Antibody for specifically recognizing programmed cell death 1 ligand 1 and application thereof

Abstract

When the PD-L1 is expressed in a tumor microenvironment in response to a proinflammatory cytokine secreted by infiltrated tumor reactive cytotoxic T lymphocytes (CTL), the combination of the PD-L1 and the CTL with the PD-1 can down-regulate the anti-tumor immunity. Therefore, blocking the PD-L1 / PD-1 pathway is an ideal therapeutic approach to restore and enhance anti-tumor immune response. The present application provides antibodies and antigen binding fragments thereof that specifically recognize programmed cell death 1 ligand 1 (PD-L1). Methods of making and using the antibodies are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. application US63 / 371900 filed on August 19, 2022, the contents of which are incorporated herein by reference in their entirety. Reference Electronic Sequence Listing

[0002] The contents of the electronic sequence listing (PDL1_seq list_20230711.xml, size: 56 KB, recording date: 2023.07.11) are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to antibodies to programmed cell death 1 ligand 1 (PD-L1), and methods for preparing and using the antibodies, including methods for treating cancer and / or infectious diseases. Background Art

[0004] The adaptive immune response includes the activation, selection, and clonal proliferation of two major types of lymphocytes, T cells and B cells. After encountering an antigen, T cells proliferate and differentiate into antigen-specific effector cells, while B cells proliferate and differentiate into antibody-secreting cells. T cell activation is a multistep process that requires multiple signaling events between T cells and antigen-presenting cells (APCs). In order to activate T cells, two types of signals must be delivered to resting T cells (Baxter and Hodgkin et al., 2002). The first type is mediated by the antigen-specific T cell receptor (TCR) and confers specificity to the immune response. The second type of co-signal, including co-stimulatory and co-inhibitory signals, regulates the magnitude of the response and is delivered through co-receptors on T cells. For example, the ligation of CD28 on T cells together with TCR ligation provides a critical secondary signal for initial T cell activation. In contrast, co-inhibitory signals of the CD28-B7 family are important for regulating immune homeostasis and host defense because these signals limit the intensity and duration of immune responses to prevent autoimmunity. At the same time, microorganisms or tumor cells can use these pathways to establish an immunosuppressive environment to suppress immune responses against themselves.

[0005] Programmed cell death 1 ligand 1 (PD-L1), also known as B7-H1, CD274 (Dong et al. 1999; Freeman et al. 2000), is a 290 amino acid type I transmembrane protein that belongs to the immunoglobulin (Ig) superfamily and a B7 homolog. PD-L1 contains Ig-V and Ig-C-like extracellular domains, a transmembrane domain, and a short cytoplasmic tail domain that does not contain a typical signaling motif (Dong et al. 1999; Keir et al. 2008; Lin et al. 2008). PD-L1 acts as a ligand that binds to the programmed cell death protein 1 (PD-1) receptor, which is a member of the CD28 receptor family (Freeman et al. 2000). The interaction between the extracellular domains of PD-L1 and PD-1 can induce conformational changes in PD-1, which leads to the phosphorylation of cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs) by Src family kinases (Gauen et al., 1994; Straus and Weiss, 1992; Zak et al., 2015). These phosphorylated tyrosine motifs subsequently recruit SHP-2 and SHP-1 protein tyrosine phosphatases to attenuate T cell activation signals. The binding of PD-1 to PD-L1 alters T cell activity in multiple ways, inhibiting T cell proliferation, survival, cytokine production (such as IL-2), and other effector functions (Butte et al., 2007; Chang et al., 1999; Curiel et al., 2003; Dong et al., 1999; Freeman et al., 2000; Keir et al., 2006; Latchman et al., 2004). In addition to its interaction with PD-1, PD-L1 can also interact with CD80, allowing it to transmit inhibitory signals to activated T cells and is believed to be important for inducing and maintaining peripheral T cell tolerance (Butte et al., 2007; Park et al., 2010).

[0006] PD-L1 is constitutively expressed on immune cells, such as T cells, B cells, macrophages, and dendritic cells (DCs), and is also expressed on a variety of non-hematopoietic cells, including vascular endothelial cells, pancreatic islet cells, and placental syncytiotrophoblast cells (Keir et al. 2008). In addition, PD-L1 is expressed by tumor cells as an "adaptive immune mechanism" to evade anti-tumor responses (Ohaegbulam KC et al. 2015) and is upregulated by any inflammatory stimulus (Yamazaki et al. 2002). It has been demonstrated that IFN-γ leads to upregulation of PD-L1 in ovarian cancer cells, which is responsible for disease progression (Abiko K et al. 2015). PD-L1 acts as a tumor-promoting factor in cancer cells by binding to its receptor and activating proliferation and survival signaling pathways (Dong p etal 2017). This finding further suggests that PD-L1 is associated with subsequent tumor progression.

[0007] When PD-L1 is expressed in the tumor microenvironment in response to proinflammatory cytokines secreted by infiltrating tumor-reactive cytotoxic T lymphocytes (CTLs), the binding of PD-L1 to PD-1 on CTLs can downregulate antitumor immunity. Therefore, blocking the PD-L1 / PD-1 pathway is an ideal therapeutic approach to restore and enhance antitumor immune responses. In preclinical models, anti-PD-1 antibodies and anti-PD-L1 antibodies have shown antitumor effects in various tumor models, especially using immunogenic tumor models, by enhancing tumor antigen-specific T cell responses, including cytokine production, survival, cell motility, and glycolysis (Chang et al. 2015; Zinselmeyer et al. 2013; Okazaki et al. 2013). In clinical trials, anti-PD-L1 antibodies represented by atezolizumab, avelumab, and durvalumab have been developed, although they were launched later than anti-PD-1 antibodies. Atezolizumab was initially developed for first-line breast and ovarian cancer. It was reported in 2021 that the drug is being developed for the treatment of gastroesophageal junction cancer. Avelumab is approved for Merkel cell carcinoma and urothelial carcinoma, while durvalumab is approved in the United States for urothelial carcinoma. WO2006 / 042237 and WO2010 / 07634A disclose anti-PD-L1 antibodies and methods of obtaining and using them. However, there is a clear unmet medical need because the best treatments for targets in this pathway are not yet commercially available.

[0008] Therefore, there remains a need in the art for therapeutic antibodies that effectively inhibit or otherwise antagonize PD-L1, as well as related methods for treating diseases or conditions mediated by PD-L1, such as cancer or infectious diseases.

[0009] The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein are incorporated by reference in their entirety. Application Overview

[0010] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising GFTFGGFG (SEQ ID NO: 1); HC-CDR2 comprising ITGDSSTI (SEQ ID NO: 6); and HC-CDR3 comprising VRGPPGTWAY (SEQ ID NO: 11); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising ESVEFYGTTL (SEQ ID NO: 17); a LC-CDR2 comprising GAS (SEQ ID NO: 24); and a LC-CDR3 comprising QQIRKVPWT (SEQ ID NO: 29).

[0011] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , the V H comprising: a HC-CDR1 comprising an amino acid sequence of SEQ ID NO: 1 or a variant thereof, said variant comprising a substitution of up to about 3 amino acids; a HC-CDR2 comprising an amino acid sequence of SEQ ID NO: 6 or a variant thereof, said variant comprising a substitution of up to about 3 amino acids; and a HC-CDR3 comprising an amino acid sequence of SEQ ID NO: 11 or a variant thereof, said variant comprising a substitution of up to about 3 amino acids; and V L , the V L Comprising: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 17 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids; LC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 24 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids; and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO: 29 or a variant thereof, wherein the variant comprises substitutions of up to about 3 amino acids.

[0012] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , which comprises V as shown in any one of the amino acid sequences of SEQ ID NOs: 35-39 H Contains HC-CDR1, HC-CDR2 and HC-CDR3, and V L , which comprises V as shown in any one of the amino acid sequences of SEQ ID NOs: 45-48 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0013] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: (i) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:35 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:45 L (ii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:36 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:46 L (iii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:37 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:47 L (iv) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:37 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:48 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (v) V H , which comprises V as shown in the amino acid sequence SEQ ID NO: 37 HHC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:46 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (vi) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:38 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:47 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (vii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:38 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:48 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (viii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:38 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:46 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (ix) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:39 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:47 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (x) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:39 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:48 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (xi) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:39 HHC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:46 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (xii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:36 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:47 L LC-CDR1, LC-CDR2 and LC-CDR3 included; (xiii) V H , which comprises V as shown in the amino acid sequence SEQ ID NO:36 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:48 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0014] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0015] In some embodiments, any of the isolated anti-PD-L1 antibodies described above, the isolated anti-PD-L1 antibody comprises: V H , comprising any one of SEQ ID NOs:35-39 or a variant thereof, wherein the variant has at least 80% sequence identity with any one of SEQ ID NOs:35-39; and VL , which comprises any one of the amino acid sequences in SEQ ID NOs: 45-48 or a variant thereof, wherein the variant has at least 80% sequence identity with any one of the amino acid sequences in SEQ ID NOs: 45-48.

[0016] In some embodiments, an isolated anti-PD-L1 antibody is provided comprising: (i) V H , comprising the amino acid sequence of SEQ ID NO: 35 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 35; and V L , which comprises the amino acid sequence of SEQ ID NO:45 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:45; (ii) V H , comprising the amino acid sequence of SEQ ID NO: 36 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 36; and V L , comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 46; (iii) V H , comprising the amino acid sequence of SEQ ID NO: 37 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 37; and V L , which comprises the amino acid sequence of SEQ ID NO: 47 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 47; (iv) V H , comprising the amino acid sequence of SEQ ID NO: 37 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 37; and V L , comprising the amino acid sequence of SEQ ID NO: 48 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 48; (v) V H , comprising the amino acid sequence of SEQ ID NO: 37 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 37; and V L , comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 46; (vi) V H , comprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 38; and VL , which comprises the amino acid sequence of SEQ ID NO: 47 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 47; (vii) V H , comprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 38; and V L , which comprises the amino acid sequence of SEQ ID NO:48 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:48; (viii) V H , comprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 38; and V L , comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 46; (ix) V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 39; and V L , comprising the amino acid sequence of SEQ ID NO: 47 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 47; (x) V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 39; and V L , comprising the amino acid sequence of SEQ ID NO: 48 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 48; (xi) V H , comprising the amino acid sequence of SEQ ID NO: 39 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 39; and V L , comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 46; (xii) V H , comprising the amino acid sequence of SEQ ID NO: 36 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 36; and V L, which comprises the amino acid sequence of SEQ ID NO: 47 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 47; (xiii) V H , comprising the amino acid sequence of SEQ ID NO: 36 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 36; and V L , which comprises the amino acid sequence of SEQ ID NO:48 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:48.

[0017] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , which comprises V as shown in the amino acid sequence SEQ ID NO:40 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:49 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0018] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0019] In some embodiments, any of the isolated anti-PD-L1 antibodies described above, the isolated anti-PD-L1 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO:40 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:40; and V L, which comprises the amino acid sequence of SEQ ID NO:49 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:49.

[0020] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , which comprises V as shown in the amino acid sequence SEQ ID NO:41 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:50 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0021] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0022] In some embodiments, any of the isolated anti-PD-L1 antibodies described above, the isolated anti-PD-L1 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO:41 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:41; and V L , which comprises the amino acid sequence of SEQ ID NO:50 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:50.

[0023] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , which comprises V as shown in the amino acid sequence SEQ ID NO:42 HHC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:51 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0024] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0025] In some embodiments, any of the isolated anti-PD-L1 antibodies described above, the isolated anti-PD-L1 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO:42 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:42; and V L , which comprises the amino acid sequence of SEQ ID NO:51 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:51.

[0026] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , which comprises V as shown in the amino acid sequence SEQ ID NO:43 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:52 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0027] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H, the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0028] In some embodiments, any of the isolated anti-PD-L1 antibodies described above, the isolated anti-PD-L1 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO:43 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:43; and V L , which comprises the amino acid sequence of SEQ ID NO:52 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:52.

[0029] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , which comprises V as shown in the amino acid sequence SEQ ID NO:43 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0030] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the VL comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0031] In some embodiments, any of the isolated anti-PD-L1 antibodies described above, the isolated anti-PD-L1 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO:43 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:43; and V L , which comprises the amino acid sequence of SEQ ID NO:53 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:53.

[0032] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , which comprises V as shown in the amino acid sequence SEQ ID NO:44 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0033] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 34, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0034] In some embodiments, any of the isolated anti-PD-L1 antibodies described above, the isolated anti-PD-L1 antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO:44 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:44; and V L , which comprises the amino acid sequence of SEQ ID NO:54 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:54.

[0035] In some embodiments, an isolated anti-PD-L1 antibody is provided that specifically binds to human PD-L1 with a Kd value of about 0.1 pM to 1 nM.

[0036] In some embodiments, an isolated anti-PD-L1 antibody is provided, which competitively binds to PD-L1 with any of the above isolated anti-PD-L1 antibodies. In some embodiments, an isolated anti-PD-L1 antibody is provided, which specifically binds to the same epitope as any of the above isolated anti-PD-L1 antibodies.

[0037] In some embodiments, any of the anti-PD-L1 antibodies isolated as described above, the isolated anti-PD-L1 antibody comprises an Fc fragment. In some embodiments, the isolated anti-PD-L1 antibody is a full-length IgG antibody. In some embodiments, the isolated anti-PD-L1 antibody is a full-length IgG1 or IgG4 antibody. In some embodiments, the isolated anti-PD-L1 antibody is chimeric, fully human or humanized. In some embodiments, the isolated anti-PD-L1 antibody is an antigen-binding fragment selected from the group consisting of Fab, Fab', F(ab)'2, Fab'-SH, single-chain antibody (scFv), Fv fragment, dAb, Fd, nanobody, double-chain antibody and linear antibody.

[0038] In some embodiments, an isolated nucleic acid molecule is provided, the nucleic acid molecule encoding any one of the anti-PD-L1 antibodies described above. In some embodiments, a vector is provided, the vector comprising any one of the nucleic acid molecules described above. In some embodiments, a host cell is provided, the host cell comprising any one of the anti-PD-L1 antibodies described above, any one of the nucleic acid molecules described above, or any one of the vectors described above. In some embodiments, a method for preparing an anti-PD-L1 antibody is provided, comprising: a) culturing any one of the host cells described above under conditions effective to express the anti-PD-L1 antibody; and b) obtaining the expressed anti-PD-L1 antibody from the host cell.

[0039] In some embodiments, a method of treating a disease or condition in a desired individual is provided, comprising administering to the individual an effective amount of any of the anti-PD-L1 antibodies described above. In some embodiments, use of any of the anti-PD-L1 antibodies described above in the preparation of a pharmaceutical composition for treating a disease or condition in a desired individual is provided. In some embodiments, use of any of the anti-PD-L1 antibodies described above or a pharmaceutical composition comprising an anti-PD-L1 antibody in the preparation of a medicament for treating a disease or condition is provided. In some embodiments, the disease or condition is associated with PD-L1, including cancer or an infectious disease or condition. In some embodiments, the disease or disorder is selected from melanoma, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, bladder cancer, lung cancer, renal cell carcinoma, cervical cancer, colon cancer, colorectal cancer, head and neck cancer, breast cancer, esophageal cancer, bone cancer, prostate cancer, basal cell carcinoma, bile duct cancer, brain and central nervous system cancer, choriocarcinoma, connective tissue cancer, digestive system cancer, endometrial cancer, eye cancer, intraepithelial carcinoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, neuroblastoma, oral cancer, ovarian cancer, rhabdomyosarcoma, sarcoma, skin cancer, testicular cancer, thyroid cancer, uterine cancer, urinary tract cancer, pancreatic cancer, and infectious diseases, including but not limited to, human immunodeficiency virus (HIV), hepatitis (A, B or C), herpes virus (e.g., VSV, HSV-1, HAV-6, HSV-II and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus.

[0040] Also provided are pharmaceutical compositions, kits, and manufactured products comprising any of the anti-PD-L1 antibodies described above. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figures 1A-1C The results shown are those of a ligand blocking assay in which an exemplary chimeric anti-human PD-L1 antibody blocks the binding of PD-L1 to PD1 as analyzed by HTRF. Figure 1A The results shown are the results of a ligand blocking assay in which exemplary chimeric anti-human PD-L1 antibodies Mab1-01 and Mab1-02 blocked the binding of PD-L1 to PD1 by HTRF analysis. Figure 1B The results shown are those of a ligand blocking assay in which an exemplary chimeric anti-human PD-L1 antibody Mab2-04 blocked the binding of PD-L1 to PD1 by HTRF analysis. Figure 1C The results shown are the results of a ligand blocking assay in which exemplary chimeric anti-human PD-L1 antibodies Mab3-14, Mab3-16, Mab3-17, and Mab3-18 blocked the binding of PD-L1 to PD1 by HTRF analysis.

[0042] Figure 2A-2EShown is an exemplary chimeric anti-human PD-L1 antibody enhancing IL-2 production in a Jurkat-Raji reporter cell assay. Figure 2A Shown are exemplary chimeric anti-human PD-L1 antibodies Mab1-01 and Mab1-02 that enhance IL-2 production in a Jurkat-Raji reporter cell assay. Figure 2B Shown is the enhancement of IL-2 production by the exemplary chimeric anti-human PD-L1 antibody Mab2-04 in a Jurkat-Raji reporter cell assay. Figure 2C Shown is the enhancement of IL-2 production by the exemplary chimeric anti-human PD-L1 antibody Mab3-14 in a Jurkat-Raji reporter cell assay. Figure 2D Shown are exemplary chimeric anti-human PD-L1 antibodies Mab3-16 and Mab3-17 that enhance IL-2 production in a Jurkat-Raji reporter cell assay. Figure 2E Shown is the enhancement of IL-2 production by the exemplary chimeric anti-human PD-L1 antibody Mab3-18 in a Jurkat-Raji reporter cell assay.

[0043] Figure 3 Shown is that in SEB-stimulated PBMCs, the exemplary chimeric anti-human PD-L1 antibody Mab3-16 enhances T cell activity as manifested by IL-2 production.

