Modified anti-PD-L1 antibodies and therapeutic methods and uses for treating neurodegenerative diseases

Abstract

Disclosed herein are modified anti-PD-L1 antibodies that abolish Fc-related effector function and enhance clearance rates while maintaining therapeutic efficacy for modifying neurodegenerative diseases. Also disclosed herein are nucleic acid sequences and expression constructs encoding such modified anti-PD-L1 antibodies, as well as methods for making such modified anti-PD-L1 antibodies. Furthermore, disclosed herein are methods of treatment and use that employ dosing regimens for the disclosed anti-PD-L1 antibodies that ensure the antibodies are present for only a specific period of time, and then sufficiently cleared from the body to ensure sustained therapeutic efficacy.

Description

[Technical Field]

[0001] This application claims priority and filing date under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 836,247, filed April 19, 2019, and this application claims priority and filing date under 35 U.S.C. §119(a) to European Patent Application No. 19170438.6, filed April 19, 2019, the contents of each of which are incorporated herein by reference in their entireties. [Background technology]

[0002] Neurodegeneration is the progressive loss of neuronal structure or function, including neuronal death. Many neurodegenerative diseases occur as a result of the neurodegenerative process, resulting in a progressive decline in behavioral, social, cognitive, or motor function. Currently, there are no effective treatments to cure, modify, or stop the progression of neurodegenerative disorders, and approved drug therapies only provide moderate and transient symptom relief.

[0003] Most neurodegenerative pathologies share a common neuroinflammatory component that is part of the disease progression and contributes to disease exacerbation. Among these pathologies are Alzheimer's disease (AD) and age-related dementia, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease, which are debilitating neurodegenerative conditions characterized by progressive cognitive and / or functional decline. However, despite the chronic neuroinflammatory component in the pathology of neurodegenerative diseases, clinical treatments with anti-inflammatory agents over the past decade have all proven ineffective or even harmful to date.

[0004] This paper provides unique insight into why targeting the inflammatory component of neurodegenerative conditions using systemic anti-inflammatory drugs is insufficient. This paper provides therapies, methods, and uses based on this understanding that overcome the shortcomings of existing treatments for neurodegenerative conditions. Summary of the Invention

[0005] Disclosed herein are engineered anti-programmed death-ligand 1 (anti-PD-L1) antibodies that exhibit higher affinity and specificity for human PD-L1, increased rates of clearance from the blood, abrogated Fc-related effector function, and an improved safety profile compared to the intact antibody, while maintaining therapeutic efficacy for modifying neurodegenerative diseases. The disclosed engineered anti-PD-L1 antibodies lack Fc-related effector function and comprise a heavy chain constant domain that includes an amino acid sequence variant that promotes faster clearance of the engineered anti-PD-L1 antibodies disclosed herein than anti-PD-L1 antibodies that do not contain the same amino acid sequence variant. For example, the disclosed engineered anti-PD-L1 antibodies comprise a heavy chain constant domain that includes an amino acid sequence variant in the lower hinge region and / or the N-terminal half of the CH2 domain that abolishes Fc-related effector function, and an amino acid sequence variant within the CH2 and / or CH3 domain that promotes faster clearance of the anti-PD-L1 antibody than anti-PD-L1 antibodies that do not contain the same amino acid variant located within the CH2 and / or CH3 domain. The disclosed modified human anti-PD-L1 antibodies that do not contain Fc-related effector functions do not contain antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and / or antibody-dependent cellular phagocytosis (ADCP).

[0006] The present specification also discloses pharmaceutical compositions comprising the modified human anti-PD-L1 antibodies disclosed herein, as well as medicaments comprising the modified human anti-PD-L1 antibodies disclosed herein.

[0007] The present specification also discloses pharmaceutical kits comprising the modified human anti-PD-L1 antibodies disclosed herein, the pharmaceutical compositions disclosed herein, or the medicaments disclosed herein.

[0008] Also disclosed herein are methods of treatment and uses employing dosing regimens that use the disclosed modified anti-PD-L1 antibodies to ensure that the antibodies are present for only a specified period of time, and then sufficiently cleared from the body to ensure that they maintain their therapeutic efficacy. [Brief explanation of the drawings]

[0009] [Figure 1] Figures 1A-1E show that blocking CCR2 abolishes the beneficial effects of anti-PD-L1 antibodies in DM-hTAU. Figure 1A illustrates the experimental design. Figure 1B shows pre-test results of cognitive behavior in DM-hTAU and wild-type animals. Figure 1C shows post-treatment cognitive behavior results using the T-maze. Figure 1D shows post-treatment cognitive behavior results using the Y-maze. Figure 1E shows post-treatment cognitive behavior results using novel object recognition (NOR). [Figure 2-1] Figures 2A-2D show that blocking CCR2 selectively affects circulating monocyte levels without affecting T cell levels. Figure 2A shows the levels of bone marrow cells in the blood. Figure 2B shows bone marrow cells in the spleen. Figure 2C shows the levels of CD4+ memory T cells in the blood. Figure 2D shows CD4+ memory T cells in the spleen. [Figure 2-2] Same as above. [Figure 3] Figures 3A-3B show flow cytometry of brains from DM-hTAU mice treated with either anti-PD-L1 or IgG antibodies analyzed for CD45low / CD11bhigh bone marrow cells. Figure 3A shows flow cytometry of brain cells gated on CD45low / CD11bhigh and CD45high / CD11bhigh bone marrow cells. Figure 3B shows the quantitative distribution of CD45low / CD11bhigh bone marrow cells in anti-PD-L1-treated and IgG-treated mice. [Figure 4-1]Figures 4A-4B show flow cytometry of brains from GFP-BM-chimeric DM-hTAU mice treated with anti-PD-L1 or IgG antibodies analyzed for CD45low / CD11bhigh bone marrow cells. Figure 4A shows flow cytometry of GFP-labeled brain cells gated on Ly6C-expressing CD45low / CD11bhigh and CD45high / CD11bhigh bone marrow cells. Figure 4B shows the quantitative distribution of CD45low / CD11bhigh bone marrow cells in anti-PD-L1-treated and IgG-treated mice. [Figure 4-2] Same as above. [Figure 5] Figures 5A-5B show confocal images of brains from GFP-BM chimeric DM-hTAU mice treated with anti-PD-L1 or IgG antibodies analyzed by immunohistochemistry. Figure 5A shows a representative projection of a confocal z-stack, demonstrating colocalization of GFP+ cells (green) with the myeloid marker IBA-1 (blue) detected within the cortex of an anti-PD-L1-treated DM-hTAUGFP / + mouse (see arrows; scale bar: 100 µm). Figure 5B shows a representative projection of a confocal z-stack, demonstrating colocalization of GFP+ cells (green), IBA-1 (blue), and IL-10 (red) in the brain of an anti-PD-L1-treated DM-hTAUGFP / + mouse (scale bar: 50 µm). [Figure 6] Figures 6A-6C show the dose-dependent effects of anti-PD-L1 on spatial learning and memory in 5XFAD mice. Figure 6A shows the experimental design, with black arrowheads indicating treatment time points and illustrating the time points for cognitive scoring using the radial arm water maze (RAWM) assay. Figure 6B shows the RAWM performance of FXFAD mice one month after treatment. Each group was treated with different doses of anti-PD-L1 antibody, with wild-type littermates serving as controls (*P<0.05, **P<0.01, ***P<0.001). Figure 6C shows the RAWM performance of three groups of FXFAD mice two months after treatment. Each group was treated with different doses of anti-PD-L1 antibody, with wild-type littermates serving as controls (*P<0.05, **P<0.01, ***P<0.001). [Figure 7] Figures 7A-7C show the dose-dependent effect of anti-PD-L1 on hippocampal astrogliosis in 5XFAD mice. Figure 7A shows the area of ​​all detected GFAP+ cells divided by the total selected area of ​​the dentate gyrus (*P<0.05, **P<0.01). Figure 7B shows the mean fluorescence of detected GFAP+ cells corrected to the mean fluorescence of the entire dentate gyrus (CTCF) (**P<0.01). Figure 7C shows the number of detected GFAP+ cells exhibiting fluorescence over 1000 pixels (**P<0.01). [Figure 8] Figures 8A-8B show the dose-response effects of anti-PD-L1 on spatial learning and memory in DM-hTAU mice. Figure 8A shows the experimental design, with black arrowheads indicating the time points of treatment and illustrating the time points of cognitive scoring using the T-maze assay. Figure 8B shows the T-maze performance of DM-hTAU mice one month after treatment, along with wild-type littermates and anti-IgG2-treated mice, both of which served as controls. Each group was treated with a different dose of anti-PD-L1 antibody (*P<0.05, **P<0.01, ***P<0.001). [Figure 9] Figures 9A-9B show the dose-response and time-dependent effects of anti-PD-L1 on spatial learning and memory in DM-hTAU mice. Figure 9A shows the T-maze performance of three groups of DM-hTAU mice after one month of treatment, with wild-type littermates and anti-IgG2-treated mice, both serving as controls. Each group was treated with a different dose of anti-PD-L1 antibody (*P<0.05, **P<0.01, ***P<0.001). Figure 9B shows the T-maze performance of three groups of DM-hTAU mice after two months of treatment, with wild-type littermates and anti-IgG2-treated mice, both serving as controls. Each group was treated with a different dose of anti-PD-L1 antibody (*P<0.05, **P<0.01, ***P<0.001). [Figure 10]Figure 10 shows the quantitative distribution of AT-180 immunoreactivity (phospho-tau (Thr231)) in the brains of wild-type and DM-hTAU mice treated with rat anti-PD-L1 antibody or rat anti-KLH as a control (both with IgG2b Fc) (error bars represent the mean ± sem; *P<0.05). [Figure 11-1] Figures 11A-11I show the dose-dependent effect of anti-PD-L1 on inflammatory cytokine profiles in DM-hTAU mice. Figure 11A shows representative images of IL-1β immunoreactivity in mice treated with an anti-IgG antibody control. Figure 11B shows representative images of IL-1β immunoreactivity in mice treated with an anti-PD-L1 antibody. Figure 11C shows representative orthogonal projections of confocal z-stacks, demonstrating that IL-1β (green) colocalizes with GFAP+ astrocytes (red), but not IBA-1+ microglia / macrophages (white), in the dentate gyrus; cell nuclei are stained with DAPI (blue) (Scale bar, 100 μm). Figure 11D shows quantitative measurements of hippocampal IL-1β protein levels measured by FRET-based ELISA in mice treated with anti-PD-L1 antibodies compared to untreated and anti-IgG antibody-treated wild-type littermates (data presented as mean ± sem; *P<0.05, **P<0.01, ***P<0.001). Figure 11E shows linear regression analysis revealing a correlation between cognitive performance of DM-hTAU mice in the T-maze assay and IL-1β protein levels in their brains. Figure 11F shows quantitative measurements of mRNA expression levels tested by RT-qPCR for the gene TNF-α. Figure 11G shows quantitative measurements of mRNA expression levels tested by RT-qPCR for the gene il-6. Figure 11H shows quantitative determination of mRNA expression levels tested by RT-qPCR for the gene il-12p40. FIG. 11I shows quantitative measurements of mRNA expression levels measured by RT-qPCR for the gene IL-1β. [Figure 11-2] Same as above. [Figure 12]Figure 12 shows the PK profiles of anti-PD-L1 antibodies in serum collected from C57BL / 6J mice and quantified using enzyme-linked immunosorbent assay (ELISA). [Figure 13] Figure 13 shows the kinetics of PD-L1 receptor occupancy on T cells in the blood from 5XFAD and C57BL / 6J wild-type mice after a single injection of different dosages of a rat anti-mouse PD-L1 monoclonal antibody (clone 10F.9G2, BioXCell) versus a rat IgG2b anti-KLH antibody-treated control (error bars represent the mean ± sem; *P<0.05, **P<0.01, ***P<0.001). [Figure 14] Figure 14 shows the levels of PD-1+ expressing effector memory T cells (CD4+CD44+ cell population) in 5XFAD and C57BL / 6J wild-type (WT) mice after a single injection of multiple doses of a rat anti-mouse PD-L1 monoclonal antibody (clone 10F.9G2, BioXCell) compared to rat anti-KLH antibody-treated mice. Each dot on the graph represents a blood sample from a different mouse (error bars represent the mean ± sem; *P<0.05, **P<0.01, ***P<0.001). [Figure 15] Figure 15 shows the PK profile of a rat anti-mouse PD-L1 monoclonal antibody (clone 10F.9G2, BioXCell) in mice quantified using ELISA. [Figure 16] Figure 16 shows the comparative treatment effects on cognitive performance of a single injection compared to repeated injections of anti-PD-L1, representing a transient response compared to continuous exposure to treatment in 5XFAD mice tested 1 and 2 months after the first injection. Cognitive performance in 5XFAD mice was tested using a radial arm water maze, and the post-treatment effects in the different treatment groups are expressed as the percentage of mice that exhibited forward learning behavior (forward learning was defined as an average of less than 3 errors in the last two trails of the cognitive task). [Figure 17]Figure 17 shows the T-maze performance of DM-hTAU mice one month after anti-PD-L1 antibody treatment and mice treated with either rat anti-PD-L1 antibody, humanized anti-PD-L1 antibody atezolizumab (ATZ; human IgG1 Fc) or variant 1-ATZ (Fc effector null) antibody, wild-type mice, untreated DM-hTAU mice, and human anti-B12 antibody as an IgG1 isotype control (each served as a control) (error bars represent the mean ± sem; *P<0.05, **P<0.01, ***P<0.001). [Figure 18] Figure 18 shows a comparison of anti-PD-L1 antibody effects (rat anti-mouse PD-L1 vs. rat IgG2b anti-KLH antibody, anti-PD-L1 atezolizumab vs. human IgG1 backbone, and variant 1-ATZ (Fc effector null)) on hippocampal astrogliosis in DM-hTAU mice based on the mean fluorescence of detected GFAP+ cells, normalized to the mean fluorescence (CTCF) of the whole dentate gyrus (error bars represent the mean ± sem; *P<0.05, **P<0.01, ***P<0.001). [Figure 19] Figure 19 shows the PK profiles of anti-human PD-L1 atezolizumab (ATZ) and four ATZ variants in serum collected from wild-type C57BL / 6J mice and quantified using reverse ELISA (error bars represent the mean ± sem). [Figure 20]Figures 20A-20D show the effects of engineered anti-PD-L1 antibody variants on spatial learning and memory in DM-hTAU mice. Figure 20A shows the experimental design, with black arrowheads indicating the time points of treatment and figures indicating the time points of cognitive scoring using the T-maze or Y-maze assay. Figure 20B shows T-maze performance of DM-hTAU mice 4 weeks after treatment. Each group was treated with a different anti-PD-L1 antibody variant and included wild-type littermates and variant 1-B12-treated mice (both of which served as controls) (error bars represent the mean ± sem; *P<0.05, **P<0.01, ***P<0.001). Figure 20C shows the Y-maze performance of DM-hTAU mice 6 weeks after treatment, with each group treated with a different anti-PD-L1 antibody variant and including wild-type littermates and variant 1-B12-treated mice (both of which served as controls) (error bars represent the mean ± sem; *P<0.05, **P<0.01, ***P<0.001). Figure 20D shows the T-maze performance of DM-hTAU mice 8 weeks after treatment, with each group treated with a different anti-PD-L1 antibody variant and including wild-type littermates and anti-B12-treated mice (both of which served as controls) (error bars represent the mean ± sem; *P<0.05, **P<0.01, ***P<0.001). [Figure 21] Figure 21 shows the effects of engineered anti-PD-L1 antibody variants on spatial learning and memory in 5XFAD mice using the RAWM cognitive task one month after treatment. Each group was treated with a different engineered anti-PD-L1 antibody variant, or a rat anti-mouse PD-L1 antibody, and also included wild-type littermates and anti-B12-treated mice (both serving as controls) (error bars represent the mean ± sem). [Figure 22]Figures 22A-B show the PK profiles using multiple doses of two different engineered anti-PD-L1 antibody variants in serum collected from C57BL / 6J mice and quantified using ELISA. Figure 22A shows the results obtained with the variant 2-ATZ (Fc effector null-H311A) antibody (error bars represent the mean ± sem). Figure 22B shows the results obtained with the variant 3-ATZ (Fc effector null-H436Q) antibody (error bars represent the mean ± sem). [Figure 23] Figures 23A-B show the kinetics of PD-L1 receptor occupancy on T cells in the blood from C57BL / 6J wild-type mice following a single injection of two different engineered anti-PD-L1 antibody variants. Figure 23A shows results obtained with the variant 2-ATZ (Fc effector null-H311A) antibody (error bars represent the mean ± sem). Figure 23B shows results obtained with the variant 3-ATZ (Fc effector null-H436Q) antibody (error bars represent the mean ± sem). [Figure 24-1] Figures 24A-B show the kinetics of circulating PD-1+CD4+CD44+ T cells in C57BL / 6J wild-type mice following a single injection of two different engineered anti-PD-L1 antibody variants. Figure 24A shows results obtained with the variant 2-ATZ (Fc effector null-H311A) antibody (error bars represent the mean ± s.e.m.). Figure 24B shows results obtained with the variant 3-ATZ (Fc effector null-H436Q) antibody (error bars represent the mean ± s.e.m.). [Figure 24-2] Same as above. [Figure 25] Figure 25 shows the dose-dependent effects of two different engineered anti-PD-L1 antibody variants on spatial learning and memory in DM-hTAU mice after 4 weeks of treatment (data are expressed as mean ± sem; *P<0.05, **P<0.01, ***P<0.001). [Figure 26]Figures 26A-C show longitudinal measures of cognitive performance at 2 and 4 weeks following anti-PD-L1 administration at 1.5 mg / mouse of variant 2-ATZ (Fc effector null-H311A) or isotype control variant 2-B12 (an anti-B12 antibody containing a human IgG1 Fc effector null and H311A substitution in the Fc portion corresponding to the same substitution in variant 2-ATZ). Figure 26A displays the time spent by individual mice in the novel arm of the T-maze measured at 2 and 4 weeks after treatment, connected by a solid line. Figure 26B shows the same data as Figure 26A, but comparing T-maze performance between different treatment groups at 2 weeks after treatment. Figure 26C shows the same data as Figure 26A, but comparing T-maze performance between different treatment groups at 4 weeks after treatment. One-way analysis of variance and Fisher's exact test post hoc analysis. Data are presented as mean ± sem. [Figure 27] Figure 27 shows the kinetics of PD-L1 receptor occupancy on CD3+ T cells isolated from the blood, cervical lymph nodes, inguinal lymph nodes, and choroid plexus (CP) of C57BL / 6J wild-type mice 3 days after a single injection of variant 2-ATZ (Fc effector null-H311A) antibody or isotype control variant 2-B12 (anti-B12 antibody containing human IgG1 Fc effector null and an H311A substitution) (error bars represent the mean ± sem). [Figure 28]Figures 28A-H show the effects of variant 2-ATZ (Fc effector null-H311A) antibody or isotype control variant 2-B12 (an anti-B12 antibody containing a human IgG1 Fc effector null and H311A substitution) on spatial learning and memory in DM-hTAU mice. Figure 28A shows the experimental design, with black arrowheads indicating treatment time points, red arrowheads indicating blood sampling and tissue collection time points, and the figure indicates cognitive scoring time points using the T-maze. Figure 28B shows T-maze performance of DM-hTAU mice and wild-type littermates 2 weeks after initial treatment with either variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody. (Error bars represent mean ± s.e.m.; ns is not significant, ***P<0.001). Figure 28C shows T-maze performance of DM-hTAU mice and wild-type littermates 4 weeks after the first treatment with either variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody (error bars represent mean ± sem; ***P<0.001). Figure 28D shows T-maze performance of DM-hTAU mice and wild-type littermates 4 weeks after the second treatment with either variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody (error bars represent mean ± sem; ***P<0.001). Figure 28E shows T-maze performance of DM-hTAU mice and wild-type littermates 2 weeks after the third treatment with either variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody (error bars represent mean ± sem; ***P<0.001). Figure 28F shows T-maze performance of DM-hTAU mice and wild-type littermates 4 weeks after the third treatment with either variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody (error bars represent mean ± sem; ***P<0.001).Figure 28G shows T-maze performance of DM-hTAU mice and wild-type littermates 6 weeks after the third treatment with either variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody (error bars represent mean ± sem; **P<0.01, ***P<0.001). Figure 28H shows T-maze performance of DM-hTAU mice and wild-type littermates 8 weeks after the third treatment with either variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody (error bars represent mean ± sem; **P<0.01, ***P<0.001). [Figure 29] Figure 29 shows the kinetics of PD-L1 receptor occupancy on CD3+ T cells isolated from blood, cervical lymph nodes, inguinal lymph nodes, and choroid plexus (CP) tissue of DM-hTAU mice at various time points after treatment with different dosages of variant 2-ATZ (Fc effector null-H311A) or isotype control variant 2-B12 (an anti-B12 antibody containing a human IgG1 Fc effector null and H311A substitution in the Fc portion corresponding to the same substitution in variant 2-ATZ) (error bars represent the mean ± sem). [Figure 30] Figure 30 shows the levels of CD4+ memory T lymphocytes expressing PD-1 (percentage of PD-1+ cells in the total CD4+ / CD44+ population) (error bars represent mean ± sem; *P<0.05, **P<0.01, ***P<0.001). [Figure 31] Figures 31A-B show relative hippocampal aggregated tau (normalized to manufacturer's negative control; arbitrary units) in DM-hTau mice. Figure 31A shows quantitative measurements of aggregation measured by FRET-based ELISA in hippocampi excised 3 and 48 days after a single injection (error bars represent mean ± sem; *P<0.05, **P<0.01, ***P<0.001). Figure 31B shows the correlation between hippocampal tau aggregation in hippocampi excised 2 weeks after testing of cognitive performance (week 4 of the study). [Figure 32]Figure 32 shows the PK profiles of engineered anti-PD-L1 antibody variants based on 84G09 in serum collected from cynomolgus monkeys and quantified using reverse ELISA. [Figure 33] Figures 33A-33D show the correlation between PD-L1 receptor occupancy and serum concentrations of engineered anti-PD-L1 antibody variants based on 84G09 in cynomolgus monkeys. Figure 33A shows the correlation between PD-L1 receptor occupancy and serum concentrations of variant 1-G09 (Fc effector null) antibody. Figure 33B shows the correlation between PD-L1 receptor occupancy and serum concentrations of variant 2-G09 (Fc effector null-H315A) antibody. Figure 33C shows the correlation between PD-L1 receptor occupancy and serum concentrations of variant 3-G09 (Fc effector null-H440Q) antibody. Figure 33D shows the correlation between PD-L1 receptor occupancy and serum concentrations of variant 4-G09 (Fc effector null-H315A+H440Q) antibody. [Figure 34] Figure 34 shows the pharmacodynamic changes in the frequency of PD-1-high effector memory CD4+ T cells in cynomolgus monkeys treated with different engineered anti-PD-L1 antibody variants based on 84G09. Values ​​represent the percentage change in PD-1-high effector memory CD4+ T cells normalized to baseline (data are expressed as mean ± sem; *P<0.05, **P<0.01, ***P<0.001). [Figure 35] Figures 35A-B show the pharmacodynamic changes in different T cell subpopulations after treatment with variant 2-G09 (Fc effector null-H315A) antibody. Figure 35A shows central memory T cells. Figure 35B shows effector memory (EM), central memory (CM), and naive CD4 T cells. Data are presented as mean ± sem. *P<0.05, **P<0.01, ***P<0.001. [Figure 36]Figures 36A-36E show ADCC dose-response assays. Figure 36A shows a dose-response ADCC assay of the positive control antibody, Rituxan, using Raji / CD-20 cells. Figure 36B shows a dose-response ADCC assay of the negative control antibody, human IgG1, using CHO-K1 / PD-L1 cells. Figure 36C shows a dose-response ADCC assay of variant 2-G09 (Fc effector null-H315A), an engineered anti-PD-L1 antibody variant disclosed herein, using CHO-K1 / PD-L1 cells. Figure 36D shows a dose-response ADCC assay of the positive control antibody, Rituxan, using Raji / CD-20 cells. Figure 36E shows a dose-response curve of a biosimilar of atezolizumab, a commercially available humanized anti-PD-L1 monoclonal antibody known to circumvent ADCC Fc activity, using CHO-K1 / PD-L1 cells. [Figure 37] Figures 37A-37D show CDC dose-response assays. Figure 36A shows a dose-response CDC assay of the positive control antibody Rituxan using Raji / CD-20 cells. Figure 36B shows a dose-response CDC assay of the negative control antibody human IgG1 using CHO-K1 / PD-L1 cells. Figure 36C shows a dose-response CDC assay of variant 2-G09 (Fc effector null-H315A), an engineered anti-PD-L1 antibody variant disclosed herein, using CHO-K1 / PD-L1 cells. Figure 36D shows a dose-response CDC assay of a biosimilar of atezolizumab, a commercially available humanized anti-PD-L1 monoclonal antibody known to circumvent ADCC Fc activity, using CHO-K1 / PD-L1 cells. [Figure 38]Figure 38 shows a comparison of two engineered anti-PD-L1 antibody variants, variant 1-ATZ (Fc effector null) and 2-ATZ (Fc effector null-H311A), and the isotype control variant 2-B12 (an anti-B12 antibody containing a human IgG1 Fc effector null and H311A substitution in the Fc portion corresponding to the same substitution in variant 2-ATZ) for diabetes-free survival after a single injection of 1.5 mg / mouse dose in 9-week-old female NOD mice (P-value=0.0030). [Figure 39] Figure 39 shows a comparison of body weight change between two engineered anti-PD-L1 antibody variants, variant 1-ATZ (Fc effector null) and 2-ATZ (Fc effector null-H311A), and the isotype control variant 2-B12 (an anti-B12 antibody containing a human IgG1 Fc effector null and H311A substitution in the Fc portion corresponding to the same substitution in variant 2-ATZ) following a single injection of 1.5 mg / mouse dose in 9-week-old female NOD mice. DETAILED DESCRIPTION OF THE INVENTION

