Modified anti-pd-l1 antibodies and methods and uses for treating neurodegenerative diseases

Abstract

The present specification discloses modified anti-PD-Ll antibodies that eliminate Fc- associated effector functions and enhance clearance while maintaining therapeutic efficacy on neurodegenerative disease alterations. The present specification also discloses nucleic acid sequences and expression constructs encoding such modified anti-PD-Ll antibodies, and methods of making such modified anti-PD-Ll antibodies. In addition, the present specification discloses methods of treatment and uses employing administration regimens of the disclosed anti-PD-Ll antibodies that ensure that the antibodies are only present for a specific period of time and then are sufficiently cleared from the body to ensure maintenance of therapeutic efficacy.

Description

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

[0002] Neurodegeneration is the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases arise as a result of neurodegenerative processes, leading to progressive decline in behavioral, social, cognitive, or motor abilities. Currently, there are no effective treatments to cure, alter, or stop the progression of neurodegenerative diseases, and approved drug therapies provide only weak and transient relief of symptoms.

[0003] Most neurodegenerative diseases share common neuroinflammatory components that are part of the disease progression and contribute to disease exacerbation. Among these diseases are Alzheimer’s disease (AD) and age-related dementia, amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease, debilitating neurodegenerative conditions characterized by progressive cognitive and / or functional decline. However, despite the presence of chronic neuroinflammatory components in neurodegenerative disease pathologies, clinical therapies using anti-inflammatory agents have been proven unsuccessful or even harmful over the past decade.

[0004] The present specification provides unique insights into why targeting the inflammatory components of neurodegenerative diseases with systemic anti-inflammatory drugs has failed. The present specification provides therapeutic agents, methods, and uses that overcome the shortcomings of existing therapies for neurodegenerative diseases based on this understanding.

[0005] SUMMARY

[0006] The present specification discloses a modified anti-Programmed Death Ligand 1 (anti-PD-L1) antibody that exhibits high affinity and specificity for human PD-L1, enhanced clearance from the blood, ablated Fc-associated effector functions, and an improved safety profile relative to unaltered antibodies, while maintaining therapeutic efficacy in neurodegenerative disease modifications. The disclosed modified anti-PD-L1 antibody comprises a heavy chain constant domain comprising an amino acid sequence variant that lacks Fc-associated effector functions and promotes faster clearance of the modified anti-PD-L1 antibody disclosed herein than an anti-PD-L1 antibody that does not comprise the same amino acid sequence variant. For example, the disclosed modified anti-PD-L1 antibody comprises a heavy chain constant domain comprising an amino acid sequence variant in the lower hinge region and / or N-terminal half of the CH2 domain that ablates Fc-associated effector functions and an amino acid sequence variant in the CH2 domain and / or CH3 domain that promotes faster clearance of the anti-PD-L1 antibody than an anti-PD-L1 antibody that does not comprise the same amino acid variant in the CH2 domain and / or CH3 domain. The disclosed modified human anti-PD-L1 antibody that lacks Fc-associated effector functions lacks antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity activity (CDC), and / or antibody-dependent cellular phagocytosis (ADCP).

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

[0008] The present specification also discloses pharmaceutical kits comprising the modified human anti-PD-L1 antibody disclosed herein, the pharmaceutical composition disclosed herein, or the medicament disclosed herein.

[0009] The present specification also discloses therapeutic methods and uses employing an administration regimen using the disclosed modified anti-PD-L1 antibody that ensures that the antibody is only present for a specific period of time and then is sufficiently cleared from the body to ensure maintenance of therapeutic efficacy. BRIEF DESCRIPTION OF DRAWINGS

[0011] Figures 1A-1E Blocking CCR2 abrogated the beneficial effects of anti-PD-L1 antibodies in DM-hTAU, where Figure 1A Experimental design is illustrated; Figure 1B Pre-test results of cognitive behavior in DM-hTAU and wild-type animals are illustrated; Figure 1C Results of cognitive behavior after treatment using T-maze testing are illustrated; Figure 1Dcognitive behavior test results after treatment using the Y-maze test; and Figure 1E cognitive behavior test results after treatment using the Novel Object recognition (NOR) test.

[0012] Figures 2A-2D showing that blocking CCR2 selectively affected only monocyte levels in circulation, but not T cell levels, wherein Figure 2A showing levels of myeloid cells in blood; Figure 2B showing myeloid cells in spleen; Figure 2C showing CD4 + memory T cell levels in blood; and Figure 2D showing CD4 + memory T cells in spleen.

[0013] Figures 3A-3B showing flow cytometry of brain cells for analysis of CD45 低 / CD11b 高 and CD45 高 / CD11b 高 myeloid cells in DM-hTAU mice treated with anti-PD-Ll antibody or IgG antibody, wherein Figure 3A showing flow cytometry of brain cells gated for CD45 低 / CD11b 高 and CD45 高 / CD11b 高 myeloid cells; and Figure 3B showing quantification of CD45 高 / CD11b 高 myeloid cells in anti-PD-Ll treated mice and IgG treated mice.

[0014] Figures 4A-4B showing flow cytometry of brain cells for analysis of CD45 低 / CD11b 高 and CD45 高 / CD11b 高 myeloid cells in GFP-BM-chimeric DM-hTAU mice treated with anti-PD-Ll antibody or IgG antibody, wherein Figure 4A showing flow cytometry of GFP-labeled brain cells gated for CD45 低 / CD11b 高 and CD45 高 / CD11b 高 myeloid cells; and Figure 4B showing quantification of CD45高 / CD11b 高 Quantitative distribution of myeloid cells.

[0015] Figures 5A-5B Confocal images from brains of GFP-BM-chimeric DM-hTAU mice treated with anti-PD-Ll antibody or IgG antibody analyzed by immunohistochemistry are shown, wherein Figure 5A Representative confocal z-axis stacks projections are shown, indicating DM-hTAU treated with anti-PD-Ll GFP / + GFP detected in the cortex of mice + Colocalization of cells (in green) with myeloid marker IBA-1 (in blue) (see arrows, scale bar: 100 pm); and Figure 5B Representative confocal z-axis stacks projections are shown, indicating DM-hTAU treated with anti-PD-Ll GFP / + GFP in the brain of mice + Colocalization of cells (green), IBA-1 (blue) and IL-10 (red) (scale bar: 50 pm).

[0016] Figures 6A-6C Dose response dependent effect of anti-PD-Ll on spatial learning and memory in 5XFAD mice is shown, wherein Figure 6A Experimental design is illustrated, wherein black arrows indicate time points of treatment and graphical illustrations indicate time points of cognitive scoring using radial arm water maze (RAWM) assay; Figure 6B RAWM performance of 5XFAD mice (each group treated with different doses of anti-PD-Ll antibody) one month after treatment, and wild type littermates used as controls, is shown (*P<0.05, **P<0.01, ***P<0.001); and Figure 6C RAWM performance of three groups of 5XFAD mice (each group treated with different doses of anti-PD-Ll antibody) two months after treatment, and wild type littermates used as controls, is shown (*P<0.05, **P<0.01, ***P<0.001).

[0017] Figures 7A-7C Dose dependent effect of anti-PD-Ll on hippocampal astrogliosis in 5XFAD mice is shown, wherein Figure 7A Area of all detected GFAP + cells divided by total selected area of dentate gyrus (*P<0.05, **P<0.01); Figure 7Bshows detected GFAP corrected for average fluorescence for the entire dentate gyrus + average fluorescence of cells (CTCF) (**P<0.01); and Figure 7C shows detected GFAP exhibiting fluorescence greater than 1000 pixels + number of cells (**P<0.01).

[0018] Figures 8A-8B shows dose response dependent effect of anti-PD-Ll on spatial learning and memory in DM-hTAU mice, wherein Figure 8A illustrates experimental design, wherein black arrows indicate time points of treatment, and figure indicates time point of cognitive scoring using T-maze assay; and Figure 8B shows T-maze performance of DM-hTAU mice one month after treatment (each group treated with different doses of anti-PD-Ll antibody) and wild type littermates and anti-IgG2 treated mice, both used as controls (*P<0.05, **P<0.01, ***P<0.001).

[0019] Figures 9A-9B shows dose response dependent and time dependent effect of anti-PD-Ll on spatial learning and memory in DM-hTAU mice, wherein Figure 9A shows T-maze performance of three groups of DM-hTAU mice one month after treatment (each group treated with different doses of anti-PD-Ll antibody) and wild type littermates and anti-IgG2 treated mice, both used as controls (*P<0.05, **P<0.01, ***P<0.001); and Figure 9B shows T-maze performance of three groups of DM-hTAU mice two months after treatment (each group treated with different doses of anti-PD-Ll antibody) and wild type littermates and anti-IgG2 treated mice, both used as controls (*P<0.05, **P<0.01, ***P<0.001).

[0020] Figure 10 shows quantification of AT-180 immunoreactivity (phospho-Tau (Thr231)) in brains of wild type mice and DM-hTAU mice treated with rat anti-PD-Ll antibody or rat anti-KLH antibody (both with IgG2b Fc) as control (error bars represent mean ± s.e.m.; *P<0.05).

[0021] Figures 11A-11I shows dose dependent effect of anti-PD-Ll on inflammatory cytokine profile in DM-hTAU mice, wherein Figure 11ARepresentative images showing IL-1 b immunoreactivity in mice treated with anti-PD-L1 antibody; Figure 11B Representative images showing IL-1 b immunoreactivity in mice treated with anti-PD-L1 antibody; Figure 11C Representative confocal z-stack orthogonal projections showing co-localization of IL-1 b (green) with GFAP+ astrocytes (red) but not with IBA-1 + microglia / macrophages (white) in the dentate gyrus; nuclei were stained with DAPI (blue) (scale bar, 100 pm); Figure 11D Quantitative measurement of hippocampal IL-1 b protein levels measured by FRET-based ELISA in mice treated with anti-PD-L1 antibody compared to untreated and anti-IgG antibody treated wild-type littermates (data represented as mean ± s.e.m; *P<0.05, **P<0.01, ***P<0.001); Figure 11E Linear regression analysis revealing the correlation between cognitive performance of DM-hTAU mice in the T-maze assay and their IL-1 b protein levels in the brain; Figure 11F Quantitative measurement of mRNA expression levels of the gene tnf-a tested by RT-qPCR; Figure 11G Quantitative measurement of mRNA expression levels of the gene il-6 tested by RT-qPCR; Figure 11H Quantitative measurement of mRNA expression levels of the gene il-12p40 tested by RT-qPCR; and Figure 11I Quantitative measurement of mRNA expression levels of the gene IL-1 b measured by RT-qPCR.

[0022] Figure 12 PK profile of anti-PD-L1 antibody in serum taken from C57BL / 6J mice and quantified using enzyme-linked immunosorbent assay (ELISA) is shown.

[0023] Figure 13 Kinetics of PD-L1 receptor occupancy on T cells in blood from 5XFAD and C57BL / 6J wild-type mice after a single injection of different doses of rat anti-mouse PD-L1 monoclonal antibody (clone 10F.9G2, BioXCell) compared to control treated with rat IgG2b anti-KLH antibody (error bars represent mean ± s.e.m.; *P<0.05, **P<0.01, ***P<0.001) are shown.

[0024] Figure 14This demonstrates PD-1 expression in 5XFAD and C57BL / 6J wild-type (WT) mice following a single injection of multiple doses of rat anti-mouse PD-L1 monoclonal antibody (clone 10F.9G2, BioXCell), compared to rat anti-KLH antibody treatment. + Effector memory T cells (CD4) + CD44 + The level of cell populations, where each point on the graph represents a blood sample from a different mouse (error bars represent mean ± sem; *P<0.05, **P<0.01, ***P<0.001).

[0025] Figure 15 The p-p-kP profile of rat anti-mouse PD-L1 monoclonal antibody (clone 10F.9G2, BioXCell) in mice, quantified by ELISA, is shown.

[0026] Figure 16 This study compares the therapeutic effects of a single injection of anti-PD-L1 versus repeated injections of anti-PD-L1 (representing transient exposure to the treatment versus continuous exposure to the treatment, respectively) on cognitive performance in 5XFAD mice tested at 1 month and 2 months after the first injection. Cognitive performance in 5XFAD mice was assessed using the radial arm water maze, and the effects of treatment in different groups are expressed as the percentage of mice exhibiting positive learning behavior (positive learning was defined as fewer than 3 average errors in the last two trials of the cognitive task).

[0027] Figure 17 T-maze performance is shown in DM-hTAU mice one month after anti-PD-L1 antibody treatment with rat anti-PD-L1 antibody, humanized anti-PD-L1 antibody atezolizumab (ATZ; with human IgG1 Fc), or variant 1-ATZ (Fc effector null) antibody, as well as wild-type mice (all as controls), untreated DM-hTAU mice, and mice treated with human anti-B12 antibody (as IgG1 isotype control) (error bars represent mean ± sem; *P<0.05, **P<0.01, ***P<0.001).

[0028] Figure 18 The detected GFAP is shown based on the average halosalpingography corrected for the entire dentate gyrus. +Comparison of the effect of the average fluorescence of cells (CTCF), anti-PD-Ll antibodies (rat anti-mouse PD-L1 with rat IgG2b anti-KLH antibody, anti-PD-Ll atezolizumab with human IgGl backbone, and variant 1-ATZ (Fc effector null)) on hippocampal astrocyte proliferation in DM-hTAU mice (error bars represent mean ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001).

[0029] Figure 19 PK profiles of anti-human PD-L1 atezolizumab (ATZ) and four ATZ variants in serum taken from wild-type C57BL / 6J mice and quantified using reverse ELISA are shown (error bars represent mean ± s.e.m.).

[0030] Figures 20A-20D Effect of modified anti-PD-Ll antibody variants on spatial learning and memory in DM-hTAU mice is shown, wherein Figure 20A Experimental design is illustrated, wherein black arrows indicate time points of treatment and graphical illustrations indicate time points of cognitive scoring using T-maze or Y-maze assays; Figure 20B T-maze performance of DM-hTAU mice (each group treated with a different anti-PD-Ll antibody variant) four weeks after treatment, as well as wild-type littermates and variant 1-B12 treated mice, both used as controls, is shown (error bars represent mean ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001); Figure 20C Y-maze performance of DM-hTAU mice (each group treated with a different anti-PD-Ll antibody variant) six weeks after treatment, as well as wild-type littermates and variant 1-B12 treated mice, both used as controls, is shown (error bars represent mean ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001); and Figure 20D T-maze performance of DM-hTAU mice (each group treated with a different anti-PD-Ll antibody variant) eight weeks after treatment, as well as wild-type littermates and variant 1-B12 treated mice, both used as controls, is shown (error bars represent mean ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001).