[0044] Figure 4 Shown is the promotion of IFN-γ secretion by the exemplary chimeric anti-human PD-L1 antibody Mab3-16 in a mixed lymphocyte reaction (MLR).

[0045] Figure 5A-5B The results shown are the results of a ligand blocking assay in which an exemplary humanized anti-human PD-L1 antibody blocks the binding of PD-L1 to PD1 as analyzed by HTRF.

[0046] Fig. 6A Shown is the enhancement of IL-2 production by the exemplary humanized anti-human PD-L1 antibody Hum-7 in a Jurkat-Raji reporter cell assay. Figure 6B Shown is the enhancement of IL-2 production by the exemplary humanized anti-human PD-L1 antibody Hum-6 in a Jurkat-Raji reporter cell assay.

[0047] Fig. 7A Shown is that in SEB-stimulated PBMCs, the exemplary humanized anti-human PD-L1 antibody Hum-6 enhances T cell activity manifested by IL-2 production levels. Figure 7BShown are exemplary humanized anti-human PD-L1 antibodies Hum-5 and Hum-7 that enhance T cell activity as manifested by IL-2 production in SEB-stimulated PBMCs.

[0048] Figure 8 Results shown are pharmacokinetic (PK) studies of an exemplary humanized anti-human PD-L1 antibody, Hum-6, in rats. DETAILED DESCRIPTION OF THE INVENTION

[0049] On the one hand, the present application provides isolated anti-PD-L1 antibodies that specifically bind to human and / or cynomolgus monkey PD-L1. By using a combination of hybridoma technology, humanized antibodies, and appropriately designed biochemical and biological experiments, highly effective antibody molecules that can bind to human and / or cynomolgus monkey PD-L1 and inhibit the binding of human and / or cynomolgus monkey PD-L1 to its receptor have been identified. The results presented herein show that the antibodies in the present application have high binding affinity to human and / or cynomolgus monkey PD-L1.

[0050] The anti-PD-L1 antibodies provided herein include, for example, full-length anti-PD-L1 antibodies, anti-PD-L1 single-chain antibodies (scFvs), anti-PD-L1 Fc fusion proteins, multispecific (such as bispecific) anti-PD-L1 antibodies, anti-PD-L1 immunoconjugates, etc.

[0051] In some embodiments, the isolated anti-PD-L1 antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising GFTFGGFG (SEQ ID NO: 1); HC-CDR2 comprising ITGDSSTI (SEQ ID NO: 6); and HC-CDR3 comprising VRGPPGTWAY (SEQ ID NO: 11); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising ESVEFYGTTL (SEQ ID NO: 17); a LC-CDR2 comprising GAS (SEQ ID NO: 24); and a LC-CDR3 comprising QQIRKVPWT (SEQ ID NO: 29).

[0052] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: a heavy chain variable domain (V H ), the V HThe invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising GYSFSGYF (SEQ ID NO: 2); HC-CDR2 comprising INPSNDDT (SEQ ID NO: 7); and HC-CDR3 comprising ARFGHASWYFDV (SEQ ID NO: 12); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SSVIY (SEQ ID NO: 18); a LC-CDR2 comprising DTS (SEQ ID NO: 25); and a LC-CDR3 comprising QQWSTYPLT (SEQ ID NO: 30).

[0053] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising GYSFSGYF (SEQ ID NO: 2); HC-CDR2 comprising INPSNDDT (SEQ ID NO: 7); and HC-CDR3 comprising ARFGHASWYLDV (SEQ ID NO: 13); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SSIIY (SEQ ID NO: 19); a LC-CDR2 comprising DTS (SEQ ID NO: 25); and a LC-CDR3 comprising QQWSTYPLT (SEQ ID NO: 30).

[0054] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising GYTFTDYA (SEQ ID NO: 3); HC-CDR2 comprising IIPSGDHT (SEQ ID NO: 8); and HC-CDR3 comprising ARGHGFHLYVMDY (SEQ ID NO: 14); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising QSIADY (SEQ ID NO: 20); a LC-CDR2 comprising YAS (SEQ ID NO: 26); and a LC-CDR3 comprising QNGHSFPPT (SEQ ID NO: 31).

[0055] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising GDSITSGY (SEQ ID NO: 4); HC-CDR2 comprising VSYSGST (SEQ ID NO: 9); and HC-CDR3 comprising ANYYGDNWPFPLDY (SEQ ID NO: 15); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising QSINGN (SEQ ID NO: 21); a LC-CDR2 comprising YAS (SEQ ID NO: 26); and a LC-CDR3 comprising QNGHGFPYT (SEQ ID NO: 32).

[0056] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising GDSITSGY (SEQ ID NO: 4); HC-CDR2 comprising VSYSGST (SEQ ID NO: 9); and HC-CDR3 comprising ANYYGDNWPFPLDY (SEQ ID NO: 15); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising KSLLHSNGNTY (SEQ ID NO: 22); a LC-CDR2 comprising RMS (SEQ ID NO: 27); and a LC-CDR3 comprising MQHLEYPFT (SEQ ID NO: 33).

[0057] In some embodiments, an isolated anti-PD-L1 antibody is provided, comprising: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising GYTFSMYY (SEQ ID NO: 5); HC-CDR2 comprising INPSNGRT (SEQ ID NO: 10); and HC-CDR3 comprising TREISYDEFAY (SEQ ID NO: 16); and a light chain variable domain (V L ), the V LIt comprises: a light chain complementary determining region (LC-CDR) 1 comprising QSLVHSNGNTY (SEQ ID NO: 23); a LC-CDR2 comprising RVS (SEQ ID NO: 28); and a LC-CDR3 comprising SQSAHLPYT (SEQ ID NO: 34).

[0058] Also provided are nucleic acids encoding anti-PD-L1 antibodies, compositions comprising anti-PD-L1 antibodies, and methods for preparing and using anti-PD-L1 antibodies. definition

[0059] As used herein, "treatment" or "treating" is a method for obtaining a beneficial or desired result, including clinical results. In view of the purpose of the present application, the beneficial or desired clinical results, including but not limited to one or more of the following: alleviating one or more symptoms caused by the disease, alleviating the degree of the disease, stabilizing the disease (e.g., preventing or delaying disease deterioration), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying disease recurrence, delaying or slowing disease progression, improving the disease state, alleviating the disease (partial or complete), reducing the dosage of one or more other drugs required for the treatment of the disease, delaying disease progression, improving or improving the quality of life, increasing body weight, and / or prolonging survival. At the same time, "treatment" also includes the reduction of disease pathology results (e.g., for cancer, tumor volume). The method of the present application takes into account any one or more aspects of these treatments.

[0060] The term "antibody" includes full-length antibodies and antigen-binding fragments thereof. Full-length antibodies include two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable regions in the two chains usually include three hypervariable loops, known as complementarity determining regions (CDRs) (light chain (LC) CDRs include LC-CDR1, LC-CDR2 and LC-CDR3, and heavy chain (HC) CDRs include HC-CDR1, HC-CDR2 and HC-CDR3). The CDR boundaries of the antibodies or antigen-binding fragments disclosed herein can be defined or identified by the Kabat, Chothia or Al-Lazikani conventions (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDR regions of the heavy or light chain are inserted between flanking segments called framework regions (FRs), which are more highly conserved than the CDR regions and form a scaffold that supports the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit a variety of effector functions. Antibodies are classified or typed based on the amino acid sequence of their heavy chain constant regions. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, characterized by having α, δ, ε, γ, and μ heavy chains, respectively. Several major antibody classes are divided into subclasses, such as IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgA1 (α1 heavy chain), or IgA2 (α2 heavy chain).

[0061] As described herein, the term "antigen binding fragment" includes antibody fragments, including, for example, diabodies, Fab, Fab', F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (dsdiabodies), single-chain Fv (scFv), scFv dimers (divalent diabodies), multispecific antibodies composed of antibody fragments comprising one or more CDRs, single-domain antibodies, nanobodies, domain antibodies, bivalent domain antibodies, or any other antibody fragment that can bind to an antigen but does not contain a complete antibody structure. Antigen binding fragments also include fusion proteins comprising antibody fragments as described above. Antigen binding fragments also include fusion proteins comprising antibody fragments as described above. Antigen binding fragments can bind to the same antigen as a parent antibody or a parent antibody fragment (such as a parent scFv). In some embodiments, an antigen-binding fragment may include one or more CDRs from a particular human antibody grafted onto framework regions from one or more different human antibodies.

[0062] As used herein, the term "epitope" refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions exhibit competitive binding to an antigen, they are likely to bind to the same epitope on the antigen.

[0063] As described herein, a first antibody "competes" for binding to a second antibody for a PD-L1 target when the first antibody inhibits binding of the second antibody to the PD-L1 target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) at equimolar concentrations, and vice versa. PCT Publication WO 03 / 48731 describes a high-throughput antibody "epitope binning" method based on cross-competition.

[0064] As used herein, the terms "specifically bind", "specifically recognize" or "specific for" refer to a measurable and reproducible interaction, such as the binding of an antibody to a target that can determine the presence of the target in a heterogeneous population of molecules, including biomolecules. For example, an antibody can specifically recognize a target (which can be an epitope) means that the antibody binds to the target with higher affinity, avidity, more readily and / or more persistently than it binds to other targets. In some embodiments, an antibody that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen with an affinity that is at least 10 times greater than its affinity for binding to other targets.

[0065] As used herein, an "isolated" anti-PD-L1 antibody refers to an anti-PD-L1 antibody that (1) is not related to naturally occurring proteins, (2) does not contain other proteins from the same source, (3) is expressed by cells of a different species, or (4) does not exist in nature.

[0066] As used herein, the term "isolated nucleic acid" refers to a nucleic acid of genomic, cDNA or synthetic origin or a combination thereof. Depending on its origin, the "isolated nucleic acid" (1) is unrelated to all or part of the polynucleotides in the "isolated nucleic acid" found in nature, (2) can be operably linked to a polynucleotide to which it is not naturally associated, or (3) does not exist as part of a longer sequence in nature.

[0067] As used herein, the term "CDR" or "complementarity determining region" refers to the non-contiguous antigen binding sites found within the variable domains of heavy and light chain polypeptides. In the literature Kabat et al., J. Biol. Chem. 252: 6609-6616 (1977); Kabat et al., USDept. of Health and Human Services, "Sequences of proteins of immunological interest" (1991); Chothia et al., J. Mol. Biol. 196: 901-917 (1987); Al-Lazikani B. et al. al., J. Mol. Biol., 273: 927-948 (1997); MacCallum et al., J. Mol. Biol. 262: 732-745 (1996); Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008); Lefranc MPet These special regions have been described in, for example, Desmond et al., Dev. Comp. Immunol., 27: 55-77 (2003); and Honegger and Plückthun, J. Mol. Biol., 309: 657-670 (2001), wherein these definitions include overlaps or subsets of amino acid residues when compared to one another. However, any definition used to indicate the CDR of an antibody or a transplanted antibody or a variant thereof is included within the scope of the terms defined and used herein. Table 1 lists the positions of the amino acid residues included in the CDRs defined by the above-cited references for comparison. Algorithms and binding interfaces for CDR prediction are known in the art, including, for example, Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008); Ehrenmann F. et al., Nucleic Acids Res., 38: D301-D307 (2010); and Adolf-Bryfogle J. et al., Nucleic Acids Res., 43: D432-D438 (2015). The contents of the references cited in this paragraph are incorporated herein by reference in their entirety for use in this application and in one or more claims that may be included in this article. Table 1: CDR definitions <![CDATA[Kabat 1 ]]> <![CDATA[Chothia 2 ]]> <![CDATA[MacCallum 3 ]]> <![CDATA[IMGT 4 ]]> <![CDATA[AHo 5 ]]> <![CDATA[V H CDR1]]> 31-35 26-32 30-35 27-38 25-40 <![CDATA[V H CDR2]]> 50-65 53-55 47-58 56-65 58-77 <![CDATA[V H CDR3]]> 95-102 96-101 93-101 105-117 109-137 <![CDATA[V L CDR1]]> 24-34 26-32 30-36 27-38 25-40 <![CDATA[V L CDR2]]> 50-56 50-52 46-55 56-65 58-77 <![CDATA[V L CDR3]]> 89-97 91-96 89-96 105-117 109-137 1The amino acid residue numbers refer to the nomenclature of Kabat et al. 2 The amino acid residue numbers refer to the nomenclature of Chothia et al. 3 The amino acid residue numbers refer to the nomenclature of MacCallum et al. 4 The amino acid residue numbers refer to the nomenclature of Lefranc et al. 5 The amino acid residue numbers refer to the nomenclature of Honegger and Plückthun above.

[0068] The term "chimeric antibody" refers to an antibody in which a portion of the heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody from a particular species or belonging to a particular antibody class or subclass, and the remainder of the chain(s) is identical or homologous to a corresponding sequence in an antibody from another genus or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they have the biological activity described in the present application (see US Patent No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)).

[0069] "Fv" is the smallest antibody fragment that contains a complete antigen recognition and binding site. This fragment is a dimer formed by a heavy chain variable domain and a light chain variable domain tightly non-covalently linked. Six hypervariable loops (3 loops each in the light chain and heavy chain) are derived from the folding of these two domains, which provide the antibody with amino acid residues for binding to the antigen and give the antibody specificity for binding to the antigen. However, even a single variable domain (or half of an Fv fragment, which contains only 3 CDRs specific for the antigen) has the ability to recognize and bind to the antigen, although its affinity is lower than that of the complete binding site.

[0070] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is a Fv comprising V linked into a single polypeptide chain. H and V L In some embodiments, the scFv polypeptide further comprises a V H and V LThe connecting polypeptide between the domains allows the scFv to form an ideal structure for antigen binding. For an overview of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0071] The term "diabodies" refers to double-chain antibodies H and V L A small antibody fragment prepared by constructing scFv fragments (see above) with short linkers (e.g., 5 to 10 residues) between domains, so that the variable domains pair between chains rather than within chains, resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. A bispecific diabody is a heterodimer of two "crossed" scFv fragments, in which the V domains of the two antibodies H and V L The domains are located on different polypeptide chains. Diabodies are fully described in EP 404,097; WO 93 / 11161; Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0072] The "humanized" form of a non-human (such as rodent) antibody is a chimeric antibody that includes minimal sequences from a non-human antibody. In most cases, a humanized antibody is a human immunoglobulin (receptor antibody) in which the hypervariable region (HVR) residues of the receptor antibody are replaced by residues from a non-human species such as a mouse, rat, rabbit or non-human primate with desirable antibody specificity, affinity and performance (donor antibody). In some cases, residues in the framework region (FR) of a human immunoglobulin are replaced by corresponding non-human residues. In addition, a humanized antibody may include residues that are not present in either the receptor antibody or the donor antibody. These modifications can further improve the performance of the antibody. Typically, a humanized antibody essentially comprises at least one, usually two variable domains, in which all or substantially all of the hypervariable loops correspond to the hypervariable loops of a non-human immunoglobulin, and all or substantially all of the framework regions are human immunoglobulin sequences. Human antibodies optionally also include at least a portion of an immunoglobulin constant region (Fc), typically a constant region of a human immunoglobulin. For details, see Jones et al., Nature 321: 522-525 (1986); Riechmann et al., Nature 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992).

[0073] The "percent (%) amino acid sequence identity" or "homology" of the polypeptide and antibody sequences identified herein is defined as the percentage of identical amino acid residues in the candidate sequence and the polypeptide sequence to be compared, when conservative substitutions are considered to be part of the sequence identity. The percentage of amino acid sequence identity can be determined by a variety of alignment methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithm required to maximize alignment over the entire length of the compared sequences. However, for the purposes of this article, the percentage of amino acid sequence identity values ​​are generated using the sequence alignment computer program MUSCLE (Edgar, RC, Nucleic Acids Research 32 (5): 1792-1797, 2004; Edgar, RC, BMC Bioinformatics 5 (1): 113, 2004).

[0074] The term "Fc receptor" or "FcR" is used to describe a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR described herein is an FcR (a gamma receptor) that binds to an IgG antibody, including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences and differ primarily in the cytoplasmic domain. The cytoplasmic domain of the activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM). The cytoplasmic domain of the inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) (see M.in Annu. Rev. Immunol. 15: 203-234 (1997)). The term also includes allotypes, such as the FcγRIIIA allotypes: FcγRIIIA-Phe158, FcγRIIIA-Val158, FcγRIIA-R131 and / or FcγRIIA-H131. FcRs are described in Ravetch and Kinet, Annu. Rev. Immunol 9: 457-92 (1991) and Capel et al., Immunomethods 4: 25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995). The term FcR in this application encompasses other types of FcRs, including those identified in the future. The term FcR also includes the neonatal receptor PD-L1, which is responsible for the transfer of maternal IgGs to the newborn (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0075] The term "PD-L1" refers to the neonatal Fc receptor (PD-L1). PD-L1 is structurally similar to the major histocompatibility complex (MHC) and consists of an α chain non-covalently bound to β2 microglobulin. The various functions of the neonatal Fc receptor PD-L1 are described in Ghetie and Ward (2000) Annu. Rev. Immunol. 18, 739-766. PD-L1 plays an important role in the passive transport of immunoglobulins IgGs from mothers to newborns and in regulating serum IgG levels. As a rescue receptor, PD-L1 can bind and transport endocytosed intact forms of IgG within and between cells and protect them from the default degradation pathway.

[0076] The "CH1 domain" of a human IgG Fc region typically stretches from amino acid 118 to amino acid 215 (EU numbering system).

[0077] The "hinge region" is generally defined as extending from Glu 216 to Pro 230 of human IgG1 (Burton, Molec. Immunol. 22: 161-206 (1985)). By placing the first and last cysteine ​​residues that form inter-heavy chain disulfide bonds in the same position as IgG1, the hinge regions of other IgG isotypes can be aligned with the IgG1 sequence.