[0010] Physiological entry of immune cells into the CNS is regulated by the choroid plexus (CP) epithelium of the brain. Transport through the CP depends on interferon gamma (IFN-γ) signaling derived from T cells present in the periphery, such as within the CP interstitium. Under pathological conditions, leukocyte transport through the CP is insufficient or even impaired. One way to enhance transport is to increase the level of IFN-γ signaling in the CP.

[0011] Immune checkpoints are regulatory pathways that maintain systemic immune homeostasis and tolerance. Without wishing to be limited by theory, selective blockade of immune checkpoints reactivates the systemic IFN-γ-dependent cascade of immune responses suppressed due to pathological conditions. Increased IFN-γ signaling leads to increased levels of leukocyte trafficking molecules expressed by CPs, which in turn induces leukocyte migration from the choroid plexus epithelium to CNS regions and recruitment of monocyte-derived macrophages and other immunoregulatory cells (T cells) to affected areas in the brain. Importantly, this recruitment leads to comprehensive effects on brain function, including reduced senile plaque burden, restoration of immune balance within the brain parenchyma, reduced neuroinflammation, reduced gliosis, reduced synapse loss, increased hippocampal neurogenesis, increased neuroprotection, and improved neuronal survival, which collectively lead to neuroprotection and / or mitigation of cognitive decline. Therefore, immune checkpoint blockade restores a healthy brain-immune dialogue via increased IFN-γ signaling, enabling brain maintenance and repair of pathological conditions.

[0012] Systemic immune responses can be induced by using neutralizing antibodies against immune checkpoints (e.g., programmed cell death protein 1 (PD-1), PD-L1, and T-cell immunoglobulin and mucin domain-containing 3 (TIM-3)). Treatment with these neutralizing antibodies, when induced in animals with established neurodegenerative disease pathology, resulted in immunological responses that cleared cerebral amyloid-β (Aβ) plaques and improved cognitive performance. Thus, the use of neutralizing antibodies against immune checkpoint members resulted in an IFN-γ-dependent immune response and reversed the disease pathology.

[0013] Furthermore, this immune response was required to migrate immune cells into the CNS in a manner shown to be IFN-γ dependent. This specification discloses experiments demonstrating that a single systemic administration of an immune checkpoint blocker (e.g., an antibody) under conditions of chronic neurodegenerative disease improves cognitive performance, which depends on the entry of peripheral monocyte-derived macrophages into the affected brain (see Example 1). These experiments further demonstrate that monocyte-derived macrophages within the affected brain parenchyma are necessary for the resolution of local inflammation and promote the local phagocytic activity required for the removal of cellular debris and pathological conformations of misfolded, aggregated proteins (see Example 1).

[0014] Furthermore, the present specification discloses experiments demonstrating that not only is continuous exposure to neutralizing antibodies of immune checkpoint members not necessary to maintain beneficial effects, but that the duration of exposure to such antibodies is therapeutically ineffective (see Example 3). These results indicate that greater therapeutic efficacy for neurodegenerative diseases can be achieved with only transient blockade of immune checkpoint pathways. This finding contrasts with cancer treatments, where continuous exposure to neutralizing antibodies of immune checkpoints is required for optimal therapeutic efficacy.

[0015] Transient blockade of immune checkpoint pathways not only shows greater efficacy in treating neurodegenerative diseases, but also helps reduce the risk of developing immune-related adverse effects such as autoimmune diseases. This specification reveals that in non-obese diabetic (NOD) mice, which naturally develop diabetes with age, exposure of immune checkpoint members to neutralizing antibodies at a young age accelerates the onset of diabetes. The acceleration of diabetes onset correlates with antibody exposure, and the shorter the antibody exposure time, the lower the incidence of diabetes at a young age. (See Example 9.)

[0016] The discovery that recruitment of peripheral immune cells across the cerebrospinal fluid barrier (BCSFB) to the brain and transient exposure to neutralizing antibodies are necessary and essential components in reversing brain pathology reveals that the immune checkpoint antibodies needed to achieve the safest and most effective outcomes in neurodegenerative diseases require a specific set of properties that are different, and even opposite, from those needed to treat cancer.

[0017] For example, antibodies against immune checkpoints with optimal therapeutic efficacy against neurodegenerative diseases must lack cytotoxic activity. Typical full-length antibodies contain a fragment crystallizable (Fc) region. Among other things, the Fc region mediates proper binding of the antibody to the appropriate Fc receptor, initiating several physiological effects, such as lysis of target cells whose membrane surface antigens are bound by the antibody. This lytic mechanism, called antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or antibody-dependent cellular phagocytosis (ADCP), is part of the humoral immune response necessary to limit and contain infection. However, because peripheral immune cell recruitment is required to initiate the systemic IFN-γ-dependent cascade of the immune response, immune checkpoint antibodies with Fc effector activity are undesirable. This is because such lytic activity would destroy peripheral immune cells and deplete the populations of cells necessary for choroidal plexus activation or for recruitment to the brain. Therefore, antibodies against immune checkpoint members that lack Fc effector function would be advantageous for use in therapeutic approaches to treat neurodegenerative diseases. However, in the context of cancer treatment, cytotoxic activity may be beneficial, as the goal of cancer immunotherapy is to eradicate tumor cells, and therefore lysis of target cancer cells is highly desirable.

[0018] As another example, an antibody against an immune checkpoint with optimal therapeutic efficacy for neurodegenerative diseases would be one that can be rapidly removed from the body, i.e., has an improved clearance rate. As described above, this specification demonstrates that transient blockade of immune checkpoint pathways exhibits greater efficacy in treating neurodegenerative diseases compared to continuous exposure to antibodies. Furthermore, continuous exposure to antibodies increases the risk of inducing an autoimmune response. Therefore, an antibody against an immune checkpoint member that can mediate an effective response but can be removed from the body in a way that avoids the harmful effects of continuous exposure to the antibody would be an advantageous property when used in a therapy for treating neurodegenerative diseases.

[0019] The present specification discloses modified anti-PD-L1 monoclonal antibodies that abolish Fc-associated effector functions and improve the clearance rate of the modified anti-PD-L1 antibodies while maintaining therapeutic efficacy for modifying neurodegenerative diseases (Examples 4-8). Additionally, the present specification discloses methods of treatment and use that employ dosing regimens for the disclosed anti-PD-L1 antibodies that ensure the antibodies are present for only a specific period of time, and then sufficiently cleared from the body to ensure sustained therapeutic efficacy (Examples 1-9).

[0020] Embodiments of the present disclosure include, in part, engineered anti-PD-L1 antibodies. The engineered anti-PD-L1 antibodies disclosed herein may be typical full-length immunoglobulin molecules composed of two immunoglobulin (Ig) heavy chains and two Ig light chains. Such antibodies comprise an antigen-binding fragment (Fab) and a fragment crystallizable (Fc) region. Preferred engineered anti-PD-L1 antibodies disclosed herein are humanized or human anti-PD-L1 antibodies. More preferred engineered anti-PD-L1 antibodies disclosed herein are humanized IgG or human IgG anti-PD-L1 antibodies. Even more preferred engineered anti-PD-L1 antibodies disclosed herein are humanized IgG1 or human IgG1 anti-PD-L1 antibodies. The engineered anti-PD-L1 antibodies disclosed herein have antagonistic or inactivating activity, preferably neutralizing activity.

[0021] The anti-PD-L1 antibodies disclosed herein may also be variants of full-length antibodies, so long as the variant exhibits the desired biological activity disclosed herein (i.e., abrogating Fc-associated effector function and increasing the clearance rate of the modified anti-PD-L1 antibody while maintaining therapeutic efficacy for modifying neurodegenerative diseases). For example, an anti-PD-L1 antibody fragment disclosed herein may comprise a light chain comprising a light chain variable region and a light chain constant region, and a heavy chain comprising only a CH2 domain and a CH3 domain. Suitable anti-PD-L1 antibody fragments disclosed herein are described, for example, in Holliger, P., and Hudson, PJ, Engineered antibody fragments and the rise of single domains. Nat. Biotechnol. Nat. Biotechnol. 23:1126-1136 (2005); Cuesta, AM, Sainz-Pastor, N., Bonet, J., Oliva, B., and Alvarez-Vallina, L., Multivalent antibodies: when design surpasses evolution. Trends Biotechnol. 28:355-362 (2010); and Nelson, AL, Antibody fragments: hope and hype. MAbs 2, 77-83 (2010), each of which is incorporated by reference in its entirety. For general disclosure regarding antibody structure and antigenic compound-binding fragments thereof, see, e.g., Pluckthun in The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore (eds.), Springer-Verlag, New York, pp. 269-315 (1994); Borrabeck, Antibody Engineering, 2nd Edition (Oxford University Press 1995), each of which is incorporated herein by reference in its entirety.Examples of variants of the engineered anti-PD-L1 antibodies disclosed herein include, but are not limited to, fragments of the engineered anti-PD-L1 antibodies, and single-chain variants of the engineered anti-PD-L1 antibodies. The anti-PD-L1 antibodies disclosed herein also include molecularly engineered antibodies, such as dimers, multimers, multispecific antibodies, humanized antibodies, human antibodies, chimeric antibodies, bifunctional antibodies, or trifunctional antibodies.

[0022] Full-length anti-PD-L1 antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, composed of two identical immunoglobulin heavy (H) chains and two identical immunoglobulin light (L) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, although the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges, while each light chain has an amino-terminal variable domain followed by a single constant domain.

[0023] There are five types of immunoglobulin heavy chains in mammals (gamma (γ), delta (δ), alpha (α), mu (μ), and epsilon (ε)), which define the classes of immunoglobulins: IgG, IgD, IgA, IgM, and IgE, respectively. The IgG and IgA heavy chains have approximately 450 amino acids. The IgM and IgE heavy chains have approximately 550 amino acids. Each heavy chain contains a constant region and a variable region. The constant region is the same for all immunoglobulins of the same class but differs between classes. Each heavy chain has a variable region containing a variable domain (VH) at the amino terminus, followed by a constant region containing multiple constant domains. The IgG, IgD, and IgA heavy chains have a constant region composed of three tandem immunoglobulin domains (CH1, CH2, and CH3) and a hinge region for additional flexibility. The heavy chains IgM and IgE have a constant region composed of four tandem immunoglobulin domains (CH1, CH2, CH3, and CH4). The variable region of the heavy chain varies between different B cells but is the same for all immunoglobulins produced by the same B cell or B cell clone. The variable domain is composed of a single immunoglobulin domain.

[0024] Mammals have two types of immunoglobulin light chains: kappa (κ) chains and lambda (λ) chains. The lambda class has four subtypes: λ1, λ2, λ3, and λ4. Because only one type of light chain exists within a typical antibody, the two light chains in each antibody are identical. Light chains are approximately 211–217 amino acids in length. Each light chain consists of two tandem immunoglobulin domains, an amino-terminal variable domain (VL), followed by a constant domain. The variable domain is important for antigen binding, and the constant domain determines the type of light chain: kappa or lambda. The light chain constant domain aligns with the first constant domain of the heavy chain, and the light chain variable domain aligns with the variable domain of the heavy chain. Specific amino acid residues are thought to form an interface between the light and heavy chain variable domains.

[0025] The complete antigen recognition and binding site is contained within the variable domain of an antibody. This site comprises a dimer of one heavy chain variable domain (VH) and one light chain variable domain (VL) in tight, noncovalent association. Each domain contains four framework regions (FRs) that primarily adopt a β-sheet configuration, connected by three hypervariable regions that form connecting loops and, in some cases, form part of the β-sheet structure. Each hypervariable region contains amino acid sequences corresponding to complementarity-determining regions (CDRs). Together, it is the three-dimensional configuration of the six CDR regions that defines the antigen-binding site on the surface of the VH-VL dimer that confers antigen-binding specificity. See, e.g., Cyrus Chothia et al., Conformations of Immunoglobulin Hypervariable Regions, Nature 342(6252):877-883 (1989); Elvin A. Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991), each of which is incorporated by reference in its entirety. The constant domains of antibodies are not involved directly in binding the antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity.

[0026] Target antigens generally have one or more binding sites, also called epitopes, which are recognized by CDR-formed antigen binding sites. "Epitope" is synonymous with "antigenic determinant" and refers to a site on target antigen, such as a peptide, polysaccharide, or lipid-containing molecule, that can specifically bind to immunoglobulin or T cell receptor, or can interact with other molecules. Each antibody that specifically binds to a different epitope has a different structure. Therefore, one antigen can be recognized by two or more antibodies.

[0027] The modified anti-PD-L1 antibodies disclosed herein can be polyclonal or monoclonal. A polyclonal antibody refers to a heterogeneous population of antibody molecules containing at least two species of antibody capable of binding to a particular antigen. By definition, a polyclonal antibody contains at least two different antibodies that bind to at least two different epitopes. A monoclonal antibody refers to a substantially homogeneous population of antibody molecules containing only one species of antibody capable of binding to a particular antigen. That is, the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. By definition, a monoclonal antibody binds to a single epitope. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In addition to their specificity, monoclonal antibodies are advantageous in that they can be synthesized uncontaminated by other antibodies. The modifier "monoclonal" indicates the character of an antibody obtained from a substantially homogeneous antibody population and should not be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. Nos. 4,816,567; 5,807,715). The monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352:624-628; Marks et al. (1991) J. Mol. Biol. 222:581-597.

[0028] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) that selectively binds to an epitope present within PD-L1 or a fragment thereof. H ) and / or a light chain variable domain (V L In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) that selectively binds to an epitope present in PD-L1 of SEQ ID NO: 1. H ) and / or a light chain variable domain (VL ). In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope present within SEQ ID NO: 1. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) that selectively binds to an epitope with, for example, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amino acid identity to PD-L1 of SEQ ID NO: 1. H ) and / or a light chain variable domain (V L In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise a heavy chain variable domain (V) that selectively binds to an epitope with amino acid identity to SEQ ID NO:1, for example, in the range of about 90% to about 100%, about 95% to about 100%, about 90% to about 99%, about 95% to about 99%, about 90% to about 97%, about 95% to about 97%, or about 97% to about 99%. H ) and / or a light chain variable domain (V L ). In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise a heavy chain variable domain (V) that selectively binds an epitope having, for example, at least one, at least two, at least three, or at least four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to SEQ ID NO: 1, or up to one, up to two, up to three, or up to four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to the PD-L1 of SEQ ID NO: 1. H ) and / or a light chain variable domain (V L In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise a heavy chain variable domain (V) that selectively binds to an epitope that has, for example, about 1 to about 2, about 1 to about 3, about 1 to about 4, about 2 to about 3, about 2 to about 4, or about 3 to about 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions relative to PD-L1 of SEQ ID NO: 1. H) and / or a light chain variable domain (V L ).

[0029] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) comprising SEQ ID NO:2. H In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V), which may comprise a sequence having, for example, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amino acid identity to SEQ ID NO:2. H ) and that selectively binds to an epitope present within PD-L1, such as the PD-L1 of SEQ ID NO: 1. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V ) that can comprise a sequence having, for example, about 90% to about 100%, about 95% to about 100%, about 90% to about 99%, about 95% to about 99%, about 90% to about 97%, about 95% to about 97%, or about 97% to about 99% amino acid identity to SEQ ID NO: 2. H ) and selectively binds to an epitope present within PD-L1, such as the PD-L1 of SEQ ID NO:1.

[0030] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V ) that may comprise a sequence having, for example, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least 11, or at least 12 contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:2. H), which may comprise a heavy chain variable domain (V) that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1, or a sequence with deletions, additions, and / or substitutions of up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, or up to 12 contiguous amino acids relative to SEQ ID NO: 2. H ), and which selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein are functional antibodies that selectively bind to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 2, e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-11, 2-12, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 3-11, 3-12, a heavy chain variable domain (V) that can comprise a sequence having deletions, additions, and / or substitutions of 10, 4, 11, 4, 12, 5, 6, 5, 7, 5, 8, 5, 9, 5, 10, 5, 11, 5, 12, 6, 7, 6, 8, 6, 9, 6, 10, 6, 11, 6, 12, 7, 8, 7, 9, 7, 10, 7, 11, 7, 12, 8, 9, 8, 10, 8, 11, 8, 12, 9, 10, 9, 11, 9, 12, 10, 11, 10, 12, or 11, 12 contiguous amino acids; H ) and selectively binds to an epitope present within PD-L1, such as the PD-L1 of SEQ ID NO:1.