[0031] Figure 21The effect of modified anti-PD-Ll antibody variants on spatial learning and memory of 5XFAD mice assessed one month after treatment using RAWM cognitive tasks is shown, each group treated with a different modified anti-PD-Ll antibody variant or rat anti-mouse PD-Ll antibody, and both wild type littermate mice and anti-B12 treated mice were used as controls (error bars represent mean ± s.e.m.).

[0032] Figures 22A-22B The PK profile quantified using ELISA in serum taken from C57BL / 6J mice using multiple doses of two different modified anti-PD-Ll antibody variants is shown, wherein Figure 22A The results obtained with variant 2-ATZ (Fc effector null - H311A) antibody are shown (error bars represent mean ± s.e.m.); and Figure 22B The results obtained by variant 3-ATZ (Fc effector null - H436Q) antibody are shown (error bars represent mean ± s.e.m.).

[0033] Figures 23A-23B The kinetics of PD-L1 receptor occupancy on T cells in blood from C57BL / 6J wild type mice after a single injection of two different modified anti-PD-Ll antibody variants is shown, wherein Figure 23A The results obtained with variant 2-ATZ (Fc effector null - H311A) antibody are shown (error bars represent mean ± s.e.m.); and Figure 23B The results obtained by variant 3-ATZ (Fc effector null - H436Q) antibody are shown (error bars represent mean ± s.e.m.).

[0034] Figures 24A-24B The PD-1 + CD4 + CD44 + T cell blood levels kinetics in C57BL / 6J wild type mice after a single injection of two different modified anti-PD-Ll antibody variants is shown, wherein Figure 24A The results obtained with variant 2-ATZ (Fc effector null - H311A) antibody are shown (error bars represent mean ± s.e.m.); and Figure 24B The results obtained by variant 3-ATZ (Fc effector null - H436Q) antibody are shown (error bars represent mean ± s.e.m.).

[0035] Figure 25Dose-dependent effects of two different modified anti-PD-Ll antibody variants on spatial learning and memory of DM-hTAU mice four weeks after treatment are shown (data are presented as mean ± s.e.m.; *P<0.05, **P<0.01, ***P<0.001).

[0036] Figures 26A-26C Longitudinal measurements of cognitive performance at 2 and 4 weeks after administration of 1.5 mg / mouse of anti-PD-Ll variant 2-ATZ (Fc effector null-H311A) or isotype control variant 2-B12 (anti-B12 antibody comprising human IgGl Fc effector null and H311A substitution in the Fc part (same substitution as for variant 2-ATZ)) are shown, wherein Figure 26A The time spent in the new arm of the T-maze by each individual mouse measured at 2 and 4 weeks after treatment is shown, presented and connected with solid lines; Figure 26B The same data, but comparing the performance in the T-maze between the different treatment groups at 2 weeks after treatment are shown; Figure 26A The same data, but comparing the performance in the T-maze between the different treatment groups at 4 weeks after treatment are shown. One-way ANOVA and Fisher’s exact test post-hoc analysis. Data are presented as mean ± s.e.m. Figure 26C Figure 26A

[0037] Figure 27 CD3 + Kinetics of PD-L1 receptor occupancy on T cells (error bars represent mean ± s.e.m.).

[0038] Figures 28A-28H Effects of variant 2-ATZ (Fc effector null-H311A) antibody or isotype control variant 2-B12 (anti-B12 antibody comprising human IgGl Fc effector null and H311A substitution) on spatial learning and memory of DM-hTAU mice are shown, wherein Figure 28A Experimental design is illustrated, wherein black arrows indicate time points of treatment, red arrows indicate time points of blood withdrawal and tissue collection, and a diagram indicates time points of cognitive scoring using the T-maze; Figure 28B ​​T-maze performance of DM-hTAU mice and wild-type littermates two weeks after first treatment with variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody is shown (error bars represent mean ± s.e.m.; n.s.: not significant, ***P<0.001); Figure 28C T-maze performance of DM-hTAU mice and wild-type littermates four weeks after first treatment with variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody is shown (error bars represent mean ± s.e.m.; ***P<0.001); Figure 28D T-maze performance of DM-hTAU mice and wild-type littermates four weeks after second treatment with variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody is shown (error bars represent mean ± s.e.m.; ***P<0.001); Figure 28E T-maze performance of DM-hTAU mice and wild-type littermates two weeks after third treatment with variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody is shown (error bars represent mean ± s.e.m.; ***P<0.001); Figure 28F T-maze performance of DM-hTAU mice and wild-type littermates four weeks after third treatment with variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody is shown (error bars represent mean ± s.e.m.; ***P<0.001); Figure 28G T-maze performance of DM-hTAU mice and wild-type littermates six weeks after third treatment with variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody is shown (error bars represent mean ± s.e.m.; **P<0.01, ***P<0.001); and Figure 28H T-maze performance of DM-hTAU mice and wild-type littermates eight weeks after third treatment with variant 2-ATZ (Fc effector null-H311A) antibody or isotype control antibody is shown (error bars represent mean ± s.e.m.; **P<0.01, ***P<0.001).

[0039] Figure 29 Isolation of CD3+T cells from blood, cervical lymph nodes, inguinal lymph nodes and choroid plexus (CP) tissues of DM-hTAU mice at different time points after treatment with different doses of variant 2-ATZ (Fc effector null-H311A) or isotype control variant 2-B12 (anti-B12 antibody comprising human IgGl Fc effector null and H311A substitution (corresponding to the same substitution of variant 2-ATZ) in the Fc part) is shown.+ Dynamics of PD-L1 receptor occupancy on T cells.

[0040] Figure 30 CD4 cells expressing PD-1 are shown. + The level of memory T lymphocytes (total CD4) + / CD44 + PD-1 in the population + Percentage of cells (error bars represent mean ± sem; *P<0.05, **P<0.01, ***P<0.001).

[0041] Figures 31A-31B The relative hippocampal aggregation of tau in DM-hTau mice is shown (normalized against manufacturer's negative control; arbitrary units), where Figure 31A The quantitative measurements of aggregation in hippocampus excised on days 3 and 48 post-injection, as measured by FRET-based ELISA, are shown (error bars represent mean ± sem; *P<0.05, **P<0.01, ***P<0.001); and Figure 31B The correlation between hippocampal tau aggregation in hippocampal cells cut from the hippocampus two weeks after cognitive performance testing (week 4 of the study) is shown.

[0042] Figure 32 The p-p ...

[0043] Figures 33A-33D The correlation between PD-L1 receptor occupancy and serum concentration of an 84G09-modified anti-PD-L1 antibody variant in cynomolgus monkeys was shown, where Figure 33A The correlation between PD-L1 receptor occupancy and serum concentration of variant 1-G09 (Fc effector null) antibody was shown; Figure 33B The correlation between PD-L1 receptor occupancy and serum concentration of variant 2-G09 (Fc effector null-H315A) antibody was shown; Figure 33C The correlation between PD-L1 receptor occupancy and serum concentration of the variant 3-G09 (Fc effector null-H440Q) antibody was shown; and Figure 33D The correlation between PD-L1 receptor occupancy and serum concentration of the variant 4-G09 (Fc effector null-H315A+H440Q) antibody is shown.

[0044] Figure 34Pharmacodynamic changes in frequency of effector memory CD4 T cells expressing high levels of PD-1 in cynomolgus monkeys treated with different modified anti-PD-L1 antibody variants based on 84G09 are shown. These values represent the percent change in effector memory CD4 T cells expressing high levels of PD-1 normalized to baseline (data presented as mean ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001).

[0045] Figures 35A-35B Pharmacodynamic changes in different T cell subsets following treatment with variant 2-G09 (Fc effector null-H315A) antibody are shown, wherein Figure 35A Central memory T cells are shown; and Figure 35B Effector memory (EM) T cells, central memory (CM) T cells, and naive CD4 - T cells are shown. Data presented as mean ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001.

[0046] Figures 36A-36E ADCC dose-response assays are shown, wherein Figure 36A Dose-response ADCC assays with positive control antibody Rituxan and Raji / CD-20 cells are shown; Figure 36B Dose-response ADCC assays with negative control antibody human IgGl and CHO-K1 / PD-L1 cells are shown; Figure 36C Dose-response ADCC assays with modified anti-PD-L1 antibody variants disclosed herein, variant 2-G09 (Fc effector null-H315A) and CHO-K1 / PD-L1 cells are shown; Figure 36D Dose-response ADCC assays with positive control antibody Rituxan and Raji / CD-20 cells are shown; and Figure 36E Dose-response curves with biosimilars of atezolizumab, a commercially available humanized anti-PD-L1 monoclonal antibody known to be deprived of ADCC Fc activity, and CHO-K1 / PD-L1 cells are shown.

[0047] Figures 37A-37D CDC dose-response assays are shown, wherein Figure 37A Dose-response CDC assays with positive control antibody Rituxan and Raji / CD-20 cells are shown; Figure 37B Dose-response CDC assays with negative control antibody human IgGl and CHO-K1 / PD-L1 cells are shown; Figure 37CDose response CDC assay of modified anti-PD-Ll antibody variants disclosed herein, variant 2-G09 (Fc effector null - H315A) with CHO-K1 / PD-L1 cells is shown; and Figure 37D Dose response assay of biosimilars of atezolizumab, a commercially available humanized anti-PD-Ll monoclonal antibody known to be deprived of ADCC Fc activity, with CHO-K1 / PD-L1 cells is shown.

[0048] Figure 38 Comparison of two modified anti-PD-Ll antibody variants (variant 1-ATZ (Fc effector null) and variant 2-ATZ (Fc effector null - H311A)) and isotype control variant 2-B12 (an anti-B12 antibody comprising a human IgGl Fc effector null and H311A substitution (corresponding to the same substitution of variant 2-ATZ) in the Fc portion) in non-diabetic survival rate after a single injection of a 1.5 mg / mouse dose to 9 week old female NOD mice is shown (P=0.0030).

[0049] Figure 39 Comparison of two modified anti-PD-Ll antibody variants (variant 1-ATZ (Fc effector null) and variant 2-ATZ (Fc effector null - H311A)) and isotype control variant 2-B12 (an anti-B12 antibody comprising a human IgGl Fc effector null and H311A substitution (corresponding to the same substitution of variant 2-ATZ) in the Fc portion) in body weight change after a single injection of a 1.5 mg / mouse dose to 9 week old female NOD mice is shown.

[0050] DETAILED DESCRIPTION

[0051] Physiological entry of immune cells into the CNS is coordinated by the choroid plexus (CP) epithelium of the brain. Transport through the CP is dependent on interferon-gamma (IFN-γ) signaling originating from T cells residing in the periphery, including within the CP stroma. Under pathological conditions, leukocyte transport through the CP is insufficient or even impaired. One approach to enhance transport is by augmenting IFN-γ signaling levels at the CP.

[0052] Immune checkpoints are regulatory pathways used to maintain systemic immunologic homeostasis and tolerance. Without wishing to be bound by any theory, selective blockade of immune checkpoints reactivates the systemic IFN-gamma-dependent immune response cascade that is suppressed due to pathological conditions. Increased IFN-gamma signaling leads to increased levels of leukocyte trafficking molecules expressed by CPs, and in turn, leukocyte migration across the choroid plexus epithelium into the CNS region, and recruitment of monocyte-derived macrophages and other immune modulatory cells (T cells) to the lesion site within the brain. Importantly, this recruitment leads to a composite effect on brain function, including reduced amyloid plaque burden, restored immune balance within the brain parenchyma, reduced neuroinflammation, reduced gliosis, reduced synaptic loss, increased hippocampal neurogenesis, increased neuronal protection and enhanced neuronal survival, collectively resulting in neuroprotection and / or mitigation of cognitive decline. Thus, blockade of immune checkpoints restores healthy brain immune dialogue via increased IFN-gamma signaling, resulting in brain maintenance and repair of pathological conditions.

[0053] The systemic immune response is elicited by the use of neutralizing antibodies against immune checkpoints such as, for example, 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 results in an immune response that clears cerebral amyloid beta protein (Aβ) plaques and improves cognitive performance when induced in animals with established neurodegenerative disease pathology. Thus, the use of neutralizing antibodies against immune checkpoint members results in an IFN-gamma-dependent immune response that reverses the disease state.

[0054] Furthermore, this immune response is required in order to mobilize immune cells to the CNS in a manner that is shown to be IFN-gamma-dependent. Experiments disclosed in this specification demonstrate that systemic single administration of a blocker (e.g., an antibody) of immune checkpoints improves cognitive performance in the context of chronic neurodegenerative disease, which is dependent on peripheral monocyte-derived macrophage entry into the diseased brain (see Example 1). These experiments further show that monocyte-derived macrophages in the diseased brain parenchyma are required to resolve local inflammation, and local phagocytic activity that is required to remove cellular debris and clear pathological conformations of misfolded and aggregated proteins (see Example 1).

[0055] Furthermore, experiments disclosed in this specification reveal that continuous exposure to neutralizing antibodies against immune checkpoint members is not only unnecessary for maintaining beneficial effects, but that prolonged exposure times to such antibodies are less therapeutically effective (see Example 3). These results suggest that the therapeutic efficacy on neurodegenerative diseases is greater when the immune checkpoint pathway is only transiently blocked. This finding is in contrast to cancer therapy, which requires continuous exposure to neutralizing antibodies against immune checkpoints for optimal therapeutic efficacy.

[0056] Not only does transient blockade of the immune checkpoint pathway show greater efficacy in treating neurodegenerative diseases, but such transient exposure should also help reduce the risk of developing immune-related adverse effects, such as autoimmune diseases. This specification discloses that exposure to neutralizing antibodies against immune checkpoint members in young age accelerates the onset of diabetes in non-obese diabetic (NOD) mice that spontaneously develop diabetes in old age. The acceleration of diabetes onset is correlated with antibody exposure, with shorter antibody exposure times resulting in lower diabetes incidence in young age. (See Example 9).

[0057] The discovery that peripheral immune cells cross the blood-cerebrospinal fluid barrier (BCSFB) to recruit into the brain and that transient exposure to neutralizing antibodies is a necessary and essential component to reverse the brain disease state reveals that immune checkpoint antibodies required to achieve the safest and most effective outcome for neurodegenerative diseases require a different and even opposite set of specific characteristics than those required for immune checkpoint antibodies to treat cancer.