[0078] The "CH2 domain" of the human IgG Fc region usually extends from amino acid 231 to amino acid 340. The uniqueness of the CH2 domain is that it does not pair closely with another region, but rather two N-terminally connected branched sugar chains are inserted between the two CH2 domains of the intact native IgG molecule. It is speculated that carbohydrates may serve as a substitute for domain-to-domain pairing, helping to keep the CH2 domain stable. Burton, Molec Immunol. 22: 161-206 (1985).

[0079] The "CH3 domain" includes a region extending from the C-terminal residue to the CH2 domain within the Fc region (from amino acid 341 to the C-terminus of the antibody sequence, generally amino acid residue 446 or 447 for IgG).

[0080] A "functional Fc fragment" has the "effector functions" possessed by a native Fc region sequence. Exemplary "effector functions" include C1q binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (such as B cell receptor; BCR), etc. Such effector functions generally require the Fc region to be combined with a binding domain (such as an antibody variable region) and can be evaluated using a variety of experimental methods known in the art.

[0081] An antibody having an IgG Fc variant with "altered" FcR binding affinity or ADCC activity has an increased or decreased FcR binding activity (e.g., FcγR or PD-L1) and / or ADCC activity compared to the parent polypeptide or a polypeptide comprising a native Fc sequence. An Fc variant exhibiting "enhanced binding" to an FcR has a higher binding affinity (e.g., lower apparent Kd or ICd) to at least one FcR compared to the parent polypeptide or a polypeptide comprising a native IgG Fc sequence. 50In some embodiments, the binding capacity is enhanced by 3-fold, such as 5, 10, 25, 50, 60, 100, 150, 200, or even up to 500-fold, or the binding capacity is increased by 25% to 1000% compared to the parent polypeptide. An Fc variant that exhibits "reduced binding" to an FcR has a lower affinity (e.g., a higher apparent Kd or ICd) for at least one FcR compared to the parent polypeptide. 50 Compared with the parent polypeptide, its binding capacity is reduced by 40% or more.

[0082] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" is a form of cytotoxicity that refers to the binding of secreted Ig to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages), enabling these cytotoxic effector cells to specifically bind to target cells bearing antigens and subsequently kill the target cells using cytotoxins. Antibodies "arm" the cytotoxic cells and are required for this killing. Of the major cell types that mediate ADCC, NK cells express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcRs on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess the ADCC activity of a target molecule, an in vitro ADCC assay can be performed, as described in U.S. Pat. Nos. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Alternatively, or in addition, ADCC activity of the target molecule can also be assessed in vivo, for example, as described in an animal model disclosed in Clynes et al. PNAS (USA) 95: 652-656 (1998).

[0083] The polypeptide comprising the Fc region variant exhibits "enhanced ADCC activity" or can more effectively mediate the ADCC effect in the presence of human effector cells compared to the polypeptide comprising the wild-type IgG Fc polypeptide or the parent polypeptide. The polypeptide comprising the Fc region variant can more effectively mediate ADCC in vitro or in vivo when the number of polypeptides comprising the wild-type IgG Fc polypeptide (or the parent polypeptide) is substantially the same during the experiment. Such variants are generally identified using any in vitro ADCC experimental method known in the art, such as an experiment or method for identifying ADCC activity, such as in an animal model, etc. In some embodiments, such variants mediate ADCC with an efficiency of 5 to 100 times, such as 25 to 50 times, compared to the wild-type Fc (or the parent polypeptide).

[0084] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to an antibody (of the appropriate structural subclass) that binds to a cognate antigen. To assess complement activation, a CDC assay, such as that described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), can be performed. Polypeptide variants having altered Fc region amino acid sequences and increased or decreased C1q binding ability are described in U.S. Patent No. 6,194,551 B1 and WO 99 / 51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0085] Unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate forms of each other and encode the same amino acid sequence. A nucleotide sequence encoding a protein or RNA may also include introns, for example, a nucleotide sequence encoding a protein contains introns in some forms.

[0086] The term "operably linked" refers to a functional connection between a regulatory sequence and a heterologous nucleotide sequence, thereby allowing the latter to be expressed. For example, a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence. For example, if a promoter affects the transcription or expression of a coding sequence, the promoter is operably linked to a coding sequence. Generally, operably linked DNA sequences are contiguous and, if necessary, two protein coding regions can be linked in the same reading frame.

[0087] "Homologous" refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same position of two compared sequences is the same base or amino acid monomer subunit, for example, the same position of two DNA molecules is adenine, then the two DNA molecules are homologous at that position. The homology percentage between two sequences refers to the ratio of the number of matching or homologous positions shared by the two sequences to the total number of positions multiplied by 100. For example, if 6 out of 10 positions in two sequences are matched or homologous, the homology of the two sequences is 60%. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. Generally speaking, when aligning two sequences, the comparison is performed with the goal of obtaining maximum homology.

[0088] An "effective amount" of an anti-PD-L1 antibody or composition disclosed herein refers to an amount sufficient to achieve a specific purpose. An "effective amount" can be determined empirically and by known methods related to the purpose.

[0089] The term "therapeutically effective amount" refers to the amount of an anti-PD-L1 antibody or composition disclosed herein that can effectively "treat" an individual's disease or condition. In the case of cancer, a therapeutically effective amount of an anti-PD-L1 antibody or composition disclosed herein can reduce the number of cancer cells; reduce tumor size and weight; inhibit (i.e., delay to some extent, preferably stop) cancer cells from infiltrating surrounding organs; inhibit (i.e., delay to some extent, preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent. To the extent that the anti-PD-L1 antibody or composition disclosed herein can prevent growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. In some embodiments, the therapeutically effective amount is a growth-inhibiting amount. In some embodiments, the therapeutically effective amount is an amount that prolongs the patient's survival. In certain embodiments, the therapeutically effective amount is an amount that improves the patient's progression-free survival.

[0090] As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" refers to materials that are free of biological activity or other undesirable properties, such as materials that can be added to a pharmaceutical composition administered to a patient without causing significant adverse biological reactions, or that do not interact in a harmful manner with any other components contained in the composition. Pharmaceutically acceptable carriers or excipients preferably meet the required standards for toxicology and manufacturing testing and / or are included in the inactive ingredient guide compiled by the U.S. Food and Drug Administration.

[0091] The embodiments of the present application described herein should be understood to include "consisting of" and / or "consisting essentially of" embodiments.

[0092] Reference herein to "about" for a value or parameter includes (and describes) variations for the value or parameter itself. For example, a description involving "about X" includes a description of "X".

[0093] As used herein, reference to "not" a value or parameter generally indicates and describes "other than" a value or parameter. For example, the method cannot be used to treat type X cancer, meaning that the method is generally used to treat other types of cancer except type X cancer.

[0094] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Anti-PD-L1 antibodies

[0095] On the one hand, the present application provides anti-PD-L1 antibodies that specifically bind to human and / or cynomolgus monkey PD-L1. The anti-PD-L1 antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibody molecules comprising heavy chain and / or light chain CDRs as described herein. On the one hand, the present application provides antibodies separated from PD-L1. Anti-PD-L1 antibodies contemplated include, for example, full-length anti-PD-L1 antibodies (such as full-length IgG1 or IgG4), anti-PD-L1 single-chain antibodies, anti-PD-L1 Fc fusion proteins, multispecific (such as bispecific) anti-PD-L1 antibodies, anti-PD-L1 immunoconjugates, and the like. In some embodiments, the anti-PD-L1 antibody is a full-length antibody (such as full-length IgG1 or IgG4) or an antigen-binding fragment thereof that specifically binds to PD-L1. In some embodiments, the anti-PD-L1 antibody is Fab, Fab', F(ab')2, Fab'-SH, single-chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, diabody or linear antibody. In some embodiments, the antibody that specifically binds to PD-L1 refers to an antibody that has an affinity for binding to PD-L1 that is at least 10 times (including, for example, 10, 10, 10) greater than the affinity for binding to a non-target. 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 In some embodiments, non-target refers to an antigen that is not PD-L1. Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence activated cell sorting (FACS) analysis, or radioimmunoprecipitation analysis (RIA). Kd values ​​can be determined by methods known in the art, such as surface plasmon resonance (SPR) technology or biolayer interferometry (BLI).

[0096] Although anti-PD-L1 antibodies comprising human sequences (e.g., human heavy and light chain variable domains comprising human CDR sequences) are discussed extensively herein, non-human anti-PD-L1 antibodies are also contemplated. In some embodiments, non-human anti-PD-L1 antibodies include human CDR sequences and non-human framework sequences of anti-PD-L1 antibodies described herein. In some embodiments, non-human framework sequences include any sequence for generating heavy and / or light chain variable domains using one or more human CDR sequences as described herein, including, for example, mammals, such as mice, rats, rabbits, pigs, cattle (e.g., cattle, bulls, buffaloes), deer, sheep, goats, chickens, cats, dogs, ferrets, primates (e.g., small apes, macaques), etc. In some embodiments, non-human anti-PD-L1 antibodies include anti-PD-L1 antibodies generated by grafting one or more human CDR sequences described herein into non-human frameworks (e.g., mouse or chicken framework sequences).

[0097] The amino acid sequence of an exemplary human PD-L1 extracellular domain (ECD) comprises or consists of the amino acid sequence set forth in SEQ ID NO: 59. The amino acid sequence of an exemplary murine PD-L1 ECD comprises or consists of the amino acid sequence set forth in SEQ ID NO: 60.

[0098] In some embodiments, the anti-PD-L1 antibodies described herein specifically recognize epitopes in human PD-L1. In some embodiments, the anti-PD-L1 antibodies cross-react with PD-L1 of species other than human. In some embodiments, the anti-PD-L1 antibodies are completely specific for human PD-L1 and do not cross-react with other non-human species.

[0099] In some embodiments, the anti-PD-L1 antibody cross-reacts with at least one allelic variant of the PD-L1 protein (or its fragment). In some embodiments, the allelic variant has up to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or 30) amino acid substitutions (e.g., conservative substitutions) compared to the naturally occurring PD-L1 protein (or its fragment). In some embodiments, the anti-PD-L1 antibody does not cross-react with any allelic variant of the PD-L1 protein (or its fragment).

[0100] In some embodiments, the anti-PD-L1 antibody cross-reacts with at least one interspecies variant of the PD-L1 protein. In some embodiments, for example, the PD-L1 protein (or a fragment thereof) is human PD-L1, and the interspecies variant of the PD-L1 protein (or a fragment thereof) is a variant in cynomolgus monkeys. In some embodiments, the anti-PD-L1 antibody does not cross-react with any interspecies variant of the PD-L1 protein.

[0101] In some embodiments, as any anti-PD-L1 antibody described herein, the anti-PD-L1 antibody comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the anti-PD-L1 antibody comprises an IgG1-type heavy chain constant region. In some embodiments, the anti-PD-L1 antibody comprises an IgG2-type heavy chain constant region. In some embodiments, the anti-PD-L1 antibody comprises an IgG3-type heavy chain constant region. In some embodiments, the anti-PD-L1 antibody comprises an IgG4-type heavy chain constant region. In some embodiments, the heavy chain constant region comprises (including or consisting of the following sequence or consisting essentially of the following sequence) the amino acid sequence SEQ ID NO: 55. In some embodiments, the heavy chain constant region comprises (including or consisting of the following sequence or consisting essentially of the following sequence) the amino acid sequence SEQ ID NO: 56. In some embodiments, the anti-PD-L1 antibody comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises (including or consisting of the following sequence or consisting essentially of the following sequence) the amino acid sequence SEQ ID NO: 57. In some embodiments, the anti-PD-L1 antibody comprises a lambda light chain constant region. In some embodiments, the light chain constant region comprises (comprises, consists of, or consists essentially of) the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-PD-L1 antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.

[0102] In some embodiments, the isolated anti-PD-L1 antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising GFTFGGFG (SEQ ID NO: 1); HC-CDR2 comprising ITGDSSTI (SEQ ID NO: 6); and HC-CDR3 comprising VRGPPGTWAY (SEQ ID NO: 11); and a light chain variable domain (V L ), the V LIt comprises: a light chain complementary determining region (LC-CDR) 1 comprising ESVEFYGTTL (SEQ ID NO: 17); a LC-CDR2 comprising GAS (SEQ ID NO: 24); and a LC-CDR3 comprising QQIRKVPWT (SEQ ID NO: 29).

[0103] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1 or a variant thereof, said variant comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 6 or a variant thereof, said variant comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11 or a variant thereof, said variant comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions.

[0104] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H It comprises: HC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 6, and HC-CDR3, which comprises the amino acid sequence of SEQ ID NO: 11.

[0105] In some embodiments, the anti-PD-L1 antibody comprises V L , the V L comprising: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 17 or a variant thereof, wherein the variant comprises up to 3 (e.g., 1, 2 or 3) amino acid substitutions, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 24 or a variant thereof, wherein the variant comprises up to 3 (e.g., 1, 2 or 3) amino acid substitutions, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO: 29 or a variant thereof, wherein the variant comprises up to 3 (e.g., 1, 2 or 3) amino acid substitutions.

[0106] In some embodiments, the anti-PD-L1 antibody comprises V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:17, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:24, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:29.

[0107] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1 or a variant thereof, said variant comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 6 or a variant thereof, said variant comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11 or a variant thereof, said variant comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions; and V L , the V L comprising: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 17 or a variant thereof, wherein the variant comprises up to 3 (e.g., 1, 2 or 3) amino acid substitutions, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 24 or a variant thereof, wherein the variant comprises up to 3 (e.g., 1, 2 or 3) amino acid substitutions, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO: 29 or a variant thereof, wherein the variant comprises up to 3 (e.g., 1, 2 or 3) amino acid substitutions.

[0108] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:17, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:24, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:29.

[0109] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V Lcomprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0110] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:17, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:24, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:29.

[0111] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in any one of the amino acid sequences of SEQ ID NOs: 35-39 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in any one of the amino acid sequences in SEQ ID NOs: 45-48 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0112] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:35 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:45 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0113] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:36 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L, which comprises V as shown in the amino acid sequence SEQ ID NO:46 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0114] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:37 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:47 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0115] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:37 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:48 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0116] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:37 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:46 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0117] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:38 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:47 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0118] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:38 HHC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:48 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0119] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:38 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:46 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0120] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:39 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:47 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0121] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:39 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:48 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0122] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:39 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:46 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0123] In some embodiments, the anti-PD-L1 antibody comprises V H, which comprises V as shown in the amino acid sequence SEQ ID NO:36 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:47 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0124] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:36 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:48 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0125] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising an amino acid sequence as shown in any one of SEQ ID NOs: 35-39 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of SEQ ID NOs: 35-39; and V L , the V L The invention relates to an anti-PD-L1 antibody comprising an amino acid sequence as shown in any one of SEQ ID NOs: 45-48 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of SEQ ID NOs: 45-48. In some embodiments, the anti-PD-L1 antibody comprises a V comprising an amino acid sequence as shown in any one of SEQ ID NOs: 35-39. H , and V comprising any one of the amino acid sequences of SEQ ID NOs:45-48 L .

[0126] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:35 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:35; and V L , the VL comprising the amino acid sequence of SEQ ID NO: 45 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 35; H , and V comprising the amino acid sequence SEQ ID NO:45 L .

[0127] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:36 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:36; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 46. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 36; H , and V comprising the amino acid sequence SEQ ID NO:46 L .

[0128] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:37 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:37; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 47 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 37; H , and V comprising the amino acid sequence SEQ ID NO:47 L .

[0129] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:37 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:37; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 48 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 37; H , and V comprising the amino acid sequence SEQ ID NO:48 L .

[0130] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:37 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:37; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 46. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 37; H , and V comprising the amino acid sequence SEQ ID NO:46 L .

[0131] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:38 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:38; and V L , the V Lcomprising the amino acid sequence of SEQ ID NO: 47 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 38; H , and V comprising the amino acid sequence SEQ ID NO:47 L .

[0132] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:38 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:38; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 48 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 38; H , and V comprising the amino acid sequence SEQ ID NO:48 L .

[0133] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:38 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:38; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 46. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 38; H , and V comprising the amino acid sequence SEQ ID NO:46 L .

[0134] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:39 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:39; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 47 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 39; H , and V comprising the amino acid sequence SEQ ID NO:47 L .

[0135] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:39 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:39; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 48 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 39; H , and V comprising the amino acid sequence SEQ ID NO:48 L .

[0136] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:39 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:39; and V L , the V Lcomprising the amino acid sequence of SEQ ID NO: 46 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 46. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 39; H , and V comprising the amino acid sequence SEQ ID NO:46 L .

[0137] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:36 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:36; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 47 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 36 H , and V comprising the amino acid sequence SEQ ID NO:47 L .

[0138] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:36 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:36; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 48 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 36 H , and V comprising the amino acid sequence SEQ ID NO:48 L .

[0139] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0140] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:18, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:25, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:30.

[0141] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:40 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:49 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0142] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V Hcomprising the amino acid sequence of SEQ ID NO:40 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:40; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 49 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 40; H , and V comprising the amino acid sequence SEQ ID NO:49 L .

[0143] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0144] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO: 19, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO: 25, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO: 30.

[0145] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:41 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:50 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0146] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:41 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:41; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 50 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 41; H , and V comprising the amino acid sequence SEQ ID NO:50 L .

[0147] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0148] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:20, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:26, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:31.

[0149] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:42 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:51 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0150] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:42 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:42; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 51 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 51. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 42; H , and V comprising the amino acid sequence SEQ ID NO:51 L .

[0151] In some embodiments, the anti-PD-L1 antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0152] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:21, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:26, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:32.

[0153] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:43 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:52 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0154] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:43 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:43; and V L , the VL comprising the amino acid sequence of SEQ ID NO: 52 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 52. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 43; H , and V comprising the amino acid sequence SEQ ID NO:52 L .

[0155] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0156] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:22, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:27, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:33.

[0157] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:43 H HC-CDR1, HC-CDR2 and HC-CDR3; and VL , which comprises V as shown in the amino acid sequence SEQ ID NO:53 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0158] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:43 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:43; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 53 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 43; H , and V comprising the amino acid sequence SEQ ID NO:53 L .

