or a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

The use of claim 1 or 2, wherein the antibody, or antigen-binding portion thereof, comprises:

(1) VH shown as SEQ ID NO. 2, and VL shown as SEQ ID NO. 4;

(2) VH shown as SEQ ID NO. 6, and VL shown as SEQ ID NO. 8;

(3) VH shown as SEQ ID NO. 10, and VL shown as SEQ ID NO. 12;

(4) VH shown as SEQ ID NO. 6, and VL shown as SEQ ID NO. 12; or

(5) VH shown as SEQ ID NO. 10, and VL shown as SEQ ID NO. 8.

The use of any one of claims 1-3, wherein said antigen binding portion is selected from the group consisting of Fab, Fab ', F (ab')₂Fd, Fv, dAb, complementarity determining region fragment, single chain antibody (e.g., scFv), or diabody.

The use of any one of claims 1-4, wherein the antibody, or antigen-binding portion thereof, has an EC of less than about 100nM, e.g., less than about 10nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM, 0.1nM or less₅₀Binds to PD-L1 protein (e.g., human PD-L1 protein); preferably, the EC is₅₀Measured by indirect ELISA method.

The use of any one of claims 1-5, wherein the antibody or antigen-binding portion thereof comprises a non-CDR region, and the non-CDR region is from a species other than murine, such as from a human antibody;

preferably, the antibody or antigen-binding portion thereof comprises a human IgG heavy chain constant region, e.g., a heavy chain constant region of human IgG1, IgG2, IgG3, or IgG 4; preferably, the antibody or antigen-binding portion thereof has ADCC and/or CDC activity;

preferably, the antibody or antigen-binding portion thereof comprises a mutated human IgG heavy chain constant region, e.g., a mutated human IgG1 or IgG4 heavy chain constant region; preferably, the mutation confers to the antibody or antigen-binding fragment reduced ADCC and/or CDC activity;

preferably, the antibody or antigen-binding fragment thereof comprises: a variant of the human IgG1 heavy chain constant region having the following substitutions in comparison to the wild type sequence from which it is derived: L234A, L235A and G237A (positions according to the EU numbering system);

preferably, the antibody, or antigen-binding portion thereof, comprises a human kappa or lambda light chain constant region.

The use of any one of claims 1-6, wherein the antibody or antigen-binding portion thereof is an antibody or antigen-binding portion thereof selected from the group consisting of: 5C10, 5C10H1L1, 5C10H1L2, 5C10H2L1, 5C10H2L2, or 5C10H2L2-IgG1 mt.

The use of any one of claims 1-7, wherein the antibody or antigen-binding portion thereof is 5C10H2L2-IgG1mt or an antigen-binding portion thereof.

The use of any one of claims 1-8, wherein the composition comprises the antibody, or antigen-binding portion thereof, and a pharmaceutically acceptable carrier and/or excipient.

The use of any one of claims 1-9, wherein the tumor has a PD-L1 expression level of no less than 1%;

preferably, the tumor has a PD-L1 expression level of about 1% to 50%;

preferably, the PD-L1 expression is detected by immunohistochemistry (e.g., automated immunohistochemistry), in situ hybridization (e.g., fluorescence in situ hybridization), in vivo imaging, or flow cytometry.

The use of any one of claims 1-10, wherein the subject is a mammal;

preferably, the individual is a human.

The use of any one of claims 1-11, wherein the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition, is administered parenterally; preferably by intravenous infusion or by subcutaneous injection; further preferably by intravenous infusion.

The use of any one of claims 1-12, wherein the medicament is for the treatment of a solid tumor and the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition, is administered once every 7 to 90 days; preferably once every 14 to 21 days; further preferably once every 14 or 21 days;

alternatively, the medicament is for the treatment of lymphoma and the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition, is administered once every 7 to 90 days; preferably once every 14 to 21 days, further preferably repeatedly every 14 days.

The use of any one of claims 1-13, wherein the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition, is administered once every 7 days (1 week) to 90 days, or every 7 days (1 week) to 3 months, as a maintenance therapy for a solid tumor; preferably once every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 1 month, every 2 months, or every 3 months;

alternatively, the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition, is administered once every 7 days (1 week) to 90 days, or every 7 days (1 week) to 3 months, as a maintenance therapy for lymphoma; preferably once every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 1 month, every 2 months or every 3 months.

The use of any one of claims 1-14, wherein each administered dose of the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is from 100mg to 5000mg per individual; preferably 300mg to 2400mg, more preferably 600mg to 2400mg, further preferably 600mg, 900mg, 1200mg, 1500mg, 1800mg, 2000mg, 2200mg or 2400 mg.

The use of any one of claims 1-14, wherein the medicament is for the treatment of a solid tumor, and each administered dose of the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is from 1mg/kg to 50mg/kg, based on the patient's body weight; preferably 2mg/kg to 40mg/kg, further preferably 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 10mg/kg, 12mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 33mg/kg, 36mg/kg or 40 mg/kg.

The use of any one of claims 1-12, wherein the medicament is for treating a solid tumor, and the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered in a first dosage regimen comprising:

1) an induction phase wherein the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 1mg/kg to 50mg/kg (preferably 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 10mg/kg, 12mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 33mg/kg, 36mg/kg or 40mg/kg) based on the patient's body weight once every 14 or 21 days; 2) a maintenance phase wherein the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 1mg/kg to 50mg/kg based on the patient's body weight once every 1, 2, 3, or 4 weeks or every 1, 2, or 3 months.

The use of any one of claims 1-12, wherein the medicament is for treating a solid tumor or lymphoma, and the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered in a second dosage regimen comprising:

1) an induction phase wherein the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 600mg to 2400mg, preferably 600mg, 900mg, 1200mg, 1500mg, 1800mg, 2000mg, 2200mg, or 2400mg per body, once every 14 or 21 days; 2) a maintenance phase wherein the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 600mg to 2400mg per individual, at least once every 1, 2, 3, or 4 weeks or every 1, 2, or 3 months;

preferably, during the induction phase, the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 900mg per individual, 1 time every 14 days, or at a dose of 1200mg, 1500mg, or 1800mg, 1 time every 21 days.

The use of any one of claims 1-18, wherein the medicament is capable of effecting Disease Control (DC); the disease control includes Complete Response (CR), Partial Response (PR), or Stable Disease (SD).

The use of any one of claims 1-19, wherein the medicament further comprises an additional ingredient having anti-tumor activity.