[0058] For example, immune checkpoint antibodies with optimal therapeutic efficacy on neurodegenerative diseases should be antibodies that lack cytotoxic activity. Typical full-length antibodies include a fragment crystallizable (Fc) region. Among other things, the Fc region mediates the proper binding of the antibody to appropriate Fc receptors, which initiates several physiological effects, including the lysis of target cells whose membrane surface antigens are bound by the antibody. This lysis mechanism, known as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxic activity (CDC), or antibody-dependent cellular phagocytosis (ADCP), is part of the humoral immune response required to limit and contain infections. However, because the recruitment of peripheral immune cells is required to initiate the reactivation of the systemic IFN-gamma-dependent immune response cascade, immune checkpoint antibodies with Fc effector activity are undesirable because such lysis activity would deplete peripheral immune cells, depleting the cell population required for choroid plexus activation and recruitment to the brain. Thus, antibodies to immune checkpoint members that lack Fc effector function would be an advantageous feature when used in therapies for treating neurodegenerative diseases. However, in the context of cancer therapy, cytotoxic activity can be beneficial because the goal of cancer immunotherapy is to eliminate tumor cells, and thus, the lysis of target cancer cells is highly desirable.

[0059] As another example, an immune checkpoint antibody that has the best therapeutic efficacy for neurodegenerative diseases should be one that can be rapidly cleared from the body (i.e., enhanced clearance rate). As discussed above, the present specification shows that transient blockade of the immune checkpoint pathway shows greater efficacy in treating neurodegenerative diseases compared to continuous exposure of the antibody. In addition, continuous exposure of the antibody increases the risk of triggering an autoimmune response. Thus, when used in a therapy for treating neurodegenerative diseases, an immune checkpoint member antibody that can mediate an effective response but then is removed from the body in a manner that avoids the deleterious effects of continuous exposure to the antibody would be an advantageous feature.

[0060] The present specification discloses a modified anti-PD-Ll monoclonal antibody that eliminates Fc-associated effector functions and enhances the clearance rate of the modified anti-PD-Ll antibody while maintaining the altered therapeutic efficacy for neurodegenerative diseases (Examples 4-8). In addition, the present specification discloses therapeutic methods and uses employing an administration regimen of the disclosed anti-PD-Ll antibody that ensures that the antibody is only present for a specific period of time and then is sufficiently cleared from the body to ensure that the therapeutic efficacy is maintained (Examples 1-9).

[0061] Aspects of the present disclosure include, in part, a modified anti-PD-Ll antibody. The modified anti-PD-Ll antibody disclosed herein can be a typical full-length immunoglobulin molecule comprising two immunoglobulin (Ig) heavy chains and two Ig light chains. Such an antibody comprises an antigen-binding fragment (Fab) and a fragment crystallizable (Fc) region. The preferred modified anti-PD-Ll antibody disclosed herein is a humanized anti-PD-Ll antibody or a human anti-PD-Ll antibody; the more preferred modified anti-PD-Ll antibody disclosed herein is a humanized IgG anti-PD-Ll antibody or a human IgG anti-PD-Ll antibody; the even more preferred modified anti-PD-Ll antibody disclosed herein is a humanized IgGl anti-PD-Ll antibody or a human IgGl anti-PD-Ll antibody. The modified anti-PD-Ll antibody disclosed herein has antagonistic or inactivating activity, preferably neutralizing activity.

[0062] The anti-PD-Ll antibodies disclosed herein can also be variants of full-length antibodies, provided that the variants exhibit the desired biological activities disclosed herein, i.e., abrogating Fc-related effector functions and enhancing clearance of the modified anti-PD-Ll antibodies while maintaining therapeutic efficacy on neurodegenerative disease alterations. For example, the anti-PD-Ll antibody fragments disclosed herein can 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-Ll antibody fragments disclosed herein are described in, e.g., Holliger, P. and Hudson, P.J., Engineered antibody fragments and the rise of single domains. Nat. Biotechnol. 23: 1126-1136 (2005); Cuesta, A.M., Sainz-Pastor, N., Bonet, J., Oliva, B., and Alvarez-Vallina, L., Multivalent antibodies: when design surpasses evolution. Trends Biotechnol. 28: 355-362 (2010); Nelson, A.L., Antibody fragments: hope and hype. MAbs 2, 77-83 (2010), each of which is incorporated herein by reference in its entirety. For general disclosure of antibody and antigen-binding fragment thereof structures, see, e.g., Pluckthun in The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); Borrebaeck, Antibody Engineering, 2nded. (Oxford University Press 1995), each of which is incorporated herein by reference in its entirety. Examples of variants of the modified anti-PD-Ll antibodies disclosed herein include, but are not limited to, fragments of the modified anti-PD-Ll antibodies, single chain variants of the modified anti-PD-Ll antibodies. The anti-PD-Ll antibodies disclosed herein also include molecularly engineered antibodies such as, e.g., diabodies, multibodies, multispecific antibodies, humanized antibodies, human antibodies, chimeric antibodies, bifunctional antibodies, or trifunctional antibodies.

[0063] Full-length anti-PD-Ll 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, while the number of disulfide linkages between heavy chains varies with the different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each light chain has a variable domain at the amino terminus, followed by a single constant domain.

[0064] There are five types of mammalian immunoglobulin heavy chains: gamma (γ), delta (δ), alpha (α), mu (μ), and epsilon (ε), which define five classes of immunoglobulins: IgG, IgD, IgA, IgM, and IgE. The heavy chains of IgG and IgA have about 450 amino acids. The heavy chains of IgM and IgE have about 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 different classes have different constant regions. Each heavy chain has a variable region at the amino terminus that contains a variable domain (VH), followed by a constant region that contains a number of constant domains. The heavy chains of IgG, IgD, and IgA have a constant region that contains three linked immunoglobulin domains (CHI, CH2, and CH3), and have a hinge region that increases flexibility. The heavy chains of IgM and IgE have a constant region that contains four linked immunoglobulin domains (CHI, CH2, CH3, and CH4). The variable region of the heavy chain is different between different B cells, but all immunoglobulins produced by the same B cell or B cell clone are the same. The variable domain contains a single immunoglobulin domain.

[0065] There are two types of mammalian immunoglobulin light chains: kappa (K) and lambda (λ). The λ class has four subtypes: λ1, λ2, λ3, and λ4. There is only one type of light chain in a typical antibody, so both light chains of an individual antibody are the same. The approximate length of a light chain is 211 to 217 amino acids. Each light chain contains two linked immunoglobulin domains: a variable domain (VL) at the amino terminus, followed by a constant domain. The variable domain is important for binding antigen, and the constant domain determines the light chain type (i.e., K or λ). The constant domain of a light chain aligns with the first constant domain of a heavy chain, and the light chain variable domain aligns with the heavy chain variable domain. Certain amino acid residues are thought to form an interface between the light chain variable domain and the heavy chain variable domain.

[0066] The complete antigen recognition and antigen binding site is contained within the variable domain of an antibody. This site is composed of a dimer of one heavy chain variable domain (VH) and one light chain variable domain (VL) in close non-covalent association. Each domain comprises four framework regions (FRs) primarily adopting a beta-sheet configuration connected by three hypervariable regions which form loops connecting, and in some cases forming part of, the beta-sheet structure. Each hypervariable region comprises amino acid sequences corresponding to complementarity determining regions (CDRs). Collectively, 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, 5thEd. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), each of which is incorporated by reference herein in its entirety. The constant domains of an antibody do not participate directly in binding of the antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity.

[0067] A target antigen typically has one or more binding sites, also called epitopes, recognized by the antigen binding site formed by the CDRs. An "epitope" is synonymous with "antigenic determinant" and refers to the site or sites on a target antigen, such as, for example, a molecule comprising a peptide, polysaccharide, or lipid, that is capable of specific binding to an immunoglobulin or T-cell receptor or otherwise interacting with the molecule. Various antibodies that specifically bind to different epitopes have different structures. Thus, one antigen can be recognized by more than one antibody.

[0068] The modified anti-PD-Ll antibodies disclosed herein can be polyclonal or monoclonal, with polyclonal referring to a heterogeneous population of antibody molecules comprising at least two different antibodies capable of binding to a particular antigen. By definition, a polyclonal antibody comprises at least two different antibodies that bind to at least two different epitopes. Monoclonal antibodies refer to a substantially homogeneous antibody population, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that can 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, the monoclonal antibodies are advantageous in that they can be synthesized uncontaminated by other antibodies. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to 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 can be made by the hybridoma method (first described by Kohler et al. (1975) Nature 256:495), or can be made by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567; U.S. Patent No. 5,807,715). The monoclonal antibodies can 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.

[0069] In one embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise a heavy chain variable domain (V H ) and / or a light chain variable domain (V L ) that selectively binds to an epitope or fragment thereof present in PD-L1. In various aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise a heavy chain variable domain (V H ) and / or a light chain variable domain (V L ) that selectively binds to an epitope present in the PD-L1 of SEQ ID NO: 1. In various aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein specifically bind to an epitope present in SEQ ID NO: 1. In various aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein can comprise a heavy chain variable domain (V H ) and / or a light chain variable domain (V L) and / or light chain variable domain (V H ) and / or light chain variable domain (V L ) of 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%. In yet other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein can comprise a heavy chain variable domain (V H ) and / or light chain variable domain (V L ) that selectively binds to an epitope having, for example, a deletion, addition, and / or substitution of at least 1, at least 2, at least 3, or at least 4 contiguous and / or non-contiguous amino acids relative to SEQ ID NO: 1; or at most 1, at most 2, at most 3, at most 4 contiguous and / or non-contiguous amino acids of PD-L1 relative to SEQ ID NO: 1. In still other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein can comprise a heavy chain variable domain (V H ) and / or light chain variable domain (V L ) that selectively binds to an epitope having, for example, a deletion, addition, and / or substitution of 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 acids of PD-L1 relative to SEQ ID NO: 1.

[0070] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H ) comprising SEQ ID NO: 2. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H) : 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%, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. In yet other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) that can comprise a sequence having an amino acid identity within the following ranges relative to SEQ ID NO: 2: e.g., 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%, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1.

[0071] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) that can comprise a sequence having the following: e.g., a deletion, addition, and / or substitution of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 contiguous amino acids relative to SEQ ID NO: 2, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. H ) : e.g., a deletion, addition, and / or substitution of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 contiguous amino acids relative to SEQ ID NO: 2, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1; or comprises a heavy chain variable domain (VH) that can comprise a sequence having the following: e.g., a deletion, addition, and / or substitution of at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, or at most 12 contiguous amino acids relative to SEQ ID NO: 2, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. H ) : e.g., a deletion, addition, and / or substitution of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 contiguous amino acids relative to SEQ ID NO: 2, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1; or comprises a heavy chain variable domain (VH) that can comprise a sequence having the following: e.g., a deletion, addition, and / or substitution of at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, or at most 12 contiguous amino acids relative to SEQ ID NO: 2, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. H) : for example, a deletion, addition, and / or substitution of from 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, 1 to 11, 1 to 12, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11, 3 to 12, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 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 contiguous amino acids relative to SEQ ID NO: 2, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1.

[0072] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) that can comprise a sequence having a deletion, addition, and / or substitution of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 non-contiguous amino acids relative to SEQ ID NO: 2, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. H ) : for example, a deletion, addition, and / or substitution of from 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, 1 to 11, 1 to 12, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11, 3 to 12, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 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 contiguous amino acids relative to SEQ ID NO: 2, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. HFor example, relative to SEQ ID NO:2, 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, 1 to 11, 1 to 12, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11, 3 to 12, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 4 to The deletion, addition, and / or substitution of 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-continuous amino acids, and is a functional antibody that selectively binds to an epitope present in PD-L1 such as SEQ ID NO:1.

[0073] In another embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V H Heavy chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions H The heavy chain variable structural domain (V) H It selectively binds to epitopes present in PD-L1. In various embodiments of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V... H Heavy chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions H The heavy chain variable structural domain (V) H It selectively binds to the epitope present in PD-L1 of SEQ ID NO:1. In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V... H Heavy chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions H The heavy chain variable structural domain (V) HThis antibody can selectively bind to epitopes present in a sequence having the following amino acid identity with respect to PD-L1 relative to SEQ ID NO:1: 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%. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V... H Heavy chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions H The heavy chain variable structural domain (V) H This can selectively bind to epitopes present in sequences having amino acid identity with respect to PD-L1 in SEQ ID NO:1 within the following ranges: 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%. In yet another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V... H Heavy chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions H The heavy chain variable structural domain (V) H The antibody can selectively bind to epitopes present in sequences having: for example, deletions, additions, and / or substitutions of at least one, at least two, at least three, or at least four consecutive and / or non-consecutive amino acids relative to PD-L1 in SEQ ID NO:1; or deletions, additions, and / or substitutions of at most one, at most two, at most three, or at most four consecutive and / or non-consecutive amino acids relative to PD-L1 in SEQ ID NO:1. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V... H Heavy chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions H The heavy chain variable structural domain (V) H It can selectively bind to epitopes present in sequences having the following: 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 consecutive and / or non-consecutive amino acids relative to PD-L1 of SEQ ID NO:1.