[0159] In some embodiments, the anti-PD-L1 antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 34, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0160] In some embodiments, the anti-PD-L1 antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:23, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:28, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:34.

[0161] In some embodiments, the anti-PD-L1 antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:44 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:54 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0162] In some embodiments, the anti-PD-L1 antibody comprises: V H , the V H comprising the amino acid sequence of SEQ ID NO:44 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:44; and V L , the V L comprising the amino acid sequence of SEQ ID NO: 54 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the anti-PD-L1 antibody comprises: a V comprising the amino acid sequence of SEQ ID NO: 44; H , and V comprising the amino acid sequence SEQ ID NO:54 L .

[0163] In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 4 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 4 of the present application.

[0164] In some embodiments, the functional epitope can be resolved by combinatorial alanine scanning. In this process, combinatorial alanine scanning technology can be used to identify amino acids in the PD-L1 protein that are necessary for interaction with the anti-PD-L1 antibody. In some embodiments, the epitope is conformational and the crystal structure of the anti-PD-L1 antibody bound to the PD-L1 protein can be used to identify the epitope.

[0165] In some embodiments, the present application provides antibodies that compete with any of the anti-PD-L1 antibodies described herein for binding to PD-L1. In some embodiments, antibodies that can compete with any of the anti-PD-L1 antibodies described herein for binding to an epitope on PD-L1 are provided. In some embodiments, anti-PD-L1 antibodies are provided that are combined with a V H and V L The anti-PD-L1 antibody molecules bind to the same epitope, wherein the V H Comprising any one of the amino acid sequences of SEQ ID NOs:35-44, and the V L In some embodiments, an anti-PD-L1 antibody is provided, which is combined with a V H and V L The anti-PD-L1 antibody competitively binds to PD-L1, wherein the V H Comprising any one of the amino acid sequences of SEQ ID NOs:35-44, and the V L Comprising any one of the amino acid sequences of SEQ ID NOs:45-54.

[0166] In some embodiments, competition experiments can be used to identify monoclonal antibodies that compete with the anti-PD-L1 antibodies described herein for binding to PD-L1. Competition experiments can determine whether two antibodies bind to the same epitope by recognizing the same or spatially overlapping epitopes or by competitively inhibiting the binding of another antibody to the antigen by one antibody. In certain embodiments, such competitive antibodies bind to the same epitope as the antibodies described herein. Some exemplary competition experiments include, but are not limited to, routine experiments as mentioned in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). Detailed exemplary methods for parsing epitopes bound by antibodies are described in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology vol.66 (Humana Press, Totowa, NJ). In some embodiments, if each antibody blocks 50% or more of the binding of another antibody, it is said to bind to the same epitope. In some embodiments, the antibody that competes with the anti-PD-L1 antibodies described herein is a chimeric antibody, a humanized antibody, or a fully human antibody.

[0167] Exemplary anti-PD-L1 antibody sequences are shown in Tables 2 and 3, wherein CDR numbering is performed according to the EU numbering system of Kabat. Those skilled in the art will recognize that there are a variety of known algorithms (Kabat definition) to predict the position of CDRs and define antibody light and heavy chain variable regions. H and / or V L Sequences, but based on prediction algorithms other than the antibodies exemplified in the table below are also within the scope of the present application. Table 2 Exemplary anti-PD-L1 antibody CDR sequences Table 3 Exemplary sequences PD-1 receptor

[0168] Programmed cell death protein 1 (PD-1, also known as CD279) is a 288 amino acid type I transmembrane protein that belongs to the immunoglobulin (Ig) superfamily. PD-1 consists of an Ig-V-like extracellular domain, a short amino acid handle, a transmembrane domain, and an intracellular domain that includes an immunoreceptor tyrosine-based inhibitory motif (ITIM) (Zhang et al. 2004; Keir et al. 2008). It was identified as a member of the Ig superfamily, which is involved in programmed cell death (Ishida et al. 1992), and was ultimately confirmed as a member of the CD28-B7 family.

[0169] PD-1 is induced by cytokine signals from T cell receptor (TCR) activation and interleukin receptors that share a common γ chain, such as IL-2, IL-7, IL-15, and IL-21 (Okazaki et al. 2013)(Kinter et al. 2008). PD-1 expression can be induced by stimulation of a variety of immune cells, including CD4+ and CD8+ T cells, NK, NKT, B cells, macrophages, and several subsets of dendritic cells (DCs) (Agata et al. 1996; Yamazaki et al. 2002). Despite widespread expression, the functional contribution of PD-1-mediated regulation is primarily in CD8+ T cell responses and the effector phase of T cell responses in peripheral tissues (Dong et al. 2004; Goldberg et al. 2007; Iwai et al. 2003; Keir et al. 2006). This is because PD-1-mediated inhibition is usually overcome by high IL-2 and CD28 co-stimulation in the presence of APCs (Carter et al. 2002; Kuipers et al. 2006). The expression of PD-L1 on parenchymal tissue cells but not hematopoietic immune cells is closely associated with PD-1-mediated peripheral T cell tolerance (Dong et al. 2004; Keir et al. 2006; Ritprajak et al. 2010).

[0170] PD-1 signaling is a key pathway that regulates the threshold of T cell activation and influences effector T cell responses, T cell differentiation, T cell tolerance, T cell exhaustion, and peripheral inflammation. PD-1 deficiency demonstrates a role for PD-1 in autoimmunity by causing moderate splenomegaly and B cell hyperactivation in response to IgM stimulation (Nishimura et al. 1998). This also leads to the development of multiple strain- and organ-specific autoimmune diseases, such as lupus-like arthritis and glomerulonephritis, and dilated cardiomyopathy in BALB / c mice in the C57BL / 6 background (Nishimura et al. 1999; Nishimura et al. 2001). PD-L1

[0171] Programmed cell death 1 ligand 1 (PD-L1, also known as B7-H1, CD274) (Dong et al. 1999; Freeman et al. 2000) is a 290 amino acid type I transmembrane protein belonging to the immunoglobulin (Ig) superfamily. PD-L1 contains Ig-V and Ig-C-like extracellular domains, a transmembrane domain, and a short cytoplasmic tail domain that does not contain a typical signaling motif (Dong et al. 1999; Keir et al. 2008; Lin et al. 2008).

[0172] PD-L1 is constitutively expressed on immune cells, such as T cells, B cells, macrophages, and dendritic cells (DCs) (Yamazaki et al. 2002). In addition, PD-L1 is also expressed on a variety of non-hematopoietic cells, including vascular endothelial cells, pancreatic islet cells, and placental syncytiotrophoblast cells (Keir et al. 2008). In particular, PD-L1 is physiologically expressed on the dorsal surface of the tongue, gingiva, and hard palate, but not on other squamous epithelia of the oral masticatory mucosa (Kang et al. 2017). The expression of the PD-L1 gene is controlled by inflammatory signals, consistent with the physiological role of the PD-1-PD-L1 axis in inhibiting T cell activation. In the past few years, several soluble factors produced by immune cells have been described as inducers of PD-L1. In one of the earliest reports, PD-L1 can be used by tumor cells as a defense mechanism against T cell attack (Dong et al., 2002), and the regulation of PD-L1 by interferon-γ (IFN-γ) can be used in various tumor types, healthy tissues and immune cells, and has been expanded in further studies (Brown et al., 2003; de Kleijn et al., 2013; Kryczek et al., 2008; Mazanet and Hughes, 2002; Nakazawa et al., 2004; Schoop et al., 2004; Wintterle et al., 2003). IFN-γ is a proinflammatory cytokine that is produced in large quantities by T cells after activation, and NK cells also produce IFN-γ. The expression of PD-L1 is also induced by interleukin (IL-17) (Zhao et al., 2011), tumor necrosis factor α (TNFα) (Mazanet and Hughes, 2002), and vascular endothelial growth factor (VEGF). In addition, the expression of PD-L1 has been found in a variety of mouse and human cancers, including human lung, ovarian and colon cancers and various myelomas (Iwai et al. (2002) PNAS 99: 12293-7; Ohigashi et al. (2005) Clin Cancer Res 11: 2947-53).

[0173] Although the regulatory role of PD-1 in T cell- and B cell-mediated immune responses has been reported, it was not until the PD-1 ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) were identified that PD-1 joined the CD28-B7 family (Latchman et al. 2001; Tseng et al. 2001). PD-L1 binding to PD-1 recruits the phosphatase SHP-2, inducing dephosphorylation of adjacent TCR signals, leading to PD-1-mediated immune regulation (Chemnitz et al. 2004; Sheppard et al. 2004; Yokosuka et al. 2012). The interaction between PD-1 and PD-L1 promotes T cell tolerance by blocking TCR-induced stop signals required for tight interaction between T and APC (Fife et al. 2009). Studies have shown that PD-L1 plays a role in tumor immunity by increasing apoptosis of antigen-specific T cell clones (Dong et al. (2002) Nat Med 8:793-800). Other studies have shown that PD-L1 may be involved in intestinal mucosal inflammation, and inhibition of PD-L1 can inhibit wasting diseases associated with colitis (Kanai et al. (2003) J Immunol 171:4156-63). Studies using neutralizing antibodies against PD-1, PD-L1 and / or PD-L2 have shown that PD-1-PD-L1-mediated regulation is involved in chronic disease and peripheral tolerance mouse models (Ansari et al. 2003; Fife et al. 2006; Habicht et al. 2007; Salama et al. 2003; Tanaka et al. 2007). Full-length anti-PD-L1 antibody

[0174] In some embodiments, the anti-PD-L1 antibody is a full-length anti-PD-L1 antibody. In some embodiments, the full-length anti-PD-L1 antibody is IgA, IgD, IgE, IgG or IgM. In some embodiments, the full-length anti-PD-L1 antibody comprises an IgG constant region, such as a constant region of IgG1, IgG2, IgG3, IgG4 or a variant thereof. In some embodiments, the full-length anti-PD-L1 antibody comprises a λ light chain constant region. In some embodiments, the full-length anti-PD-L1 antibody comprises a κ light chain constant region. In some embodiments, the full-length anti-PD-L1 antibody is a full-length human anti-PD-L1 antibody. In some embodiments, the full-length anti-PD-L1 antibody comprises a mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-PD-L1 antibody comprises an Fc sequence that has been altered or otherwise altered so that it has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effector functions.

[0175] Thus, for example, in some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody specifically binds to PD-L1. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0176] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG2 constant region is provided, wherein the anti-PD-L1 antibody specifically binds to PD-L1. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0177] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG3 constant region is provided, wherein the anti-PD-L1 antibody specifically binds to PD-L1. In some embodiments, the IgG3 is a human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0178] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody specifically binds to PD-L1. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0179] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 1-5 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 6-10 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 11-16 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 17-23 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions, LC-CDR2 comprising SEQ ID NOs: NOs: any one of 24-28 amino acid sequences or variants thereof, the variant comprising up to 3 (e.g., 1, 2, or 3) amino acid substitutions; and LC-CDR3 comprising any one of SEQ ID NOs: 29-34 amino acid sequences or variants thereof, the variant comprising up to 3 (e.g., 1, 2, or 3) amino acid substitutions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0180] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG2 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 1-5 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 6-10 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 11-16 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 17-23 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions, LC-CDR2 comprising SEQ ID NOs: NOs: any one of 24-28 amino acid sequences or variants thereof, the variant comprising up to 3 (e.g., 1, 2, or 3) amino acid substitutions; and LC-CDR3 comprising any one of SEQ ID NOs: 29-34 amino acid sequences or variants thereof, the variant comprising up to 3 (e.g., 1, 2, or 3) amino acid substitutions. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0181] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG3 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 1-5 or a variant thereof, wherein the variant comprises up to 3 (e.g., 1, 2 or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 6-10 or a variant thereof, wherein the variant comprises up to 3 (e.g., 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 11-16 or a variant thereof, wherein the variant comprises up to 3 (e.g., 1, 2 or 3) amino acid substitutions; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 17-23 or a variant thereof, wherein the variant comprises up to 3 (e.g., 1, 2 or 3) amino acid substitutions, LC-CDR2 comprising SEQ ID NOs: NOs: any one of 24-28 amino acid sequences or variants thereof, the variant comprising up to 3 (e.g., 1, 2, or 3) amino acid substitutions; and LC-CDR3 comprising any one of SEQ ID NOs: 29-34 amino acid sequences or variants thereof, the variant comprising up to 3 (e.g., 1, 2, or 3) amino acid substitutions. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0182] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 1-5 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 6-10 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 11-16 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 17-23 or a variant thereof, the variant comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions, LC-CDR2 comprising SEQ ID NOs: NOs: any one of 24-28 amino acid sequences or variants thereof, the variant comprising up to 3 (e.g., 1, 2, or 3) amino acid substitutions; and LC-CDR3 comprising any one of SEQ ID NOs: 29-34 amino acid sequences or variants thereof, the variant comprising up to 3 (e.g., 1, 2, or 3) amino acid substitutions. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0183] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 1-5; HC-CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 6-10; and HC-CDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 11-16, or a variant of the heavy chain variable domain comprising a substitution of up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acids in the HC-CDR sequence; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 17-23; LC-CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 24-28; and LC-CDR3 comprising an amino acid sequence of SEQ ID NOs: NOs: any amino acid sequence in 29-34, or a variant of the light chain variable domain, comprising a substitution of up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acids in its LC-CDR sequence. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0184] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 1-5; HC-CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 6-10; and HC-CDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 11-16, or a variant of the heavy chain variable domain comprising a substitution of up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acids in the HC-CDR sequence; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 17-23; LC-CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 24-28; and LC-CDR3 comprising an amino acid sequence of SEQ ID NOs: NOs: any of the amino acid sequences in 29-34, or a variant of the light chain variable domain, comprising a substitution of up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acids in its LC-CDR sequence. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0185] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1, comprising any one of SEQ ID NOs: 1-5 amino acid sequences; HC-CDR2, comprising any one of SEQ ID NOs: 6-10 amino acid sequences; and HC-CDR3, comprising any one of SEQ ID NOs: 11-16 amino acid sequences; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1, comprising any one of SEQ ID NOs: 17-23 amino acid sequences; LC-CDR2, comprising any one of SEQ ID NOs: 24-28 amino acid sequences; and LC-CDR3, comprising any one of SEQ ID NOs: 29-34 amino acid sequences. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0186] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1, which comprises any one of SEQ ID NOs: 1-5 amino acid sequences; HC-CDR2, which comprises any one of SEQ ID NOs: 6-10 amino acid sequences; and HC-CDR3, which comprises any one of SEQ ID NOs: 11-16 amino acid sequences; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1, which comprises any one of SEQ ID NOs: 17-23 amino acid sequences; LC-CDR2, which comprises any one of SEQ ID NOs: 24-28 amino acid sequences; and LC-CDR3, which comprises any one of SEQ ID NOs: 29-34 amino acid sequences. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0187] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0188] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0189] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0190] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0191] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0192] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0193] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0194] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0195] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0196] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0197] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0198] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0199] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0200] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0201] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H The invention relates to a light chain variable domain V having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of the amino acid sequences in SEQ ID NOs: 35-44; and a light chain variable domain V having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of the amino acid sequences in SEQ ID NOs: 35-44. L , the light chain variable domain V LComprising an amino acid sequence as shown in any one of SEQ ID NOs:45-54 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of SEQ ID NOs:45-54. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0202] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG2 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H The invention relates to a light chain variable domain V having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of the amino acid sequences in SEQ ID NOs: 35-44; and a light chain variable domain V having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of the amino acid sequences in SEQ ID NOs: 35-44. L , the light chain variable domain V L The invention relates to an IgG2 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 45-54 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of SEQ ID NOs: 45-54. In some embodiments, the IgG2 is a human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0203] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG3 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V HThe invention relates to a light chain variable domain V having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of the amino acid sequences in SEQ ID NOs: 35-44; and a light chain variable domain V having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of the amino acid sequences in SEQ ID NOs: 35-44. L , the light chain variable domain V L The invention relates to an IgG3 polypeptide comprising an amino acid sequence as shown in any one of SEQ ID NOs: 45-54 or a variant thereof, wherein the variant has at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of SEQ ID NOs: 45-54. In some embodiments, the IgG3 is a human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0204] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H The invention relates to a light chain variable domain V having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of the amino acid sequences in SEQ ID NOs: 35-44; and a light chain variable domain V having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of the amino acid sequences in SEQ ID NOs: 35-44. L , the light chain variable domain V LComprising an amino acid sequence as shown in any one of SEQ ID NOs:45-54 or a variant thereof, the variant having at least 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with any one of SEQ ID NOs:45-54. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0205] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising an amino acid sequence as shown in any one of SEQ ID NOs: 35-44; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0206] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V Hcomprising an amino acid sequence as shown in any one of SEQ ID NOs: 35-44; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0207] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:35; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0208] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:36; and a light chain variable domain V L , the light chain variable domain VL In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0209] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:37; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0210] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:37; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0211] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:37; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0212] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:38; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0213] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:38; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0214] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:38; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0215] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:39; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0216] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:39; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0217] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:39; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0218] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:36; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0219] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:36; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0220] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:40; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0221] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:41; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0222] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:42; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0223] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:43; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0224] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:43; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0225] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG1 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:44; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0226] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:35; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0227] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:36; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0228] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:37; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0229] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:37; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0230] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:37; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0231] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:38; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0232] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:38; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0233] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:38; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0234] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:39; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0235] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:39; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0236] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:39; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0237] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:36; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0238] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:36; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0239] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:40; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0240] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:41; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0241] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:42; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0242] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:43; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0243] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:43; and a light chain variable domain V L , the light chain variable domain V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58.