[0031] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V ) that may comprise a sequence with, for example, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least 11, or at least 12 non-contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:2. H), which may comprise a heavy chain variable domain (V) that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1, or a sequence with deletions, additions, and / or substitutions of up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, or up to 12 non-contiguous amino acids relative to SEQ ID NO: 2. H ), and which selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein are functional antibodies that selectively bind to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 2, e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-11, 2-12, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 3-11, 3-12, a heavy chain variable domain (V) that can comprise a sequence having deletions, additions, and / or substitutions of up to 10, 4 to 11, 4 to 12, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6 to 12, 7 to 8, 7 to 9, 7 to 10, 7 to 11, 7 to 12, 8 to 9, 8 to 10, 8 to 11, 8 to 12, 9 to 10, 9 to 11, 9 to 12, 10 to 11, 10 to 12, or 11 to 12 non-contiguous amino acids; H ) and selectively binds to an epitope present within PD-L1, such as the PD-L1 of SEQ ID NO:1.

[0032] In another embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) that selectively binds to an epitope present in PD-L1. H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; H In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) that selectively binds to an epitope present in PD-L1 of SEQ ID NO: 1. H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions;H In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) that can selectively bind to an epitope present within a sequence having, e.g., at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amino acid identity to PD-L1 of SEQ ID NO: 1. H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; H In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) capable of selectively binding to an epitope present within a sequence having, for example, about 90% to about 100%, about 95% to about 100%, about 90% to about 99%, about 95% to about 99%, about 90% to about 97%, about 95% to about 97%, or about 97% to about 99% amino acid identity to PD-L1 of SEQ ID NO: 1. H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; H In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) that can selectively bind to an epitope present within a sequence that has, for example, at least one, at least two, at least three, or at least four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to PD-L1 of SEQ ID NO: 1, or that has up to one, up to two, up to three, or up to four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions relative to PD-L1 of SEQ ID NO: 1. H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; HIn yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) capable of selectively binding to an epitope present in a sequence that has, for example, about 1 to about 2, about 1 to about 3, about 1 to about 4, about 2 to about 3, about 2 to about 4, or about 3 to about 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions relative to PD-L1 of SEQ ID NO: 1. H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; H ) is included.

[0033] In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) comprising SEQ ID NO:3 (IMGT) or SEQ ID NO:4 (Kabat). H ) a heavy chain variable domain (V) containing the CDR1 region H In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) with a single amino acid deletion, addition, and / or substitution relative to SEQ ID NO: 3 (IMGT) or SEQ ID NO: 4 (Kabat). H a heavy chain variable domain (V) that may include a CDR1 region; H ) is included.

[0034] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) comprising SEQ ID NO:5 (IMGT) or SEQ ID NO:6 (Kabat). H ) a heavy chain variable domain (V) containing the CDR2 region H In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) as disclosed herein that has one or two amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:5 (IMGT) or SEQ ID NO:6 (Kabat). H a heavy chain variable domain (V) that may include a CDR2 region; H ) is included.

[0035] In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) comprising SEQ ID NO:7 (IMGT) or SEQ ID NO:8 (Kabat).H ) a heavy chain variable domain (V) containing the CDR3 region H In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) with a single amino acid deletion, addition, and / or substitution relative to SEQ ID NO:7 (IMGT) or SEQ ID NO:8 (Kabat). H a heavy chain variable domain (V) that may include a CDR3 region; H ) is included.

[0036] In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) comprising SEQ ID NO:3 (IMGT) or SEQ ID NO:4 (Kabat). H ) a heavy chain variable domain (V) comprising the CDR1 region, SEQ ID NO: 5 (IMGT) or SEQ ID NO: 6 (Kabat) H ) CDR2 region, and a heavy chain variable domain (V) comprising SEQ ID NO: 7 (IMGT) or SEQ ID NO: 8 (Kabat) H ) CDR3 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) comprising a single amino acid deletion, addition, and / or substitution relative to SEQ ID NO:3 (IMGT) or SEQ ID NO:4 (Kabat). H ) CDR1 region, a heavy chain variable domain (V) having one or two amino acid deletions, additions, and / or substitutions relative to SEQ ID NO: 5 (IMGT) or SEQ ID NO: 6 (Kabat) H ) a heavy chain variable domain (V) having a CDR2 region and one amino acid deletion, addition, and / or substitution relative to SEQ ID NO: 7 (IMGT) or SEQ ID NO: 8 (Kabat); H a heavy chain variable domain (V) that may include a CDR3 region; H ) is included.

[0037] In another embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (VL) CDR1 region, CDR2 region, and CDR3 region that selectively bind to an epitope disclosed herein. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (VL) that selectively binds to an epitope present within PD-L1 of SEQ ID NO: 1. L ) including the CDR1 region, the CDR2 region, and the CDR3 region.

[0038] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) comprising SEQ ID NO: 9. L In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) comprising a sequence having, e.g., at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amino acid identity to SEQ ID NO:9. L ) and that selectively binds to an epitope present within PD-L1, such as the PD-L1 of SEQ ID NO: 1. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V ) comprising a sequence having, for example, about 90% to about 100%, about 95% to about 100%, about 90% to about 99%, about 95% to about 99%, about 90% to about 97%, about 95% to about 97%, or about 97% to about 99% amino acid identity to SEQ ID NO: 9. L ) and selectively binds to an epitope present within PD-L1, such as the PD-L1 of SEQ ID NO:1.

[0039] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein include a light chain variable domain (V ) that may comprise a sequence having, for example, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:9.L ), which may comprise deletions, additions, and / or substitutions of up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, or up to 10 contiguous amino acids relative to SEQ ID NO: 9. L ) and selectively binds to an epitope present within PD-L1, such as the PD-L1 of SEQ ID NO:1. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (VL) that may comprise a sequence with deletions, additions, and / or substitutions of, e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9, 7-10, 8-9, 8-10, or 9-10 contiguous amino acids relative to SEQ ID NO:9. L ) and selectively binds to an epitope present within PD-L1, such as the PD-L1 of SEQ ID NO:1.

[0040] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein include a light chain variable domain (V ) that may comprise a sequence with, for example, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten non-contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:9. L ), which may comprise deletions, additions, and / or substitutions of up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, or up to 10 contiguous amino acids relative to SEQ ID NO: 9. L) and selectively binds to an epitope present within PD-L1, such as the PD-L1 of SEQ ID NO:1. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (VL) that may comprise a sequence with deletions, additions, and / or substitutions of, e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9, 7-10, 8-9, 8-10, or 9-10 non-contiguous amino acids relative to SEQ ID NO: 9. L ) and selectively binds to an epitope present within PD-L1, such as the PD-L1 of SEQ ID NO:1.

[0041] In another embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) that selectively binds to an epitope present in PD-L1. L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) that selectively binds to an epitope present within PD-L1 of SEQ ID NO: 1. L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) that selectively binds to an epitope present within a sequence that has, for example, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amino acid identity to PD-L1 of SEQ ID NO: 1. L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; LIn another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) that selectively binds to an epitope present within a sequence having, for example, about 90% to about 100%, about 95% to about 100%, about 90% to about 99%, about 95% to about 99%, about 90% to about 97%, about 95% to about 97%, or about 97% to about 99% amino acid identity to PD-L1 of SEQ ID NO: 1. L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) that selectively binds to an epitope present within a sequence that has, for example, at least one, at least two, at least three, or at least four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to the PD-L1 of SEQ ID NO: 1, or has up to one, up to two, up to three, or up to four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to the PD-L1 of SEQ ID NO: 1. L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) that selectively binds to an epitope present in a sequence that has, for example, about 1 to about 2, about 1 to about 3, about 1 to about 4, about 2 to about 3, about 2 to about 4, or about 3 to about 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions relative to PD-L1 of SEQ ID NO: 1. L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L ) is included.

[0042] In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) comprising SEQ ID NO: 10 (IMGT) or SEQ ID NO: 11 (Kabat). L ) a light chain variable domain (V) containing the CDR1 region LIn aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) with a single amino acid deletion, addition, and / or substitution relative to SEQ ID NO: 10 (IMGT) or SEQ ID NO: 11 (Kabat). L a light chain variable domain (V) that may include a CDR3 region; L ) is included.

[0043] In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) comprising SEQ ID NO: 12 (IMGT) or SEQ ID NO: 13 (Kabat). L ) a light chain variable domain (V) containing the CDR2 region L In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) with one amino acid deletion, addition, and / or substitution relative to SEQ ID NO: 13 (Kabat). H a light chain variable domain (V) that may include a CDR3 region; H ) is included.

[0044] In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) comprising SEQ ID NO: 14 (IMGT) or SEQ ID NO: 15 (Kabat). L ) a light chain variable domain (V) containing the CDR3 region L In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) with a single amino acid deletion, addition, and / or substitution relative to SEQ ID NO: 14 (IMGT) or SEQ ID NO: 15 (Kabat). H a light chain variable domain (V) that may include a CDR3 region; H ) is included.

[0045] In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) comprising SEQ ID NO: 10 (IMGT) or SEQ ID NO: 11 (Kabat). L ) a light chain variable domain (V) comprising the CDR1 region, SEQ ID NO: 12 (IMGT) or SEQ ID NO: 13 (Kabat) L) CDR2 region, and a light chain variable domain (V) comprising SEQ ID NO: 14 (IMGT) or SEQ ID NO: 15 (Kabat) L ) CDR3 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V) comprising a single amino acid deletion, addition, and / or substitution relative to SEQ ID NO: 10 (IMGT) or SEQ ID NO: 11 (Kabat). H ) CDR3 region, a light chain variable domain (V) with one amino acid deletion, addition, and / or substitution relative to SEQ ID NO: 13 (Kabat) H ) a light chain variable domain (V) having a CDR3 region and one amino acid deletion, addition, and / or substitution relative to SEQ ID NO: 14 (IMGT) or SEQ ID NO: 15 (Kabat); H a light chain variable domain (V) that may include a CDR3 region; H ) is included.

[0046] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) comprising SEQ ID NO:2. H ) and a light chain variable domain (V L In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V), which may comprise a sequence having, for example, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amino acid identity to SEQ ID NO:2. H ), and a light chain variable domain (V) that can include a sequence having, for example, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amino acid identity to SEQ ID NO:9. LIn yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) that may comprise a sequence with, for example, about 90% to about 100%, about 95% to about 100%, about 90% to about 99%, about 95% to about 99%, about 90% to about 97%, about 95% to about 97%, or about 97% to about 99% amino acid identity to SEQ ID NO:2. H ), and a light chain variable domain (V) that may include a sequence having, for example, about 90% to about 100%, about 95% to about 100%, about 90% to about 99%, about 95% to about 99%, about 90% to about 97%, about 95% to about 97%, or about 97% to about 99% amino acid identity to SEQ ID NO: 9. L ) is included.

[0047] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein include a heavy chain variable domain (V ) that may comprise, for example, a sequence with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:2, or up to one, up to two, up to three, up to four, up to five, up to six, up to seven, up to eight, up to nine, up to ten, up to eleven, or up to twelve contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:2. H ), and a light chain variable domain (V) that can include a sequence having, for example, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:9, or a sequence having up to one, up to two, up to three, up to four, up to five, up to six, up to seven, up to eight, up to nine, or up to ten contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:9. LIn another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein include any of the following sequences with respect to SEQ ID NO: 2, for example, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-11, 2-12, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 4-5, 4-6, 4-7, 4-8, 4- a heavy chain variable domain (V) that can comprise a sequence having deletions, additions, and / or substitutions of 9, 4-10, 4-11, 4-12, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 7-8, 7-9, 7-10, 7-11, 7-12, 8-9, 8-10, 8-11, 8-12, 9-10, 9-11, 9-12, 10-11, 10-12, or 11-12 contiguous amino acids; H ), as well as a light chain variable domain (V), which may comprise a sequence having, for example, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 7 to 8, 7 to 9, 7 to 10, 8 to 9, 8 to 10, or 9 to 10 contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO: 9. L ) is included.

[0048] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise a heavy chain variable domain (V ) that may comprise a sequence that has, for example, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve non-contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:2, or a sequence that has up to one, up to two, up to three, up to four, up to five, up to six, up to seven, up to eight, up to nine, up to ten, up to eleven, or up to twelve non-contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:2. H ), and a light chain variable domain (V), which may comprise a sequence having, for example, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten non-contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:9, or a sequence having up to one, up to two, up to three, up to four, up to five, up to six, up to seven, up to eight, up to nine, or up to ten non-contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:9. L In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein include any of the following sequences with respect to SEQ ID NO: 2, for example, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-11, 2-12, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-14, 4-15, 4-16, 4-17, 4-18, 4-19, 4-20, 4-21, 4-22, 4-23, 4-24, 4-25, 4-26, 4-27, 4-28, 4-29, 4-30, 4-31, 4-32, 4-33, 4-34, 4-35, 4-36, 4-37, 4-38, 4-39, 4-31, 4-32 ...3, 4-34, a heavy chain variable domain (V) that can comprise a sequence having deletions, additions, and / or substitutions of 10, 4 to 11, 4 to 12, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6 to 12, 7 to 8, 7 to 9, 7 to 10, 7 to 11, 7 to 12, 8 to 9, 8 to 10, 8 to 11, 8 to 12, 9 to 10, 9 to 11, 9 to 12, 10 to 11, 10 to 12, or 11 to 12 non-contiguous amino acids; H), and a light chain variable domain (V) that can include a sequence having, for example, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 7 to 8, 7 to 9, 7 to 10, 8 to 9, 8 to 10, or 9 to 10 non-contiguous amino acid deletions, additions, and / or substitutions relative to SEQ ID NO: 9. L ) is included.

[0049] In another embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; H ), and the light chain variable domain (V L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L ) and selectively bind to an epitope present in PD-L1. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; H ), and the light chain variable domain (V L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L ) and selectively binds to an epitope present within PD-L1 of SEQ ID NO: 1. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; H ), and the light chain variable domain (V L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L), and may selectively bind to an epitope present within a sequence having, for example, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amino acid identity to PD-L1 of SEQ ID NO: 1. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; H ), and the light chain variable domain (V L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L ), and may selectively bind to an epitope present within a sequence having, for example, about 90% to about 100%, about 95% to about 100%, about 90% to about 99%, about 95% to about 99%, about 90% to about 97%, about 95% to about 97%, or about 97% to about 99% amino acid identity to PD-L1 of SEQ ID NO: 1. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; H ), and a deletion, addition, and / or substitution of, for example, at least one, at least two, at least three, or at least four contiguous and / or non-contiguous amino acids compared to the PD-L1 of SEQ ID NO: 1; or a light chain variable domain (V L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L ) and may selectively bind to an epitope present within a sequence that has up to one, up to two, up to three, or up to four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to PD-L1 of SEQ ID NO: 1. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H ) a heavy chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; H), and a light chain variable domain (V) capable of selectively binding to an epitope present in a sequence having, for example, about 1 to about 2, about 1 to about 3, about 1 to about 4, about 2 to about 3, about 2 to about 4, or about 3 to about 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to PD-L1 of SEQ ID NO: 1. L ) a light chain variable domain (V) comprising CDR1, CDR2, and CDR3 regions; L ) is included.

[0050] In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) CDR1 region comprising SEQ ID NO:3 (IMGT) or SEQ ID NO:4 (Kabat), a heavy chain variable domain (VH) CDR2 region comprising SEQ ID NO:5 (IMGT) or SEQ ID NO:6 (Kabat), and a heavy chain variable domain (VH) CDR3 region comprising SEQ ID NO:7 (IMGT) or SEQ ID NO:8 (Kabat). H ) a heavy chain variable domain (VH) comprising the CDR3 region, and a light chain variable domain (V) comprising SEQ ID NO: 10 (IMGT) or SEQ ID NO: 11 (Kabat) L ) a light chain variable domain (V) comprising the CDR1 region, SEQ ID NO: 12 (IMGT) or SEQ ID NO: 13 (Kabat) L ) a light chain variable domain (V) comprising the CDR2 region, SEQ ID NO: 14 (IMGT) or SEQ ID NO: 15 (Kabat) L ) a light chain variable domain (V) containing the CDR3 region L In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V) with a single amino acid deletion, addition, and / or substitution relative to SEQ ID NO: 3 (IMGT) or SEQ ID NO: 4 (Kabat). H ) a heavy chain variable domain (V) having one or two amino acid deletions, additions, and / or substitutions relative to the CDR1 region, SEQ ID NO: 5 (IMGT) or SEQ ID NO: 6 (Kabat); H ) a heavy chain variable domain (V) having one amino acid deletion, addition, and / or substitution relative to the CDR2 region, SEQ ID NO: 7 (IMGT) or SEQ ID NO: 8 (Kabat); H a heavy chain variable domain (V) that may include a CDR3 region;H ), and a light chain variable domain (V) having one amino acid deletion, addition, and / or substitution relative to SEQ ID NO: 10 (IMGT) or SEQ ID NO: 11 (Kabat). H ) a light chain variable domain (V) with one amino acid deletion, addition, and / or substitution relative to the CDR3 region, SEQ ID NO: 13 (Kabat); H ) a light chain variable domain (V) having one amino acid deletion, addition, and / or substitution relative to the CDR3 region, SEQ ID NO: 14 (IMGT) or SEQ ID NO: 15 (Kabat); H a light chain variable domain (V) that may include a CDR3 region; H ) is included.

[0051] In another embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain comprising a light chain variable region and a light chain constant region disclosed herein. In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a kappa light chain comprising a light chain variable region and a light chain constant region disclosed herein. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a kappa light chain comprising a light chain variable region disclosed herein and a light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a kappa light chain of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25.

[0052] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a lambda light chain comprising a light chain variable region and a light chain constant region disclosed herein. In this aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a lambda light chain comprising a light chain variable region disclosed herein and a light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31. In this aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a lambda light chain comprising a light chain variable region disclosed herein and a light chain constant region of SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37.

[0053] In one embodiment, the anti-PD-L1 antibodies disclosed herein contain a heavy chain constant domain (C) that does not contain Fc effector functions. H In another embodiment, the anti-PD-L1 antibodies disclosed herein comprise a heavy chain constant domain (C) that does not contain a cytotoxicity component. H In aspects of this embodiment, the anti-PD-L1 antibodies disclosed herein comprise a heavy chain constant domain (C) that does not contain antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and / or antibody-dependent cellular phagocytosis (ADCP). H In an aspect of this embodiment, the heavy chain constant domain (C) does not contain Fc effector functions. H ) is an IgG immunoglobulin. In another aspect of this embodiment, the heavy chain constant domain (C) without Fc effector functions is an IgG immunoglobulin. H ) is an IgG1 immunoglobulin, an IgG2 immunoglobulin, an IgG3 immunoglobulin, or an IgG4 immunoglobulin.

[0054] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a cytotoxic-free IgG1 immunoglobulin heavy chain constant domain (C H ), which comprises a deletion, addition, or substitution of 1, 2, 3, 4, or 5 amino acids located within the lower hinge region and / or the N-terminal half of the CH2 domain. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H ), and may contain deletions, additions, or substitutions of 1, 2, 3, 4, or 5 amino acids located within the lower hinge region and / or the N-terminal half of the CH2 domain, which reduce or eliminate cytotoxicity. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H), and may include an amino acid deletion, addition, or substitution at position L239, L240, K327, or any combination thereof, which reduces or eliminates cytotoxicity. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, which may include an A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y amino acid substitution at position L239, an A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y amino acid substitution at position L240, an A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y amino acid substitution at position K327, or any combination thereof, which reduces or eliminates cytotoxicity. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may include an A, C, W, or Y amino acid substitution at position L239, an A, C, W, or Y amino acid substitution at position L240, and an A, D, G, H, M, N, P, S, or T at K327, or any combination thereof. H ), which reduces or eliminates cytotoxicity. In a further aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 that contains an amino acid substitution of A at position L239 (L239A), an amino acid substitution of A at position L240 (L240A), an amino acid substitution of A at position K327 (K327A), or any combination thereof. H ), which have reduced or eliminated cytotoxicity. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (CH) that has no or reduced cytotoxicity and is set forth in SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44.

[0055] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a cytotoxic-free IgG2 immunoglobulin heavy chain constant domain (C H ), which may include deletions, additions, or substitutions of 1, 2, 3, 4, or 5 amino acids located in the lower hinge region and / or the N-terminal half of the CH2 domain. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H ), and may contain deletions, additions, or substitutions of 1, 2, 3, 4, or 5 amino acids located within the lower hinge region and / or the N-terminal half of the CH2 domain, which reduce or eliminate cytotoxicity. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H ), and may include amino acid deletions, additions, or substitutions at positions V236, A237, K323, or any combination thereof, which reduce or eliminate cytotoxicity. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include an amino acid substitution of A, C, D, E, F, G, H, K, N, P, Q, R, S, T, W, vY at position V236, an amino acid substitution of C, D, E, F, H, I, K, M, N, L, P, Q, R, V, Y, or W at position A237, an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y at position K323, or any combination thereof. H), which reduces or eliminates cytotoxicity. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include an amino acid substitution of A, C, F, T, or Y at position V236, an amino acid substitution of C, E, I, K, M, L, P, Q, R, or V at position A237, an amino acid substitution of A, D, G, H, M, N, P, S, or T at position K323, or any combination thereof. H ), which reduces or eliminates cytotoxicity. In a further aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H ), and may include an amino acid substitution at position V236 with an A (V236A), an amino acid substitution at position A237 with an L (A237L), an amino acid substitution at position K323 with an A (K323A), or any combination thereof, which reduces or eliminates cytotoxicity. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H ), and may include an amino acid substitution of A at position V236 (V236A), an amino acid substitution of A at position K323 (K323A), or any combination thereof, which reduces or eliminates cytotoxicity.