[0074] In one aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein includes a heavy chain variable domain (V... H The heavy chain variable structural domain (V) H) comprising a heavy chain variable domain (VH) comprising a CDR1 region comprising SEQ ID NO: 3 (IMGT) or SEQ ID NO: 4 (Kabat) H ) CDR1 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR1 region comprising SEQ ID NO: 3 (IMGT) or SEQ ID NO: 4 (Kabat) H ) CDR1 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR1 region comprising SEQ ID NO: 3 (IMGT) or SEQ ID NO: 4 (Kabat) H ) CDR1 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR1 region comprising SEQ ID NO: 3 (IMGT) or SEQ ID NO: 4 (Kabat) H ) CDR1 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR1 region comprising SEQ ID NO: 3 (IMGT) or SEQ ID NO: 4 (Kabat)

[0075] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR2 region comprising SEQ ID NO: 5 (IMGT) or SEQ ID NO: 6 (Kabat) H ) CDR2 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR2 region comprising SEQ ID NO: 5 (IMGT) or SEQ ID NO: 6 (Kabat) H ) CDR2 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR2 region comprising SEQ ID NO: 5 (IMGT) or SEQ ID NO: 6 (Kabat) H ) CDR2 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR2 region comprising SEQ ID NO: 5 (IMGT) or SEQ ID NO: 6 (Kabat) H ) CDR2 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR2 region comprising SEQ ID NO: 5 (IMGT) or SEQ ID NO: 6 (Kabat) H ) CDR2 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR2 region comprising SEQ ID NO: 5 (IMGT) or SEQ ID NO: 6 (Kabat)

[0076] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR3 region 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 (VH) comprising a CDR3 region 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 (VH) comprising a CDR3 region 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 (VH) comprising a CDR3 region 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 (VH) comprising a CDR3 region 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 (VH) comprising a CDR3 region 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 (VH) comprising a CDR3 region comprising SEQ ID NO: 7 (IMGT) or SEQ ID NO: 8 (Kabat)

[0077] In another aspect of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) comprising a CDR3 region comprising SEQ ID NO: 7 (IMGT) or SEQ ID NO: 8 (Kabat) HThe heavy chain variable structural domain (V) H ) contains a heavy-chain variable structural domain (V) containing SEQ ID NO:3 (IMGT) or SEQ ID NO:4 (Kabat). H CDR1 region, heavy chain variable domain (V) containing SEQ ID NO:5 (IMGT) or SEQ ID NO:6 (Kabat) H The CDR2 region and the heavy chain variable domain (V) containing SEQ ID NO:7 (IMGT) or SEQ ID NO:8 (Kabat) H The CDR3 region. In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein includes a heavy chain variable domain (V... H The heavy chain variable structural domain (V) H It may contain a heavy chain variable domain (V) with an amino acid deletion, addition, and / or substitution relative to SEQ ID NO:3 (IMGT) or SEQ ID NO:4 (Kabat). H The CDR1 region, and the heavy chain variable domain (V) with one or two amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:5 (IMGT) or SEQ ID NO:6 (Kabat) H The CDR2 region and the heavy chain variable domain (V) having an amino acid deletion, addition, and / or substitution relative to SEQ ID NO:7 (IMGT) or SEQ ID NO:8 (Kabat) H CDR3 area.

[0078] In another embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V) that selectively binds to the epitope disclosed herein. L The CDR1, CDR2, and CDR3 regions. In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V) that selectively binds to an epitope present in PD-L1 of SEQ ID NO:1. L CDR1, CDR2 and CDR3.

[0079] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V) containing SEQ ID NO:9. L In another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V) containing a sequence having the following amino acid identity with respect to SEQ ID NO:9. L) : 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%, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V L ) : e.g., 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%, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1.

[0080] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V L ) : e.g., at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 contiguous amino acid deletions, additions and / or substitutions relative to SEQ ID NO: 9, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1; or comprises a light chain variable domain (V L ) : e.g., at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 contiguous amino acid deletions, additions and / or substitutions relative to SEQ ID NO: 9, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. In yet other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V L) : for example, a deletion, addition, and / or substitution of from 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 acids of SEQ ID NO: 9, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1.

[0081] In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V L ) : for example, a deletion, addition, and / or substitution of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 noncontiguous amino acids of SEQ ID NO: 9, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1; or a light chain variable domain (V L ) : a deletion, addition, and / or substitution of at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 noncontiguous amino acids of SEQ ID NO: 9, and is a functional antibody that selectively binds to an epitope present in PD-L1, such as the PD-L1 of SEQ ID NO: 1. In yet other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V LFor example, relative to SEQ ID NO:9, 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 The antibody is a functional antibody that selectively binds to epitopes present in PD-L1 such as SEQ ID NO:1, consisting of 1 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-continuous amino acid deletions, additions, and / or substitutions.

[0082] In another embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V L The light chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions L The light chain variable structural domain (V) L It selectively binds to epitopes present in PD-L1. In various embodiments of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V... L The light chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions L The light chain variable structural domain (V) L It selectively binds to the epitope present in PD-L1 of SEQ ID NO:1. In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V... L The light chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions L The light chain variable structural domain (V) L The antibody selectively binds to epitopes present in a sequence having the following amino acid identity with respect to PD-L1 relative to SEQ ID NO:1: 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%. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V... LThe light chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions L The light chain variable structural domain (V) L The antibody selectively binds to epitopes present in a sequence having amino acid identity with respect to PD-L1 in SEQ ID NO:1 within the following ranges: 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%. In another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V... L The light chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions L The light chain variable structural domain (V) L The antibody selectively binds to epitopes present in sequences having: for example, deletions, additions, and / or substitutions of at least one, at least two, at least three, or at least four consecutive and / or non-consecutive amino acids relative to PD-L1 in SEQ ID NO:1; or deletions, additions, and / or substitutions of at most one, at most two, at most three, or at most four consecutive and / or non-consecutive amino acids relative to PD-L1 in SEQ ID NO:1. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain variable domain (V... L The light chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions L The light chain variable structural domain (V) L It selectively binds to epitopes present in sequences having the following: 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 consecutive and / or non-consecutive amino acids relative to PD-L1 of SEQ ID NO:1.

[0083] In one aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein includes a light chain variable domain (V L The light chain variable structural domain (V) L ) contains a light chain variable domain (V) containing SEQ ID NO:10 (IMGT) or SEQ ID NO:11 (Kabat). L The CDR1 region. In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein includes a light chain variable domain (V). L The light chain variable structural domain (V) LIt may contain a light chain variable domain (V) with a deletion, addition, and / or substitution of one amino acid relative to SEQ ID NO:10 (IMGT) or SEQ ID NO:11 (Kabat). L CDR1 area.

[0084] In one aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein includes a light chain variable domain (V L The light chain variable structural domain (V) L ) contains a light chain variable domain (V) containing SEQ ID NO:12 (IMGT) or SEQ ID NO:13 (Kabat). L The CDR2 region. In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein includes a light chain variable domain (V... L The light chain variable structural domain (V) L It may contain a light chain variable domain (V) with a deletion, addition, and / or substitution of one amino acid relative to SEQ ID NO:12 (IMGT) or SEQ ID NO:13 (Kabat). L CDR2 area.

[0085] In one aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein includes a light chain variable domain (V L The light chain variable structural domain (V) L ) contains a light chain variable domain (V) containing SEQ ID NO:14 (IMGT) or SEQ ID NO:15 (Kabat). L The CDR3 region. In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein includes a light chain variable domain (V... L The light chain variable structural domain (V) L It may contain a light chain variable domain (V) with an amino acid deletion, addition, and / or substitution relative to SEQ ID NO:14 (IMGT) or SEQ ID NO:15 (Kabat). L CDR3 area.

[0086] In one aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein includes a light chain variable domain (V L The light chain variable structural domain (V) L ) contains a light chain variable domain (V) containing SEQ ID NO:10 (IMGT) or SEQ ID NO:11 (Kabat). L) a CDR1 region, a light chain variable domain (V L ) a CDR2 region, and a light chain variable domain (V L ) a CDR3 region. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a light chain variable domain (V L ) that can comprise a light chain variable domain (V L ) having one amino acid deletion, addition and / or substitution relative to SEQ ID NO: 10 (IMGT) or SEQ ID NO: 11 (Kabat) L ) a CDR1 region, a light chain variable domain (V L ) a CDR2 region, and a light chain variable domain (V L ) a CDR3 region.

[0087] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H ) comprising SEQ ID NO: 2 and a light chain variable domain (V L ) comprising SEQ ID NO: 9. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H ) that can comprise a sequence having 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, and a light chain variable domain (V L ) that can comprise a sequence having 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. In yet other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (V H) : e.g., 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%. L ) : e.g., 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%.

[0088] In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (VH) that can comprise a sequence having: H ) : e.g., a deletion, addition, and / or substitution of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 contiguous amino acids relative to SEQ ID NO: 2, or a deletion, addition, and / or substitution of at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, or at most 12 contiguous amino acids relative to SEQ ID NO: 2; and a light chain variable domain (VL) that can comprise a sequence having: L ) : e.g., a deletion, addition, and / or substitution of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 contiguous amino acids relative to SEQ ID NO: 9, or a deletion, addition, and / or substitution of at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 contiguous amino acids relative to SEQ ID NO: 9. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (VH) that can comprise a sequence having: H) : 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, 1 to 11, 1 to 12, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11, 3 to 12, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 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 contiguous amino acid deletions, additions and / or substitutions relative to SEQ ID NO: 2, and can comprise a heavy chain variable domain (VH) having a sequence of L ) : 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.

[0089] In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein comprise a heavy chain variable domain (VH) that can comprise a sequence having H) : for example, at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 noncontiguous amino acid deletions, additions and / or substitutions relative to SEQ ID NO: 2, or at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, or at most 12 noncontiguous amino acid deletions, additions and / or substitutions relative to SEQ ID NO: 2; and the light chain variable domain (V L ) : for example, at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 noncontiguous amino acid deletions, additions and / or substitutions relative to SEQ ID NO: 9, or at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 noncontiguous amino acid deletions, additions and / or substitutions relative to SEQ ID NO: 9. In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises a heavy chain variable domain (V H ) : 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, 1 to 11, 1 to 12, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11, 3 to 12, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 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 noncontiguous amino acid deletions, additions and / or substitutions relative to SEQ ID NO: 2, and the light chain variable domain (V LFor example, relative to SEQ ID NO:9, 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 One, four to five, four to six, four to seven, four to eight, four to nine, four to ten, five to six, five to seven, five to eight, five to nine, five to ten, six to seven, six to eight, six to nine, six to ten, seven to eight, seven to nine, seven to ten, eight to nine, eight to ten or nine to ten non-continuous amino acid deletions, additions and / or substitutions.

[0090] In another embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V H Heavy chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions H ) and containing light chain variable structural domains (V L The light chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions L The heavy chain variable structural domain (V) H ) and light chain variable structural domain (V L It selectively binds to epitopes present in PD-L1. In various embodiments of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V... H Heavy chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions H ) and containing light chain variable structural domains (V L The light chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions L The heavy chain variable structural domain (V) H ) and light chain variable structural domain (V L It selectively binds to the epitope present in PD-L1 of SEQ ID NO:1. In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V... H Heavy chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions H ) and containing light chain variable structural domains (V L The light chain variable structural domains (V) in CDR1, CDR2, and CDR3 regions L The heavy chain variable structural domain (V) H) and a light chain variable domain (V L ) can selectively bind to an epitope present in a sequence having 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 other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V H ) comprising a heavy chain variable domain (V H ) CDR1 region, a CDR2 region, and a CDR3 region and a light chain variable domain (V L ) comprising a light chain variable domain (V L ) CDR1 region, a CDR2 region, and a CDR3 region, which heavy chain variable domain (V H ) and light chain variable domain (V L ) can selectively bind to an epitope present in a sequence having in the range of, 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 other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V H ) comprising a heavy chain variable domain (V H ) CDR1 region, a CDR2 region, and a CDR3 region and a light chain variable domain (V L ) comprising a light chain variable domain (V L ) CDR1 region, a CDR2 region, and a CDR3 region, which heavy chain variable domain (V H ) and light chain variable domain (V L ) can selectively bind to an epitope present in a sequence having, for example, at least 1, at least 2, at least 3, or at least 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions relative to PD-L1 of SEQ ID NO: 1; or at most 1, at most 2, at most 3, at most 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions relative to PD-L1 of SEQ ID NO: 1. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V H ) comprising a heavy chain variable domain (V H ) CDR1 region, a CDR2 region, and a CDR3 region and a light chain variable domain (V L) CDR1 region, a CDR2 region, and a CDR3 region of a light chain variable domain (V L ), the heavy chain variable domain (V H ) and the light chain variable domain (V L ) can selectively bind 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 relative to PD-L1 of SEQ ID NO: 1.

[0091] In an aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V H ) and a light chain variable domain (V L ), the heavy chain variable domain (V H ) comprising a heavy chain variable domain (V H ) CDR1 region comprising SEQ ID NO: 3 (IMGT) or SEQ ID NO: 4 (Kabat), a heavy chain variable domain (V H ) CDR2 region comprising SEQ ID NO: 5 (IMGT) or SEQ ID NO: 6 (Kabat), and a heavy chain variable domain (V H ) CDR3 region comprising SEQ ID NO: 7 (IMGT) or SEQ ID NO: 8 (Kabat), the light chain variable domain (V L ) comprising a light chain variable domain (V L ) CDR1 region comprising SEQ ID NO: 10 (IMGT) or SEQ ID NO: 11 (Kabat), a light chain variable domain (V L ) CDR2 region comprising SEQ ID NO: 12 (IMGT) or SEQ ID NO: 13 (Kabat), and a light chain variable domain (V L ) CDR3 region comprising SEQ ID NO: 14 (IMGT) or SEQ ID NO: 15 (Kabat). In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain variable domain (V H ) and a light chain variable domain (V L ), the heavy chain variable domain (V H ) can comprise a heavy chain variable domain (V HThe CDR1 region, and the heavy chain variable domain (V) with one or two amino acid deletions, additions, and / or substitutions relative to SEQ ID NO:5 (IMGT) or SEQ ID NO:6 (Kabat) H The CDR2 region and the heavy chain variable domain (V) having an amino acid deletion, addition, and / or substitution relative to SEQ ID NO:7 (IMGT) or SEQ ID NO:8 (Kabat) H The CDR3 region, the variable structural domain of the light chain (V L It may contain a light chain variable domain (V) with an amino acid deletion, addition, and / or substitution relative to SEQ ID NO:10 (IMGT) or SEQ ID NO:11 (Kabat). L The CDR1 region has a light chain variable domain (V) with an amino acid deletion, addition, and / or substitution relative to SEQ ID NO:12 (IMGT) or SEQ ID NO:13 (Kabat). L The CDR2 region and the light chain variable domain (V) having an amino acid deletion, addition, and / or substitution relative to SEQ ID NO:14 (IMGT) or SEQ ID NO:15 (Kabat) L CDR3 area.

[0092] In another embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a light chain including the light chain variable region and light chain constant region disclosed herein. In one aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a κ light chain including the light chain variable region and light chain constant region disclosed herein. In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a κ light chain including the light chain variable region disclosed herein and the 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 various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the κ light chain of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, or SEQ ID NO:25.

[0093] In another aspect of this embodiment, the modified anti-PD-Ll 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 aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise 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.