[0244] In some embodiments, a full-length anti-PD-L1 antibody comprising an IgG4 constant region is provided, wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain V H , the heavy chain variable domain V H comprising the amino acid sequence SEQ ID NO:44; and a light chain variable domain V L , the light chain variable domain V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:57. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:56 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:58. Binding affinity

[0245] Binding affinity can be expressed as Kd, Koff, Kon or Ka. As used herein, the term "Koff" refers to the rate constant at which an antibody dissociates from an antigen / antibody complex, measured by a kinetic selection device. The term "Kon" used herein refers to the association rate constant at which an antibody binds to an antigen to form an antigen / antibody complex. The term dissociation constant "Kd" used herein refers to the dissociation constant when a specific antibody-antigen interacts, describing the antigen concentration required when the antigen occupies half of all antibody binding sites and reaches equilibrium in an antibody molecule solution, which is equal to Koff / Kon. The determination of Kd assumes that all binding molecules are in solution. In the case where an antibody is attached to a cell wall, for example in a yeast expression system, the corresponding dissociation rate constant is expressed using EC50, which is a good approximation of Kd. The affinity binding constant Ka is the reciprocal of the dissociation constant Kd.

[0246] The dissociation constant (Kd) can be used as an indicator of the affinity of the reactive antibody moiety for the antigen. For example, simple analysis can be performed by the Scatchard method using antibodies labeled with various markers and a Biacore instrument (manufactured by Amersham Biosciences) to analyze the interaction between biomolecules by surface plasmon resonance according to the user manual or the accompanying kit. The Kd values ​​obtained using these methods are expressed in units of M. An antibody that specifically binds to a target may have, for example, ≤10 -7 M, ≤10 -8 M, ≤10 -9 M, ≤10 -10 M, ≤10 -11 M, ≤10 -12 M or ≤10 -13 Kd value of M.

[0247] The binding specificity of the antibody can be experimentally determined by methods known in the art, including, but not limited to, Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore assays, and peptide scanning.

[0248] In some embodiments, the anti-PD-L1 antibody specifically binds to the PD-L1 target with a Kd value of 10 -7 M to 10 -13 M (e.g. 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M or 10 -10 M to 10 -12 M). Therefore, in some embodiments, the Kd value of the binding between the anti-PD-L1 antibody and PD-L1 is 10 -7 M to 10 -13 M, 1×10 -7 M to 5×10 -13 M, 10 -7 M to 10 -12 M, 10 -7 M to 10 -11 M, 10 -7 M to 10 -10 M, 10 -7 M to 10 -9 M, 10 -8 M to 10 -13 M, 1×10 -8 M to 5×10 -13 M, 10 -8 M to 10 - 12 M, 10 -8 M to 10 -11 M, 10 -8 M to 10 -10 M, 10 -8 M to 10 -9 M, 5×10 -9 M to 1×10 -13 M, 5×10 -9 M to 1×10 -12 M, 5×10 -9 M to 1×10 -11 M, 5×10 -9 M to 1×10 -10 M, 10 -9 M to 10 -13 M, 10 -9 M to 10-12 M, 10 -9 M to 10 -11 M, 10 -9 M to 10 -10 M, 5×10 -10 M to 1×10 -13 M, 5×10 -10 M to 1×10 -12 M, 5×10 -10 M to 1×10 -11 M, 10 -10 M to 10 - 13 M, 1×10 -10 M to 5×10 -13 M, 1×10 -10 M to 1×10 -12 M, 1×10 -10 M to 5×10 -12 M, 1×10 -10 M to 1×10 - 11 M, 10 -11 M to 10 -13 M, 1×10 -11 M to 5×10 -13 M, 10 -11 M to 10 -12 M, 10 -12 M to 10 -13 M. In some embodiments, the Kd value of the binding between the anti-PD-L1 antibody and PD-L1 is 10 -7 M to 10 -13 M.

[0249] In some embodiments, the Kd value of the binding between the anti-PD-L1 antibody and the non-target is higher than the Kd value of the anti-PD-L1 antibody and the target, and in some embodiments cited herein, the binding affinity of the anti-PD-L1 antibody to the target (e.g., PD-L1) is higher than the binding affinity of the anti-PD-L1 antibody to the non-target. In some embodiments, the non-target refers to an antigen other than PD-L1. In some embodiments, the Kd value of the binding between the anti-PD-L1 antibody (for PD-L1) and the non-PD-L1 target differs by at least 10 times, for example, 10-100 times, 100-1000 times, 10 3 -10 4 times, 10 4 -10 5 times, 10 5 -10 6 times, 10 6 -10 7 times, 10 7 -10 8times, 10 8 -10 9 times, 10 9 -10 10 times, 10 10 -10 11 times, 10 11 -10 12 times.

[0250] In some embodiments, the anti-PD-L1 antibody has a Kd value of 10 for binding to a non-target -1 M to 10 -6 M (e.g. 10 - 1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M). In some embodiments, the non-target refers to an antigen other than PD-L1. Therefore, in some embodiments, the Kd value of the binding between the anti-PD-L1 antibody and the non-PD-L1 target is 10 -1 M to 10 -6 M, 1×10 -1 M to 5×10 -6 M, 10 -1 M to 10 -5 M, 1×10 -1 M to 5×10 -5 M, 10 -1 M to 10 -4 M, 1×10 -1 M to 5×10 -4 M, 10 -1 M to 10 -3 M, 1×10 -1 M to 5×10 -3 M, 10 -1 M to 10 -2 M, 10 -2 M to 10 -6 M, 1×10 -2 M to 5×10 -6 M, 10 -2 M to 10 - 5 M, 1×10 -2 M to 5×10 -5 M, 10 -2 M to 10 -4 M, 1×10 -2 M to 5×10 -4 M, 10 -2 M to 10 -3 M, 10 -3M to 10 -6 M, 1×10 -3 M to 5×10 -6 M, 10 -3 M to 10 -5 M, 1×10 -3 M to 5×10 -5 M, 10 -3 M to 10 -4 M, 10 -4 M to 10 -6 M, 1×10 -4 M to 5×10 -6 M, 10 -4 M to 10 -5 M, 10 -5 M to 10 -6 M.

[0251] In some embodiments, when it is mentioned that the anti-PD-L1 antibody specifically recognizes the PD-L1 target with high binding affinity and binds to a non-target with low binding affinity, the Kd value of the anti-PD-L1 antibody binding to the PD-L1 target is 10 -7 M to 10 - 13 M (e.g. 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M, 10 -10 M to 10 -12 M), and the Kd value for binding to non-target is 10 -1 M to 10 -6 M (e.g. 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M).

[0252] In some embodiments, when referring to the anti-PD-L1 antibody specifically recognizing PD-L1, the binding affinity of the anti-PD-L1 antibody is compared with the binding affinity of a control anti-PD-L1 antibody (e.g., Ref). In some embodiments, the Kd of the control anti-PD-L1 antibody binding to PD-L1 may be at least about 2 times, such as about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 10-100 times, about 100-1000 times, about 10 3 -10 4 times. Nucleic Acids

[0253] Nucleic acid molecules encoding anti-PD-L1 antibodies are also contemplated. In some embodiments, a nucleic acid (or a group of nucleic acids) encoding a full-length anti-PD-L1 antibody is provided, including any full-length anti-PD-L1 antibody described herein. In some embodiments, the nucleic acid (or a group of nucleic acids) of the anti-PD-L1 antibody described herein may also include a nucleic acid sequence encoding a polypeptide tag (such as a protein purification tag, for example, a His-tag, an HA tag).

[0254] Also contemplated herein are isolated host cells comprising an anti-PD-L1 antibody, isolated nucleic acids encoding an anti-PD-L1 antibody polypeptide component, or vectors comprising nucleic acids encoding an anti-PD-L1 antibody polypeptide component as described herein.

[0255] The present application also includes variants of these nucleic acid sequences. For example, the variant includes a nucleotide sequence that hybridizes with a nucleic acid sequence encoding an anti-PD-L1 antibody of the present application under at least moderately stringent hybridization conditions.

[0256] The present application also provides a vector into which the nucleic acid sequence of the present application can be inserted.

[0257] In brief, a natural or synthetic nucleic acid encoding an anti-PD-L1 antibody is inserted into a suitable expression vector so that the nucleic acid is operably linked to 5' and 3' regulatory elements, such as a promoter (e.g., a lymphocyte-specific promoter) and a 3' untranslated region (UTR), and an anti-PD-L1 antibody (e.g., a full-length anti-PD-L1 antibody) can be expressed. The vector can be suitable for replication and integration in eukaryotic host cells. Typical cloning and expression vectors contain transcription and translation terminators, initiation sequences, and promoters that regulate the expression of the target nucleic acid sequence.

[0258] The nucleic acids described herein can also be used for nucleic acid immunization and gene therapy by using standard gene delivery protocols. Nucleic acid delivery methods are known in the art. For example, see US Pat. Nos. 5,399,346, 5,580,859, 5,589,466, which are incorporated herein by reference in their entirety. In some embodiments, the present application also provides gene therapy vectors.

[0259] Nucleic acids can be cloned into many types of vectors. For example, nucleic acids can be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses, and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.

[0260] In addition, the expression vector can be provided to the cell in the form of a viral vector. Viral vector technology is well known in the art and is described in, for example, Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and other virology or molecular biology manuals. Viruses that can be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and slow viruses. Typically, suitable vectors include a replication origin that works in at least one organism, a promoter sequence, a convenient restriction endonuclease site, and one or more selection markers (see, for example, WO 01 / 96584; WO 01 / 29058; and US Pat. No. 6,326,193).

[0261] Many virus-based systems have been developed for transferring genes into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. The selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art. The recombinant virus is then isolated and delivered to the cells of the subject in vivo or in vitro. Many retroviral systems are known in the art. In some embodiments, adenoviral vectors are used. Many adenoviral vectors are known in the art. In some embodiments, lentiviral vectors are used. Vectors derived from retroviruses, such as lentiviruses, are suitable tools for achieving long-term gene transfer because they allow long-term stable integration of transgenes and reproduction in daughter cells. Lentiviral vectors have additional advantages over retroviruses derived from tumors, such as mouse leukemia viruses, because they can transduce non-dividing cells, such as hepatocytes. At the same time, it also has the additional advantage of low immunogenicity.

[0262] Other promoter elements, such as enhancers, regulate the frequency of transcription initiation. They are usually located 30-110 bp upstream of the start site, although recently it has been discovered that many promoters also contain functional elements downstream of the start site. The spacing between promoter elements is often flexible, so that promoter function is maintained when elements are swapped or moved relative to each other. In the thymidine kinase (tk) promoter, activity begins to decline only when the spacing between promoter elements increases to 50 bp.

[0263] An example of a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a very strong constitutive promoter sequence that can drive any polynucleotide sequence operably connected thereto to express at a high level. Another example of a suitable promoter is the elongation factor 1α (EF-1α) promoter. However, other constitutive promoters may also be used, including but not limited to, simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus long terminal repeat (HIV-LTR) promoter, MoMuLV promoter, avian leukosis virus promoter, Epstein-Barr virus immediate early promoter, Rous sarcoma virus promoter, and human gene promoters, such as but not limited to, actin promoter, myosin promoter, hemoglobin promoter, and creatine kinase promoter. In addition, the present application should not be limited to using only constitutive promoters. Inducible promoters are also considered in the present application. The use of an inducible promoter provides a molecular switch that can turn on the expression of a polynucleotide sequence to which it is operably linked when such expression is desired, and turn off expression when such expression is not desired. Inducible promoters include, but are not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.

[0264] In some embodiments, expression of the anti-PD-L1 antibody is inducible. In some embodiments, the nucleic acid sequence encoding the anti-PD-L1 antibody is operably linked to an inducible promoter, including any inducible promoter described herein. Inducible promoter

[0265] The use of an inducible promoter provides a molecular switch that can turn on the expression of a polynucleotide sequence operably linked thereto when expression is desired, and turn off expression when expression is not desired. Exemplary inducible promoters suitable for use in eukaryotic cells include, but are not limited to, hormone-regulated elements (e.g., see Mader, S. and White, JH (1993) Proc. Natl. Acad. Sci. USA 90:5603-5607), synthetic ligand-regulated elements (see Spencer, DM et al (1993) Science 262:1019-1024), and ionizing radiation-regulated elements (see Manome, Y. et al. (1993) Biochemistry 32:10607-10613; Datta, R. et al. (1992) Proc. Natl. Acad. Sci. USA 89:1014-10153). Other exemplary inducible promoters suitable for use in in vivo or in vitro mammalian systems are described in Gingrich et al. (1998) Annual Rev. Neurosci 21: 377-405. In some embodiments, the inducible promoter system used to express anti-PD-L1 antibodies is the Tet system. In some embodiments, the inducible promoter system used to express anti-PD-L1 antibodies is the E. coli lac repression system.

[0266] An exemplary inducible promoter system used in the present application is the Tet system. The system is based on the Tet system described by Gossen et al. (1993). In an exemplary embodiment, the target polynucleotide is controlled by a promoter comprising one or more Tet operator (TetO) sites. In the inactive state, the Tet repressor (TetR) binds to the TetO site and inhibits transcription of the promoter. In the activated state, for example, in the presence of an inducer such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox) or its active analogs, the inducer releases TetR from TetO, thereby causing transcription to occur. Doxycycline is a member of the tetracycline antibiotic family, and its chemical name is 1-dimethylamino-2,4a,5,7-pentahydroxy-11-methyl-4,6-dioxy-1,4a,11,11a,12,12a-hexahydrotetraene-3-carboxamide.

[0267] In one embodiment, TetR is codon optimized for expression in mammalian cells, such as mice or human cells. Due to the degeneracy of the genetic code, most amino acids are encoded by more than one codon, so that the sequence of a given nucleic acid has a large number of variants, and the amino acid sequence encoded by it does not change at all. However, many organisms have differences in codon usage, also known as "codon preference" (i.e., the preference for using specific codons for a given amino acid). Codon preference is generally related to the presence of a dominant tRNA species for a specific codon, which in turn improves the efficiency of mRNA translation. Therefore, coding sequences derived from specific species (e.g., prokaryotes) can be customized by codon optimization to improve their expression in different species (e.g., eukaryotes).

[0268] Other specific variants of the Tet system include the following "Tet-Off" and "Tet-On" systems. In the Tet-off system, transcription is inactivated in the presence of Tc or Dox. In this system, a tetracycline-regulated transcription activator protein (tTA), composed of a fusion of TetR with the strong transcription activation domain of herpes simplex virus VP16, regulates the expression of the target nucleic acid under the transcriptional control of a tetracycline-responsive promoter element (TRE). The TRE element consists of a TetO sequence fused in series with a promoter (usually a minimal promoter sequence derived from the immediate early promoter of human cytomegalovirus). In the absence of Tc or Dox, tTA binds to TRE and activates transcription of the target gene. In the presence of Tc or Dox, tTA cannot bind to TRE and the target gene cannot be expressed.

[0269] In contrast, in the Tet-On system, transcription is activated in the presence of Tc or Dox. The Tet-On system is based on the reverse tetracycline-regulated transcription activator rtTA. Like tTA, rtTA is a fusion protein consisting of the TetR repressor and the VP16 transactivation domain. However, changes in four amino acids in the DNA binding region of TetR alter the binding properties of rtTA, allowing it to only recognize the tetO sequence on the target transgene TRE in the presence of Dox. Therefore, in the Tet-On system, rtTA can only activate the transcription of the target gene regulated by the TRE in the presence of Dox.

[0270] Another inducible promoter system is the lac repressor system of Escherichia coli (see Brown et al., Cell 49: 603-612 (1987)). The lac repressor system functions by regulating the transcription of a target polynucleotide operably linked to a promoter comprising a lac operator (lacO). The lac repressor (lacR) binds to LacO, thereby preventing transcription of the target polynucleotide. Expression of the target polynucleotide is induced by a suitable inducer, for example, isopropyl-β-D-thiogalactopyranoside (IPTG).

[0271] In order to evaluate the expression of polypeptide or part thereof, the expression vector to be introduced into the cell may also contain a selectable marker gene or a reporter gene or both, so as to identify and select expressing cells from a cell population transfected or infected by a viral vector. In other aspects, the selectable marker may be carried on a separate DNA fragment and used in a co-transfection experiment. Either the selectable marker gene or the reporter gene may be flanked by a suitable regulatory sequence to enable expression in the host cell. Useful selectable markers include, for example, antibiotic resistance genes, such as neo and similar genes.

[0272] Reporter genes can be used to identify potential transfected cells and evaluate the function of regulatory sequences. Generally, reporter genes are genes that are not present in or expressed by receptor organisms or tissues, and encode a polypeptide whose expression is expressed as some easily detectable characteristics, such as enzyme activity. After DNA is introduced into the receptor cells, the expression of the reporter gene is detected at the appropriate time. Suitable reporter genes may include genes encoding luciferase, β-galactosidase, chloramphenicol acetyltransferase, secreted alkaline phosphatase or green fluorescent protein (e.g., Ui-Tel et al., 2000 FEBS Letters 479: 79-82). Suitable expression systems are well known and can be prepared by known techniques or obtained commercially. Generally, a construct with a minimum 5' flanking region that can show the highest expression level of a reporter gene is identified as a promoter. Such a promoter region can be connected to a reporter gene and used to assess the ability of certain substances in regulating promoter-driven transcription.

[0273] In some embodiments, nucleic acids encoding any of the full-length anti-PD-L1 antibodies described herein are provided. In some embodiments, the nucleic acid comprises one or more nucleic acid sequences encoding the heavy and light chains of the full-length anti-PD-L1 antibodies. In some embodiments, each of the one or more nucleic acid sequences is contained in a separate vector. In some embodiments, at least some of the nucleic acid sequences are contained in the same vector. In some embodiments, all nucleic acid sequences are contained in the same vector. The vector may be selected from, for example, a mammalian expression vector and a viral vector (such as a vector derived from a retrovirus, an adenovirus, an adeno-associated virus, a herpes virus, and a lentivirus).

[0274] Methods for introducing genes into cells and expressing them are known in the art. In the context of expression vectors, the vectors can be easily introduced into host cells, such as mammalian cells, bacteria, yeast or insect cells, by any method in the art. For example, expression vectors can be introduced into host cells by physical, chemical or biological methods.

[0275] Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, liposome transfection, biolistic methods, microinjection, electroporation, and the like. Methods for preparing cells containing vectors and / or exogenous nucleic acids are well known in the art. See, for example, Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). In some embodiments, polynucleotides are introduced into host cells by calcium phosphate transfection.