[0056] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a cytotoxic-free IgG4 immunoglobulin heavy chain constant domain (C H ), which may include deletions, additions, or substitutions of 1, 2, 3, 4, or 5 amino acids located in the lower hinge region and / or the N-terminal half of the CH2 domain. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53.H ), and may contain deletions, additions, or substitutions of 1, 2, 3, 4, or 5 amino acids located within the lower hinge region and / or the N-terminal half of the CH2 domain, which reduce or eliminate cytotoxicity. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H ), and may include amino acid deletions, additions, or substitutions at positions F / V236, L / A / E237, K324, or any combination thereof, which reduce or eliminate cytotoxicity. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, and may include an amino acid substitution of A, C, D, E, F, G, H, K, N, P, Q, R, S, T, W, or Y at position V236, an amino acid substitution of A, C, D, E, G, H, I, K, N, P, Q, R, S, T, or V at position F236, an amino acid substitution of A, C, D, E, G, H, I, K, N, P, Q, R, S, T, or V at position L237, an amino acid substitution of A, C, D, E, G, H ... or Y amino acid substitution at position A237; A, C, F, G, H, I, L, M, N, P, R, S, T, V, W, or Y amino acid substitution at position E237; A, C, F, G, H, I, L, M, N, P, R, S, T, V, W, or Y amino acid substitution at position K324; or any combination thereof, which reduce or eliminate cytotoxicity. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H), and may include an amino acid substitution of A, C, F, T, or Y at position V236, an amino acid substitution of C, I, or V at position F236, an amino acid substitution of A, C, W, or Y at position L237, an amino acid substitution of C, E, I, K, M, L, P, Q, R, or V at position A237, an amino acid substitution of A, H, N, P, R, S, or T at position E237, an amino acid substitution of A, D, G, H, M, N, P, S, or T at position K324, or any combination thereof, which reduce or eliminate cytotoxicity. In a further aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, and may include an amino acid substitution of A at position V236 (V236A), an amino acid substitution of I at position F236 (F236I), an amino acid substitution of A at position L237 (L237A), an amino acid substitution of L at position A237 (A237L), an amino acid substitution of A at position E237 (E237A), an amino acid substitution of A at position K324 (K324A), or any combination thereof, which reduces or eliminates cytotoxicity.

[0057] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain constant domain (C ) that comprises an amino acid sequence variant that enhances the clearance of the modified anti-PD-L1 antibody more rapidly than an anti-PD-L1 antibody that does not contain the same amino acid sequence variant (unmodified anti-PD-L1 reference antibody). H). For all embodiments, faster clearance refers to either or both of: (i) an increased amount of clearance of the modified anti-PD-L1 antibodies disclosed herein compared to the unmodified anti-PD-L1 reference antibody over the same time period; or (ii) substantially all of the clearance of the modified anti-PD-L1 antibodies disclosed herein over a shortened time period compared to the unmodified anti-PD-L1 reference antibody. Preferably, over a period of time, the clearance rate (amount of antibody removed in a given period of time) is increased by at least 25%, at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500% compared to the unmodified anti-PD-L1 reference antibody. More preferably, the predetermined period of time begins at or shortly after administration of the antibody, and may be 30, 36, or 42 hours in duration. The modified anti-PD-L1 antibodies disclosed herein may be substantially completely cleared in a time period that is reduced compared to the time required for substantially all of the unmodified anti-PD-L1 reference antibody to be cleared, preferably by at least 25%, at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500% compared to the unmodified anti-PD-L1 reference antibody. In aspects of this embodiment, the heavy chain constant domain (CH) comprising an amino acid sequence variant that promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same amino acid sequence variant is an IgG immunoglobulin. In another aspect of this embodiment, the IgG immunoglobulin heavy chain constant domain (CH) comprises an amino acid sequence variant that promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not comprise the same amino acid sequence variant, over the same time period, where ... IgG1 immunoglobulin, an IgG2 immunoglobulin, an IgG3 immunoglobulin, or an IgG4 immunoglobulin.

[0058] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (CH) that comprises amino acid sequence variants within the CH2 and / or CH3 domain that promote faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not comprise the same amino acid variants located within the CH2 and / or CH3 domain over the same period of time. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (CH) that comprises deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domain. H ), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions or substitutions located within the CH2 and / or CH3 domains over the same period of time.

[0059] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domains. H), which enhances the clearance of the modified anti-PD-L1 antibody more rapidly than anti-PD-L1 antibodies that do not contain the same amino acid deletions, additions, or substitutions located within the CH2 and / or CH3 domains. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein contain an IgG1 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may contain amino acid deletions, additions, or substitutions at positions H315, H440, or both, which enhances the clearance of the modified anti-PD-L1 antibody more rapidly than anti-PD-L1 antibodies that do not contain the same amino acid deletions, additions, or substitutions at positions H315 and H440. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may include an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H315, an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H440, or any combination thereof. H ), which enhances the clearance of the modified anti-PD-L1 antibody more rapidly than an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H315 and H440. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, which may include an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H315, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H440, or any combination thereof, which enhances the clearance of the modified anti-PD-L1 antibody more rapidly than an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H315 and H440. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 that comprises an amino acid substitution of A at position H315 (H315A), an amino acid substitution of Q at position H440 (H440Q), or any combination thereof.H ), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same H315 and H440 amino acid substitutions over the same period of time.

[0060] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 that comprises the H315A variant, the H440Q variant, or any combination thereof, which promotes clearance of the modified anti-PD-L1 antibody by, for example, at least 25%, at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500% faster, compared to an anti-PD-L1 antibody that does not comprise the H315A or H440Q variant, over the same time period. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, comprising the H315A variant, the H440Q variant, or any combination thereof. H ), which promotes clearance of the modified anti-PD-L1 antibody by, for example, up to 10%, up to 25%, up to 50%, up to 75%, up to 100%, up to 125%, up to 150%, up to 175%, up to 200%, up to 250%, up to 300%, up to 350%, up to 400%, up to 450%, up to 500% faster, compared to an anti-PD-L1 antibody that does not contain the H315A and H440Q variants, over the same time period. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 comprising an H315A variant, an H440Q variant, or any combination thereof. H), which may exhibit, for example, about 25% to about 50%, about 25% to about 100%, about 25% to about 150%, about 25% to about 200%, about 25% to about 250%, about 25% to about 300%, about 25% to about 350%, about 25% to about 400%, or about 35% to about 400%, or about 35% to about 500%, or about 35% to about 500%, or about 35% to about 600%, or about 35% to about 650%, or about 35% to about 700%, or about 35% to about 750%, or about 35% to about 800%, or about 35% to about 850%, or about 35% to about 900%, or about 35% to about 950%, or about 35% to about 1000%, or about 35% to about 1000%, or about 35% to about 15 ... Approximately 25% to approximately 450%, approximately 25% to approximately 500%, approximately 50% to approximately 100%, approximately 50% to approximately 150%, approximately 50% to approximately 200%, approximately 50% to approximately 250%, approximately 50% to approximately 300%, approximately 50% to approximately 350%, approximately 50% to approximately 400%, approximately 50% to approximately 450%, approximately 50% to approximately 500%, approximately 100% to approximately 150%, approximately 100% to approximately 200%, approximately 100% to approximately 25 0%, approx. 100% to approx. 300%, approx. 100% to approx. 350%, approx. 100% to approx. 400%, approx. 100% to approx. 450%, approx. 100% to approx. 500%, approx. 150% to approx. 200%, approx. 150% to approx. 250%, approx. 150% to approx. 300%, approx. 150% to approx. 350%, approx. 150% to approx. 400%, approx. 150% to approx. 450%, approx. 150% to approx. 500%, approx. 200% to The clearance of the modified anti-PD-L1 antibody is accelerated by about 250%, about 200% to about 300%, about 200% to about 350%, about 200% to about 400%, about 200% to about 450%, about 200% to about 500%, about 250% to about 300%, about 250% to about 350%, about 250% to about 400%, about 250% to about 450%, or about 250% to about 500% faster.

[0061] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, comprising the H315A variant, the H440Q variant, or any combination thereof. H), which enhances clearance of the modified anti-PD-L1 antibody by, for example, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 comprising an H315A variant, an H440Q variant, or any combination thereof, which enhances clearance of the modified anti-PD-L1 antibody by, for example, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 comprising an H315A variant, an H440Q variant, or any combination thereof. H ), which enhance clearance of the modified anti-PD-L1 antibody for, for example, up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, or up to 7 days. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, comprising the H315A variant, the H440Q variant, or any combination thereof. H ), which may enhance clearance of the modified anti-PD-L1 antibody for, for example, about 1 to about 2 days, about 1 to about 3 days, about 1 to about 4 days, about 1 to about 5 days, about 1 to about 6 days, about 1 to about 7 days, about 2 to about 3 days, about 2 to about 4 days, about 2 to about 5 days, about 2 to about 6 days, about 2 to about 7 days, about 3 to about 4 days, about 3 to about 5 days, about 3 to about 6 days, about 3 to about 7 days, about 4 to about 5 days, about 4 to about 6 days, about 4 to about 7 days, about 5 to about 6 days, about 5 to about 7 days, or about 6 to about 7 days.

[0062] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) that comprises an amino acid sequence variant within the CH2 and / or CH3 domain. H), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same amino acid variant located within the CH2 and / or CH3 domain over the same period of time. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C ) that contains one, two, three, four, or five amino acid deletions, additions, or substitutions located within the CH2 and / or CH3 domain. H ), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions or substitutions located within the CH2 and / or CH3 domains over the same period of time.

[0063] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domains. H ), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same amino acid deletion, addition, or substitution located within the CH2 and / or CH3 domains over the same period of time. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may contain an amino acid deletion, addition, or substitution at position H315, H440, or both. H), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same H315 and H440 amino acid deletions, additions, or substitutions over the same time period. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H315, an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H440, or any combination thereof. H ), which promotes faster clearance of the modified anti-PD-L1 antibody over the same time period than an anti-PD-L1 antibody that does not comprise the same amino acid substitutions at H315 and H440. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include a C, D, E, K, Q, R, S, T, or W amino acid substitution at position H315, a C, D, E, K, Q, R, S, T, or W amino acid substitution at position H440, or any combination thereof, which promotes faster clearance of the modified anti-PD-L1 antibody over the same time period than an anti-PD-L1 antibody that does not comprise the same amino acid substitutions at H315 and H440. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include an amino acid substitution of A at position H315 (H315A), an amino acid substitution of Q at position H440 (H440Q), or any combination thereof. H ), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same H315 and H440 amino acid substitutions over the same period of time.

[0064] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H315A variant, the H440Q variant, or any combination thereof. H ), which promotes clearance of the modified anti-PD-L1 antibody by, for example, at least 25%, at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500% faster, compared to an anti-PD-L1 antibody that does not contain the H315A and H440Q variants over the same time period. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include the H315A variant, the H440Q variant, or any combination thereof. H), which promotes clearance of the modified anti-PD-L1 antibody by, for example, up to 25%, up to 50%, up to 75%, up to 100%, up to 125%, up to 150%, up to 175%, up to 200%, up to 250%, up to 300%, up to 350%, up to 400%, up to 450%, or up to 500% faster, compared to an anti-PD-L1 antibody that does not contain the H315A and H440Q variants, over the same time period. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include an H315A variant, an H440Q variant, or any combination thereof, which promotes clearance of the modified anti-PD-L1 antibody by, for example, up to 25%, up to 50%, up to 75%, up to 100%, up to 125%, up to 150%, up to 175%, up to 200%, up to 250%, up to 300%, up to 350%, up to 400%, up to 450%, or up to 500% faster, compared to an anti-PD-L1 antibody that does not contain the H315A and H440Q variants, over the same time period. -L1 antibody, for example, about 25% to about 50%, about 25% to about 100%, about 25% to about 150%, about 25% to about 200%, about 25% to about 250%, about 25% to about 300%, about 25% to about 350%, about 25% to about 400%, about 25% to about 450%, about 25% to about 500%, about 50% to about 100%, about 50% to about 150%, about 50% to about 200%, about 50% to about 250%, about 50% to about 300%, about 50% to about 350% %, about 50% to about 400%, about 50% to about 450%, about 50% to about 500%, about 100% to about 150%, about 100% to about 200%, about 100% to about 250%, about 100% to about 300%, about 100% to about 350%, about 100% to about 400%, about 100% to about 450%, about 100% to about 500%, about 150% to about 200%, about 150% to about 250%, about 150% to about 300%, about 150% to about 350%, about 150% to about 4 00%, about 150% to about 450%, about 150% to about 500%, about 200% to about 250%, about 200% to about 300%, about 200% to about 350%, about 200% to about 400%, about 200% to about 450%, about 200% to about 500%, about 250% to about 300%, about 250% to about 350%, about 250% to about 400%, about 250% to about 450%, or about 250% to about 500% faster clearance of the modified anti-PD-L1 antibody.

[0065] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H315A variant, the H440Q variant, or any combination thereof. H ), which enhances clearance of the modified anti-PD-L1 antibody for, for example, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H315A variant, the H440Q variant, or any combination thereof. H ), which enhance clearance of the modified anti-PD-L1 antibody for, for example, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include the H315A variant, the H440Q variant, or any combination thereof. H ), which enhance clearance of the modified anti-PD-L1 antibody for, for example, up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, or up to 7 days. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H315A variant, the H440Q variant, or any combination thereof. H), which may facilitate clearance of the modified anti-PD-L1 antibody for, for example, about 1 to about 2 days, about 1 to about 3 days, about 1 to about 4 days, about 1 to about 5 days, about 1 to about 6 days, about 1 to about 7 days, about 2 to about 3 days, about 2 to about 4 days, about 2 to about 5 days, about 2 to about 6 days, about 2 to about 7 days, about 3 to about 4 days, about 3 to about 5 days, about 3 to about 6 days, about 3 to about 7 days, about 4 to about 5 days, about 4 to about 6 days, about 4 to about 7 days, about 5 to about 6 days, about 5 to about 7 days, or about 6 to about 7 days.

[0066] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) that comprises an amino acid sequence variant within the CH2 and / or CH3 domain. H ), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same amino acid variant located within the CH2 and / or CH3 domain over the same period of time. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C ) that contains one, two, three, four, or five amino acid deletions, additions, or substitutions located within the CH2 and / or CH3 domain. H ), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions or substitutions located within the CH2 and / or CH3 domains over the same period of time.

[0067] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C ) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domains. H), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same amino acid deletion, addition, or substitution located within the CH2 and / or CH3 domains over the same period of time. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include an amino acid deletion, addition, or substitution at position H312, H437, or both. H ), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same H312 and H437 amino acid deletions, additions, or substitutions over the same period of time. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may contain an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H ), and may comprise an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H312, an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H437, or any combination thereof, which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not comprise the same amino acid substitutions at H312 and H437 over the same period of time. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H), and may comprise an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H312, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H437, or any combination thereof, which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not comprise the same amino acid substitutions at H312 and H437 over the same period of time. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may comprise an amino acid substitution of A at position H312 (H312A), an amino acid substitution of Q at position H437 (H437Q), or any combination thereof. H ), which promotes faster clearance of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same H312 and H437 amino acid substitutions over the same period of time.

[0068] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which may include the H312A variant, the H437Q variant, or any combination thereof. H), which promotes clearance of the modified anti-PD-L1 antibody by, for example, at least 25%, at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500% faster, compared to an anti-PD-L1 antibody that does not contain the H312A and H437Q variants, over the same time period. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which promotes clearance of the modified anti-PD-L1 antibody by, for example, up to 25%, up to 50%, up to 75%, up to 100%, up to 125%, up to 150%, up to 175%, up to 200%, up to 250%, up to 300%, up to 350%, up to 400%, up to 450%, or up to 500% faster, compared to an anti-PD-L1 antibody that does not contain the H312A and H437Q variants, over the same time period. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H), which may include, for example, about 25% to about 50%, about 25% to about 100%, about 25% to about 150%, about 25% to about 200%, about 25% to about 250%, about 25% to about 300%, about 25% to about 350%, or about 25% to about 400%, compared to an anti-PD-L1 antibody that does not contain the H312A and H437Q variants, over the same time period. , about 25% to about 450%, about 25% to about 500%, about 50% to about 100%, about 50% to about 150%, about 50% to about 200%, about 50% to about 250%, about 50% to about 300%, about 50% to about 350%, about 50% to about 400%, about 50% to about 450%, about 50% to about 500%, about 100% to about 150%, about 100% to about 200%, about 100% to about 2 50%, approximately 100% to approximately 300%, approximately 100% to approximately 350%, approximately 100% to approximately 400%, approximately 100% to approximately 450%, approximately 100% to approximately 500%, approximately 150% to approximately 200%, approximately 150% to approximately 250%, approximately 150% to approximately 300%, approximately 150% to approximately 350%, approximately 150% to approximately 400%, approximately 150% to approximately 450%, approximately 150% to approximately 500%, approximately 200% to The clearance of the modified anti-PD-L1 antibody is accelerated by about 250%, about 200% to about 300%, about 200% to about 350%, about 200% to about 400%, about 200% to about 450%, about 200% to about 500%, about 250% to about 300%, about 250% to about 350%, about 250% to about 400%, about 250% to about 450%, or about 250% to about 500% faster.

[0069] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which may include the H312A variant, the H437Q variant, or any combination thereof. H), which enhances clearance of the modified anti-PD-L1 antibody for, for example, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which enhance clearance of the modified anti-PD-L1 antibody for, for example, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which facilitate clearance of the modified anti-PD-L1 antibody for, for example, up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, or up to 7 days. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which may facilitate clearance of the modified anti-PD-L1 antibody for, for example, about 1 to about 2 days, about 1 to about 3 days, about 1 to about 4 days, about 1 to about 5 days, about 1 to about 6 days, about 1 to about 7 days, about 2 to about 3 days, about 2 to about 4 days, about 2 to about 5 days, about 2 to about 6 days, about 2 to about 7 days, about 3 to about 4 days, about 3 to about 5 days, about 3 to about 6 days, about 3 to about 7 days, about 4 to about 5 days, about 4 to about 6 days, about 4 to about 7 days, about 5 to about 6 days, about 5 to about 7 days, or about 6 to about 7 days.

[0070] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain constant domain (C) that comprises an amino acid sequence variant that shortens the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid sequence variant. H ). In an aspect of this embodiment, the heavy chain constant domain (CH) comprising an amino acid sequence variant that reduces the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not comprise the same amino acid sequence variant is an IgG immunoglobulin. In another aspect of this embodiment, the IgG immunoglobulin heavy chain constant domain (CH) comprising an amino acid sequence variant that reduces the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not comprise the same amino acid sequence variant is an IgG immunoglobulin. H ) is an IgG1 immunoglobulin, an IgG2 immunoglobulin, an IgG3 immunoglobulin, or an IgG4 immunoglobulin.

[0071] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) that comprises an amino acid sequence variant within the CH2 and / or CH3 domain. H ), which shortens the half-life of the modified anti-PD-L1 antibody relative to anti-PD-L1 antibodies that do not contain the same amino acid variants located within the CH2 and / or CH3 domains. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) that contains one, two, three, four, or five amino acid deletions, additions, or substitutions located within the CH2 and / or CH3 domains. H ) that decrease the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions or substitutions located within the CH2 and / or CH3 domains.

[0072] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domains. H ), which shortens the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid deletion, addition, or substitution located within the CH2 and / or CH3 domain. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may contain an amino acid deletion, addition, or substitution at position H315, H440, or both. H ), which shortens the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions, or substitutions at H315 and H440. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may include an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H315, an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H440, or any combination thereof. H), which reduces the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H315 and H440. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may include a C, D, E, K, Q, R, S, T, or W amino acid substitution at position H315, a C, D, E, K, Q, R, S, T, or W amino acid substitution at position H440, or any combination thereof, which reduces the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H315 and H440. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 that comprises an amino acid substitution of A at position H315 (H315A), an amino acid substitution of Q at position H440 (H440Q), or any combination thereof. H ), which result in a shorter half-life of the modified anti-PD-L1 antibody than an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H315 and H440.