[0094] In one embodiment, the anti-PD-Ll antibodies disclosed herein comprise a heavy chain constant domain (CH) that lacks Fc effector function. H In another embodiment, the anti-PD-Ll antibodies disclosed herein comprise a heavy chain constant domain (CH) that lacks cellular cytotoxicity. H In aspects of this embodiment, the anti-PD-Ll antibodies disclosed herein comprise a heavy chain constant domain (CH) that lacks antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity activity (CDC), and / or antibody-dependent cellular phagocytosis (ADCP). H In aspects of this embodiment, the heavy chain constant domain (CH) that lacks Fc effector function is an IgG immunoglobulin. H In other aspects of this embodiment, the heavy chain constant domain (CH) that lacks Fc effector function of an IgG immunoglobulin is an IgGl immunoglobulin, an IgG2 immunoglobulin, an IgG3 immunoglobulin, or an IgG4 immunoglobulin. H

[0095] In one embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl immunoglobulin heavy chain constant domain (CH) that lacks cellular cytotoxicity comprising one, two, three, four, or five amino acid deletions, additions, or substitutions in the lower hinge region and / or the N-terminal half of the CH2 domain. H In aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H H In aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40.​​H ) can comprise one, two, three, four, or five amino acid deletions, additions, or substitutions in the N-terminal half of the lower hinge region and / or the CH2 domain that reduce or eliminate cellular toxicity. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid deletion, addition, or substitution at position L239, L240, K327, or any combination thereof that reduces or eliminates cellular toxicity. In yet other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L239, an amino acid substitution of A, C, D, E, G, H, K, N, P, Q, R, S, T, W, or Y at position L240, an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y at position K327, or any combination thereof that reduces or eliminates cellular toxicity. In yet other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid substitution of A, C, W, or Y at position L239, an amino acid substitution of A, C, W, or Y at position L240, an amino acid substitution of A, D, G, H, M, N, P, S, or T at position K327, or any combination thereof that reduces or eliminates cellular toxicity. In further aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H) 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. In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (C H ) that lacks or has reduced cellular cytotoxicity.

[0096] In one embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) that lacks cellular cytotoxicity. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) that can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions at the N-terminal half of the lower hinge region and / or CH2 domain. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48. In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) that can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions at the N-terminal half of the lower hinge region and / or CH2 domain that reduce or eliminate cellular cytotoxicity. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48. In yet other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) that can comprise an amino acid deletion, addition, or substitution at position V236, A237, K323, or any combination thereof that reduces or eliminates cellular cytotoxicity. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48. In yet other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H) can comprise 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 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. In yet other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise 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. In further aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid substitution of A at position V236 (V236A), an amino acid substitution of L at position A237 (A237L), an amino acid substitution of A at position K323 (K323A), or any combination thereof. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid substitution of A at position V236 (V236A), an amino acid substitution of A at position K323 (K323A), or any combination thereof.

[0097] In one embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) that lacks cytotoxicity, which IgG4 immunoglobulin heavy chain constant domain (C H) can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions 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 can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C H ) can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions located in the lower hinge region and / or the N-terminal half of the CH2 domain that reduce or eliminate cytotoxicity. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C H ) can comprise amino acid deletions, additions, or substitutions at positions F / V236, L / A / E237, K324, or any combination thereof that reduce or eliminate cytotoxicity. In yet other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C H) can comprise 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, K, N, P, Q, R, S, T, W, or Y at position L237, 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, F, G, H, I, L, M, N, P, R, S, T, V, W, or Y at position E237, an amino acid substitution of A, C, D, F, G, H, I, L, M, N, P, S, T, V, W, or Y at position K324, or any combination thereof. In yet other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which can comprise 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. In further aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which can comprise 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. In further aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which can comprise 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. In further aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which can comprise 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.

[0098] In one embodiment, the modified anti-PD-Ll antibody disclosed herein comprises a heavy chain constant domain (C H ) comprising an amino acid sequence variant that facilitates faster clearance of the modified anti-PD-Ll antibody relative to an anti-PD-Ll antibody that does not contain the same amino acid sequence variant (unmodified anti-PD-Ll reference antibody). With respect to all embodiments, faster clearance refers to one or both of: (i) an increase in the amount of the modified anti-PD-Ll antibody disclosed herein that is cleared relative to the unmodified anti-PD-Ll reference antibody within the same given time period; and (ii) a substantial clearance of the entire amount of the modified anti-PD-Ll antibody disclosed herein relative to the unmodified anti-PD-Ll reference antibody within a reduced time period. Suitably, the clearance rate (the amount of antibody that is cleared within a given time period) 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%, at least 500% relative to the unmodified anti-PD-Ll reference antibody for a given time period. More suitably, the given time period begins at or shortly after antibody administration and can have a duration of 30 hours, 36 hours, or 42 hours. The modified anti-PD-Ll antibody disclosed herein can be substantially entirely cleared within a time period that is reduced relative to the time period required for the unmodified anti-PD-Ll reference antibody to be substantially entirely cleared, suitably reduced 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%, at least 500% relative to the unmodified anti-PD-Ll reference antibody. In aspects of this embodiment, the heavy chain constant domain (C H ) comprising an amino acid sequence variant that facilitates faster clearance of the modified anti-PD-Ll antibody relative to an anti-PD-Ll antibody that does not contain the same amino acid sequence variant within the same time period. In other aspects of this embodiment, the IgG immunoglobulin heavy chain constant domain (C H ) comprising an amino acid sequence variant that facilitates faster clearance of the modified anti-PD-Ll antibody relative to an anti-PD-Ll antibody that does not contain the same amino acid sequence variant within the same time period is an IgGl immunoglobulin, an IgG2 immunoglobulin, an IgG3 immunoglobulin, or an IgG4 immunoglobulin.

[0099] In all aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgG1 immunoglobulin heavy chain constant domain (C1C1) containing an amino acid sequence variant in the CH2 domain and / or CH3 domain. H The amino acid sequence variants promote faster clearance of the modified anti-PD-L1 antibody within the same time period compared to anti-PD-L1 antibodies lacking the same amino acid variant located in the CH2 and / or CH3 domains. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgG1 immunoglobulin heavy chain constant domain (C1) containing one, two, three, four, or five amino acid deletions, additions, or substitutions located in the CH2 and / or CH3 domains. H Anti-PD-L1 antibodies with amino acid deletions, additions, or substitutions that promote modification are cleared faster over the same time period than anti-PD-L1 antibodies without the same amino acid deletions, additions, or substitutions located in the CH2 and / or CH3 domains.

[0100] In all aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C1646) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain one, two, three, four, or five amino acid deletions, additions, or substitutions in the CH2 and / or CH3 domains, wherein the deletions, additions, or substitutions promote faster clearance of the modified anti-PD-L1 antibody compared to an anti-PD-L1 antibody without the same amino acid deletions, additions, or substitutions in the CH2 and / or CH3 domains. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain amino acid deletions, additions, or substitutions at positions H315, H440, or both, wherein the deletions, additions, or substitutions promote faster clearance of the modified anti-PD-L1 antibody compared to anti-PD-L1 antibodies without the same deletions, additions, or substitutions at H315 and H440. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C)H ) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, or any combination thereof, that facilitates 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. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (CH) 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, that facilitates 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. H ) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, or any combination thereof, that facilitates 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. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (CH) 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, that facilitates 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. H ) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, or any combination thereof, that facilitates 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. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (CH) 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, that facilitates 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. H ) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, or any combination thereof, that facilitates 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. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (CH) 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, that facilitates 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. H ) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, or any combination thereof, that facilitates 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. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (CH) 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, that facilitates 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.

[0101] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (CH) 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, that facilitates 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. H ) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, or any combination thereof, that facilitates 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. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (CH) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (CH) 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, that facilitates 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. HThe modified anti-PD-L1 antibody comprises the H315A variant, the H440Q variant, or any combination thereof, and promotes faster clearance of the modified anti-PD-L1 antibody over the same time period compared to anti-PD-L1 antibodies without the H315A and H440Q variants, for example, 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%. In another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C15A, H440Q, or SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody contains the H315A variant, the H440Q variant, or any combination thereof, and promotes faster clearance of the modified anti-PD-L1 antibody over the same time period compared to anti-PD-L1 antibodies without the H315A and H440Q variants, 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%, or up to 500%. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein contains the IgG1 immunoglobulin heavy chain constant domain (C15A, H440Q, or SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H The IgG1 immunoglobulin heavy chain constant domain (C) HContaining the H315A variant, the H440Q variant, or any combination thereof, promotes the modified anti-PD-L1 antibody to be cleared faster over the same time period compared to anti-PD-L1 antibodies without the H315A and H440Q variants, 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 2 5% 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 400%, about 150% 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%.

[0102] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C1646) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody comprises the H315A variant, the H440Q variant, or any combination thereof, and promotes clearance of the modified anti-PD-L1 antibody within, 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 another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C15A, H440Q ... H The IgG1 immunoglobulin heavy chain constant domain (C) HThe modified anti-PD-L1 antibody comprises the H315A variant, the H440Q variant, or any combination thereof, and promotes clearance of the modified anti-PD-L1 antibody within, 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 other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C15A, H440Q ... H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody comprises the H315A variant, the H440Q variant, or any combination thereof, and promotes clearance of the modified anti-PD-L1 antibody within, 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 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C15A) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The antibody contains the H315A variant, the H440Q variant, or any combination thereof, and promotes the clearance of the modified anti-PD-L1 antibody within, for example, about 1 to 2 days, about 1 to 3 days, about 1 to 4 days, about 1 to 5 days, about 1 to 6 days, about 1 to 7 days, about 2 to 3 days, about 2 to 4 days, about 2 to 5 days, about 2 to 6 days, about 2 to 7 days, about 3 to 4 days, about 3 to 5 days, about 3 to 6 days, about 3 to 7 days, about 4 to 5 days, about 4 to 6 days, about 4 to 7 days, about 5 to 6 days, about 5 to 7 days, or about 6 to 7 days.

[0103] In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (CH) containing an amino acid sequence variant in the CH2 and / or CH3 domains, said amino acid sequence variant promoting faster clearance of the modified anti-PD-L1 antibody within the same time period than an anti-PD-L1 antibody not containing the same amino acid variant located in the CH2 and / or CH3 domains. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C) containing one, two, three, four, or five amino acids deleted, added, or substituted in the CH2 and / or CH3 domains. HAnti-PD-L1 antibodies with amino acid deletions, additions, or substitutions that promote modification are cleared faster over the same time period than anti-PD-L1 antibodies without the same amino acid deletions, additions, or substitutions located in the CH2 and / or CH3 domains.

[0104] In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain one, two, three, four, or five amino acid deletions, additions, or substitutions located in the CH2 and / or CH3 domains, wherein the amino acid deletions, additions, or substitutions promote faster clearance of the modified anti-PD-L1 antibody within the same time period than anti-PD-L1 antibodies without the same amino acid deletions, additions, or substitutions located in the CH2 and / or CH3 domains. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain amino acid deletions, additions, or substitutions at positions H315, H440, or both, which promote faster clearance of the modified anti-PD-L1 antibody within the same time period compared to anti-PD-L1 antibodies without the same H315 and H440 amino acid deletions, additions, or substitutions. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C10) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, or any combination thereof, that facilitates 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 time period. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise 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, that facilitates 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 time period. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid substitution of A at position H315 (H315A), an amino acid substitution of Q at position H440 (H440Q), or any combination thereof, that facilitates 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 time period.

[0105] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), which IgG2 immunoglobulin heavy chain constant domain (C H) can comprise the H315A variant, the H440Q variant, or any combination thereof, facilitating faster clearance of the modified anti-PD-Ll antibody relative to an anti-PD-Ll antibody that does not contain the H315A variant and the H440Q variant over the same time period, e.g., 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. In still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise the IgG2 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise the H315A variant, the H440Q variant, or any combination thereof, facilitating faster clearance of the modified anti-PD-Ll antibody relative to an anti-PD-Ll antibody that does not contain the H315A variant and the H440Q variant over the same time period, e.g., at most 25%, at most 50%, at most 75%, at most 100%, at most 125%, at most 150%, at most 175%, at most 200%, at most 250%, at most 300%, at most 350%, at most 400%, at most 450%, at most 500% faster. In still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise the IgG2 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which IgG2 immunoglobulin heavy chain constant domain (C HThe modified anti-PD-L1 antibody may contain the H315A variant, the H440Q variant, or any combination thereof, promoting faster clearance of the modified anti-PD-L1 antibody over the same time period compared to anti-PD-L1 antibodies without the H315A and H440Q variants, 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%, etc. 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%. 0%, 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 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%.

[0106] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain the H315A variant, the H440Q variant, or any combination thereof, to promote clearance of the modified anti-PD-L1 antibody within, 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 another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C15A) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C)H The modified anti-PD-L1 antibody may contain the H315A variant, the H440Q variant, or any combination thereof, to promote clearance of the modified anti-PD-L1 antibody within, 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 other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C1500) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain the H315A variant, the H440Q variant, or any combination thereof, to promote clearance of the modified anti-PD-L1 antibody within, 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 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The antibody may contain the H315A variant, the H440Q variant, or any combination thereof, which promotes the clearance of the modified anti-PD-L1 antibody within, for example, about 1 to 2 days, about 1 to 3 days, about 1 to 4 days, about 1 to 5 days, about 1 to 6 days, about 1 to 7 days, about 2 to 3 days, about 2 to 4 days, about 2 to 5 days, about 2 to 6 days, about 2 to 7 days, about 3 to 4 days, about 3 to 5 days, about 3 to 6 days, about 3 to 7 days, about 4 to 5 days, about 4 to 6 days, about 4 to 7 days, about 5 to 6 days, about 5 to 7 days, or about 6 to 7 days.

[0107] In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (CH) containing an amino acid sequence variant in the CH2 and / or CH3 domains, said amino acid sequence variant promoting faster clearance of the modified anti-PD-L1 antibody within the same time period than an anti-PD-L1 antibody not containing the same amino acid variant located in the CH2 and / or CH3 domains. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C) containing one, two, three, four, or five amino acids deleted, added, or substituted in the CH2 and / or CH3 domains. HAnti-PD-L1 antibodies with amino acid deletions, additions, or substitutions that promote modification are cleared faster over the same time period than anti-PD-L1 antibodies without the same amino acid deletions, additions, or substitutions located in the CH2 and / or CH3 domains.

[0108] In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG4 immunoglobulin heavy chain constant domain (C4) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain one, two, three, four, or five amino acid deletions, additions, or substitutions in the CH2 and / or CH3 domains, wherein the deletions, additions, or substitutions promote faster clearance of the modified anti-PD-L1 antibody within the same time period compared to anti-PD-L1 antibodies without the same amino acid deletions, additions, or substitutions in the CH2 and / or CH3 domains. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG4 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain amino acid deletions, additions, or substitutions at positions H312, H437, or both, which promote faster clearance of the modified anti-PD-L1 antibody within the same time period compared to anti-PD-L1 antibodies without the same H312 and H437 amino acid deletions, additions, or substitutions. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG4 immunoglobulin heavy chain constant domain (C10) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H312, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H437, or any combination thereof, that facilitates 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 time period. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C H ) can 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, that facilitates 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 time period. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C H ) can 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, that facilitates 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 time period.