[0276] Biological methods for introducing target polynucleotides into host cells include the use of DNA and RNA vectors. Viral vectors, particularly retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells. Other viral vectors can be derived from lentiviruses, poxviruses, herpes simplex virus type 1, adenoviruses, and adeno-associated viruses, etc. See, for example, US Pat. Nos. 5,350,674 and 5,585,362.

[0277] Chemical methods for introducing polynucleotides into host cells include colloidal dispersion systems, such as polymer complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system used as a delivery vehicle in vivo and in vitro is a liposome (e.g., an artificial membrane vesicle).

[0278] In the case of using a non-viral delivery system, an exemplary delivery vehicle is a liposome. It is contemplated that a lipid formulation is used to introduce nucleic acid into a host cell (in vitro, in vitro or in vivo). On the other hand, the nucleic acid can be combined with a lipid. Nucleic acids combined with lipids can be wrapped into the aqueous interior of the liposome, dispersed in the lipid bilayer of the liposome, connected to the liposome by a linker molecule combined with the liposome and the oligonucleotide, embedded in the liposome, forming a complex with the liposome, dispersed in a solution containing lipids, mixed with lipids, combined with lipids, suspended in lipids, contained in micelles or mixed with micelles, or otherwise combined with lipids. The compositions related to lipids, lipid / DNA or lipid / expression vectors are not limited to any particular structure in solution. For example, they may exist in a bilayer structure, in micelles or in a "collapsed" structure. They can also be simply dispersed in a solution, possibly forming aggregates of uneven size or shape. Lipids are fatty substances, which can be naturally occurring or synthetic lipids. For example, lipids include fat droplets naturally present in the cytoplasm, as well as a class of compounds containing long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.

[0279] Regardless of the method used to introduce exogenous nucleic acid into the host cell or otherwise expose the cell to the inhibitor of the present application, a variety of experiments can be performed to confirm that the recombinant DNA sequence is present in the host cell. Such experiments include, for example, "molecular biology" experiments well known to those skilled in the art. For example, Southern and Northern blotting, RT-PCR and PCR; "biochemical" experiments, such as detecting the presence or absence of a particular polypeptide, such as by immunological methods (ELISAs and Western blots) or by the experiments described herein, are all within the scope of the present application. Preparation of anti-PD-L1 antibody

[0280] In some embodiments, the anti-PD-L1 antibody is a monoclonal antibody or is derived from a monoclonal antibody. In some embodiments, the anti-PD-L1 antibody comprises a V from a monoclonal antibody. H and V L , or a variant thereof. In some embodiments, the anti-PD-L1 antibody further comprises a C from a monoclonal antibody H 1 and C L Region, or variants thereof. Monoclonal antibodies can be prepared using methods known in the art, such as hybridoma cell methods, phage display methods, or using recombinant DNA methods. In addition, exemplary phage display methods are described herein and in the following examples.

[0281] In the hybridoma method, hamsters, mice or other suitable host animals are usually immunized with an immunizing agent to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to the immunizing agent. Alternatively, lymphocytes can be immunized in vitro. The immunizing agent may include a polypeptide or fusion protein of the target protein. Typically, if human cells are required, peripheral blood lymphocytes (PBLs) are used, and if non-human mammalian cells are required, spleen cells or lymph node cells are used. Lymphocytes are fused with immortal cell lines using an appropriate fusion agent, such as polyethylene glycol, to form hybridoma cells. Immortal cell lines are typically transformed mammalian cells, especially myeloma cells of rodents, bovines and humans. Rat or mouse myeloma cell lines are typically used. Hybridoma cells can be cultured in a suitable culture medium, which preferably contains one or more substances that inhibit the growth or survival of unfused immortal cells. For example, if the parental cells lack the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), the hybridoma cell culture medium typically includes hypoxanthine, aminopterin, and thymidine (HAT medium), which prevents the growth of HGPRT-deficient cells.

[0282] In some embodiments, the immortalized cell line is effectively fused, and the antibody is stably expressed at a high level by the selected antibody production cells, and is sensitive to certain culture media, such as HAT culture media. In some embodiments, the immortalized cell line is a mouse myeloma cell line, which can be obtained from, for example, the Salk Cell Collection in San Diego, California and the American Type Culture Collection in Manassas, Virginia. Human myeloma and mouse-human hybrid myeloma cell lines are also described for the preparation of human monoclonal antibodies.

[0283] The presence of monoclonal antibodies against the polypeptide in the culture medium of the hybridoma cells can then be determined. The binding specificity of the monoclonal antibodies produced by the hybridoma cells can be determined by immunoprecipitation or in vitro binding experiments, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art. The binding affinity of the monoclonal antibodies can be determined by, for example, Scatchard analysis as described in Munson and Pollard, Anal. Biochem., 107:220 (1980).

[0284] After identifying the desired hybridoma cells, the target clones can be subcloned by limiting dilution and cultured by standard methods. Suitable culture media for this purpose include, for example, modified Eagle medium (DMEM) and RPMI-1640 culture media. Alternatively, hybridoma cells can be grown in mammals in the form of ascites.

[0285] The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures, such as protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0286] In some embodiments, according to any anti-PD-L1 antibody described herein, the anti-PD-L1 antibody comprises a sequence of a clone selected from an antibody library (e.g., a phage library displaying scFv or Fab fragments). The clone can be identified by a method for screening a combinatorial library of antibody fragments having the desired activity. For example, various methods are known in the art for generating phage display libraries and screening these libraries to obtain antibodies with desired binding properties. These methods are reviewed, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and 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, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J. Mol. Biol. 339(3):294-315 (2005). 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).

[0287] In some phage display methods, V H and V LAll components of the gene are randomly recombined in a phage library, and then phages that can bind to the antigen are screened, as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). Phages usually display antibody fragments in the form of scFv fragments or Fab fragments. Library phages of immune origin provide high-affinity antibodies against immunogens without the need to construct hybridoma cells. Alternatively, natural libraries (e.g., from humans) can be cloned to provide a single source of antibodies against a variety of non-self antigens and self antigens without any immunization, as described in Griffiths et al., EMBO J, 12: 725-734 (1993). Finally, natural libraries can also be prepared by cloning non-rearranged V-gene fragments from stem cells and using PCR primers containing random sequences to encode CDR3 hypervariable regions and complete rearrangement in vitro, as described in Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example, US Pat. No. 5,750,373, and US Patent Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936 and 2009 / 0002360.

[0288] The anti-PD-L1 antibody is prepared by screening the anti-PD-L1 antibody portion in the library by phage display. The library can be a human scFv phage display library with at least 1×10 9 (For example, at least 1×10 9 , 2.5×10 9 , 5×10 9 , 7.5×10 9 , 1×10 10 , 2.5×10 10 , 5×10 10 , 7.5×10 10 or 1×10 11) kinds of diverse unique human antibody fragments. In certain embodiments, the library is a human natural library, constructed by DNA extracted from PMBCs and spleen of healthy subjects, comprising all heavy and light chain subfamilies. In certain embodiments, the library is a human natural library, constructed by DNA extracted from PMBCs isolated from various disease patients, such as patients with autoimmune diseases, cancer patients and patients with infectious diseases. In certain embodiments, the library is a semisynthetic human library, wherein the heavy chain CDR3 is completely random, and all amino acids (except cysteine) are present in any given position with the same probability. (See, e.g., Hoet, RMet al., Nat.Biotechnol.23(3):344-348,2005). In certain embodiments, the heavy chain CDR3 length of the semisynthetic human library is between 5 and 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24) amino acids. In some embodiments, the library is a fully synthetic phage display library. In some embodiments, the library is a non-human phage display library.

[0289] Phage clones with high affinity for the target PD-L1 can be screened by iterative binding of phage to the target PD-L1, which is bound to a solid support (e.g., beads for solution panning or mammalian cells for cell panning), followed by removal of unbound phage and elution of specifically bound phage. Subsequently, the bound phage clones are eluted and used to infect suitable host cells, such as E. coli XL1-Blue, for expression and purification. Multiple rounds of panning (e.g., 2, 3, 4, 5, 6 or more rounds), such as solution panning, cell panning, or a combination of both, can be performed to enrich phage clones that specifically bind to PD-L1. The specific binding of the enriched phage clones to the target PD-L1 can be detected by any method known in the art, including, for example, ELISA and FACS.

[0290] Another method for screening antibody libraries is to display proteins on the surface of yeast cells. Wittrup et al. (US Patent Nos. 6,699,658 and 6,696,25 1) developed a method for displaying libraries in yeast cells. In the yeast display system, a component involving yeast lectin protein (Aga1) is fixed to the yeast cell wall. Another component involving the second subunit of the lectin protein Aga2 can be displayed on the surface of yeast cells by binding to the Aga1 protein through a disulfide bond. The Aga1 protein is expressed from the yeast chromosome after the Aga1 gene is integrated. The single-chain variable fragment (scFv) library is genetically fused with the Aga2 sequence in the yeast display plasmid, and the converted Aga2 sequence is retained in the yeast in a free form through a nutritional marker. Both Aga1 and Aga2 proteins are expressed under the control of a galactose-inducible promoter.

[0291] Human antibody V gene library (V H and V K The fragments were obtained by PCR using degenerate primers (Sblattero, D. & Bradbury, A. Immunotechnology 3, 271–278 1998). The PCR templates were commercially available RNA or cDNA, including PBMC, spleen, lymph node, bone marrow and tonsil. H and V K PCR libraries were combined and then assembled together in scFv format by overlap extension PCR (Sheets, MD et al. Proc. Natl. Acad. Sci. USA 95, 6157–6162 1998). To construct a yeast scFv display library, the resulting scFv PCR products were cloned into a yeast display plasmid in yeast by homologous recombination. (Chao, G, et al, Nat Protoc. 2006; 1(2): 755-68. Miller KD, et al. Current Protocols in Cytometry 4.7.1-4.7.30, 2008).

[0292] Mammalian cell display systems can be used to screen anti-PD-L1 antibodies, in which the antibody portion is displayed on the cell surface and antibodies that specifically target PD-L1 are isolated by antigen-directed screening methods (as described in US patent No. 7,732,195B2). A Chinese hamster ovary (CHO) cell library displaying a large number of human IgG antibody genes can be established and used to find clones expressing high-affinity antibody genes. Another display system has been developed that allows the same protein to be displayed and secreted on the cell surface at the same time through alternative splicing, in which the displayed protein phenotype remains associated with the genotype, so that the secreted soluble antibody can be characterized in both biophysical and cell function-based analyses. This method overcomes many limitations of previous mammalian cell displays and is able to directly screen and mature full-length, glycosylated IgGs-based antibodies (Peter M. Bowers, et al, Methods 2014, 65: 44-56). The transient expression system is suitable for a single round of antigen selection before the recovery of the antibody gene, and is therefore most useful for selecting antibodies from a smaller library. Stable exosome vectors offer an attractive alternative. Exosome vectors can be efficiently transfected and stably maintained at low copy numbers, allowing multiple rounds of panning and the resolution of more complex antibody repertoires.

[0293] The IgG library was constructed based on the ligation of germline sequence V gene segments isolated from a group of human donors and rearranged (D)J regions. RNA collected from 2000 human blood samples was reverse transcribed into cDNA and the V H and V K Specific primers amplify V H and V K The fragment was purified by gel extraction. H and V K The fragments were subcloned into display vectors containing IgG1 or K constant regions, and then electroporated or transduced into 293T cells to prepare IgG libraries. H and V K To generate scFv, which is then subcloned into a display vector and electroporated or transduced into 293T cells. As is well known, IgG libraries are constructed based on germline sequence V gene segments and rearranged (D)J regions isolated from a group of donors, which can be mice, rats, rabbits or monkeys.

[0294] Monoclonal antibodies can also be prepared by recombinant DNA methods, such as described in US Patent No. 4,816,567. The DNA encoding the monoclonal antibodies described in the present application can be easily isolated and sequenced by conventional methods (e.g., by oligonucleotide probes that can specifically bind to the light and heavy chain genes encoding mouse antibodies). The hybridoma cells described above or the PD-L1-specific phage clones of the present application can be used as the source of such DNA. After isolation, the DNA can be placed in an expression vector, which is then transfected into a host cell, such as a monkey COS cell, a Chinese hamster ovary carcinoma (CHO) cell, or a myeloma cell that does not produce immunoglobulins, to obtain a monoclonal antibody synthesized in a recombinant host cell. The DNA can also be modified, such as replacing the human heavy and light chain constant regions with coding sequences and / or replacing homologous non-human sequences with framework regions (US Patent No. 4,816,567; Morrison et al., supra), or by covalently linking the coding sequence of an immunoglobulin to all or part of the coding sequence of a non-immunoglobulin polypeptide. This non-immunoglobulin polypeptide can replace the constant region of the antibody in the present application, or can replace one antigen binding site in the variable domain of the antibody in the present application to form a chimeric bivalent antibody.

[0295] The antibody can be a monovalent antibody. Methods for preparing monovalent antibodies are known in the art. For example, a recombinant expression method involving immunoglobulin light chains and modified heavy chains. The heavy chains are usually truncated at any position in the Fc region to prevent the heavy chains from cross-linking with each other. Alternatively, the relevant cysteine ​​residues are replaced by other amino acid residues or are deleted to prevent cross-linking.

[0296] In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, can be accomplished using any method known in the art.

[0297] The antibody variable domains with the desired binding specificity (antibody-antigen binding site) can be fused to an immunoglobulin constant region. Preferably, the fusion is performed with an immunoglobulin heavy chain constant region, which includes at least a portion of the hinge, CH2 and CH3 regions. In some embodiments, the first heavy chain constant region (CH1) containing the necessary sites for light chain binding is present in at least one fusion. The DNA encoding the immunoglobulin heavy chain fusion, if desired, may also include DNA encoding the immunoglobulin light chain, is inserted into a separate expression vector, and co-transfected into a suitable host organism. Fully human and humanized antibodies

[0298] The anti-PD-L1 antibody (such as a full-length anti-PD-L1 antibody) can be a humanized antibody or a fully human antibody. The humanized form of the non-human (such as mouse) antibody portion is a chimeric immunoglobulin, immunoglobulin chain, or fragment thereof (e.g., Fv, Fab, Fab', F(ab')2, scFv, or other antigen-binding subsequences of an antibody), which generally includes a minimum of sequences derived from non-human immunoglobulins. Humanized antibodies include human immunoglobulins, immunoglobulin chains, or fragments thereof (receptor antibodies), wherein the residues of the receptor CDR are replaced by non-human (donor antibody) CDR residues having the desired specificity, affinity, and performance, such as mouse, rat, or rabbit CDRs. In some embodiments, human immunoglobulin Fv framework region residues are replaced by corresponding non-human residues. Humanized antibodies may also include amino acid residues that are neither in the receptor antibody nor in the introduced CDR or framework region sequence. Generally, a humanized antibody comprises at least one, and typically two, variable domains, in which all or substantially all CDR regions correspond to those of a non-human immunoglobulin and all or substantially all framework regions are human immunoglobulin consensus sequences.

[0299] Typically, a humanized antibody contains one or more amino acid residues introduced from a non-human source. Those non-human amino acid residues are generally referred to as "imported" residues, usually from "imported" variable domains. According to some embodiments, humanization can be performed substantially according to the following method of Winter and his colleagues (Jones et al., Nature, 321: 522-525 (1986); Riechmann et al., Nature, 332: 323-327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988)), by replacing the corresponding sequence of a human antibody with rodent CDRs or CDR sequences. Therefore, this "humanized" antibody portion (US Patent No. 4,816,567), which is substantially less than a complete human antibody, has its variable domains replaced by corresponding sequences from non-human sources. In practice, the humanized antibody portion is a typical human antibody portion in which some CDR residues and possibly some framework region residues are substituted by residues from analogous sites in rodent antibodies.

[0300] Fully human antibodies are an alternative to humanization. For example, transgenic animals (e.g., mice) that can produce a complete library of fully human antibodies after immunization without producing endogenous immunoglobulins can now be prepared. For example, it has been reported that homozygous deletion of the antibody heavy chain joining region (JH) gene in chimeric and germline mutant mice completely inhibits the production of endogenous antibodies. Transferring the human germline immunoglobulin gene array into such germline mutant mice can produce fully human antibodies under antigen stimulation, see, for example, akobovits et al., PNAS USA, 90: 2551 (1993); Jakobovits et al., Nature, 362: 255-258 (1993); Bruggemann et al., Year in Immunol., 7: 33 (1993); US Patent Nos. 5,545,806, 5,569,825, 5,591,669; 5,545,807; and WO 97 / 17852. Alternatively, fully human antibodies can be prepared by introducing human immunoglobulin loci into transgenic animals (e.g., mice in which endogenous immunoglobulin genes have been partially or completely silenced). After antigen stimulation, it can be found that the production of fully human antibodies is very similar to that in humans in all aspects, including gene rearrangement, assembly, and antibody libraries. This method is described in, for example, US Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016, and Marks et al., Bio / Technology, 10:779-783 (1992); Lonberg et al., Nature, 368:856-859 (1994); Morrison, Nature, 368:812-813 (1994); Fishwild et al., Nature Biotechnology, 14:845-851 (1996); Neuberger, Nature Biotechnology, 14:826 (1996); Described in Lonberg and Huszar, Intern. Rev. Immunol., 13:65-93 (1995).

[0301] Fully human antibodies can also be produced by in vitro activated B cells (see US Patents 5,567,610 and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). The techniques of Cole et al. and Boerner et al. can also be used to prepare fully human monoclonal antibodies. See Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985) and Boerner et al., J. Immunol., 147 (1): 86-95 (1991). Anti-PD-L1 antibody variants

[0302] In some embodiments, the amino acid sequences of anti-PD-L1 antibody variants (e.g., full-length anti-PD-L1 antibodies) provided herein are also under consideration. For example, it may be necessary to improve the binding affinity and / or other biological activities of the antibody. The amino acid sequence of the antibody variant 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 antibody amino acid sequence. The final construction can be completed by any combination of amino acid residue deletions, insertions and substitutions to give it the desired characteristics. For example, antigen binding.