[0073] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, comprising the H315A variant, the H440Q variant, or any combination thereof. H), which reduces the half-life of the modified anti-PD-L1 antibody by, for example, at least 25%, at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500%, relative to an anti-PD-L1 antibody that does not contain the H315A variant and H440Q variant. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 comprising an H315A variant, an H440Q variant, or any combination thereof. H ), which reduces the half-life of the modified anti-PD-L1 antibody by, for example, up to 25%, up to 50%, up to 75%, up to 100%, up to 125%, up to 150%, up to 175%, up to 200%, up to 250%, up to 300%, up to 350%, up to 400%, up to 450%, or up to 500%, compared to an anti-PD-L1 antibody that does not contain the H315A variant and H440Q variant. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 comprising an H315A variant, an H440Q variant, or any combination thereof. H), which may exhibit, for example, about 25% to about 50%, about 25% to about 100%, about 25% to about 150%, about 25% to about 200%, about 25% to about 250%, about 25% to about 300%, about 25% to about 350%, about 25% to about 400%, about 25% to about 450%, approximately 25% to approximately 500%, approximately 50% to approximately 100%, approximately 50% to approximately 150%, approximately 50% to approximately 200%, approximately 50% to approximately 250%, approximately 50% to approximately 300%, approximately 50% to approximately 350%, approximately 50% to approximately 400%, approximately 50% to approximately 450%, approximately 50% to approximately 500%, approximately 100% to approximately 150%, approximately 100% to approximately 200%, approximately 100% to approximately 250% , about 100% to about 300%, about 100% to about 350%, about 100% to about 400%, about 100% to about 450%, about 100% to about 500%, about 150% to about 200%, about 150% to about 250%, about 150% to about 300%, about 150% to about 350%, about 150% to about 400%, about 150% to about 450%, about 150% to about 500%, about 200% or about 250% to about 250%, about 200% to about 300%, about 200% to about 350%, about 200% to about 400%, about 200% to about 450%, about 200% to about 500%, about 250% to about 300%, about 250% to about 350%, about 250% to about 400%, about 250% to about 450%, or about 250% to about 500%.

[0074] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H), for example, an H315A variant, an H440Q variant, or any combination thereof, with a half-life of about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, for example, an H315A variant, an H440Q variant, or any combination thereof, with a half-life of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least ... H ), for example, including a H315A variant, a H440Q variant, or any combination thereof, which have a half-life of up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, or up to 7 days. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H ), for example, an H315A variant, an H440Q variant, or any combination thereof, having a half-life of about 1 to about 2 days, about 1 to about 3 days, about 1 to about 4 days, about 1 to about 5 days, about 1 to about 6 days, about 1 to about 7 days, about 2 to about 3 days, about 2 to about 4 days, about 2 to about 5 days, about 2 to about 6 days, about 2 to about 7 days, about 3 to about 4 days, about 3 to about 5 days, about 3 to about 6 days, about 3 to about 7 days, about 4 to about 5 days, about 4 to about 6 days, about 4 to about 7 days, about 5 to about 6 days, about 5 to about 7 days, or about 6 to about 7 days.

[0075] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H), for example, the H315A variant, the H440Q variant, or any combination thereof, which have a half-life of about 30 hours, about 32 hours, about 34 hours, about 36 hours, about 38 hours, about 40 hours, about 42 hours, about 44 hours, about 46 hours, or about 48 hours. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H ), for example, including the H315A variant, the H440Q variant, or any combination thereof, which have a half-life of at least 30 hours, at least 32 hours, at least 34 hours, at least 36 hours, at least 38 hours, at least 40 hours, at least 42 hours, at least 44 hours, at least 46 hours, or at least 48 hours. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H ), for example, including a H315A variant, a H440Q variant, or any combination thereof, which have a half-life of up to 30 hours, up to 32 hours, up to 34 hours, up to 36 hours, up to 38 hours, up to 40 hours, up to 42 hours, up to 44 hours, up to 46 hours, or up to 48 hours. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H ), for example, an H315A variant, an H440Q variant, or any combination thereof, having a half-life of about 30 hours to about 36 hours, about 30 hours to about 42 hours, about 30 hours to about 48 hours, about 32 hours to about 36 hours, about 32 hours to about 42 hours, about 32 hours to about 48 hours, about 34 hours to about 36 hours, about 34 hours to about 42 hours, about 34 hours to about 48 hours, about 36 hours to about 42 hours, about 36 hours to about 48 hours, or about 42 hours to about 48 hours.

[0076] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) that comprises an amino acid sequence variant within the CH2 and / or CH3 domain. H ), which shorten the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid variant located within the CH2 and / or CH3 domain. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may contain an IgG2 immunoglobulin heavy chain constant domain (C) that may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domain. H ) that reduce the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions or substitutions located within the CH2 and / or CH3 domains.

[0077] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domains. H), which reduces the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not comprise the same amino acid deletion, addition, or substitution located within the CH2 and / or CH3 domain. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may comprise an amino acid deletion, addition, or substitution at positions H311, H436, or both, which reduces the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not comprise the same amino acid deletion, addition, or substitution at positions H311 and H436. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H311, an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H436, or any combination thereof. H ), which shortens the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H311 and H436. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H311, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H436, or any combination thereof. H), which shortens the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at positions H311 and H436. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48 that contains an amino acid substitution of A at position H311 (H311A), an amino acid substitution of Q at position H436 (H436Q), or any combination thereof. H ) which decrease the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H311 and H436.

[0078] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H311A variant, the H436Q variant, or any combination thereof. H ), which reduces the half-life of the modified anti-PD-L1 antibody by, for example, at least 25%, at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500%, relative to an anti-PD-L1 antibody that does not contain the H311A variant and H436Q variant. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include an H311A variant, an H436Q variant, or any combination thereof. H), which reduces the half-life of the modified anti-PD-L1 antibody by, for example, up to 25%, up to 50%, up to 75%, up to 100%, up to 125%, up to 150%, up to 175%, up to 200%, up to 250%, up to 300%, up to 350%, up to 400%, up to 450%, or up to 500%, compared to an anti-PD-L1 antibody that does not contain the H311A variant and H436Q variant. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48 comprising an H311A variant, an H436Q variant, or any combination thereof. H ), which may include, for example, about 25% to about 50%, about 25% to about 100%, about 25% to about 150%, about 25% to about 200%, about 25% to about 250%, about 25% to about 300%, about 25% to about 350%, about 25% to about 400%, about 25% to about 450%, approximately 25% to approximately 500%, approximately 50% to approximately 100%, approximately 50% to approximately 150%, approximately 50% to approximately 200%, approximately 50% to approximately 250%, approximately 50% to approximately 300%, approximately 50% to approximately 350%, approximately 50% to approximately 400%, approximately 50% to approximately 450%, approximately 50% to approximately 500%, approximately 100% to approximately 150%, approximately 100% to approximately 200%, approximately 100% to approximately 250% , about 100% to about 300%, about 100% to about 350%, about 100% to about 400%, about 100% to about 450%, about 100% to about 500%, about 150% to about 200%, about 150% to about 250%, about 150% to about 300%, about 150% to about 350%, about 150% to about 400%, about 150% to about 450%, about 150% to about 500%, about 200% or about 250% to about 250%, about 200% to about 300%, about 200% to about 350%, about 200% to about 400%, about 200% to about 450%, about 200% to about 500%, about 250% to about 300%, about 250% to about 350%, about 250% to about 400%, about 250% to about 450%, or about 250% to about 500%.

[0079] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H311A variant, the H436Q variant, or any combination thereof. H ), which have a half-life of, for example, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include the H311A variant, the H436Q variant, or any combination thereof. H ), which have a half-life of, for example, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include the H311A variant, the H436Q variant, or any combination thereof. H ), for example, with a half-life of up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, or up to 7 days. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H311A variant, the H436Q variant, or any combination thereof. H ), which have a half-life of, for example, about 1 day to about 2 days, about 1 day to about 3 days, about 1 day to about 4 days, about 1 day to about 5 days, about 1 day to about 6 days, about 1 day to about 7 days, about 2 days to about 3 days, about 2 days to about 4 days, about 2 days to about 5 days, about 2 days to about 6 days, about 2 days to about 7 days, about 3 days to about 4 days, about 3 days to about 5 days, about 3 days to about 6 days, about 3 days to about 7 days, about 4 days to about 5 days, about 4 days to about 6 days, about 4 days to about 7 days, about 5 days to about 6 days, about 5 days to about 7 days, or about 6 days to about 7 days.

[0080] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H311A variant, the H436Q variant, or any combination thereof. H ), which have a half-life of, for example, about 30 hours, about 32 hours, about 34 hours, about 36 hours, about 38 hours, about 40 hours, about 42 hours, about 44 hours, about 46 hours, or about 48 hours. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include the H311A variant, the H436Q variant, or any combination thereof. H ), which have a half-life of, for example, at least 30 hours, at least 32 hours, at least 34 hours, at least 36 hours, at least 38 hours, at least 40 hours, at least 42 hours, at least 44 hours, at least 46 hours, or at least 48 hours. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include the H311A variant, the H436Q variant, or any combination thereof. H ), for example, with a half-life of up to 30 hours, up to 32 hours, up to 34 hours, up to 36 hours, up to 38 hours, up to 40 hours, up to 42 hours, up to 44 hours, up to 46 hours, or up to 48 hours. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include the H311A variant, the H436Q variant, or any combination thereof. H), and may have a half-life of, for example, about 30 hours to about 36 hours, about 30 hours to about 42 hours, about 30 hours to about 48 hours, about 32 hours to about 36 hours, about 32 hours to about 42 hours, about 32 hours to about 48 hours, about 34 hours to about 36 hours, about 34 hours to about 42 hours, about 34 hours to about 48 hours, about 36 hours to about 42 hours, about 36 hours to about 48 hours, or about 42 hours to about 48 hours.

[0081] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) that comprises an amino acid sequence variant within the CH2 and / or CH3 domain. H ), which shortens the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid variant located within the CH2 and / or CH3 domain. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may contain an IgG4 immunoglobulin heavy chain constant domain (C) that may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domain. H ) that reduce the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions or substitutions located within the CH2 and / or CH3 domains.

[0082] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C ) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domains. H), which reduces the half-life of the anti-PD-L1 antibodies disclosed herein relative to anti-PD-L1 antibodies that do not comprise the same amino acid deletions, additions, or substitutions located within the CH2 and / or CH3 domains. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may comprise an amino acid deletion, addition, or substitution at positions H312, H437, or both, which reduces the half-life of the modified anti-PD-L1 antibody relative to anti-PD-L1 antibodies that do not comprise the same amino acid deletions, additions, or substitutions at positions H312 and H437. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H312, an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H437, or any combination thereof. H ), which shortens the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H312 and H437. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H312, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H437, or any combination thereof. H), which reduces the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at positions H312 and H437. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include an amino acid substitution of A at position H312 (H312A), an amino acid substitution of Q at position H437 (H437Q), or any combination thereof. H ) which decrease the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H312 and H437.

[0083] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which reduces the half-life of the modified anti-PD-L1 antibody by, for example, at least 25%, at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500%, relative to an anti-PD-L1 antibody that does not contain the H312A and H437Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H), which reduces the half-life of the modified anti-PD-L1 antibody by, for example, up to 25%, up to 50%, up to 75%, up to 100%, up to 125%, up to 150%, up to 175%, up to 200%, up to 250%, up to 300%, up to 350%, up to 400%, up to 450%, or up to 500%, compared to an anti-PD-L1 antibody that does not contain the H312A and H437Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which may include, for example, about 25% to about 50%, about 25% to about 100%, about 25% to about 150%, about 25% to about 200%, about 25% to about 250%, about 25% to about 300%, about 25% to about 350%, about 25% to about 400%, about 25% to about 450%, approximately 25% to approximately 500%, approximately 50% to approximately 100%, approximately 50% to approximately 150%, approximately 50% to approximately 200%, approximately 50% to approximately 250%, approximately 50% to approximately 300%, approximately 50% to approximately 350%, approximately 50% to approximately 400%, approximately 50% to approximately 450%, approximately 50% to approximately 500%, approximately 100% to approximately 150%, approximately 100% to approximately 200%, approximately 100% to approximately 250% , about 100% to about 300%, about 100% to about 350%, about 100% to about 400%, about 100% to about 450%, about 100% to about 500%, about 150% to about 200%, about 150% to about 250%, about 150% to about 300%, about 150% to about 350%, about 150% to about 400%, about 150% to about 450%, about 150% to about 500%, about 200% or about 250% to about 250%, about 200% to about 300%, about 200% to about 350%, about 200% to about 400%, about 200% to about 450%, about 200% to about 500%, about 250% to about 300%, about 250% to about 350%, about 250% to about 400%, about 250% to about 450%, or about 250% to about 500%.

[0084] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which have a half-life of, for example, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which have a half-life of, for example, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which have a half-life of, for example, up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, or up to 7 days. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which have a half-life of, for example, about 1 day to about 2 days, about 1 day to about 3 days, about 1 day to about 4 days, about 1 day to about 5 days, about 1 day to about 6 days, about 1 day to about 7 days, about 2 days to about 3 days, about 2 days to about 4 days, about 2 days to about 5 days, about 2 days to about 6 days, about 2 days to about 7 days, about 3 days to about 4 days, about 3 days to about 5 days, about 3 days to about 6 days, about 3 days to about 7 days, about 4 days to about 5 days, about 4 days to about 6 days, about 4 days to about 7 days, about 5 days to about 6 days, about 5 days to about 7 days, or about 6 days to about 7 days.

[0085] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which have a half-life of, for example, about 30 hours, about 32 hours, about 34 hours, about 36 hours, about 38 hours, about 40 hours, about 42 hours, about 44 hours, about 46 hours, or about 48 hours. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which have a half-life of, for example, at least 30 hours, at least 32 hours, at least 34 hours, at least 36 hours, at least 38 hours, at least 40 hours, at least 42 hours, at least 44 hours, at least 46 hours, or at least 48 hours. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H ), which has a half-life of, for example, up to 30 hours, up to 32 hours, up to 34 hours, up to 36 hours, up to 38 hours, up to 40 hours, up to 42 hours, up to 44 hours, up to 46 hours, or up to 48 hours. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H), which may have a half-life of, for example, about 30 hours to about 36 hours, about 30 hours to about 42 hours, about 30 hours to about 48 hours, about 32 hours to about 36 hours, about 32 hours to about 42 hours, about 32 hours to about 48 hours, about 34 hours to about 36 hours, about 34 hours to about 42 hours, about 34 hours to about 48 hours, about 36 hours to about 42 hours, about 36 hours to about 48 hours, or about 42 hours to about 48 hours.

[0086] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain constant domain (C) that comprises an amino acid sequence variant that reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid sequence variant. H In aspects of this embodiment, the modified anti-PD-L1 antibody may comprise a heavy chain constant domain (C) that comprises an amino acid sequence variant that reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid sequence variant. H ) is an IgG immunoglobulin. In another aspect of this embodiment, an IgG immunoglobulin heavy chain constant domain (C) comprises an amino acid sequence variant that reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid sequence variant. H ) is an IgG1 immunoglobulin, an IgG2 immunoglobulin, an IgG3 immunoglobulin, or an IgG4 immunoglobulin.

[0087] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) that comprises an amino acid sequence variant within the CH2 and / or CH3 domain. H), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to anti-PD-L1 antibodies that do not contain the same amino acid variants located within the CH2 and / or CH3 domains. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may contain an IgG1 immunoglobulin heavy chain constant domain (C ), which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domains. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid deletion, addition, or substitution located within the CH2 and / or CH3 domain.

[0088] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domains. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to anti-PD-L1 antibodies that do not contain the same amino acid deletions, additions, or substitutions located within the CH2 and / or CH3 domains. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may contain an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may contain an amino acid deletion, addition, or substitution at positions H315, H440, or both. H), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to anti-PD-L1 antibodies that do not contain the same amino acid deletions, additions, or substitutions at H315 and H440. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may include an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H315, an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H440, or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H315 and H440. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which may include an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H315, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H440, or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H315 and H440. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 that contains an amino acid substitution of A at position H315 (H315A), an amino acid substitution of Q at position H440 (H440Q), or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H315 and H440.

[0089] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, comprising the H315A variant and the H440Q variant, or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, relative to an anti-PD-L1 antibody that does not include the H315A and H440Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG1 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 comprising the H315A variant and the H440Q variant, or any combination thereof, which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, up to 10%, up to 20%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, or up to 90%, compared to an anti-PD-L1 antibody that does not comprise the H315A variant and the H440Q variant. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG1 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 comprising the H315A variant, the H440Q variant, or any combination thereof. H), which may reduce the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 80%, about 50% to about 90%, about 50% to about 90%, about 60% to about 90%, about 60% to about 100%, about 10% to about 100%, about 10% to about 110%, about 10% to about 110%, about 10% to about 120%, about 10% to about 120%, about 10% to about 130%, about 10% to about 140%, about 10% to about 150%, about 10% to about 150%, about 10% to about 160%, about 10% to about 170%, about 10% to about 180%, about 10% to about 190%, about 10% to about 210%, about 10% Decrease by 0% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90%.

[0090] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, comprising the H315A variant and the H440Q variant, or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500%, compared to an anti-PD-L1 antibody that does not comprise the H315A and H440Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 comprising the H315A and H440Q variants, or any combination thereof. H), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, up to 100%, up to 125%, up to 150%, up to 175%, up to 200%, up to 250%, up to 300%, up to 350%, up to 400%, up to 450%, or up to 500%, compared to an anti-PD-L1 antibody that does not include the H315A and H440Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 comprising an H315A variant, an H440Q variant, or any combination thereof. H ), which may include, for example, about 100% to about 150%, about 100% to about 200%, about 100% to about 250%, about 100% to about 300%, about 100% to about 350%, about 100% to about 400%, about 100% to about 450%, about 100% to about 500%, about 150% to about 200%, about 150% to about 250%, about 150% to about 300%, about 150% to about 350%, The interaction of the modified anti-PD-L1 antibody with the FcRn receptor is reduced by about 150% to about 400%, about 150% to about 450%, about 150% to about 500%, about 200% to about 250%, about 200% to about 300%, about 200% to about 350%, about 200% to about 400%, about 200% to about 450%, about 200% to about 500%, about 250% to about 300%, about 250% to about 350%, about 250% to about 400%, about 250% to about 450%, or about 250% to about 500%.

[0091] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) that comprises an amino acid sequence variant within the CH2 and / or CH3 domain. H), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid variant located within the CH2 and / or CH3 domain. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may contain an IgG2 immunoglobulin heavy chain constant domain (C ), which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domain. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid deletion, addition, or substitution located within the CH2 and / or CH3 domain.

[0092] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domains. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to anti-PD-L1 antibodies that do not contain the same amino acid deletions, additions, or substitutions located within the CH2 and / or CH3 domains. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may contain an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may contain an amino acid deletion, addition, or substitution at positions H311, H436, or both. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions, or substitutions at H311 and H436. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may contain an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H), and may include an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H311, an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H436, or any combination thereof, which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not comprise the same amino acid substitutions at H311 and H436. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H ), and may include an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H311, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H436, or any combination thereof, which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H311 and H436. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include an amino acid substitution of A at position H311 (H311A), an amino acid substitution of Q at position H436 (H436Q), or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H311 and H436.

[0093] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H311A variant and the H436Q variant, or any combination thereof. H), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, compared to an anti-PD-L1 antibody that does not contain the H311A and H436Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include the H311A and H436Q variants, or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, up to 10%, up to 20%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, or up to 90%, compared to an anti-PD-L1 antibody that does not contain the H311A and H436Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H311A variant, the H436Q variant, or any combination thereof. H), which may reduce the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, or about 30% compared to an anti-PD-L1 antibody that does not contain the H311A and H436Q variants. Decrease by 0% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90%.

[0094] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which may include the H311A variant and the H436Q variant, or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500%, compared to an anti-PD-L1 antibody that does not contain the H311A and H436Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include the H311A and H436Q variants, or any combination thereof. H), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, up to 100%, up to 125%, up to 150%, up to 175%, up to 200%, up to 250%, up to 300%, up to 350%, up to 400%, up to 450%, or up to 500%, compared to an anti-PD-L1 antibody that does not contain the H311A and H436Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48, which may include the H311A variant, the H436Q variant, or any combination thereof. H ), which may include, for example, about 100% to about 150%, about 100% to about 200%, about 100% to about 250%, about 100% to about 300%, about 100% to about 350%, about 100% to about 400%, about 100% to about 450%, about 100% to about 500%, about 150% to about 200%, about 150% to about 250%, about 150% to about 300%, about 150% to about 350%, The interaction of the modified anti-PD-L1 antibody with the FcRn receptor is reduced by about 150% to about 400%, about 150% to about 450%, about 150% to about 500%, about 200% to about 250%, about 200% to about 300%, about 200% to about 350%, about 200% to about 400%, about 200% to about 450%, about 200% to about 500%, about 250% to about 300%, about 250% to about 350%, about 250% to about 400%, about 250% to about 450%, or about 250% to about 500%.

[0095] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) that comprises an amino acid sequence variant within the CH2 and / or CH3 domain. H), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid variant located within the CH2 and / or CH3 domain. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may contain an IgG4 immunoglobulin heavy chain constant domain (C ), which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domain. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid deletion, addition, or substitution located within the CH2 and / or CH3 domain.

[0096] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C ) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include deletions, additions, or substitutions of one, two, three, four, or five amino acids located within the CH2 and / or CH3 domains. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to anti-PD-L1 antibodies that do not contain the same amino acid deletions, additions, or substitutions located within the CH2 and / or CH3 domains. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may contain an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may contain an amino acid deletion, addition, or substitution at position H312, H437, or both. H), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to anti-PD-L1 antibodies that do not contain the same amino acid deletions, additions, or substitutions at H312 and H437. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H312, an A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W amino acid substitution at position H437, or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H312 and H437. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H ), and may include an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H312, an amino acid substitution of C, D, E, K, Q, R, S, T, or W at position H437, or any combination thereof, which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H312 and H437. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include an amino acid substitution of A at position H312 (H312A), an amino acid substitution of Q at position H437 (H437Q), or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor compared to an anti-PD-L1 antibody that does not contain the same amino acid substitutions at H312 and H437.