[0109] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C H) can comprise the H312A variant, the H437Q variant, or any combination thereof, facilitating faster clearance of the modified anti-PD-Ll antibody relative to an anti-PD-Ll antibody that does not contain the H315A variant and the H440Q variant over the same time period, e.g., 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. In still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise the IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C H ) can comprise the H312A variant, the H437Q variant, or any combination thereof, facilitating faster clearance of the modified anti-PD-Ll antibody relative to an anti-PD-Ll antibody that does not contain the H315A variant and the H440Q variant over the same time period, e.g., at most 25%, at most 50%, at most 75%, at most 100%, at most 125%, at most 150%, at most 175%, at most 200%, at most 250%, at most 300%, at most 350%, at most 400%, at most 450%, at most 500% faster. In still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise the IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C HThe modified anti-PD-L1 antibody may contain the H312A variant, the H437Q variant, or any combination thereof, promoting faster clearance of the modified anti-PD-L1 antibody over the same time period compared to anti-PD-L1 antibodies without the H315A and H440Q variants, 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%, etc. 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%. 0%, 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 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%.

[0110] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG4 immunoglobulin heavy chain constant domain (C15) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain the H312A variant, the H437Q variant, or any combination thereof, to promote clearance of the modified anti-PD-L1 antibody at, 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 another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG4 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H), the IgG4 immunoglobulin heavy chain constant domain (C H ) can comprise a H312A variant, a H437Q variant, or any combination thereof, that facilitates clearance of the modified anti-PD-L1 antibody, e.g., for 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 other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise the IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53. H ) can comprise a H312A variant, a H437Q variant, or any combination thereof, that facilitates clearance of the modified anti-PD-L1 antibody, e.g., for at most 1 day, at most 2 days, at most 3 days, at most 4 days, at most 5 days, at most 6 days, or at most 7 days. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise the IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53. H ) can comprise a H312A variant, a H437Q variant, or any combination thereof, that facilitates clearance of the modified anti-PD-L1 antibody, e.g., for 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.

[0111] In one embodiment, the modified anti-PD-L1 antibody disclosed herein comprises a heavy chain constant domain (C H ) comprising an amino acid sequence variant that decreases 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. In aspects of this embodiment, the heavy chain constant domain (C H) is an IgG immunoglobulin. In other aspects of this embodiment, the IgG immunoglobulin heavy chain constant domain (C H ) is an IgG1 immunoglobulin, an IgG2 immunoglobulin, an IgG3 immunoglobulin, or an IgG4 immunoglobulin.

[0112] In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgG1 immunoglobulin heavy chain constant domain (C H ) comprising an amino acid sequence variant in the CH2 domain and / or the CH3 domain that decreases the half-life of the modified anti-PD-L1 antibody compared to an anti-PD-L1 antibody that does not contain the same amino acid variant in the CH2 domain and / or the CH3 domain. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgG1 immunoglobulin heavy chain constant domain (C H ) comprising 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain that decreases the half-life of the modified anti-PD-L1 antibody compared to an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain.

[0113] In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgG1 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgG1 immunoglobulin heavy chain constant domain (C H ) can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain that decreases the half-life of the modified anti-PD-L1 antibody compared to an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgG1 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgG1 immunoglobulin heavy chain constant domain (C HThe modified anti-PD-L1 antibody may contain an amino acid deletion, addition, or substitution at positions H315, H440, or both, such deletion, addition, or substitution causing a decrease in the half-life of the modified anti-PD-L1 antibody compared to an anti-PD-L1 antibody without the same deletion, addition, or substitution of amino acids at positions H315 and H440. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain amino acid substitutions of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, amino acid substitutions of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced compared to an anti-PD-L1 antibody without the same H315 and H440 amino acid substitutions. In another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C15) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain amino acid substitutions of C, D, E, K, Q, R, S, T, or W at position H315, amino acid substitutions of C, D, E, K, Q, R, S, T, or W at position H440, or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced compared to an anti-PD-L1 antibody without the same H315 and H440 amino acid substitutions. In another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody 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, such that the half-life of the modified anti-PD-L1 antibody is reduced compared to that of an anti-PD-L1 antibody without the same H315 and H440 amino acid substitutions.

[0114] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C1646) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody comprises an H315A variant, an H440Q variant, or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced relative to anti-PD-L1 antibodies without the H315A and H440Q variants, for example, 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%. In yet another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C15A, H440Q, or SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody comprises an H315A variant, an H440Q variant, or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced relative to anti-PD-L1 antibodies without the H315A and H440Q variants, for example, by 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%. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C15A, H440Q, or SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. H The IgG1 immunoglobulin heavy chain constant domain (C) HThe modified anti-PD-L1 antibody contains the H315A variant, the H440Q variant, or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced relative to anti-PD-L1 antibodies without the H315A and H440Q variants, for example, by 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%, or about 25% to about 35%. 0%, 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 1 00% 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 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%.

[0115] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C1646) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The antibody comprises the H315A variant, the H440Q variant, or any combination thereof, having 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 another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises the IgG1 immunoglobulin heavy chain constant domain (C15A / C440Q / C440) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H) comprising a H315A variant, a H440Q variant, or any combination thereof, having a half-life of, e.g., 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 still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises the IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) comprises a H315A variant, a H440Q variant, or any combination thereof, having a half-life of, e.g., at most 1 day, at most 2 days, at most 3 days, at most 4 days, at most 5 days, at most 6 days, or at most 7 days. In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises the IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) comprises a H315A variant, a H440Q variant, or any combination thereof, having a half-life of, e.g., from about 1 day to about 2 days, from about 1 day to about 3 days, from about 1 day to about 4 days, from about 1 day to about 5 days, from about 1 day to about 6 days, from about 1 day to about 7 days, from about 2 days to about 3 days, from about 2 days to about 4 days, from about 2 days to about 5 days, from about 2 days to about 6 days, from about 2 days to about 7 days, from about 3 days to about 4 days, from about 3 days to about 5 days, from about 3 days to about 6 days, from about 3 days to about 7 days, from about 4 days to about 5 days, from about 4 days to about 6 days, from about 4 days to about 7 days, from about 5 days to about 6 days, from about 5 days to about 7 days, or from about 6 days to about 7 days.

[0116] In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises the IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) comprises a H315A variant, a H440Q variant, or any combination thereof, having a half-life of, e.g., 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 still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises the IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H) comprising a H315A variant, a H440Q variant, or any combination thereof, having, for example, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (C H ) comprising a H315A variant, a H440Q variant, or any combination thereof, having, for example, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (C H ) comprising a H315A variant, a H440Q variant, or any combination thereof, having, for example, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (C H ) comprising a H315A variant, a H440Q variant, or any combination thereof, having, for example, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (C H ) comprising a H315A variant, a H440Q variant, or any combination thereof, having, for example, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain constant domain (C

[0117] In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ) comprising an amino acid sequence variant in the CH2 domain and / or the CH3 domain that decreases the half-life of the modified anti-PD-Ll antibody compared to an anti-PD-Ll antibody that does not contain the same amino acid variant in the CH2 domain and / or the CH3 domain. In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H), the amino acid deletion, addition, or substitution reduces the half-life of the modified anti-PD-Ll antibody compared to an anti-PD-Ll antibody that does not contain the same amino acid deletion, addition, or substitution in the CH2 domain and / or the CH3 domain.

[0118] In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), the IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain that reduce the half-life of the modified anti-PD-Ll antibody compared to an anti-PD-Ll antibody that does not contain the same amino acid deletion, addition, or substitution in the CH2 domain and / or the CH3 domain. In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), the IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid deletion, addition, or substitution at position H311, H436, or both positions that reduces the half-life of the modified anti-PD-Ll antibody compared to an anti-PD-Ll antibody that does not contain the same H311 and H436 amino acid deletion, addition, or substitution. In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), the IgG2 immunoglobulin heavy chain constant domain (C H) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H311, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H436, or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced compared to an anti-PD-L1 antibody that does not contain the same H311 and H436 amino acid substitutions. In yet other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise 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, such that the half-life of the modified anti-PD-L1 antibody is reduced compared to an anti-PD-L1 antibody that does not contain the same H311 and H436 amino acid substitutions. In yet other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid substitution of A at position H311 (H311A), an amino acid substitution of Q at position H436 (H436Q), or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced compared to an anti-PD-L1 antibody that does not contain the same H311 and H436 amino acid substitutions.

[0119] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), which IgG2 immunoglobulin heavy chain constant domain (C HThe modified anti-PD-L1 antibody may contain the H311A variant, the H436Q variant, or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced relative to anti-PD-L1 antibodies without the H311A and H436Q variants, for example, 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%. In yet another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain the H311A variant, the H436Q variant, or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced relative to anti-PD-L1 antibodies without the H311A and H436Q variants, for example, by 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%. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H) can comprise a H311A variant, a H436Q variant, or any combination thereof, reducing the half-life of the modified anti-PD-Ll antibody relative to an anti-PD-Ll antibody that does not contain the H311A variant and the H436Q variant, e.g., by 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 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%.

[0120] In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise a H311A variant, a H436Q variant, or any combination thereof, having a half-life of, e.g., about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In yet other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), which IgG2 immunoglobulin heavy chain constant domain (C HThe modified anti-PD-L1 antibody may comprise an H311A variant, an H436Q variant, or any combination thereof, having 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 other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may comprise an H311A variant, an H436Q variant, or any combination thereof, having 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 antibody disclosed herein may comprise the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H It may contain H311A variants, H436Q variants, or any combination thereof, having 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.

[0121] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) HThe modified anti-PD-L1 antibody may comprise the H311A variant, the H436Q variant, or any combination thereof, having 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 another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise the IgG2 immunoglobulin heavy chain constant domain (C15) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may comprise the H311A variant, the H436Q variant, or any combination thereof, having 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 other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may comprise the H311A variant, the H436Q variant, or any combination thereof, having 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 antibody disclosed herein may comprise the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H It may contain H311A variants, H436Q variants, or any combination thereof, having 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.

[0122] In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain an IgG4 immunoglobulin heavy chain constant domain (C2 domain) containing an amino acid sequence variant in the CH2 domain and / or CH3 domain. H The amino acid sequence variant causes the modified anti-PD-L1 antibody to have a shorter half-life than an anti-PD-L1 antibody that does not contain the same amino acid variant located in the CH2 and / or CH3 domains. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise an IgG4 immunoglobulin heavy chain constant domain (C1000C4) that may contain one, two, three, four, or five amino acid deletions, additions, or substitutions located in the CH2 and / or CH3 domains. H The deletion, addition, or substitution of the amino acids causes the modified anti-PD-L1 antibody to have a shorter half-life than an anti-PD-L1 antibody that does not contain the same amino acid deletion, addition, or substitution located in the CH2 and / or CH3 domains.

[0123] In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG4 immunoglobulin heavy chain constant domain (C4) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain one, two, three, four, or five amino acid deletions, additions, or substitutions in the CH2 and / or CH3 domains, wherein the deletion, addition, or substitution reduces the half-life of the disclosed anti-PD-L1 antibody compared to an anti-PD-L1 antibody without the same amino acid deletion, addition, or substitution in the CH2 and / or CH3 domains. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG4 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H) can comprise an amino acid deletion, addition, or substitution at position H312, H437, or both that decreases the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same H312 and H437 amino acid deletion, addition, or substitution. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which IgG4 immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H312, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H437, or any combination thereof, that decreases the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same H312 and H437 amino acid substitution. In yet other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which IgG4 immunoglobulin heavy chain constant domain (C H ) can 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, that decreases the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same H312 and H437 amino acid substitution. In yet other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which IgG4 immunoglobulin heavy chain constant domain (C H ) can 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, that decreases the half-life of the modified anti-PD-L1 antibody relative to an anti-PD-L1 antibody that does not contain the same H312 and H437 amino acid substitution.

[0124] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG4 immunoglobulin heavy chain constant domain (C15) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain the H312A variant, the H437Q variant, or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced relative to anti-PD-L1 antibodies without the H312A and H437Q variants, for example, 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%. In yet another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG4 immunoglobulin heavy chain constant domain (C10) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain the H312A variant, the H437Q variant, or any combination thereof, such that the half-life of the modified anti-PD-L1 antibody is reduced relative to anti-PD-L1 antibodies without the H312A and H437Q variants, for example, by 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%. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG4 immunoglobulin heavy chain constant domain (C10) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H) can comprise a H312A variant, a H437Q variant, or any combination thereof, having 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C

[0125] In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C H ) can comprise a H312A variant, a H437Q variant, or any combination thereof, having 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (CH ) can comprise a H312A variant, a H437Q variant, or any combination thereof, having a half-life of, e.g., 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 still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise the IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C H ) can comprise a H312A variant, a H437Q variant, or any combination thereof, having a half-life of, e.g., at most 1 day, at most 2 days, at most 3 days, at most 4 days, at most 5 days, at most 6 days, or at most 7 days. In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise the IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C H ) can comprise a H312A variant, a H437Q variant, or any combination thereof, having a half-life of, e.g., 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.

[0126] In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise the IgG4 immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53, which IgG4 immunoglobulin heavy chain constant domain (C HThe antibody may comprise the H312A variant, the H437Q variant, or any combination thereof, having 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 another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise the IgG4 immunoglobulin heavy chain constant domain (C15) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may comprise the H312A variant, the H437Q variant, or any combination thereof, having 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 other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise the IgG4 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H The antibody may comprise the H312A variant, the H437Q variant, or any combination thereof, having 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 antibody disclosed herein may comprise the IgG4 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H It may contain H312A variants, H437Q variants or any combination thereof, having, for example, 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.

[0127] In an embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise a heavy chain constant domain (C H ) comprising an amino acid sequence variant that reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor relative to an anti-PD-L1 antibody that does not contain the same amino acid sequence variant. In aspects of this embodiment, the heavy chain constant domain (C H ) comprising the amino acid sequence variant that reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor relative to an anti-PD-L1 antibody that does not contain the same amino acid sequence variant is an IgG immunoglobulin. In other aspects of this embodiment, the IgG immunoglobulin heavy chain constant domain (C H ) comprising the amino acid sequence variant that reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor relative to an anti-PD-L1 antibody that does not contain the same amino acid sequence variant is an IgGl immunoglobulin, an IgG2 immunoglobulin, an IgG3 immunoglobulin, or an IgG4 immunoglobulin.