[0303] In some embodiments, anti-PD-L1 antibody variants having one or more amino acid substitutions are provided. The target sites of the substitution mutations include hypervariable regions (HVRs) and framework regions (FRs). Amino acid substitutions can be introduced into the target antibody and the product of the desired activity can be screened, for example, improved biological activity, maintaining / improving antigen binding ability, reduced immunogenicity, or improved ADCC or CDC.

[0304] Conservative substitutions are shown in Table 4 below. Table 4 Conservative substitutions Original residue Exemplary substitutions Preferred substitution 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; Norleucine Leu Leu(L) Norleucine;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; Norleucine Leu

[0305] Amino acids are divided into different categories based on the properties of their side chains: a. Hydrophobic amino acids: Norleucine, Met, Ala, Val, Leu, Ile; b. Neutral hydrophilic amino acids: cysteine ​​Cys, serine Ser, threonine Thr, asparagine Asn, glutamine Gln; c. Acidic amino acids: Aspartic acid Asp, glutamic acid Glu; d. Basic amino acids: histidine His, lysine Lys, arginine Arg; e. Amino acids that affect the chain direction: glycine Gly, proline Pro; f. Aromatic amino acids: tryptophan Trp, tyrosine Tyr, phenylalanine Phe.

[0306] Non-conservative amino acid substitutions include substitutions of one species for another.

[0307] An exemplary substitution variant is an affinity-matured antibody, which can be conveniently produced using, for example, affinity maturation techniques based on phage display. In short, one or more CDR residues are mutated, the variant antibody portion is displayed on the phage, and variants with specific biological activity (e.g., biological activity based on IgG circulation assay or binding affinity) are screened. Changes (e.g., substitutions) can be made in the HVRs region, for example, to improve biological activity based on IgG circulation assay or binding affinity. Changes can be made in the "hotspots" of the HVR, i.e., residues encoded by codons that undergo high-frequency mutations during somatic maturation (see, e.g., Chowdhury, Methods Mol. Biol. 207: 179-196 (2008)), and / or at specific determinant residues (SDRs), and the resulting variant V is detected. H and V L Methods for constructing and reselecting affinity maturation from secondary libraries have been described in some literature, for example, Hoogenboom et al. in Methods in Molecular Biology 178: 1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)).

[0308] In some affinity maturation embodiments, diversity is introduced into the variable genes selected for affinity maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide directed mutagenesis). A secondary library is then created. The library is screened to identify antibody variants with the desired affinity. Another method for introducing diversity includes HVR-mediated approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically identified, for example, using alanine scanning mutagenesis or modeling. Typically, CDR-H3 and CDR-L3 regions are particularly key targets.

[0309] In some embodiments, substitutions, insertions or deletions may occur within 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 provided herein) that do not substantially reduce binding affinity may be produced in HVRs. These changes may occur outside of HVR "hot spots" or SDRs regions. In some embodiments, the variant V provided above H and V L Sequences, each HVR is either unchanged or contains no more than 1, 2 or 3 amino acid substitutions.

[0310] A useful method for identifying amino acid residues or regions in antibodies that can be targeted for mutation is called "alanine scanning mutagenesis", as described in Cunningham and Wells (1989) Science, 244: 1081-1085. In this method, one or a group of target residues (e.g., charged residues such as arginine, aspartic acid, histidine, lysine and glutamic acid) are replaced by neutral or negatively charged amino acids (e.g., alanine or glutamic acid) to determine whether the antibody-antigen interaction is affected. Substitutions can be further introduced at the position of the amino acid to demonstrate that the position is functionally sensitive to the initial substitution. Alternatively or additionally, the contact sites between the antibody and the antigen are identified by the crystal structure of the antigen-antibody complex. These contact site residues and adjacent residues can be targeted or eliminated as substitution candidates. Variants are screened to determine whether they have the desired properties.

[0311] Insertions of amino acid sequences include fusions at the amino and / or carboxyl termini, ranging in length from 1 residue to polypeptides containing 100 or more residues, and also include insertions of 1 or more amino acid residues within a sequence. Examples of terminal insertions include antibodies with a methionyl residue at the N-terminus. Other insertion variants of antibody molecules include fusions of an enzyme (e.g., ADEPT) or a polypeptide that increases the serum half-life of the antibody molecule to the N-terminus or C-terminus of the antibody molecule. Fc region variants

[0312] In some embodiments, one or more amino acid modifications are introduced into the Fc region of an antibody described herein (e.g., a full-length anti-PD-L1 antibody or an anti-PD-L1 antibody fusion protein), thereby generating an Fc region variant. In some embodiments, the Fc region variant has enhanced ADCC potency, which is generally associated with receptors that bind to Fc (FcRs). In some embodiments, the Fc region variant has reduced ADCC potency. There are many examples of changes or mutations in Fc sequences that affect their potency, for example, WO 00 / 42072 and Shields et al. J Biol. Chem. 9 (2): 6591-6604 (2001) describe antibody variants with enhanced or reduced binding to FcRs. The contents of these publications are incorporated herein by reference.

[0313] Antibody-dependent cell-mediated cytotoxicity (ADCC) is the mechanism of action of therapeutic antibodies against tumor cells. ADCC is a cell-mediated immune defense in which effector cells of the immune system actively lyse target cells (e.g., cancer cells) when antigens on the surface of the target cell membrane are bound by specific antibodies (e.g., anti-PD-L1 antibodies). Usually the ADCC effect involves NK cells activated by antibodies. NK cells express the Fc receptor CD16. This receptor recognizes and binds to the Fc portion of antibody molecules bound to the surface of target cells. The most common Fc receptors on the surface of NK cells are CD16 or FcγRIII. The binding of Fc receptors to the Fc region of antibodies leads to the activation of NK cells, the release of cell lytic granules, and subsequent apoptosis of target cells. The killing effect of ADCC on tumor cells can be determined by specific experiments of NK-92 cells transfected with high-affinity FcR. The results are compared with wild-type NK-92 that do not express FcR.

[0314] In some embodiments, the present application also provides an anti-PD-L1 antibody variant (e.g., a full-length anti-PD-L1 antibody variant) comprising an Fc region with some but not all effector functions, so that it has an extended half-life in vivo, but a specific effector function (e.g., CDC or ADCC) is non-essential or harmful, and this anti-PD-L1 antibody becomes an ideal candidate for the present application. The reduction / elimination of CDC and / or ADCC activity is confirmed by performing cytotoxicity tests in vitro and / or in vivo. For example, the antibody lacks FcγR binding ability (and therefore may lack ADCC activity) but still retains PD-L1 binding ability by an Fc receptor (FcR) binding assay. Among the main cells that mediate ADCC, NK cells express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. Ravetch and Kinet Annu.Rev.Immunol.9:457-492 (1991) Table 3 on page 464 summarizes the expression of FcR on hematopoietic cells. Non-limiting examples of in vitro assessment of ADCC activity of target molecules are described in US Pat. No. 5,500,362 (see, e.g., 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); US Pat. No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive detection methods can be used (see, e.g., ACTI TM Flow cytometry nonradioactive cytotoxicity assay (Cell Technology, Inc. Mountain View, Calif.) and CYTOTOX 96 TMNon-radioactive cytotoxicity assays (Promega, Madison, Wis.). Effector cells used in such assays include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Alternatively, ADCC activity of the target molecule is tested in vivo, for example, in an animal model, as described in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q and thus lacks CDC activity. See, for example, C1q and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay can be performed (see, e.g., 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)). PD-L1 binding and in vivo clearance / half-life can be determined using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18 (12): 1759-1769 (2006)).

[0315] Antibodies with reduced effector function include substitutions of one or more residues at residues 238, 265, 269, 270, 297, 327, and 329 in the Fc region (US Pat. No. 6,737,056). These Fc variants include Fc variants with substitutions of two or more residues at positions 265, 269, 270, 297, and 327, including an Fc variant known as "DANA" in which residues 265 and 297 are substituted with alanine (US Pat. No. 7,332,581).

[0316] Such antibody variants with improved or reduced binding to FcRs have been described (see, e.g., US Pat. No. 6,737,056; WO 2004 / 056312, and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001)).

[0317] In some embodiments, an anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) variant is provided, comprising an Fc region variant having one or more amino acid substitutions capable of enhancing the ADCC effect. In some embodiments, the Fc region variant comprises one or more amino substitutions capable of enhancing the ADCC effect, and the positions of these substitutions are at positions 298, 333, and / or 334 (EU residue numbering) in the Fc region. In some embodiments, the anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) variant comprises amino acid substitutions at positions S298A, E333A, and K334A in the Fc region.

[0318] In some embodiments, alterations in the Fc region result in altered (ie, enhanced or reduced) C1q binding and / or complement dependent cytotoxicity (CDC), as described in US Pat. No. 6,194,551, WO 99 / 51642, and Idusogie et al., J. Immunol. 164:4178-4184 (2000).

[0319] In some embodiments, an anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) variant is provided, which comprises an Fc region variant having one or more amino acid substitutions, which can prolong the half-life and / or enhance the binding to the Fc receptor (PD-L1). Antibodies with extended half-life and improved PD-L1 binding are described in US2005 / 0014934A1 (Hinton et al.). These antibody Fc regions comprise one or more amino acid substitutions, which enhance the binding of the Fc region to PD-L1. These Fc variants comprise one or more substitutions at residues 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424 or 434 in the Fc region, such as a substitution at residue 434 in the Fc region ( US Pat. No. 7,371,826 ).

[0320] See also Duncan & Winter, Nature 322:738-40 (1988); US Pat. No. 5,648,260; US Pat. No. 5,624,821 and WO 94 / 29351 for other examples of Fc region variants.

[0321] The present application contemplates an anti-PD-L1 antibody (eg, a full-length anti-PD-L1 antibody) comprising any one of the Fc variants described herein or a combination thereof. Glycosylation variants

[0322] In some embodiments, the anti-PD-L1 antibodies (e.g., full-length anti-PD-L1 antibodies) provided herein are altered to increase or decrease the degree of glycosylation of the anti-PD-L1 antibodies. Adding or deleting glycosylation sites on the anti-PD-L1 antibodies can be conveniently achieved by changing the amino acid sequence of the anti-PD-L1 antibodies or their polypeptide portions to increase or remove one or more glycosylation sites.

[0323] Wherein the anti-PD-L1 antibody comprises an Fc region, the sugars connected thereto can be changed. Natural antibodies produced by mammalian cells generally contain branched biantennary oligosaccharides, which are generally connected to the Fc region CH2 domain Asn297 via an N-link, see, for example, Wright et al., TIBTECH 15: 26-32 (1997). The oligosaccharides may include a variety of carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, and trehalose connected to the GlcNAc of the "stem" of the biantennary oligosaccharide structure. In some embodiments, the anti-PD-L1 antibodies of the present application may be oligosaccharide-modified to produce anti-PD-L1 antibody variants with certain improved properties.

[0324] The N-glycans attached to the CH2 domain of the Fc region are heterogeneous. Antibodies or Fc fusion proteins produced in CHO cells are fucosylated by fucosyltransferase activity, see Shoji-Hosaka et al., J. Biochem. 2006, 140: 777-83. Typically, a small fraction of naturally occurring non-fucosylated IgGs can be detected in human serum. N-glycosylation of the Fc region is important for its binding to FcγR; while non-fucosylated N-glycans enhance the binding ability of Fc to FcγRIIIa. Enhanced binding ability to FcγRIIIa enhances the ADCC effect, which is advantageous in certain antibody therapeutic applications requiring cytotoxicity.

[0325] In some embodiments, when Fc-mediated cytotoxicity is not required, the enhanced effector function may be detrimental. In some embodiments, the Fc fragment or CH2 domain is non-glycosylated. In some embodiments, the N-glycosylation site in the CH2 domain is mutated to prevent glycosylation.

[0326] In some embodiments, an anti-PD-L1 antibody (e.g., a full-length anti-PD-L1 antibody) variant is provided, which comprises an Fc region, wherein the carbohydrate structure attached to the Fc region has reduced fucose or lacks fucose, which may enhance ADCC function. Specifically, anti-PD-L1 antibodies are provided herein, which have reduced fucose relative to the same anti-PD-L1 antibody produced by wild-type CHO cells. That is, they are characterized in that they have a smaller amount of fucose than antibodies produced by natural CHO cells (e.g., CHO cells that produce natural glycosylation forms, CHO cells containing natural FUT8 genes). In some embodiments, the N-linked glycans of the anti-PD-L1 antibody have less than 50%, 40%, 30%, 20%, 10% or 5% fucose. For example, the fucose content of the anti-PD-L1 antibody may be 1%-80%, 1%-65%, 5%-65% or 20%-40%. In some embodiments, the N-linked glycans of the anti-PD-L1 antibody do not contain fucose, that is, the anti-PD-L1 antibody is completely free of fucose, or has no fucose or is defucosylated. The content of fucose is determined by calculating the average content of fucose in the sugar chain attached to Asn297 relative to the total amount of all sugar structures (such as complex, hybrid or mannose structures) attached to Asn297 measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546. Asn297 refers to the asparagine residue at position 297 of the Fc region (EU Fc region residue numbering system). However, due to minor sequence variations of antibodies, Asn297 may also be located ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. These fucosylated variants may have enhanced ADCC function. See, for example, US Patent Publication Nos.US 2003 / 0157108 (Presta, L.), US2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd.). Examples of publications related to "defucosylated" or "fucose-deficient" antibody variants include US2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US2003 / 0115614; US2002 / 0164328; US2004 / 0093621; US2004 / 0132140; US2004 / 0110704; US2004 / 0110282; US2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; WO2005 / 053742; WO2002 / 031140; Okazaki et al. al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004). Cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking protein fucosylation function (Ripka et al. Arch. Biochem. Biophys. 249: 533-545 (1986); US Pat Appl No US2003 / 0157108 A1, Presta, L; and WO 2004 / 056312 A1, Adams et al., especially Example 11), and gene knockout cell lines, such as CHO cells in which the α-1,6-fucosyltransferase gene, FUT8 gene is knocked out (see Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94 (4): 680-688 (2006); and WO2003 / 085107).

[0327] Anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) variants further involve bisected oligosaccharides, for example, wherein the biantennary oligosaccharide attached to the Fc region of the anti-PD-L1 antibody is bisected by GlcNAc. Such anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) variants may have reduced fucosylation and / or enhanced ADCC function. Examples of such antibody variants are described in WO2003 / 011878 (Jean-Mairet et al.); US Pat. No. 6,602,684 (Umana et al.); US 2005 / 0123546 (Umana et al.), and Ferrara et al., Biotechnology and Bioengineering, 93 (5): 851-861 (2006). Anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) variants are also provided, which have at least one galactose residue in the oligosaccharide attached to the Fc region. Such anti-PD-L1 antibody variants may have enhanced CDC function. Such variants are described in, for example, WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S.).

[0328] In some embodiments, the anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) variant can comprise an Fc region that can bind to FcγRIII. In some embodiments, the anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) variant comprising an Fc region has ADCC activity in the presence of human effector cells (e.g., T cells), or has enhanced ADCC activity in the presence of human effector cells compared to an otherwise identical anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) having a human wild-type IgG1 Fc region. Cysteine ​​engineered variants

[0329] In some embodiments, it is desirable to prepare a cysteine ​​engineered anti-PD-L1 antibody (e.g., a full-length anti-PD-L1 antibody) in which one or more amino acid residues are substituted with a cysteine ​​residue. In some embodiments, the substituted residues occur at accessible sites of the anti-PD-L1 antibody. By replacing those residues with cysteine, active sulfhydryl groups are located at accessible sites of the anti-PD-L1 antibody, which can be used to couple the anti-PD-L1 antibody to other moieties, such as a drug moiety or a linker-drug moiety, to prepare an anti-PD-L1 immunoconjugate as further described herein. Cysteine ​​engineered anti-PD-L1 antibodies (e.g., full-length anti-PD-L1 antibodies) can be prepared as described, for example, in US Pat. No. 7,521,541. derivative

[0330] In some embodiments, the anti-PD-L1 antibodies (e.g., full-length anti-PD-L1 antibodies) provided herein may be further modified to include other non-protein moieties known in the art and readily available. Suitable moieties for derivatizing anti-PD-L1 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 copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers), dextran or poly (n-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, propylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde has advantages in manufacturing due to its stability in water. The polymer may have any molecular weight and may be branched or unbranched. The number of polymers attached to the anti-PD-L1 antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. In general, the number and / or type of polymers used for derivatization can be determined based on the following considerations, including, but not limited to, whether the properties or functions of the anti-PD-L1 antibody need to be improved, whether the anti-PD-L1 antibody derivative is used for treatment of a specific condition, etc. Pharmaceutical composition

[0331] Also provided herein are compositions (e.g., pharmaceutical compositions, also referred to herein as formulations) comprising any anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody), nucleic acids encoding antibodies, vectors comprising nucleic acids encoding antibodies, or host cells comprising nucleic acids or vectors described herein. In some embodiments, a pharmaceutical composition is provided, comprising any anti-PD-L1 antibody described herein and a pharmaceutically acceptable carrier.

[0332] Suitable anti-PD-L1 antibody preparations can be obtained by mixing an anti-PD-L1 antibody having the desired purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)) and prepared in the form of a lyophilized preparation or a liquid preparation. Acceptable carriers, excipients or stabilizers are non-toxic to recipients at the dosages and concentrations used, and include buffers such as phosphates, citric acid and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethylammonium 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-cresol); low molecular weight (less than 1 0 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, 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 counterions such as sodium; metal complexes (such as zinc-protein complexes); and / or nonionic surfactants such as TWEEN TM , PLURONICS TM Or polyethylene glycol (PEG); exemplary formulations are described in WO98 / 56418 and are expressly incorporated herein by reference. Lyophilized formulations suitable for subcutaneous administration are described in WO97 / 04801. Such lyophilized formulations can be reconstituted into high protein concentration formulations by suitable diluents, and the reconstituted formulations can be administered to the individual to be treated herein by subcutaneous administration. Cationic liposomes or liposomes can be used to deliver the anti-PD-L1 antibodies in the present application to cells.