[0097] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which may include the H312A variant and the H437Q variant, or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, compared to an anti-PD-L1 antibody that does not contain the H312A and H437Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A and H437Q variants, or any combination thereof. H), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, up to 10%, up to 20%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, or up to 90%, compared to an anti-PD-L1 antibody that does not include the H312A and H437Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which may include the H312A variant, the H437Q variant, or any combination thereof, which may reduce the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 110%, compared to an anti-PD-L1 antibody that does not include the H312A variant and the H437Q variant. 0% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, Reduce by about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90%.

[0098] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which may include the H312A variant and the H437Q variant, or any combination thereof. H), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, or at least 500%, compared to an anti-PD-L1 antibody that does not contain the H312A and H437Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A and H437Q variants, or any combination thereof. H ), which reduces the interaction of the modified anti-PD-L1 antibody with the FcRn receptor by, for example, up to 100%, up to 125%, up to 150%, up to 175%, up to 200%, up to 250%, up to 300%, up to 350%, up to 400%, up to 450%, or up to 500%, compared to an anti-PD-L1 antibody that does not contain the H312A and H437Q variants. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG4 immunoglobulin heavy chain constant domain (C) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53, which may include the H312A variant, the H437Q variant, or any combination thereof. H), which may include, for example, about 100% to about 150%, about 100% to about 200%, about 100% to about 250%, about 100% to about 300%, about 100% to about 350%, about 100% to about 400%, about 100% to about 450%, about 100% to about 500%, about 150% to about 200%, about 150% to about 250%, about 150% to about 300%, about 150% to about 350%, The interaction of the modified anti-PD-L1 antibody with the FcRn receptor is reduced by about 150% to about 400%, about 150% to about 450%, about 150% to about 500%, about 200% to about 250%, about 200% to about 300%, about 200% to about 350%, about 200% to about 400%, about 200% to about 450%, about 200% to about 500%, about 250% to about 300%, about 250% to about 350%, about 250% to about 400%, about 250% to about 450%, or about 250% to about 500%.

[0099] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein have a half-life of, for example, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In other aspects of this embodiment, the anti-PD-L1 antibodies disclosed herein have a half-life of, for example, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. In yet other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein have a half-life of, for example, up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, or up to 7 days. In yet another aspect of this embodiment, the anti-PD-L1 antibodies disclosed herein have a half-life of, for example, about 1 to about 2 days, about 1 to about 3 days, about 1 to about 4 days, about 1 to about 5 days, about 1 to about 6 days, about 1 to about 7 days, about 2 to about 3 days, about 2 to about 4 days, about 2 to about 5 days, about 2 to about 6 days, about 2 to about 7 days, about 3 to about 4 days, about 3 to about 5 days, about 3 to about 6 days, about 3 to about 7 days, about 4 to about 5 days, about 4 to about 6 days, about 4 to about 7 days, about 5 to about 6 days, about 5 to about 7 days, or about 6 to about 7 days.

[0100] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a light chain of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37. In an aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a kappa light chain of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25. In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:44, and a kappa light chain of SEQ ID NO:21. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a lambda light chain of SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37.

[0101] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a light chain comprising the light chain variable region of SEQ ID NO: 9. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a light chain comprising the light chain variable region of SEQ ID NO:9 and the light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a light chain comprising a light chain variable region of SEQ ID NO:9 and a kappa light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a light chain comprising a light chain variable region of SEQ ID NO:9 and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0102] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain comprising the light chain variable region of SEQ ID NO: 9. In an aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain comprising the light chain variable region of SEQ ID NO: 9 and a light chain constant region of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, or SEQ ID NO: 31. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain comprising the light chain variable region of SEQ ID NO: 9 and a kappa light chain constant region of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain comprising a light chain variable region of SEQ ID NO: 9 and a kappa light chain constant region of SEQ ID NO: 16. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain comprising a light chain variable region of SEQ ID NO: 9 and a lambda light chain constant region of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, or SEQ ID NO: 31.

[0103] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a light chain comprising a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a light chain that comprises a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20. In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a light chain that comprises a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain variable region of SEQ ID NO:16.In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44, and a light chain comprising a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0104] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and CDR3 of SEQ ID NO: 14 or SEQ ID NO: 15. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain variable region, such as CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and CDR3 of SEQ ID NO: 14 or SEQ ID NO: 15, and a light chain constant region of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, or SEQ ID NO: 31. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain that comprises a light chain variable region such as CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and CDR3 of SEQ ID NO: 14 or SEQ ID NO: 15, and a kappa light chain constant region of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20. In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain that comprises a light chain variable region such as CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or CDR3 of SEQ ID NO: 14 or SEQ ID NO: 15, and a kappa light chain variable region of SEQ ID NO: 16. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain of SEQ ID NO:44, and a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0105] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO:2, and a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO:2, and a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a kappa light chain of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25. In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, and a kappa light chain of SEQ ID NO: 21. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57, and a lambda light chain of SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, or SEQ ID NO: 37.

[0106] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57, and a light chain comprising a light chain variable region of SEQ ID NO: 9. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57, and a light chain comprising a light chain variable region of SEQ ID NO: 9 and a light chain constant region of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, or SEQ ID NO: 31. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO:2, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain comprising a light chain variable region of SEQ ID NO:9 and a kappa light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO:2, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain comprising a light chain variable region of SEQ ID NO:9 and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0107] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, and a light chain comprising a light chain variable region of SEQ ID NO: 9. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, and a light chain comprising a light chain variable region of SEQ ID NO: 9 and a light chain constant region of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, or SEQ ID NO: 31. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, and a light chain comprising a light chain variable region of SEQ ID NO: 9 and a kappa light chain constant region of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, and a light chain comprising a light chain variable region of SEQ ID NO: 9 and a lambda light chain constant region of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, or SEQ ID NO: 31.

[0108] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO:2, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain comprising a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO:2, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a light chain comprising the light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO:2, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain comprising a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20. In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO:2, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain comprising a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16.In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO:2, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0109] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, and a light chain comprising a light chain variable region, such as CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and CDR3 of SEQ ID NO: 14 or SEQ ID NO: 15. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, and a light chain variable region, such as CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and CDR3 of SEQ ID NO: 14 or SEQ ID NO: 15, and a light chain constant region of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, or SEQ ID NO: 31. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, and a light chain variable region such as CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and CDR3 of SEQ ID NO: 14 or SEQ ID NO: 15, and a kappa light chain constant region of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20. In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, and a light chain variable region such as CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or CDR3 of SEQ ID NO: 14 or SEQ ID NO: 15, and a kappa light chain constant region of SEQ ID NO: 16.In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO:2, a heavy chain constant region of SEQ ID NO:57, and a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0110] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, and a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57; and a light chain of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a kappa light chain of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25. In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a kappa light chain of SEQ ID NO:21. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a lambda light chain of SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37.

[0111] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain that comprises a light chain variable region of SEQ ID NO:9. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region of CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain that comprises a light chain variable region of SEQ ID NO:9 and a light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain comprising a light chain variable region of SEQ ID NO:9 and a kappa light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain comprising a light chain variable region of SEQ ID NO:9 and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0112] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain that comprises a light chain variable region of SEQ ID NO:9. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region of CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain that comprises a light chain variable region of SEQ ID NO:9 and a light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain that comprises a light chain variable region of SEQ ID NO:9 and a kappa light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain that comprises a light chain variable region of SEQ ID NO:9 and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0113] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain that comprises a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region of CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain that comprises a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20.In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain comprising a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0114] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain that comprises a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20.In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain comprising a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0115] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a light chain constant region, such as SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20.In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain comprising a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0116] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain comprising a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain comprising a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20.In one aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain comprising a heavy chain variable region such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain comprising a light chain variable region such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, or CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a kappa light chain constant region of SEQ ID NO:16. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise an IgG1 immunoglobulin heavy chain that comprises a heavy chain variable region, such as CDR1 of SEQ ID NO:3 or SEQ ID NO:4, CDR2 of SEQ ID NO:5 or SEQ ID NO:6, and CDR3 of SEQ ID NO:7 or SEQ ID NO:8, a heavy chain constant region of SEQ ID NO:57, and a light chain that comprises a light chain variable region, such as CDR1 of SEQ ID NO:10 or SEQ ID NO:11, CDR2 of SEQ ID NO:12 or SEQ ID NO:13, and CDR3 of SEQ ID NO:14 or SEQ ID NO:15, and a lambda light chain constant region of SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, or SEQ ID NO:31.

[0117] Whether two sequences have high sequence identity (or homology) is routinely calculated using percentage similarity or identity (terms well known in the art). The sequence of a PD-L1 antigen may be compared to SEQ ID NO: 1. The sequence of an anti-PD-L1 antibody may be compared to SEQ ID NOs: 2-15. With respect to any of SEQ ID NOs: 1-15 with respect to a reference polypeptide sequence, the term "percent (%) amino acid sequence identity" is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in any of SEQ ID NOs: 1-15, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without taking into account any conservative substitutions as part of the sequence identity. Any of a variety of sequence alignment methods can be used to determine percent identity, including, but not limited to, global methods, local methods, and hybrid methods, such as segment approach methods. Protocols for determining percent identity are routine procedures within the purview of one skilled in the art and given the teachings herein.

[0118] Global methods align sequences from the beginning to the end of the molecule, sum up the scores of each residue pair, and determine the optimal alignment by applying gap penalties. Non-limiting examples include CLUSTAL W (see, for example, Julie D. Thompson et al., CLUSTAL W: Improving the Sensitivity of Progressive Multiple Sequence Alignment Through Sequence Weighting, Position-Specific Gap Penalties and Weight Matrix Choice, 22(22) Nucleic Acids Research 4673-4680 (1994)); and iterative refinement (see, for example, Osamu Gotoh, Significant Improvement in Accuracy of Multiple Protein Sequence Alignments by Iterative Refinement as Assessed by Reference to Structural Alignments, 264(4) J. Mol. Biol. 823-838 (1996)).

[0119] Local methods align sequences by identifying one or more conserved motifs shared by all of the input sequences. Non-limiting methods include, for example, Matchbox (see, for example, Eric Depiereux and Ernest Feytmans, Match-Box: A Fundamentally New Algorithm for the Simultaneous Alignment of Several Protein Sequences, 8 (5) CABIOS 501-509 (1992)); Gibbs sampling (see, for example, CE Lawrence et al., Detecting Subtle Sequence Signals: A Gibbs Sampling Strategy for Multiple Alignment, 262 (5131) Science 208-214 (1993)); Align-M (see, for example, Ivo Van Walle et al., Align-MA New Algorithm for Multiple Alignment of Highly Divergent Sequences, 20 (9) Bioinformatics: 1428-1435 (2004)).

[0120] Hybrid methods combine functional aspects of both global and local alignment methods. Non-limiting methods include, for example, segment-to-segment comparison (see, e.g., Burkhard Morgenstern et al., Multiple DNA and Protein Sequence Alignment Based on Segment-To-Segment Comparison, 93(22) Proc. Natl. Acad. Sci. USA 12098-12103 (1996)); T-Coffee (see, e.g., Cedric Notredame et al., T-Coffee: A Novel Algorithm for Multiple Sequence Alignment, 302(1) J. Mol. Biol. 205-217 (2000)); MUSCLE (see, e.g., Robert C. Edgar, MUSCLE: Multiple Sequence Alignment With High Score Accuracy and High Throughput, 32(5) Nucleic Acids Res. 1792-1797 (2004)); and DIALIGN-T (see, e.g., Amarendran R See Subramanian et al., DIALIGN-T: An Improved Algorithm for Segment-Based Multiple Sequence Alignment, 6(1) BMC Bioinformatics 66 (2005).

[0121] The present specification provides, for example, a PD-L1 antigen, a heavy chain variable domain (V H ), light chain variable domain (V L ), and CDR1 region, CDR2 region, and CDR3 region, various polypeptide variants in which one amino acid is substituted for another amino acid are described. Substitutions can be evaluated based on various factors, such as the physical properties of the substituted amino acid (Table 1) or how well the original amino acid tolerates the substitution (Table 2). The selection of which amino acid can be substituted for another amino acid in a polypeptide is known to those skilled in the art.

Table 1

Table 2

[0122] In an aspect of this embodiment, a hydrophilic amino acid at a particular position in an insulin-like protein disclosed herein can be substituted with another hydrophilic amino acid. Examples of hydrophilic amino acids include, for example, C, F, I, L, M, V, and W. In another aspect of this embodiment, an aliphatic amino acid at a particular position in an insulin-like protein disclosed herein can be substituted with another aliphatic amino acid. Examples of aliphatic amino acids include, for example, A, I, L, P, and V. In yet another aspect of this embodiment, an aromatic amino acid at a particular position in an insulin-like protein disclosed herein can be substituted with another aromatic amino acid. Examples of aromatic amino acids include, for example, F, H, W, and Y. In yet another aspect of this embodiment, a stacking amino acid at a particular position in an insulin-like protein disclosed herein can be substituted with another stacking amino acid. Examples of stacking amino acids include, for example, F, H, W, and Y. In a further aspect of this embodiment, a polar amino acid at a particular position in an insulin-like protein disclosed herein can be substituted with another polar amino acid. Examples of polar amino acids include, for example, D, E, K, N, Q, and R. In a further aspect of this embodiment, a less polar or less important amino acid at a particular position in an insulin-like protein disclosed herein is substituted with another less polar or less important amino acid. Examples of less polar or less important amino acids include, for example, A, H, G, P, S, T, and Y. In yet another aspect of this embodiment, a positively charged amino acid at a particular position in an insulin-like protein disclosed herein can be substituted with another positively charged amino acid. Examples of positively charged amino acids include, for example, K, R, and H. In yet another aspect of this embodiment, a negatively charged amino acid at a particular position in an insulin-like protein disclosed herein can be substituted with another negatively charged amino acid. Examples of negatively charged amino acids include, for example, D and E.In another aspect of this embodiment, a small amino acid at one position in the insulin-like proteins disclosed herein can be substituted with another small amino acid. Examples of small amino acids include, for example, A, D, G, N, P, S, and T. In yet another aspect of this embodiment, a C-beta branching amino acid at one particular position in the insulin-like proteins disclosed herein can be substituted with another C-beta branching amino acid. Examples of C-beta branching amino acids include, for example, I, T, and V.

[0123] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope disclosed herein. The modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope present within PD-L1 of SEQ ID NO: 1. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope that shares, for example, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amino acid identity compared to PD-L1 of SEQ ID NO: 1. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope with amino acid identity in the range of, for example, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, about 75% to about 99%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%, about 95% to about 99%, about 75% to about 97%, about 80% to about 97%, about 85% to about 97%, about 90% to about 97%, about 95% to about 97%, or about 97% to about 99% relative to PD-L1 of SEQ ID NO: 1. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope that has, for example, at least one, at least two, at least three, or at least four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to the PD-L1 of SEQ ID NO:1, or up to one, up to two, up to three, or up to four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to the PD-L1 of SEQ ID NO:1.In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope that has, for example, about 1 to about 2, about 1 to about 3, about 1 to about 4, about 2 to about 3, about 2 to about 4, or about 3 to about 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions relative to PD-L1 of SEQ ID NO: 1.

[0124] As used herein, the terms "selectively binds" or "selective binding," when used with reference to an antibody, refer to the differential binding of the antibody to a designated target epitope such that the antibody does not substantially cross-react with non-target epitopes. The minimum size of a peptide epitope as defined herein is approximately 5 amino acids, and peptide epitopes typically contain at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 20 amino acids. Peptide epitopes can be discontinuous, i.e., contain amino acid residues that are not adjacent in the primary structure of the peptide but are joined into the epitope by the secondary, tertiary, or quaternary structure of the peptide. Furthermore, it should be noted that epitopes can include portions of a molecule other than the amino acid sequence, such as carbohydrate moieties, lipid moieties such as lipoproteins or glycolipids, or chemically modified amino acid moieties such as phosphorylated amino acids.

[0125] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein may selectively bind to an epitope present on PD-L1. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein selectively bind to an epitope present within PD-L1 of SEQ ID NO: 1. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein selectively bind to an epitope with, for example, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amino acid identity compared to PD-L1 of SEQ ID NO: 1. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein selectively bind to an epitope with amino acid identity in the range of, for example, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, about 75% to about 99%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%, about 95% to about 99%, about 75% to about 97%, about 80% to about 97%, about 85% to about 97%, about 90% to about 97%, about 95% to about 97%, or about 97% to about 99% relative to PD-L1 of SEQ ID NO: 1. In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein selectively bind to an epitope that has, for example, at least one, at least two, at least three, or at least four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to the PD-L1 of SEQ ID NO:1, or up to one, up to two, up to three, or up to four contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions compared to the PD-L1 of SEQ ID NO:1.In yet another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein selectively bind to an epitope that has, for example, about 1 to about 2, about 1 to about 3, about 1 to about 4, about 2 to about 3, about 2 to about 4, or about 3 to about 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions relative to PD-L1 of SEQ ID NO: 1.

[0126] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein bind to an epitope present within PD-L1 that includes, for example, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 20 amino acids. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein bind to an epitope that includes, for example, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, or up to 20 amino acids. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may be, for example, from about 5 to about 7, from about 5 to about 8, from about 7 to about 9, from about 5 to about 10, from about 5 to about 12, from about 5 to about 15, from about 5 to about 18, from about 5 to about 20, from about 6 to about 7, from about 6 to about 8, from about 6 to about 9, from about 6 to about 10, from about 6 to about 12, from about 6 to about 15, from about 6 to about 18, from about 6 to about 20, from about 7 to about 8, from about 7 to about 9, from about 7 to about 10, and about 7 to about 12, about 7 to about 15, about 7 to about 18, about 7 to about 20, about 8 to about 9, about 8 to about 10, about 8 to about 12, about 8 to about 15, about 8 to about 18, about 8 to about 20, about 9 to about 10, about 9 to about 12, about 9 to about 15, about 9 to about 18, about 9 to about 20, about 10 to about 12, about 10 to about 15, about 10 to about 18, or about 10 to about 20.

[0127] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein bind to an epitope that includes, for example, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 20 amino acids from the PD-L1 of SEQ ID NO: 1. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein bind to an epitope that includes, for example, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, or up to 20 amino acids from the PD-L1 of SEQ ID NO: 1. In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may be modified to any of the following sequences: about 5 to about 7, about 5 to about 8, about 7 to about 9, about 5 to about 10, about 5 to about 12, about 5 to about 15, about 5 to about 18, about 5 to about 20, about 6 to about 7, about 6 to about 8, about 6 to about 9, about 6 to about 10, about 6 to about 12, about 6 to about 15, about 6 to about 18, about 6 to about 20, about 7 to about 8, about 7 to about 9, about 7 to about 10, about 7 to about 12, about 7 to about 15, about 7 to about 18, about 7 to about 20, about 8 to about 9, about 8 to about 10, about 8 to about 12, about 8 to about 15, about 8 to about 18, about 8 to about 20, about 9 to about 10, about 9 to about 12, about 9 to about 15, about 9 to about 18, about 9 to about 20, about 10 to about 12, about 10 to about 15, about 10 to about 18, or about 10 to about 20.

[0128] Selective binding includes, for example, binding affinity, binding specificity, and binding avidity. Binding affinity refers to the length of time an antibody resides at its epitope-binding site and can be considered the strength with which an antibody binds to its epitope. Binding affinity can be described as the equilibrium dissociation constant (KD) of an antibody. It is defined as the ratio Kd / Ka at equilibrium, where Ka is the antibody's association rate constant and kd is the antibody's dissociation rate constant. Binding affinity is determined by both association and dissociation, and neither high association nor low dissociation alone can ensure high affinity. The association rate constant (Ka) or binding rate constant (Kon) measures the number of binding events per unit time, or the tendency of an antibody and an antigen to reversibly associate into the antibody-antigen complex. The association rate constant is expressed in M-1s-1 and is given as follows: [Ab]x[Ag]xKon. The higher the association rate constant, the faster the antibody binds to its antigen or the higher the binding affinity between the antibody and antigen. The dissociation rate constant (Kd) or off-rate constant (Koff) measures the number of dissociation events per unit time that an antibody-antigen complex reversibly separates (dissociates) into its constituent molecules, i.e., antibody and antigen. The dissociation rate constant is expressed in s and is given as: [Ab + Ag] x Koff. The smaller the dissociation rate constant, the tighter the antibody binds to its antigen, or the higher the binding affinity between the antibody and antigen. The equilibrium dissociation constant (KD) measures the rate at which a newly formed antibody-antigen complex dissociates at equilibrium. The equilibrium dissociation constant is expressed in M ​​and is defined as Koff / Kon = [Ab] x [Ag] / [Ab + Ag], where [Ab] is the molar concentration of antibody, [Ag] is the molar concentration of antigen, and [Ab + Ag] is the molar concentration of the antibody-antigen complex. Here, all concentrations are those of the components when the system is at equilibrium. The smaller the equilibrium dissociation constant, the tighter the antibody binds to its antigen, or the higher the binding affinity between the antibody and the antigen.