[0128] In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgGl immunoglobulin heavy chain constant domain (C H ) comprising an amino acid sequence variant in the CH2 domain and / or the CH3 domain that reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor relative to an anti-PD-L1 antibody that does not contain the same amino acid variant in the CH2 domain and / or the CH3 domain. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgGl immunoglobulin heavy chain constant domain (C H ) that can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain that reduce the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor relative to an anti-PD-L1 antibody that does not contain the same amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain.

[0129] In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H) can comprise one, two, three, four, or five amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain that reduce 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 in the CH2 domain and / or the CH3 domain. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein can comprise the IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) can comprise amino acid deletions, additions, or substitutions at positions H315, H440, or both that reduce 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 H315 and H440 amino acid deletions, additions, or substitutions. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein can comprise the IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H315, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H440, or any combination thereof, 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 H315 and H440 amino acid substitutions. In yet other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein can comprise the IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H) can comprise 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, such that the modified anti-PD-Ll antibody has reduced interaction with its cognate FcRn receptor than an anti-PD-Ll antibody that does not contain the same H315 and H440 amino acid substitutions. In yet other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgGl immunoglobulin heavy chain constant domain (C H ), of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) 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, such that the modified anti-PD-Ll antibody has reduced interaction with its cognate FcRn receptor than an anti-PD-Ll antibody that does not contain the same H315 and H440 amino acid substitutions.

[0130] In other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgGl immunoglobulin heavy chain constant domain (C H ), of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) comprises an H315A variant, an H440Q variant, or any combination thereof, such that the modified anti-PD-Ll antibody has reduced interaction with the FcRn receptor relative to an anti-PD-Ll antibody that does not contain the H315A variant and the H440Q variant, e.g., 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%. In yet other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgGl immunoglobulin heavy chain constant domain (C H ), of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C HThe modified anti-PD-L1 antibody comprises an H315A variant, an H440Q variant, or any combination thereof, such that the interaction of the modified anti-PD-L1 antibody with the FcRn receptor is reduced relative to anti-PD-L1 antibodies without the H315A and H440Q variants, for example, 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%, or up to 90%. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise the IgG1 immunoglobulin heavy chain constant domain (C15A, H440Q, H440Q, H315A, H440Q, H440Q) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody contains the H315A variant, the H440Q variant, or any combination thereof, such that the interaction between the modified anti-PD-L1 antibody and the FcRn receptor is reduced relative to anti-PD-L1 antibodies without the H315A and H440Q variants, for example, by 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 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%.

[0131] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG1 immunoglobulin heavy chain constant domain (C1) of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40. H The IgG1 immunoglobulin heavy chain constant domain (C) H) comprising the H315A variant, the H440Q variant, or any combination thereof, such that the interaction of the modified anti-PD-Ll antibody with the FcRn receptor is reduced relative to an anti-PD-Ll antibody that does not contain the H315A variant and the H440Q variant, e.g., by 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%. In still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise the IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) comprises the H315A variant, the H440Q variant, or any combination thereof, such that the interaction of the modified anti-PD-Ll antibody with the FcRn receptor is reduced relative to an anti-PD-Ll antibody that does not contain the H315A variant and the H440Q variant, e.g., by at most 100%, at most 125%, at most 150%, at most 175%, at most 200%, at most 250%, at most 300%, at most 350%, at most 400%, at most 450%, at most 500%. In still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise the IgGl immunoglobulin heavy chain constant domain (C H ) of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, which IgGl immunoglobulin heavy chain constant domain (C H ) comprises the H315A variant, the H440Q variant, or any combination thereof, such that the interaction of the modified anti-PD-Ll antibody with the FcRn receptor is reduced relative to an anti-PD-Ll antibody that does not contain the H315A variant and the H440Q variant, e.g., by 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 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%.

[0132] In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain an IgG2 immunoglobulin heavy chain constant domain (C2 domain) containing an amino acid sequence variant in the CH2 domain and / or CH3 domain. H The amino acid sequence variant reduces the interaction between the modified anti-PD-L1 antibody and its homologous FcRn receptor compared to anti-PD-L1 antibodies lacking the same amino acid variant located in the CH2 and / or CH3 domains. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may comprise an IgG2 immunoglobulin heavy chain constant domain (C1500) that may contain one, two, three, four, or five amino acid deletions, additions, or substitutions located in the CH2 and / or CH3 domains. H The deletion, addition, or substitution of the amino acids reduces the interaction between the modified anti-PD-L1 antibody and its homologous FcRn receptor compared to anti-PD-L1 antibodies that do not contain the same amino acid deletion, addition, or substitution located in the CH2 and / or CH3 domains.

[0133] In various aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain one, two, three, four, or five amino acid deletions, additions, or substitutions in the CH2 and / or CH3 domains, wherein the deletion, addition, or substitution reduces the interaction between the modified anti-PD-L1 antibody and its homologous FcRn receptor compared to an anti-PD-L1 antibody without the same amino acid deletion, addition, or substitution in the CH2 and / or CH3 domains. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H) can comprise an amino acid deletion, addition, or substitution at position H311, H436, or both 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 H311 and H436 amino acid deletion, addition, or substitution. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H311, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H436, or any combination thereof, 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 H311 and H436 amino acid substitution. In yet other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise 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, 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 H311 and H436 amino acid substitution. In yet other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise an amino acid substitution of A at position H311 (H311A), an amino acid substitution of Q at position H436 (H436Q), or any combination thereof, 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 H311 and H436 amino acid substitution.

[0134] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The anti-PD-L1 antibody may contain the H311A variant, the H436Q variant, or any combination thereof, such that the interaction between the anti-PD-L1 antibody and the FcRn receptor is reduced relative to an anti-PD-L1 antibody without the H311A and H436Q variants, for example, 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%, or at least 90%. In yet another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C18) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain the H311A variant, the H436Q variant, or any combination thereof, such that the interaction of the modified anti-PD-L1 antibody with the FcRn receptor is reduced relative to anti-PD-L1 antibodies without the H311A and H436Q variants, for example, 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%, or up to 90%. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C18) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) HThe modified anti-PD-L1 antibody may contain the H311A variant, the H436Q variant, or any combination thereof, such that the interaction between the modified anti-PD-L1 antibody and the FcRn receptor is reduced relative to anti-PD-L1 antibodies without the H311A and H436Q variants, for example, by 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%, and so on. 0%, 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 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%.

[0135] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain the H311A variant, the H436Q variant, or any combination thereof, such that the interaction of the modified anti-PD-L1 antibody with the FcRn receptor is reduced relative to anti-PD-L1 antibodies without the H311A and H436Q variants, for example, by 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%. In yet another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG2 immunoglobulin heavy chain constant domain (C16) of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. H The IgG2 immunoglobulin heavy chain constant domain (C) H) can comprise a H311A variant, a H436Q variant, or any combination thereof, such that the interaction of the modified anti-PD-L1 antibody with the FcRn receptor is reduced relative to an anti-PD-L1 antibody that does not contain the H311A variant and the H436Q variant, e.g., by at most 100%, by at most 125%, by at most 150%, by at most 175%, by at most 200%, by at most 250%, by at most 300%, by at most 350%, by at most 400%, by at most 450%, by at most 500%. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG2 immunoglobulin heavy chain constant domain (C H ), which IgG2 immunoglobulin heavy chain constant domain (C H ) can comprise a H311A variant, a H436Q variant, or any combination thereof, such that the interaction of the modified anti-PD-L1 antibody with the FcRn receptor is reduced relative to an anti-PD-L1 antibody that does not contain the H311A variant and the H436Q variant, e.g., from about 100% to about 150%, from about 100% to about 200%, from about 100% to about 250%, from about 100% to about 300%, from about 100% to about 350%, from about 100% to about 400%, from about 100% to about 450%, from about 100% to about 500%, from about 150% to about 200%, from about 150% to about 250%, from about 150% to about 300%, from about 150% to about 350%, from about 150% to about 400%, from about 150% to about 450%, from about 150% to about 500%, from about 200% to about 250%, from about 200% to about 300%, from about 200% to about 350%, from about 200% to about 400%, from about 200% to about 450%, from about 200% to about 500%, from about 250% to about 300%, from about 250% to about 350%, from about 250% to about 400%, from about 250% to about 450%, or from about 250% to about 500%.

[0136] In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) comprising an amino acid sequence variant in the CH2 domain and / or the CH3 domain, which amino acid sequence variant reduces the interaction of the modified anti-PD-L1 antibody with its cognate FcRn receptor relative to an anti-PD-L1 antibody that does not contain the same amino acid variant in the CH2 domain and / or the CH3 domain. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which IgG4 immunoglobulin heavy chain constant domain (C H) can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain that reduce 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 in the CH2 domain and / or the CH3 domain.

[0137] In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) that can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain that reduce 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 in the CH2 domain and / or the CH3 domain. H In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) that can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain that reduce 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 in the CH2 domain and / or the CH3 domain. H In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ) that can comprise 1, 2, 3, 4, or 5 amino acid deletions, additions, or substitutions in the CH2 domain and / or the CH3 domain that reduce 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 in the CH2 domain and / or the CH3 domain. H) can comprise an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H312, an amino acid substitution of A, C, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, or W at position H437, or any combination thereof, such that the modified anti-PD-L1 antibody has reduced interaction with its cognate FcRn receptor than an anti-PD-L1 antibody that does not contain the same H312 and H437 amino acid substitutions. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which IgG4 immunoglobulin heavy chain constant domain (C H ) can 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, such that the modified anti-PD-L1 antibody has reduced interaction with its cognate FcRn receptor than an anti-PD-L1 antibody that does not contain the same H312 and H437 amino acid substitutions. In still other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which IgG4 immunoglobulin heavy chain constant domain (C H ) can 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, such that the modified anti-PD-L1 antibody has reduced interaction with its cognate FcRn receptor than an anti-PD-L1 antibody that does not contain the same H312 and H437 amino acid substitutions.

[0138] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which IgG4 immunoglobulin heavy chain constant domain (C H) can comprise a H312A variant, a H437Q variant, or any combination thereof, such that the interaction of the modified anti-PD-Ll antibody with the FcRn receptor is reduced, 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%, or at least 90%, relative to an anti-PD-Ll antibody that does not contain the H312A variant and the H437Q variant. In still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which IgG4 immunoglobulin heavy chain constant domain (C H ) can comprise a H312A variant, a H437Q variant, or any combination thereof, such that the interaction of the modified anti-PD-Ll antibody with the FcRn receptor is reduced, e.g., by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, or at most 90%, relative to an anti-PD-Ll antibody that does not contain the H312A variant and the H437Q variant. In still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein can comprise an IgG4 immunoglobulin heavy chain constant domain (C H ), which IgG4 immunoglobulin heavy chain constant domain (C HThe modified anti-PD-L1 antibody may contain the H312A variant, the H437Q variant, or any combination thereof, such that the interaction between the modified anti-PD-L1 antibody and the FcRn receptor is reduced relative to anti-PD-L1 antibodies without the H312A and H437Q variants, for example, by 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%, and so on. 0%, 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 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%.

[0139] In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may include the IgG4 immunoglobulin heavy chain constant domain (C15) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain the H312A variant, the H437Q variant, or any combination thereof, such that the interaction of the modified anti-PD-L1 antibody with the FcRn receptor is reduced relative to anti-PD-L1 antibodies without the H312A and H437Q variants, for example, by 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%. In yet another aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG4 immunoglobulin heavy chain constant domain (C10) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) HThe modified anti-PD-L1 antibody may contain the H312A variant, the H437Q variant, or any combination thereof, such that the interaction of the modified anti-PD-L1 antibody with the FcRn receptor is reduced relative to anti-PD-L1 antibodies without the H312A and H437Q variants, for example, by 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%. In other aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein may contain the IgG4 immunoglobulin heavy chain constant domain (C10) of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. H The IgG4 immunoglobulin heavy chain constant domain (C) H The modified anti-PD-L1 antibody may contain the H312A variant, the H437Q variant, or any combination thereof, such that the interaction between the modified anti-PD-L1 antibody and the FcRn receptor is reduced relative to anti-PD-L1 antibodies without the H312A and H437Q variants, for example, by 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%. 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% 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%.

[0140] In aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein have a half-life of, e.g., 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-Ll antibodies disclosed herein have a half-life of, e.g., 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 still other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein have a half-life of, e.g., at most 1 day, at most 2 days, at most 3 days, at most 4 days, at most 5 days, at most 6 days, or at most 7 days. In yet other aspects of this embodiment, the anti-PD-Ll antibodies disclosed herein have a half-life of, e.g., 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.

[0141] In an embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl 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 aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl 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 an aspect of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl immunoglobulin heavy chain of SEQ ID NO: 44 and a kappa light chain of SEQ ID NO: 21. In other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl 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.

[0142] In an embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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.

[0143] In an embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain of SEQ ID NO: 44 and a light chain comprising a light chain variable region of SEQ ID NO: 9. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20. In yet other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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 still other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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.

[0144] In an embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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 comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a CDR3 of SEQ ID NO: 14 or SEQ ID NO: 15. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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 comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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-Ll antibody disclosed herein comprises an IgGl 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 comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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 an aspect of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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 comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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-Ll antibody disclosed herein comprises an IgGl 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 comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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.

[0145] In an embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a CDR3 of SEQ ID NO: 14 or SEQ ID NO 15. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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 an aspect of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain of SEQ ID NO: 44, and a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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.

[0146] In an embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl 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 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-Ll antibodies disclosed herein comprise an IgGl 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 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 aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl 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 other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl 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.

[0147] In an embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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-Ll antibody disclosed herein comprises an IgGl 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, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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, 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.

[0148] In an embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl 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-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region of SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, 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.

[0149] In an embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising 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 comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a CDR3 of SEQ ID NO: 14 or SEQ ID NO 15. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising 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, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising 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, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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 aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising 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, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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-Ll antibodies disclosed herein comprise an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising 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, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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.

[0150] In an embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, and a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a CDR3 of SEQ ID NO: 14 or SEQ ID NO 15. In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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 aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising SEQ ID NO: 2, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising 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: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, or SEQ ID NO: 31.

[0151] In an embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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 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-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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 aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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 other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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 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.

[0152] In an embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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 comprising a light chain variable region of SEQ ID NO: 9. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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, 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 other aspects of the embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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, 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.