[0333] In addition to anti-PD-L1 antibodies (e.g., full-length anti-PD-L1 antibodies), the formulations described herein may also contain one or more other active substances required for the treatment of specific conditions, preferably substances with complementary activities and no adverse reactions to each other. For example, in addition to anti-PD-L1 antibodies, it may be necessary to further include, for example, anti-tumor agents, growth inhibitory agents, cytotoxic agents, or chemotherapeutic agents. These molecules are present in combination in amounts effective for the intended purpose. The effective amount of these other substances depends on the content of the anti-PD-L1 antibody in the formulation, the type of disease or condition or treatment, and other factors as described above. These drugs are generally used in the same dosages and routes of administration as described herein, or at 1% to 99% of the currently used dosages.

[0334] The anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) can also be embedded in microcapsules prepared, for example, by coacervation techniques and interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions, respectively. Sustained release formulations can be prepared.

[0335] Sustained-release formulations of anti-PD-L1 antibodies (e.g., full-length anti-PD-L1 antibodies) can be prepared. Suitable examples of sustained-release formulations include solid hydrophobic polymer semipermeable matrices containing antibodies (or fragments thereof), which are in the form of molded articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid (US Pat. No. 3,773,919), copolymers of L-glutamic acid and ethyl L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D(-)-3-hydroxybutyric acid. Although polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid can enable the release of molecules for more than 100 days, certain hydrogels can release proteins in shorter time periods. When encapsulated antibodies remain in the body for a long time, they can denature or aggregate due to exposure to a humid environment at 37°C, which may lead to loss of biological activity or altered immunogenicity. Rational strategies can be designed to stabilize anti-PD-L1 antibodies based on the corresponding mechanisms. For example, if the aggregation mechanism is found to be the formation of intermolecular SS bonds through thiodisulfide exchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing in acidic solutions, controlling the water content, using appropriate additives, and developing specific polymer matrix compositions.

[0336] In some embodiments, the anti-PD-L1 antibody (e.g., full-length anti-PD-L1 antibody) is formulated in a buffer containing citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 (Tween 80), or any combination thereof.

[0337] Preparations for in vivo administration must be sterile. This can be easily achieved, for example, by filtration through sterile filtration membranes. Treatment with anti-PD-L1 antibodies

[0338] Anti-PD-L1 antibodies (e.g., full-length anti-PD-L1 antibodies) and / or compositions described herein can be administered to an individual (e.g., a mammal such as a human) to treat a disease or disorder (e.g., cancer or an infectious disease) associated with the activity and / or expression of PD-L1 or T cell dysfunction. The diseases include, but are not limited to, melanoma, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, bladder cancer, lung cancer, renal cell carcinoma, cervical cancer, colon cancer, colorectal cancer, head and neck cancer, breast cancer, esophageal cancer, bone cancer, prostate cancer, basal cell carcinoma, bile duct cancer, brain and central nervous system cancer, choriocarcinoma, connective tissue cancer, digestive system cancer, endometrial cancer, eye cancer, intraepithelial carcinoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, neuroblastoma, oral cancer, ovarian cancer, rhabdomyosarcoma, sarcoma, skin cancer, testicular cancer, thyroid cancer, uterine cancer, urinary tract cancer, pancreatic cancer, and infectious diseases, including, but not limited to, human immunodeficiency virus (HIV), hepatitis (A, B or C), herpes virus (e.g., VSV, HSV-1, HAV-6, HSV-II and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus. In some embodiments, the present application provides a method of treating a disease or disorder (e.g., cancer or infectious disease) associated with the activity and / or expression of PD-L1 or T cell dysfunction in an individual, comprising administering to the individual an effective amount of a composition (e.g., a pharmaceutical composition) comprising an anti-PD-L1 antibody (e.g., a full-length anti-PD-L1 antibody), such as any anti-PD-L1 antibody (e.g., a full-length anti-PD-L1 antibody) described herein. In some embodiments, such modulation inhibits the interaction between PD-L1 and IgG Fc. In some embodiments, the individual is human.

[0339] For example, in some embodiments, a method for treating an individual suffering from a disease or condition (e.g., cancer or infectious disease) associated with the activity and / or expression of PD-L1 or T cell dysfunction is provided, comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-PD-L1 antibody (e.g., a full-length anti-PD-L1 antibody) that specifically binds to a human PD-L1 epitope, wherein the epitope comprises amino acid residues of human PD-L1. In some embodiments, the anti-PD-L1 antibody is a full-length anti-PD-L1 antibody. In some embodiments, the full-length anti-PD-L1 antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from melanoma, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, bladder cancer, lung cancer, renal cell carcinoma, cervical cancer, colon cancer, colorectal cancer, head and neck cancer, breast cancer, esophageal cancer, bone cancer, prostate cancer, basal cell carcinoma, bile duct cancer, brain and central nervous system cancer, choriocarcinoma, connective tissue cancer, digestive system cancer, endometrial cancer, eye cancer, intraepithelial carcinoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, neuroblastoma, oral cancer, ovarian cancer, rhabdomyosarcoma, sarcoma, skin cancer, testicular cancer, thyroid cancer, uterine cancer, urinary tract cancer, pancreatic cancer, and infectious diseases, including but not limited to, human immunodeficiency virus (HIV), hepatitis (A, B or C), herpes virus (e.g., VSV, HSV-1, HAV-6, HSV-II and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus. In some embodiments, the individual is a human.

[0340] For example, in some embodiments, a method of treating an individual suffering from a disease or condition associated with the activity and / or expression of PD-L1 or T cell dysfunction (e.g., cancer or infectious disease) is provided, comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-PD-L1 antibody (e.g., a full-length anti-PD-L1 antibody), wherein the anti-PD-L1 antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising GFTFGGFG (SEQ ID NO: 1); HC-CDR2 comprising ITGDSSTI (SEQ ID NO: 6); and HC-CDR3 comprising VRGPPGTWAY (SEQ ID NO: 11); and a light chain variable domain (V L ), the V LThe invention relates to a light chain complementary determining region (LC-CDR) 1 comprising ESVEFYGTTL (SEQ ID NO: 17); a LC-CDR2 comprising GAS (SEQ ID NO: 24); and a LC-CDR3 comprising QQIRKVPWT (SEQ ID NO: 29). In some embodiments, the anti-PD-L1 antibody is a full-length anti-PD-L1 antibody. In some embodiments, the full-length anti-PD-L1 antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from melanoma, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, bladder cancer, lung cancer, renal cell carcinoma, cervical cancer, colon cancer, colorectal cancer, head and neck cancer, breast cancer, esophageal cancer, bone cancer, prostate cancer, basal cell carcinoma, bile duct cancer, brain and central nervous system cancer, choriocarcinoma, connective tissue cancer, digestive system cancer, endometrial cancer, eye cancer, intraepithelial carcinoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, neuroblastoma, oral cancer, ovarian cancer, rhabdomyosarcoma, sarcoma, skin cancer, testicular cancer, thyroid cancer, uterine cancer, urinary tract cancer, pancreatic cancer, and infectious diseases, including but not limited to, human immunodeficiency virus (HIV), hepatitis (A, B or C), herpes virus (e.g., VSV, HSV-1, HAV-6, HSV-II and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus. In some embodiments, the individual is a human.

[0341] In some embodiments, a method of treating an individual suffering from a disease or condition associated with the activity and / or expression of PD-L1 or T cell dysfunction (e.g., cancer or infectious disease) is provided, comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-PD-L1 antibody (e.g., a full-length anti-PD-L1 antibody), wherein the anti-PD-L1 antibody comprises: V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0342] In some embodiments, a method of treating an individual suffering from a disease or condition associated with the activity and / or expression of PD-L1 or T cell dysfunction (e.g., cancer or infectious disease) is provided, comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-PD-L1 antibody (e.g., a full-length anti-PD-L1 antibody), wherein the anti-PD-L1 antibody comprises: V H , comprising any one of SEQ ID NOs:35-39 or a variant thereof, wherein the variant has at least 80% sequence identity with any one of SEQ ID NOs:35-39; and V L , which comprises any one of the amino acid sequences in SEQ ID NOs: 45-48 or a variant thereof, wherein the variant has at least 80% sequence identity with any one of the amino acid sequences in SEQ ID NOs: 45-48.

[0343] In some embodiments, the anti-PD-L1 antibodies provided herein are full-length anti-PD-L1 antibodies comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 58.

[0344] In some embodiments, the anti-PD-L1 antibodies provided herein include: H , the V H comprising the amino acid sequence SEQ ID NO: 35; and V L , the V L Comprising the amino acid sequence SEQ ID NO:45. In some embodiments, the anti-PD-L1 antibody provided herein is a full-length anti-PD-L1 antibody comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0345] In some embodiments, the anti-PD-L1 antibodies provided herein include: H , the V H comprising the amino acid sequence SEQ ID NO: 36; and V L , the V L Contains the amino acid sequence SEQ ID NO:46. In some embodiments, the anti-PD-L1 antibody provided herein is a full-length anti-PD-L1 antibody comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0346] In some embodiments, the anti-PD-L1 antibodies provided herein include: H , the V H comprising the amino acid sequence SEQ ID NO: 37; and V L , the V L Comprising the amino acid sequence SEQ ID NO:47. In some embodiments, the anti-PD-L1 antibody provided herein is a full-length anti-PD-L1 antibody comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0347] In some embodiments, the anti-PD-L1 antibodies provided herein include: H , the V H comprising the amino acid sequence SEQ ID NO: 37; and V L , the V LComprising the amino acid sequence SEQ ID NO:48. In some embodiments, the anti-PD-L1 antibody provided herein is a full-length anti-PD-L1 antibody comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0348] In some embodiments, the anti-PD-L1 antibodies provided herein include: H , the V H comprising the amino acid sequence SEQ ID NO: 37; and V L , the V L Contains the amino acid sequence SEQ ID NO:46. In some embodiments, the anti-PD-L1 antibody provided herein is a full-length anti-PD-L1 antibody comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0349] In some embodiments, the anti-PD-L1 antibodies provided herein include: H , the V H comprising the amino acid sequence SEQ ID NO: 38; and V L , the V LComprising the amino acid sequence SEQ ID NO:47. In some embodiments, the anti-PD-L1 antibody provided herein is a full-length anti-PD-L1 antibody comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0350] In some embodiments, the anti-PD-L1 antibodies provided herein include: H , the V H comprising the amino acid sequence SEQ ID NO: 38; and V L , the V L Comprising the amino acid sequence SEQ ID NO:48. In some embodiments, the anti-PD-L1 antibody provided herein is a full-length anti-PD-L1 antibody comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0351] In some embodiments, the anti-PD-L1 antibodies provided herein include: H , the V H comprising the amino acid sequence SEQ ID NO: 38; and V L , the V LContains the amino acid sequence SEQ ID NO:46. In some embodiments, the anti-PD-L1 antibody provided herein is a full-length anti-PD-L1 antibody comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0352] In some embodiments, the anti-PD-L1 antibodies provided herein include: H , the V H comprising the amino acid sequence SEQ ID NO: 39; and V L , the V L Comprising the amino acid sequence SEQ ID NO:47. In some embodiments, the anti-PD-L1 antibody provided herein is a full-length anti-PD-L1 antibody comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:57. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:58.

[0353] In some embodiments, the anti-PD-L1 antibodies provided herein include: H , the V H comprising the amino acid sequence SEQ ID NO: 39; and V L , the V LComprising the amino acid sequence SEQ ID NO:48. In some embodiments, the anti-PD-L1 antibody provided herein is a full-length anti-PD-L1 antibody comprising an IgG1 or IgG4 constant domain. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:55. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:56. In some embodiments, the l...

Claims

1. An isolated anti-PD-L1 antibody, wherein the anti-PD-L1 antibody comprises: Heavy chain variable domain (V H ), the V H Include: a heavy chain complementarity determining region (HC-CDR) 1 comprising GFTFGGFG (SEQ ID NO: 1) or a variant thereof comprising a substitution of up to about 3 amino acids; HC-CDR2 comprising ITGDSST1 (SEQ ID NO: 6) or a variant thereof comprising a substitution of up to about 3 amino acids; and HC-CDR3 comprising VRGPPGTWAY (SEQ ID NO: 11) or a variant thereof comprising a substitution of up to about 3 amino acids; and Light chain variable domain (V L ), the V L Include: a light chain complementarity determining region (LC-CDR) 1 comprising ESVEFYGTTL (SEQ ID NO: 17) or a variant thereof comprising a substitution of up to about 3 amino acids; LC-CDR2 comprising GAS (SEQ ID NO: 24) or a variant thereof comprising a substitution of up to about 3 amino acids; and A LC-CDR3 comprising QQIRKVPWT (SEQ ID NO: 29) or a variant thereof comprising a substitution of up to about 3 amino acids.

2. The isolated anti-PD-L1 antibody according to claim 1, comprising: (i)V H , comprising the amino acid sequence of SEQ ID NO: 35 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 35; and V L , comprising the amino acid sequence of SEQ ID NO:45 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:45; (ii) V H , comprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 38; and V L , comprising the amino acid sequence of SEQ ID NO:47 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:47; (iii)V H , comprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 38; and V L , which comprises the amino acid sequence of SEQ ID NO:48 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:48; or (iv)V H , comprising the amino acid sequence of SEQ ID NO: 38 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 38; and V L , which comprises the amino acid sequence of SEQ ID NO:46 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:

46.

3. An isolated anti-PD-L1 antibody, wherein the anti-PD-L1 antibody comprises: (i)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31, or the V L A variant comprising substitutions of up to about 5 amino acids in its LC-CDRs; (ii) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32, or the V L A variant comprising substitutions of up to about 5 amino acids in its LC-CDRs; (iii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or the V L A variant of the invention comprising substitutions of up to about 5 amino acids in the LC-CDRs; or (iv)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 34, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

4. The isolated anti-PD-L1 antibody according to claim 3, comprising: (i)V H , comprising the amino acid sequence of SEQ ID NO:42 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:42; and V L , comprising the amino acid sequence of SEQ ID NO:51 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:51; (ii) V H , comprising the amino acid sequence of SEQ ID NO:43 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:43; and V L , comprising the amino acid sequence of SEQ ID NO:52 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:52; (iii)V H , comprising the amino acid sequence of SEQ ID NO:43 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:43; and V L , which comprises the amino acid sequence of SEQ ID NO:53 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:53; or (iv)V H , comprising the amino acid sequence of SEQ ID NO:44 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:44; and V L , which comprises the amino acid sequence of SEQ ID NO:54 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:

54.

5. The isolated anti-PD-L1 antibody according to any one of claims 1-4, wherein the anti-PD-L1 antibody binds to human PD-L1 with a Kd value of about 0.1 pM to about 1 nM.

6. The isolated anti-PD-L1 antibody according to any one of claims 1-5, wherein the anti-PD-L1 antibody comprises an Fc fragment.

7. The isolated anti-PD-L1 antibody of claim 6, wherein the anti-PD-L1 antibody is a full-length IgG antibody.

8. The isolated anti-PD-L1 antibody of claim 7, wherein the anti-PD-L1 antibody is a full-length IgG1, IgG2, IgG3 or IgG4 antibody.

9. The isolated anti-PD-L1 antibody according to any one of claims 1-8, wherein the anti-PD-L1 antibody is a chimeric, human or humanized antibody.

10. The isolated anti-PD-L1 antibody according to any one of claims 1 to 5, wherein the anti-PD-L1 antibody is an antigen-binding fragment selected from Fab, Fab', F(ab)'2, Fab'-SH, single-chain Fv (scFv), Fv fragment, dAb, Fd or diabody.

11. An isolated nucleic acid molecule encoding the anti-PD-L1 antibody of any one of claims 1-10.

12. A vector comprising the isolated nucleic acid molecule of claim 11.

13. An isolated host cell comprising the isolated anti-PD-L1 antibody of any one of claims 1-10, the isolated nucleic acid molecule of claim 11, or the vector of claim 12.

14. A method for preparing an isolated anti-PD-L1 antibody, comprising: a) culturing the host cell of claim 13 under conditions that effectively express the anti-PD-L1 antibody; and b) obtaining the expressed anti-PD-L1 antibody from the host cells.

15. A pharmaceutical composition comprising the anti-PD-L1 antibody according to any one of claims 1 to 10, the nucleic acid molecule according to claim 11, the vector according to claim 12, the isolated host cell according to claim 13, the antibody prepared by the method according to claim 14, and a pharmaceutically acceptable carrier.

16. A method of treating a disease or condition in an individual in need thereof, comprising administering to the individual an effective amount of the isolated anti-PD-L1 antibody of any one of claims 1-10, the nucleic acid molecule of claim 11, the vector of claim 12, the isolated host cell of claim 13, the antibody prepared by the method of claim 14, or the pharmaceutical composition of claim 15.

17. The method according to claim 16, wherein the disease or disorder is cancer or an infectious disease, preferably, the disease or disorder is associated with the activity and / or expression of PD-L1 or T cell dysfunction.

18. The method of claim 17, wherein the disease or condition is selected from melanoma, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, bladder cancer, lung cancer, renal cell carcinoma, cervical cancer, colon cancer, colorectal cancer, head and neck cancer, breast cancer, esophageal cancer, bone cancer, prostate cancer, basal cell carcinoma, biliary tract cancer, brain and central nervous system cancer, choriocarcinoma, connective tissue cancer, digestive system cancer, endometrial cancer, eye cancer, intraepithelial carcinoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, neuroblastoma, oral cancer, ovarian cancer, rhabdomyosarcoma, sarcoma, skin cancer, testicular cancer, thyroid cancer, uterine cancer, urinary tract cancer, pancreatic cancer, and infectious diseases, including but not limited to, human immunodeficiency virus (HIV), hepatitis (A, B or C), herpes virus (e.g., VSV, HSV-1, HAV-6, HSV-II and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus.

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