[0129] Thus, in one embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein to an epitope present within PD-L1 is, for example, 1x10 5 M -1 s -1 Less than 1x10 6 M -1 s -1 Less than 1x10 7 M -1 s -1 Less than or 1x10 8 M -1 s -1 In another embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein to an epitope present within PD-L1 may be less than, for example, 1x10 5 M -1 s -1 Ultra, 1x10 6 M -1 s -1 Ultra, 1x10 7 M -1 s -1 Ultra, or 1x10 8 M -1 s -1 In other embodiments, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein for an epitope present within PD-L1 may be greater than or equal to 1x10 5 M -1 s -1 ~1x10 8 M -1 s-1,1x10 6 M -1 s -1 ~1x10 8 M -1 s -1 , 1x10 5 M -1 s -1 ~1x10 7 M -1 s -1 , or 1x10 6 M -1 s -1 ~1x10 7 M -1 s -1 may have an association rate constant of

[0130] In another embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein to an epitope other than an epitope present on PD-L1 is, for example, 1x10 0 M -1 s -1 Less than 1x10 1 M -1 s -1 Less than 1x10 2 M -1 s -1 Less than 1x10 3 M -1 s -1 Less than or 1x10 4 M -1 s -1 In another embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein may be, for example, up to 1x10 for an epitope other than an epitope present on PD-L1. 0 M -1 s -1 , up to 1x10 1 M -1 s -1 , up to 1x10 2 M -1 s -1 , up to 1x10 3 M -1 s -1 , or up to 1x10 4 M -1 s -1 may have an association rate constant of

[0131] In another embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein to an epitope present in PD-L1 is, for example, 1 x 10 -3 s -1 Less than 1x10 -4 s -1 Less than or 1x10 -5 s -1 In another aspect of this embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein to an epitope present within PD-L1 may be, for example, 1.0x10 -4 s -1 Less than 2.0x10 -4 s -1Less than 3.0x10 -4 s -1 Less than 4.0x10 -4 s -1 Less than 5.0x10 -4 s -1 Less than 6.0x10 -4 s -1 Less than 7.0x10 -4 s -1 Less than 8.0x10 -4 s -1 Less than or 9.0x10-4s -1 In another embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein to an epitope present within PD-L1 may be less than, for example, 1 x 10 -3 s -1 Larger, 1x10 -4 s -1 Greater than, or 1x10 -5 s -1 In another aspect of this embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein to an epitope present within PD-L1 may be greater than or equal to 1.0x10 -4 s -1 Larger, 2.0x10 -4 s -1 Larger, 3.0x10 -4 s -1 Larger, 4.0x10 -4 s -1 Larger, 5.0x10 -4 s -1 Larger, 6.0x10 -4 s -1 Larger, 7.0x10 -4 s -1 Larger, 8.0x10 -4 s -1 Greater than or 9.0x10 -4 s -1 In other aspects, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein to an epitope present within PD-L1 may be greater than or equal to, for example, 1x10 -3 s -1 ~1x10 -5 s -1 ,1x10-3 s -1 ~1x10 -4 s -1 , or 1x10 -4 s -1 ~1x10 -5 s -1 may have a dissociation rate constant of

[0132] In another embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein, for an epitope present within PD-L1, may have an equilibrium dissociation constant of less than 0.500 nM. In aspects of this embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein, for an epitope present within PD-L1, may have an equilibrium dissociation constant of less than 0.500 nM, less than 0.450 nM, less than 0.400 nM, less than 0.350 nM, less than 0.300 nM, less than 0.250 nM, less than 0.200 nM, less than 0.150 nM, less than 0.100 nM, or less than 0.050 nM. In another embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein, for an epitope present within PD-L1, may have an equilibrium dissociation constant of greater than 0.500 nM. In aspects of this embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein, for an epitope present within PD-L1, may have an equilibrium dissociation constant of, for example, greater than 0.500 nM, greater than 0.450 nM, greater than 0.400 nM, greater than 0.350 nM, greater than 0.300 nM, greater than 0.250 nM, greater than 0.200 nM, greater than 0.150 nM, greater than 0.100 nM, or greater than 0.050 nM.

[0133] Binding specificity is the ability of an antibody to distinguish between molecules containing its epitope and molecules that do not contain that epitope. One way to measure binding specificity is to compare the K on-rate of the antibody for molecules containing its epitope to the K on-rate of the antibody for molecules that do not contain its epitope. For example, the association rate constant (Ka) of an engineered anti-PD-L1 antibody disclosed herein that selectively binds to an epitope present in PD-L1 is compared to an epitope not present in PD-L1. In aspects of this embodiment, the engineered anti-PD-L1 antibodies disclosed herein can bind to an epitope present in PD-L1, for example, at a binding rate constant of 1x10 0 M -1 s -1 Less than 1x10 1 M -1 s -1 Less than 1x10 2 M -1 s -1 Less than 1x10 3 M -1 s -1 Less than or 1x10 4 M -1 s -1 In another aspect of this embodiment, the binding affinity of the modified anti-PD-L1 antibodies disclosed herein may be, for example, up to 1x10 for an epitope not present in PD-L1. 0 M -1 s -1 , up to 1x10 1 M -1 s -1 , up to 1x10 2 M -1 s -1 , up to 1x10 3 M -1 s -1 , or up to 1x10 4 M -1 s -1 The enzyme may have an association rate constant (Ka) of

[0134] In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may have an association rate constant (Ka) for their epitope that is at least 2-fold higher, at least 3-fold higher, at least 4-fold higher, at least 5-fold higher, at least 6-fold higher, at least 7-fold higher, at least 8-fold higher, or at least 9-fold higher than an epitope that is not present in PD-L1. In yet other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may have an association rate constant (Ka) for their epitope that is at least 10-fold higher, at least 100-fold higher, at least 1,000-fold higher, or at least 10,000-fold higher than an epitope that is not present in PD-L1.

[0135] In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein may have an association rate constant (Ka) for its epitope that is, for example, up to 1-fold or more, up to 2-fold or more, up to 3-fold or more, up to 4-fold or more, up to 5-fold or more, up to 6-fold or more, up to 7-fold or more, up to 8-fold or more, or up to 9-fold or more, relative to an epitope that is not present in PD-L1. In yet other aspects of this embodiment, the anti-PD-L1 antibodies disclosed herein may have an association rate constant (Ka) for its epitope that is, for example, up to 10-fold or more, up to 100-fold or more, up to 1,000-fold or more, or up to 10,000-fold or more, relative to an epitope that is not present in PD-L1.

[0136] The binding specificity of the engineered anti-PD-L1 antibodies disclosed herein may also be characterized as the ratio at which such engineered anti-PD-L1 antibodies disclosed herein can discriminate between that epitope relative to epitopes not present within PD-L1. In aspects of this embodiment, the engineered anti-PD-L1 antibodies disclosed herein may have a binding specificity ratio for that epitope relative to epitopes not present within PD-L1 of, for example, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 64:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least 40:1.

[0137] Binding avidity, also known as functional affinity, refers to the total functional binding strength between a multivalent antibody and its antigen. Antibody molecules can have multiple binding sites (e.g., two for IgG), and many antigens contain multiple antigenic sites. The binding avidity of an antibody depends on the binding affinity of each individual antibody binding site, but binding avidity is greater than binding affinity because complete dissociation of the antibody requires simultaneous cleavage of all antibody-antigen interactions. It is contemplated that the modified anti-PD-L1 antibodies disclosed herein may selectively bind to any and all epitopes of the antibody.

[0138] Aspects of the present specification disclose, in part, therapeutic compositions. The therapeutic compositions disclosed herein may comprise one or more anti-PD-L1 antibodies disclosed herein and, optionally, may further comprise one or more pharmaceutically acceptable carriers. As used herein, "pharmaceutically acceptable" refers to any molecular entity or composition that does not produce an adverse, allergic, or other harmful or undesirable reaction when administered to an individual. As used herein, the term "therapeutic composition" is synonymous with "pharmaceutically acceptable therapeutic composition" and refers to a therapeutically effective concentration of an active ingredient, such as a modified anti-PD-L1 antibody disclosed herein. Therapeutic compositions comprising the modified anti-PD-L1 antibodies disclosed herein are useful for medical and veterinary applications. Therapeutic compositions can be administered to an individual alone or in combination with other supplementary active ingredients, agents, drugs, or hormones. Therapeutic compositions can be manufactured using any of a variety of processes, including, but not limited to, conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping, and lyophilizing. Therapeutic compositions can take any of a variety of forms, including but not limited to, sterile solutions, suspensions, emulsions, lyophilisates, tablets, pills, pellets, capsules, powders, syrups, elixirs, or any other dosage form suitable for administration.

[0139] The amount of modified anti-PD-L1 antibody disclosed herein included in a therapeutic composition is an amount sufficient to elicit an appropriate therapeutic response in an individual. Typically, this amount will also not cause significant side effects. Thus, the amount of modified anti-PD-L1 antibody disclosed herein included in a therapeutic composition is an effective and safe amount of modified anti-PD-L1 antibody disclosed herein. Such an amount will vary depending on the particular anti-PD-L1 antibody(ies) used. The optimal amount for a particular therapeutic composition can be ascertained by one of skill in the art using standard and routine studies involving observation of antibody titers and other responses in individuals.

[0140] The therapeutic compositions disclosed herein may optionally contain one or more pharmaceutically acceptable carriers that facilitate the processing of the active ingredient into a therapeutic composition. As used herein, the term "pharmacologically acceptable carrier" is synonymous with "pharmacological carrier" and refers to any compound that has no substantial long-term or permanent adverse effects when administered, and includes terms such as "pharmacologically acceptable vehicle, stabilizer, diluent, additive, adjuvant, or excipient." Such carriers are generally capable of being mixed with, or diluting or encapsulating, the active compound, and may be solid, semi-solid, or liquid. It is understood that the active ingredient may be soluble or may be delivered as a suspension in the desired carrier. Any of various pharmaceutically acceptable carriers can be used, including but not limited to, aqueous medium such as water, saline, glycine, hyaluronic acid, etc., solid carrier such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc.; solvent; dispersion medium; coating; antibacterial and antifungal agent; isotonic and absorption delaying agent; or any other inactive ingredient.The choice of pharmaceutically acceptable carrier can depend on the mode of administration.Unless any pharmaceutically acceptable carrier is incompatible with active ingredient, its use in pharmaceutically acceptable composition is contemplated.Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed., 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro, ed., Lippincott, Williams & Wilkins, 20th ed., 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10th ed., 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th ed., 2003). These protocols are routine procedures, and any modifications are within the scope of those skilled in the art and are well within the scope of the teachings herein.

[0141] The therapeutic compositions disclosed herein can optionally contain, but are not limited to, other pharmaceutically acceptable ingredients (or pharmaceutical ingredients), buffers, preservatives, tonicity adjusting agents, salts, antioxidants, osmotic pressure adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifiers, wetting agents, sweeteners or flavoring agents, etc. Various buffers and means for adjusting pH can be used to prepare the therapeutic compositions disclosed herein, provided that the resulting preparation is pharmaceutically acceptable. Such buffers include, but are not limited to, acetate buffer, citrate buffer, phosphate buffer, neutral buffered saline, phosphate buffered saline, and borate buffer. It is understood that the pH of the composition can be adjusted as needed using an acid or base. Pharmaceutically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, stabilized oxychloro compositions, and chelating agents, such as DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjusters useful in pharmaceutical compositions include, but are not limited to, salts such as sodium chloride, potassium chloride, mannitol, or glycerin, and other pharmaceutically acceptable tonicity adjusters. For example, active ingredients, such as the modified anti-PD-L1 antibodies disclosed herein, may be provided as salts, which can be formed with many acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, and succinic acid. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology may be included in therapeutic compositions.

[0142] Embodiments herein disclose, in part, pharmaceutical kits. The kits disclosed herein can include one or more containers containing an engineered anti-PD-L1 antibody or therapeutic composition disclosed herein. The kits disclosed herein can further include labels or instructions that provide useful information, such as, but not limited to, details about the engineered anti-PD-L1 antibody or therapeutic composition disclosed herein, instructions about how to prepare and use the engineered anti-PD-L1 antibody or therapeutic composition disclosed herein to treat and / or prevent a neurodegenerative disease disclosed herein, instructions about how to detect serum levels of the engineered anti-PD-L1 antibody disclosed herein in an individual after administration of the engineered anti-PD-L1 antibody or therapeutic composition disclosed herein, and / or a marketing authorization number (e.g., an FDA or EMA approval number). The kits disclosed herein can further include a delivery system, such as an injection device, useful for administering the engineered anti-PD-L1 antibody or therapeutic composition disclosed herein. The kits disclosed herein may further comprise one or more containers containing a modified anti-PD-L1 antibody or another pharmaceutical composition for use as adjunctive therapy with the therapeutic compositions disclosed herein. The contents of the kit may be contained in an outer casing. The outer casing may be a box, a sealed bag, a foil pouch, or the like. In one embodiment, the contents of the kits disclosed herein are enclosed within a box.

[0143] Aspects of the present specification, in part, disclose methods for treating neurodegenerative diseases. In another aspect, the present specification, in part, discloses methods for reducing Aβ plaque burden in individuals diagnosed with Alzheimer's disease. In another aspect, the present specification, in part, discloses methods for reducing hippocampal gliosis in patients diagnosed with Alzheimer's disease.

[0144] Such methods include therapeutic (after onset) and preventive (before onset or pathology). For example, therapeutic and preventive methods for treating individuals with neurodegenerative diseases include treating individuals with or at risk of having a neurodegenerative disease or pathology, treating individuals with neurodegenerative diseases, and protecting individuals from neurodegenerative diseases, to reduce or reduce the likelihood of, reduce or reduce the susceptibility of, or inhibit or prevent neurodegenerative diseases in individuals. Such methods include administering the immunogenic compositions disclosed herein to therapeutically or prophylactically treat individuals with or at risk of having a neurodegenerative disease or pathology. Thus, the methods can treat neurodegenerative diseases or pathologies or provide individuals with protection (e.g., prophylactic protection) from neurodegenerative diseases.

[0145] In one embodiment, a method of treating a neurodegenerative disease comprises administering to an individual in need thereof a modified anti-PD-L1 antibody disclosed herein or a therapeutic composition disclosed herein, in an amount sufficient to alleviate one or more physiological conditions or symptoms associated with the neurodegenerative disease or condition, thereby treating the neurodegenerative disease. In aspects of this embodiment, the therapeutic composition comprises one or more anti-PD-L1 antibodies disclosed herein.

[0146] In one embodiment, the modified anti-PD-L1 antibodies disclosed herein or therapeutic compositions disclosed herein are used to treat a neurodegenerative disease. The use of the modified anti-PD-L1 antibodies disclosed herein or therapeutic compositions disclosed herein treats the neurodegenerative disease by alleviating one or more physiological conditions or symptoms associated with neurodegeneration or the pathology. In aspects of this embodiment, administration of the anti-PD-L1 or therapeutic composition disclosed herein is in an amount sufficient to alleviate one or more physiological conditions or symptoms associated with neurodegeneration or the pathology, thereby treating the neurodegenerative disease.

[0147] Neurodegenerative disease refers to any condition, disease or disorder whose pathophysiological effects are caused by the progressive loss of neuronal structure or function, such as neuronal death.Neurodegenerative diseases include, but are not limited to, age-related dementia, Alzheimer's disease, amyotrophic lateral sclerosis, dementia, Parkinson's disease, Huntington's disease, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, corticobasal degeneration, Rett syndrome, tauopathy, retinal degenerative disorders, anterior ischemic optic neuropathy, glaucoma, uveitis, depression, trauma-related stress or post-traumatic stress disorder, frontotemporal dementia, dementia with Lewy bodies, mild cognitive impairment, posterior cortical atrophy, primary progressive aphasia, progressive supranuclear palsy or CNS damage.

[0148] Tauopathies are a clinically, morphologically, and biochemically heterogeneous class of neurodegenerative disorders characterized by the pathological aggregation of tau protein in neurofibrillary tangles or neurofibrillary changes in the human brain. Tau is a microtubule-associated protein (MAP) that binds to microtubules and promotes their polymerization. It plays a critical role in maintaining axonal transport and neuronal integrity, but has a physiological role in dendrites and is expressed at low levels in glial cells. In tauopathies, hyperphosphorylation of tau leads to the formation of neurofibrillary tangles and the aggregation of tau in an insoluble form. Non-limiting examples of tauopathies include Alzheimer's disease, argyrophilic grain dementia, chronic traumatic encephalopathy, corticobasal degeneration, chronic traumatic encephalopathy, frontotemporal dementia, frontotemporal lobar degeneration, Hallervorden-Spatz disease, Huntington's disease, ganglioglioma, gangliocytoma, globular glial tauopathy, lead encephalopathy, lipofuscinosis, Litico-Bodig disease (Parkinson-Dementia Complex of Guam), meningioangiomatosis, chromosome 17-linked Parkinson's disease, Pick's disease, primary age-related taupathies (PART), formerly known as neurofibrillary tangle dementia (NFT dementia), postencephalitic parkinsonism, progressive supranuclear palsy, subacute sclerosing panencephalitis, and tuberous sclerosis.

[0149] Retinal degenerative disorders are disorders that cause deterioration of the retina due to the death of photoreceptor cells. Retinal degeneration has several causes, such as arterial or venous blockage, diabetic retinopathy, retrolental fibroplasia / retinopathy of prematurity, or disease (usually hereditary). Symptoms include, but are not limited to, blurred vision, night blindness, retinal detachment, light sensitivity, glare sensitivity, tunnel vision, loss of depth perception, loss of contrast, night blindness, loss of central vision, loss of peripheral vision, and complete loss of vision. Retinal degenerative disorders include, but are not limited to, age-related macular degeneration (wet and dry), retinitis pigmentosa, choroideremia, cone dystrophy, gyrate atrophy, juvenile retinoschisis, vitelliform macular dystrophy (Best disease), abetalipoproteinemia (Bassen-Kornzweig), Bardet-Biedl syndrome, blue cone monochromacy, dominantly inherited drusen, Goldman-Fabre vitreoretinal dystrophy (Enhanced S-cone Syndrome), Kearns-Sayre syndrome, Laurence-Moon syndrome, Leber congenital amaurosis, Leber hereditary optic neuropathy, Oguchi disease, peripapillary (pericentral) choroidal dystrophy, pigment pattern dystrophy, Sorsby macular dystrophy, and others. Dystrophy), Stargardt's disease, Stickler's syndrome, Usher's syndrome, and Wagner's vitreoretinal dystrophy.

[0150] Injuries to the CNS include, but are not limited to, spinal cord injury, closed head trauma, blunt trauma, penetrating trauma, hemorrhagic stroke, ischemic stroke, cerebral ischemia, optic nerve injury, myocardial infarction, organophosphate poisoning, and tumor resection injury.

[0151] Aspects herein provide, in part, an individual. The individual includes any mammal, such as a human, and the human can be a patient.

[0152] The methods disclosed herein include the treatment of neurodegenerative diseases. Treatment includes any therapeutic or beneficial effect, such as any objective or individually measurable or detectable improvement or benefit provided to a specific individual. A therapeutic or beneficial effect may be, but need not necessarily be, the complete removal of all or any specific adverse conditions, symptoms, disorders, illnesses, diseases, or complications caused by or associated with a neurodegenerative disease or condition. Thus, a satisfactory clinical endpoint is achieved when there is a gradual improvement or partial reduction of adverse conditions, symptoms, disorders, illnesses, diseases, or complications caused by or associated with a neurodegenerative disease or condition, or when there is an inhibition, reduction, alleviation, suppression, prevention, restriction, or control of the worsening or progression of one or more conditions, adverse symptoms, disorders, illnesses, diseases, or complications caused by or associated with a neurodegenerative disease or condition over the short or long term.

[0153] In aspects of this embodiment, the methods of treatment or use disclosed herein may alleviate, reduce, inhibit, limit, delay, or prevent a neurodegenerative disease or condition. In other aspects of this embodiment, the methods of treatment or use disclosed herein may reduce, alleviate, inhibit, suppress, prevent, control, or limit one or more adverse conditions, symptoms, disorders, illnesses, diseases, or complications caused by or associated with a neurodegenerative disease or condition. In yet other aspects of this embodiment, the methods of treatment or use disclosed herein may improve, accelerate, promote, enhance, potentiate, or hasten an individual's recovery from a neurodegenerative disease or condition, or from one or more adverse symptoms, disorders, illnesses, diseases, or complications caused by or associated with a neurodegenerative disease or condition.

[0154] In another aspect of this embodiment, the methods of treatment or use disclosed herein may stabilize adverse conditions, symptoms, disorders, illnesses, diseases, or complications caused by or associated with a neurodegenerative disease or condition. In yet another aspect of this embodiment, the methods of treatment or use disclosed herein may reduce or eliminate the need for, frequency of administration, or amount of concurrent or subsequent treatment, such as another drug or other agent used to treat an individual having or at risk of having a neurodegenerative disease or condition. For example, reducing the amount of adjunctive therapy, e.g., reducing or reducing treatment for a neurodegenerative disease or condition.

[0155] One or more physiological conditions or symptoms associated with a neurodegenerative disease or condition may respond to the treatment methods disclosed herein. Symptoms of a neurodegenerative disease or condition vary depending on the stage of the disease, but may include, but are not limited to, improvements in CNS function, cognition, learning, memory, and plasticity.

[0156] As used herein, the term "CNS function" refers to, among other things, receiving and processing sensory information, thinking, learning, remembering, perceiving, producing and understanding language, controlling motor functions and auditory and visual responses, maintaining balance and equilibrium, motor coordination, transmitting sensory information, and controlling autonomic functions such as breathing, heart rate, and digestion.

[0157] The terms "cognition," "cognitive function," and "cognitive ability" are used interchangeably herein and relate to any mental process or state, including, but not limited to, learning, memory, image generation, thinking, recognition, reasoning, spatial ability, speech and language skills, language acquisition, and judgment. Cognition is formed in multiple regions of the brain, including the hippocampus, cortex, and other brain structures. However, long-term memory is postulated to be stored, at least in part, in the cortex, and sensory information is known to be acquired, integrated, and retrieved by a specific cortical structure, the gustatory cortex, located within the insular cortex.

[0158] In humans, cognitive function can be measured by any known method, for example, but not limited to, the Global Clinical Assessment of Individuals (CIBIC-plus scale), Mini-Mental State Examination (MMSE); Neuropsychiatric Inventory (NPI); Clinical Dementia Rating Scale (CDR); Cambridge Neuropsychological Automated Test (CANTAB) or the Sandoz Clinical Assessment-Geriatric (SCAG). Cognitive function can also be measured indirectly using imaging techniques such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single-photon emission computed tomography (SPECT), or any other imaging techniques that can measure brain function.

[0159] Improving one or more processes that affect a patient's cognition means improving cognitive function in the patient; thus, in certain embodiments, improving cognition includes improving learning, plasticity, and / or long-term memory. The terms "improve" and "enhance" can be used interchangeably. The term "learning" refers to acquiring or obtaining, or modifying or strengthening existing knowledge, behavior, skills, values, or preferences. The term "memory" refers to the process by which information is coded, stored, and retrieved. Memory has three distinct categories: sensory memory, short-term memory, and long-term memory.

[0160] The term "long-term memory" refers to the ability to retain information for extended periods or indefinitely. Long-term memory is comprised of two major divisions: explicit (declarative) and implicit (non-declarative) memory. Long-term memory is achieved through memory consolidation, a category of processes that stabilizes memory traces after initial acquisition. Consolidation is differentiated into two specific processes: synaptic consolidation, which occurs within the first few hours after learning, and systems consolidation, where hippocampus-dependent memories become independent of the hippocampus over weeks to years.

[0161] The term "plasticity" refers to synaptic plasticity, brain plasticity, or neuroplasticity, which refers to the brain's ability to change with learning and alter previously acquired memories. One measurable parameter that reflects plasticity is memory extinction.

[0162] Aspects of the present specification provide, in part, for administering a modified anti-PD-L1 antibody disclosed herein or a therapeutic composition disclosed herein. As used herein, the term "administering" refers to any delivery mechanism that provides an immunogenic composition or therapeutic composition disclosed herein to an individual, which may result in a clinically, therapeutically, or experimentally beneficial outcome. The actual delivery mechanism used to administer a composition disclosed herein to an individual can be determined by one of skill in the art by taking into consideration factors such as, but not limited to, the type of neurodegenerative disease, the location of the neurodegenerative disease, the cause of the neurodegenerative disease, the severity of the neurodegenerative disease, the desired degree of relief of the neurodegenerative disease, the desired duration of relief of the neurodegenerative disease, the particular anti-PD-L1 antibody and / or therapeutic composition used, the excretion rate of the particular anti-PD-L1 antibody and / or therapeutic composition used, the pharmacodynamics of the particular anti-PD-L1 antibody and / or therapeutic composition used, the nature of other compounds included in the therapeutic composition, the particular route of administration, the specific characteristics, and the individual's history and risk factors, such as age, weight, general health, etc., or any combination thereof.

[0163] The compositions disclosed herein can be administered to an individual using a cellular uptake approach. Administration of the compositions disclosed herein using a cellular uptake approach includes, but is not limited to, various enteral or parenteral approaches, such as oral administration in any acceptable form (e.g., tablets, liquids, capsules, powders, etc.), topical administration in any acceptable form (e.g., drops, sprays, creams, gels, or ointments), intravascular administration in any acceptable form (e.g., intravenous injection, intravenous infusion, intraarterial injection, intraarterial infusion into the vascular system, and catheter infusion), peri- and intra-tissue administration in any acceptable form (e.g., intraperitoneal injection, intramuscular injection, subcutaneous injection, intraocular injection, retinal injection, or subretinal or epidural injection), intravesicular administration in any acceptable form (e.g., catheter infusion), and via a placement device (e.g., implant, patch, pellet, catheter, osmotic pump, suppository, bioerodible delivery system, non-bioerodible delivery system, or another implanted sustained or sustained release system). An exemplary list of biodegradable polymers and uses can be found, for example, in Handbook of Biodegradable Polymers (Abraham J. Domb et al., eds., Overseas Publishers Association, 1997).

[0164] The modified anti-PD-L1 antibodies disclosed herein and / or therapeutic compositions disclosed herein are administered in an amount sufficient to treat a neurodegenerative disease. In aspects of this embodiment, the amount of anti-PD-L1 antibody and / or therapeutic composition administered is sufficient to alleviate one or more physiological conditions or symptoms associated with a neurodegenerative disease or condition, or to protect the individual against a neurodegenerative disease or condition. As used herein, the term "sufficient amount" includes an "effective amount," "effective dose," "therapeutically effective amount," or "therapeutically effective dose," and refers to the minimum amount of a modified anti-PD-L1 antibody and / or therapeutic composition disclosed herein needed to achieve the desired therapeutic effect, including an amount sufficient to alleviate or inhibit one or more physiological conditions or symptoms associated with a neurodegenerative disease or condition.

[0165] In aspects of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a neurodegenerative disease or condition, e.g., by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In other aspects of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a neurodegenerative disease or condition, e.g., by up to 10%, up to 20%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, up to 90%, or up to 100%. In yet another aspect of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein may alleviate one or more physiological conditions or symptoms associated with a neurodegenerative disease or condition by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, or more than about 10%. %, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50% reduction or inhibition. In yet another aspect of this embodiment, an effective amount of a modified anti-PD-L1 antibody and / or therapeutic composition disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with a neurodegenerative disease or condition, for example, at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0166] The actual effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein to be administered to an individual can be determined by one of skill in the art by taking into consideration factors such as, but not limited to, the type of neurodegenerative disease, the location of the neurodegenerative disease, the cause of the neurodegenerative disease, the severity of the neurodegenerative disease, the desired degree of relief of the neurodegenerative disease, the desired duration of relief of the neurodegenerative disease, the particular anti-PD-L1 antibody and / or therapeutic composition used, the excretion rate of the particular anti-PD-L1 antibody and / or therapeutic composition used, the pharmacodynamics of the particular anti-PD-L1 antibody and / or therapeutic composition used, the immunogenicity or properties of other compounds included within the therapeutic composition, the particular route of administration, the particular characteristics, history and risk factors of the individual, such as age, weight, general health, etc., or any combination thereof. Furthermore, when repeated administration of the modified anti-PD-L1 antibodies disclosed herein and / or therapeutic compositions disclosed herein is used, the actual therapeutically effective amount will further depend on factors such as, but not limited to, the frequency of administration, the half-life of the modified anti-PD-L1 antibodies disclosed herein and / or therapeutic compositions disclosed herein, or any combination thereof. Those skilled in the art will recognize that effective amounts of the modified anti-PD-L1 antibodies disclosed herein and / or therapeutic compositions disclosed herein can be estimated from in vitro assays using animal models and in vivo administration studies prior to administration to humans. Given the differing efficiencies of various administration routes, wide variations in the required effective amount are to be expected. For example, oral administration would generally be expected to require higher dosage levels than administration by intravenous or intravitreal injection. These variations in dosage levels can be adjusted using standard empirical optimization routines, which are well known to those skilled in the art. The precise therapeutically effective dosage level and pattern is preferably determined by the attending physician, taking into account the factors identified above.

[0167] In other aspects of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein generally ranges from about 0.001 mg / kg / day to about 100 mg / kg / day. In aspects of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein can be, for example, at least 0.001 mg / kg / day, at least 0.01 mg / kg / day, at least 0.1 mg / kg / day, at least 1.0 mg / kg / day, or at least 5.0 mg / kg / day. In other aspects of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein may range, for example, from about 0.001 mg / kg / day to about 0.01 mg / kg / day, from about 0.001 mg / kg / day to about 0.1 mg / kg / day, from about 0.001 mg / kg / day to about 1.0 mg / kg / day, or from about 0.001 mg / kg / day to about 5.0 mg / kg / day. kg / day, about 0.01 mg / kg / day to about 0.1 mg / kg / day, about 0.01 mg / kg / day to about 1.0 mg / kg / day, about 0.01 mg / kg / day to about 5.0 mg / kg / day, about 0.1 mg / kg / day to about 1.0 mg / kg / day, about 0.1 mg / kg / day to about 5.0 mg / kg / day, or about 1.0 mg / kg / day to about 5.0 mg / kg / day.

[0168] In other aspects of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein generally ranges from about 0.001 mg / day to about 100 mg / day. In aspects of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein can be, for example, at least 0.001 mg / day, at least 0.01 mg / day, at least 0.1 mg / day, at least 1.0 mg / day, at least 5.0 mg / day, at least 10 mg / day, at least 15 mg / day, at least 20 mg / day, at least 25 mg / day, at least 30 mg / day, at least 35 mg / day, at least 40 mg / day, at least 45 mg / day, or at least 50 mg / day.

[0169] In other aspects of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein may be in the range of, for example, about 0.001 mg / day to about 10 mg / day, about 0.001 mg / day to about 15 mg / day, about 0.001 mg / day to about 20 mg / day, about 0.001 mg / day to about 25 mg / day, about 0.001 mg / day to about 30 mg / day, about 0.001 mg / day to about 35 mg / day, about 0.001 mg / day to about 40 mg / day, about 0.001 mg / day to about 45 mg / day, about 0.001 mg / day to about 50 mg / day, about 0.001 mg / day to about 75 mg / day, or about 0.001 mg / day to about 100 mg / day. In yet another aspect of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein may be in the range of, for example, about 0.01 mg / day to about 10 mg / day, about 0.01 mg / day to about 15 mg / day, about 0.01 mg / day to about 20 mg / day, about 0.01 mg / day to about 25 mg / day, about 0.01 mg / day to about 30 mg / day, about 0.01 mg / day to about 35 mg / day, about 0.01 mg / day to about 40 mg / day, about 0.01 mg / day to about 45 mg / day, about 0.01 mg / day to about 50 mg / day, about 0.01 mg / day to about 75 mg / day, or about 0.01 mg / day to about 100 mg / day. In yet another aspect of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein may be in the range of, for example, about 0.1 mg / day to about 10 mg / day, about 0.1 mg / day to about 15 mg / day, about 0.1 mg / day to about 20 mg / day, about 0.1 mg / day to about 25 mg / day, about 0.1 mg / day to about 30 mg / day, about 0.1 mg / day to about 35 mg / day, about 0.1 mg / day to about 40 mg / day, about 0.1 mg / day to about 45 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 75 mg / day, or about 0.1 mg / day to about 100 mg / day.

[0170] In other aspects of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein may be in the range of, for example, about 1 mg / day to about 10 mg / day, about 1 mg / day to about 15 mg / day, about 1 mg / day to about 20 mg / day, about 1 mg / day to about 25 mg / day, about 1 mg / day to about 30 mg / day, about 1 mg / day to about 35 mg / day, about 1 mg / day to about 40 mg / day, about 1 mg / day to about 45 mg / day, about 1 mg / day to about 50 mg / day, about 1 mg / day to about 75 mg / day, or about 1 mg / day to about 100 mg / day. In yet another aspect of this embodiment, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein may be in the range of, for example, about 5 mg / day to about 10 mg / day, about 5 mg / day to about 15 mg / day, about 5 mg / day to about 20 mg / day, about 5 mg / day to about 25 mg / day, about 5 mg / day to about 30 mg / day, about 5 mg / day to about 35 mg / day, about 5 mg / day to about 40 mg / day, about 5 mg / day to about 45 mg / day, about 5 mg / day to about 50 mg / day, about 5 mg / day to about 75 mg / day, or about 5 mg / day to about 100 mg / day.

[0171] Dosing can be a single dose or cumulative (sequential dosing) and can be readily determined by one of skill in the art. For example, treating a neurodegenerative disease can involve a single administration of an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein. As a non-limiting example, an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein can be administered to an individual once, for example, as a single injection or deposition. Alternatively, treating a neurodegenerative disease can involve multiple administrations of an effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein, administered over a range of time periods, such as daily, once every few days, weekly, monthly, or yearly. As a non-limiting example, a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein can be administered to an individual once, twice, three times, four times, five times, or six times per year. The timing of administration can vary from individual to individual, depending on factors such as the severity of the individual's symptoms. For example, an effective amount of an engineered anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein may be administered to an individual once every three months, indefinitely, or until the individual no longer requires treatment. One of skill in the art will recognize that the individual's condition can be monitored throughout the course of treatment and the effective amount of an engineered anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein administered can be adjusted accordingly.

[0172] Compositions comprising the modified anti-PD-L1 antibodies disclosed herein and / or therapeutic compositions disclosed herein may also be administered to an individual in combination with other therapeutic compounds to increase the overall therapeutic effect of the treatment. The use of multiple compounds to treat an indication can increase beneficial effects while reducing the presence of side effects.

[0173] In one embodiment, the method or use for treating a neurodegenerative disease comprises a dosing regimen comprising at least two treatment courses, each course of treatment comprising, in sequence, a treatment session followed by an interval session without treatment.The disclosed method or use comprises administering to an individual in need thereof a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein, wherein the anti-PD-L1 antibody and / or therapeutic composition disclosed herein is administered by a dosing regimen comprising at least two treatment courses, each course of treatment comprising, in sequence, a treatment session followed by an interval session without treatment.

[0174] The term "treatment session" is used interchangeably herein with the terms "treatment period" or "period of treatment" and refers to a session in which a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein is administered to an individual undergoing treatment. A treatment session does not result in a therapeutically effective amount of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein being consistently maintained throughout the treatment session. As discussed in more detail below, sub-therapeutic levels of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein occur during a treatment session. A treatment session may be a single dosing event, or may be a multiple dosing regimen administered over a period of time.

[0175] The term "non-treatment session" is used interchangeably herein with the terms "non-treatment period," "period of no treatment," "interval session," or "non-treatment interval session," and refers to a period of time during which a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein is not administered to an individual receiving treatment. During a non-treatment session, the level of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein is sub-therapeutic in the individual receiving treatment. As disclosed herein, a "non-treatment session" is not the same event as the intervening period between dosing events that make up the multiple dosing regimen that occur over a period of time during a treatment session. When the administration of a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein during a treatment session is repeated, the non-treatment session is longer than the intervening period between these repeated doses during the treatment session.

[0176] Dosing regimens can be determined in multiple ways. For example, the level of immunosuppression can be calibrated to a desired level for each patient being treated by individually monitoring the level or activity of IFN-γ-producing leukocytes or the rate of leukocyte proliferation in response to stimulation, and empirically and individually adjusting treatment sessions, frequency of administration, and interval sessions as determined from the results of the monitoring (personalized medicine).

[0177] In one embodiment, a treatment session comprises administering to an individual an modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein to achieve half the maximal effective concentration (EC 50 ) and this EC 50is maintained during the treatment session for a specified period of time, at which point administration is then stopped to reduce the level of the modified anti-PD-L1 antibody disclosed herein and / or therapeutic composition disclosed herein to a sub-therapeutic level. The non-treatment period is maintained for a specified period of time, and / or for as long as the beneficial effect on cognition is maintained above levels before treatment began or above cognitive levels before the last treatment session. In aspects of this embodiment, a beneficial effect on cognition is maintained is one that represents, for example, at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 80%, or at least a 90% improvement over levels before treatment began or cognitive levels before the last treatment session.

[0178] In certain embodiments, a treatment session involves administering a modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein to an individual to achieve at or above a minimum effective concentration (MEC), which is maintained during the treatment session for a specified period of time, at which point administration is stopped to reduce the level of the modified anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein to a sub-therapeutic level. The non-treatment period is maintained for a specified period of time and / or for as long as the beneficial effect on cognition is maintained above levels before treatment began or above cognitive levels before the last treatment session. In aspects of this embodiment, a beneficial effect on cognition is maintained is an effect that shows an improvement of, for example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% over levels before treatment began or above cognitive levels before the last treatment session.

[0179] In one embodiment, a treatment session comprises administering to an individual an engineered anti-PD-L1 antibody disclosed herein and / or a therapeutic composition disclosed herein to achieve half-maximal inhibitory concentration (IC 50 ) and this IC 50is maintained during the treatment session for a specified period of time, at which point administration is then stopped to reduce the level of the modified anti-PD-L1 antibody disclosed herein and / or therapeutic composition disclosed herein to a sub-therapeutic level. The non-treatment period is maintained for a specified period of time, and / or for as long as the beneficial effect on cognition is maintained above levels before treatment began or above cognitive levels before the last treatment session. In aspects of this...

Claims

1. 1. An engineered anti-programmed death-ligand 1 (PD-L1) antibody, comprising: a heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO:3, a CDR2 of SEQ ID NO:5, and a CDR3 of SEQ ID NO:7, and a heavy chain constant region of SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57; and a light chain comprising a light chain variable region comprising CDR1 of SEQ ID NO: 10, CDR2 of SEQ ID NO: 12, and CDR3 of SEQ ID NO: 14; Contains, or a heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO:4, a CDR2 of SEQ ID NO:6, and a CDR3 of SEQ ID NO:8, and a heavy chain constant region of SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57; and a light chain comprising a light chain variable region comprising CDR1 of SEQ ID NO: 11, CDR2 of SEQ ID NO: 13, and CDR3 of SEQ ID NO: 15; Including, the modified anti-PD-L1 antibody has an improved clearance rate from the blood compared to an anti-PD-L1 antibody having a heavy chain constant region of SEQ ID NO: 54 or SEQ ID NO: 108; the engineered anti-PD-L1 antibody lacks Fc-associated effector functions; Engineered anti-PD-L1 antibodies.

2. The anti-PD-L1 antibody of claim 1, wherein the heavy chain variable region is SEQ ID NO:

2.

3. 3. The anti-PD-L1 antibody of claim 2, wherein the heavy chain is SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:

44.

4. The anti-PD-L1 antibody of claim 3, wherein the heavy chain is SEQ ID NO:

42.

5. The anti-PD-L1 antibody of any one of claims 1 to 4, wherein the light chain further comprises a kappa light chain constant region.

6. The anti-PD-L1 antibody of claim 5, wherein the kappa light chain constant region is SEQ ID NO:

16.

7. The anti-PD-L1 antibody of any one of claims 1 to 5, wherein the light chain is SEQ ID NO:

21.

8. 1. An engineered anti-programmed death-ligand 1 (PD-L1) antibody, comprising: a heavy chain comprising a heavy chain variable region of SEQ ID NO:2 and a heavy chain constant region of SEQ ID NO:55, SEQ ID NO:56, or SEQ ID NO:57; and a light chain comprising a light chain variable region of SEQ ID NO: 9 and a light chain constant region of SEQ ID NO: 16; Including, the modified anti-PD-L1 antibody has an improved clearance rate from the blood compared to an unmodified anti-PD-L1 antibody having a heavy chain constant region of SEQ ID NO: 54 or SEQ ID NO: 108; the engineered anti-PD-L1 antibody lacks Fc-associated effector functions; Engineered anti-PD-L1 antibodies.

9. The anti-PD-L1 antibody of claim 8, wherein the heavy chain constant region is SEQ ID NO:

55.

10. A pharmaceutical composition comprising the modified anti-PD-L1 antibody of any one of claims 1 to 9.

11. A pharmaceutical kit comprising the modified anti-PD-L1 antibody of any one of claims 1 to 9 or the pharmaceutical composition of claim 10.

12. The modified anti-PD-L1 antibody of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 for use in the treatment of Alzheimer's disease.

13. 11. Use of the modified anti-PD-L1 antibody of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 in the manufacture of a medicament for the treatment of Alzheimer's disease.

14. A polynucleotide comprising a nucleic acid sequence encoding a heavy chain from the modified anti-PD-L1 antibody of any one of claims 1 to 9 or a nucleic acid sequence encoding a light chain from the modified anti-PD-L1 antibody of any one of claims 1 to 9.

15. 15. The polynucleotide of claim 14, wherein the nucleic acid sequence encoding the heavy chain comprises SEQ ID NO:59, SEQ ID NO:63, SEQ ID NO:75, or SEQ ID NO:79, and the nucleic acid sequence encoding the light chain comprises SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:86, or SEQ ID NO:

87.

16. 16. An expression construct comprising a nucleic acid sequence encoding a heavy chain from the modified anti-PD-L1 antibody of claim 14 or 15.

17. 16. An expression construct comprising a nucleic acid sequence encoding a light chain from the modified anti-PD-L1 antibody of claim 14 or 15.

18. 18. A method of making an engineered anti-PD-L1 antibody, comprising expressing in a host cell a first and a second expression construct, wherein the first expression construct is described in claim 16 and the second expression construct is described in claim 17.

Images