[0153] In an embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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 of SEQ ID NO: 9. In aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, 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 other aspects of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, 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 other aspects of the embodiment, the modified anti-PD-Ll antibodies disclosed herein comprise an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, 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.

[0154] In an embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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 comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a CDR3 of SEQ ID NO: 14 or SEQ ID NO 15. In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, and a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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 an aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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.

[0155] In an embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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 comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a CDR3 of SEQ ID NO: 14 or SEQ ID NO 15. In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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 an aspect of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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.

[0156] In an embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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 comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a CDR3 of SEQ ID NO: 14 or SEQ ID NO 15. In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, and a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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 an aspect of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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.

[0157] In an embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a 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 comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a CDR3 of SEQ ID NO: 14 or SEQ ID NO 15. In aspects of this embodiment, the modified anti-PD-L1 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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 antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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, or SEQ ID NO: 20.In an aspect of this embodiment, the modified anti-PD-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, or a 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-Ll antibody disclosed herein comprises an IgGl immunoglobulin heavy chain comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, a heavy chain constant region of SEQ ID NO: 57, a light chain comprising a light chain variable region comprising a CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13, and a 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.

[0158] Whether two sequences have high sequence identity (or homology) is typically ascertained using the term percent similarity or percent identity as is well known in the art. The sequence of the PD-L1 antigen can be compared to SEQ ID NO: 1. The sequence of the anti-PD-L1 antibody can be compared to SEQ ID NOs: 2-15. The term "percent (%) amino acid sequence identity" with respect to any one of SEQ ID NOs: 1-15 is defined as the percentage of amino acid residues in the candidate sequence that are identical with the amino acid residues in any one of the SEQ ID NOs: 1-15 amino acid sequences, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Percent identity can be determined using any of a variety of sequence alignment methods, including, but not limited to, global methods, local methods, and hybrid methods, such as, for example, the segment method. Protocols for determining percent identity are routine procedures within the skill in the art and from the teachings herein.

[0159] Global methods align sequences from the beginning to the end of the molecules and determine the best alignment by adding the scores of individual residue pairs and imposing a gap penalty. Non-limiting methods include, for example, CLUSTAL W, see, e.g., 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, e.g., 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).

[0160] Local methods align sequences by identifying one or more conserved motifs common to all input sequences. Non-limiting methods include, for example, Match-box, see, e.g., 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, e.g., C. E. Lawrence et al., Detecting Subtle Sequence Signals: A Gibbs Sampling Strategy for Multiple Alignment, 262(5131) Science 208-214 (1993); Align-M, see, e.g., Ivo Van Walle et al., Align-M - A New Algorithm for Multiple Alignment of Highly Divergent Sequences, 20(9) Bioinformatics,: 1428-1435 (2004).

[0161] 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. U.S.A. 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 Subramanian et al., DIALIGN-T: An Improved Algorithm for Segment-Based Multiple Sequence Alignment, 6(1) BMC Bioinformatics 66 (2005).

[0162] The present specification describes a variety of polypeptide variants in which one amino acid is substituted for another amino acid, such as, for example, PD-L1 antigen, heavy chain variable domain (V H ), light chain variable domain (V L ), and CDR 1 region, CDR2 region, and CDR3 region. Substitutions can be evaluated by a variety of factors, such as, for example, the physical properties of the amino acid being substituted (Table 1) or how the original amino acid would tolerate the substitution (Table 2). The selection of which amino acid in a polypeptide can be substituted for another amino acid is known to one of ordinary skill in the art.

[0163]

[0164]

[0165] In aspects of this embodiment, a hydrophobic amino acid at a particular position in the modified anti-PD-Ll antibodies disclosed herein can be substituted with another hydrophobic amino acid. Examples of hydrophobic amino acids include, e.g., C, F, I, L, M, V, and W. In another aspect of this embodiment, an aliphatic amino acid at a particular position in the modified anti-PD-Ll antibodies disclosed herein can be substituted with another aliphatic amino acid. Examples of aliphatic amino acids include, e.g., A, I, L, P, and V. In yet another aspect of this embodiment, an aromatic amino acid at a particular position in the modified anti-PD-Ll antibodies disclosed herein can be substituted with another aromatic amino acid. Examples of aromatic amino acids include, e.g., F, H, W, and Y. In still another aspect of this embodiment, a stacking amino acid at a particular position in the modified anti-PD-Ll antibodies disclosed herein can be substituted with another stacking amino acid. Examples of stacking amino acids include, e.g., F, H, W, and Y. In further aspects of this embodiment, a polar amino acid at a particular position in the modified anti-PD-Ll antibodies disclosed herein can be substituted with another polar amino acid. Examples of polar amino acids include, e.g., D, E, K, N, Q, and R. In additional aspects of this embodiment, a less polar or indifferent amino acid at a particular position in the modified anti-PD-Ll antibodies disclosed herein can be substituted with another less polar or indifferent amino acid. Examples of less polar or indifferent amino acids include, e.g., A, H, G, P, S, T, and Y. In still further aspects of this embodiment, a positively charged amino acid at a particular position in the modified anti-PD-Ll antibodies disclosed herein can be substituted with another positively charged amino acid. Examples of positively charged amino acids include, e.g., K, R, and H. In additional aspects of this embodiment, a negatively charged amino acid at a particular position in the modified anti-PD-Ll antibodies disclosed herein can be substituted with another negatively charged amino acid. Examples of negatively charged amino acids include, e.g., D and E. In another aspect of this embodiment, a small amino acid at a particular position in the modified anti-PD-Ll antibodies disclosed herein can be substituted with another small amino acid. Examples of small amino acids include, e.g., A, D, G, N, P, S, and T. In yet another aspect of this embodiment, a C-beta branched amino acid at a particular position in the modified anti-PD-Ll antibodies disclosed herein can be substituted with another C-beta branched amino acid. Examples of C-beta branched amino acids include, e.g., I, T, and V.

[0166] In an embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope disclosed herein. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope present in the 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 having 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 to the PD-L1 of SEQ ID NO: 1. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope having within a range of 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% amino acid identity to the PD-L1 of SEQ ID NO: 1. In yet other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope having at least 1, at least 2, at least 3, or at least 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions relative to the PD-L1 of SEQ ID NO: 1; or at most 1, at most 2, at most 3, at most 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions relative to the PD-L1 of SEQ ID NO: 1. In still other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein specifically bind to an epitope having 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 the PD-L1 of SEQ ID NO: 1.

[0167] As used herein, the term "selectively binds" or "selectively binding" when referring to an antibody refers to the distinctive binding of the antibody to the indicated target epitope such that the antibody does not substantially cross-react with non-target epitopes. As defined herein, the minimum size of a peptide epitope is about 5 amino acids, and a peptide epitope typically comprises 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. A peptide epitope can be discontinuous, i.e., it comprises amino acid residues that are not adjacent in the primary structure of the peptide but are brought together to form the epitope by the secondary, tertiary or quaternary structure of the peptide. Furthermore, it is also noted that an epitope can comprise molecular moieties other than amino acid sequences, such as, for example, carbohydrate moieties, lipid moieties like lipoproteins or glycolipids, or chemically modified amino acid moieties like phosphorylated amino acids.

[0168] In an embodiment, the modified anti-PD-L1 antibodies disclosed herein can 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 in the 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 having 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 to the PD-L1 of SEQ ID NO: 1. In other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein selectively bind to an epitope having within the following ranges of amino acid identity to the PD-L1 of SEQ ID NO: 1: e.g., 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%. In yet other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein selectively bind to an epitope having at least 1, at least 2, at least 3, or at least 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions to the PD-L1 of SEQ ID NO: 1; or at most 1, at most 2, at most 3, at most 4 contiguous and / or non-contiguous amino acid deletions, additions, and / or substitutions to the PD-L1 of SEQ ID NO: 1. In still other aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein selectively bind to an epitope having 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 to the PD-L1 of SEQ ID NO: 1.

[0169] In aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein bind to an epitope present in PD-L1 comprising, 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-Ll antibodies disclosed herein bind to an epitope comprising, for example, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, or at most 20 amino acids. In other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein bind to an epitope present in PD-L1 comprising, 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, from about 7 to about 12, from about 7 to about 15, from about 7 to about 18, from about 7 to about 20, from about 8 to about 9, from about 8 to about 10, from about 8 to about 12, from about 8 to about 15, from about 8 to about 18, from about 8 to about 20, from about 9 to about 10, from about 9 to about 12, from about 9 to about 15, from about 9 to about 18, from about 9 to about 20, from about 10 to about 12, from about 10 to about 15, from about 10 to about 18, or from about 10 to about 20 amino acids.

[0170] In other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein bind to an epitope comprising: e.g., 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 PD-L1 of SEQ ID NO: 1. In other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein bind to an epitope comprising: e.g., at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, or at most 20 amino acids from PD-L1 of SEQ ID NO: 1. In other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein bind to an epitope comprising: e.g., 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, from about 7 to about 12, from about 7 to about 15, from about 7 to about 18, from about 7 to about 20, from about 8 to about 9, from about 8 to about 10, from about 8 to about 12, from about 8 to about 15, from about 8 to about 18, from about 8 to about 20, from about 9 to about 10, from about 9 to about 12, from about 9 to about 15, from about 9 to about 18, from about 9 to about 20, from about 10 to about 12, from about 10 to about 15, from about 10 to about 18, or from about 10 to about 20 amino acids from PD-L1 of SEQ ID NO: 1.

[0171] Selectively binding includes binding properties such as, 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 viewed as the strength of the antibody's binding to its epitope. Binding affinity can be described as the equilibrium dissociation constant (KD) of the antibody, which is defined as the ratio of Kd / Ka at equilibrium. Where Ka is the on-rate constant of the antibody, and kd is the off-rate constant of the antibody. Binding affinity is determined by both association and dissociation, and neither high association alone nor low dissociation alone can ensure high affinity. The on-rate constant (Ka) or on-rate constant (Kon) measures the number of binding events per unit time, or the tendency of the antibody and antigen to reversibly bind to its antibody-antigen complex. The on-rate constant is expressed in M -1 s -1 and is symbolized as follows: [Ab] x [Ag] x Kon. The greater the on-rate constant, the faster the antibody binds to its antigen, or the higher the binding affinity between the antibody and antigen. The off-rate constant (Kd) or off-rate constant (Koff) measures the tendency of the antibody-antigen complex to reversibly separate (dissociate) into its constituent molecules (i.e., the antibody and antigen), the number of dissociation events per unit time. The off-rate constant is expressed in s -1 and is symbolized as follows: [Ab + Ag] x Koff. The smaller the off-rate constant, the more tightly 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 new antibody-antigen complexes form equals the rate at which antibody-antigen complexes dissociate 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 the antibody, [Ag] is the molar concentration of the antigen, and [Ab + Ag] is the molar concentration of the antibody-antigen complex, where all components are at such concentrations when the system is at equilibrium. The smaller the equilibrium dissociation constant, the more tightly the antibody binds to its antigen, or the higher the binding affinity between the antibody and antigen.

[0172] Thus, in one embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have an on-rate constant for the epitope present in PD-L1 of, for example, less than 1 x 10 5 M -1 s -1 , less than 1 x 10 6 M -1 s -1 , less than 1 x 10 7 M -1 s-1 or less than 1 x 10 8 M -1 s -1 In another embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have an association rate constant for an epitope present in PD-L1 of, for example, more than 1 x 10 5 M -1 s -1 , more than 1 x 10 6 M -1 s -1 , more than 1 x 10 7 M -1 s -1 , or more than 1 x 10 8 M -1 s -1 In other aspects, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have an association rate constant for an epitope present in PD-L1 of between 1 x 10 5 M -1 s -1 and 1 x 10 8 M -1 s -1 , 1 x 10 6 M -1 s -1 and 1 x 10 8 M -1 s -1 , 1 x 10 5 M -1 s -1 and 1 x 10 7 M - 1 s -1 , or 1 x 10 6 M -1 s -1 and 1 x 10 7 M -1 s -1 .

[0173] In another embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have an association rate constant for an epitope other than an epitope present on PD-L1 of, for example, less than 1 x 10 0 M -1 s -1 , less than 1 x 10 1 M -1 s -1 , less than 1 x 10 2 M -1 s -1 , less than 1 x 103 M -1 s -1 or less than 1 x 10 4 M -1 s -1 In another embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have an off rate constant for an epitope other than the epitope present on PD-L1 of, for example, at most 1 x 10 0 M -1 s -1 , at most 1 x 10 1 M -1 s -1 , at most 1 x 10 2 M -1 s -1 , at most 1 x 10 3 M -1 s -1 , or at most 1 x 10 4 M -1 s -1 .

[0174] In another embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have an off rate constant for an epitope present in PD-L1 of, for example, less than 1 x 10 -3 s -1 , less than 1 x 10 -4 s -1 , or less than 1 x 10 -5 s -1 In other aspects of this embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have an off rate constant for an epitope present in PD-L1 of, for example, less than 1.0 x 10 -4 s -1 , less than 2.0 x 10 -4 s -1 , less than 3.0 x 10 -4 s -1 , less than 4.0 x 10 -4 s -1 , less than 5.0 x 10 -4 s -1 , less than 6.0 x 10 -4 s -1 , less than 7.0 x 10 -4 s -1 , less than 8.0 x 10 -4 s -1 , or less than 9.0 x 10 -4 s -1In another embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have a dissociation rate constant for an epitope present in PD-L1 of, for example, more than 1 x 10 -3 s -1 , more than 1 x 10 -4 s -1 , or more than 1 x 10 -5 s -1 In other aspects of this embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have a dissociation rate constant for an epitope present in PD-L1 of, for example, more than 1.0 x 10 -4 s -1 , more than 2.0 x 10 -4 s -1 , more than 3.0 x 10 -4 s -1 , more than 4.0 x 10 -4 s -1 , more than 5.0 x 10 -4 s -1 , more than 6.0 x 10 -4 s -1 , more than 7.0 x 10 -4 s -1 , more than 8.0 x 10 -4 s -1 , or more than 9.0 x 10 -4 s -1 In other aspects, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have a dissociation rate constant for an epitope present in PD-L1 of between, for example, 1 x 10 -3 s -1 and 1 x 10 -5 s -1 , 1 x 10 -3 s -1 and 1 x 10 -4 s -1 , or 1 x 10 -4 s -1 and 1 x 10 -5 s -1 .

[0175] In another embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have a dissociation constant for an epitope present in PD-Ll of less than 0.500 nM. In aspects of this embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have a dissociation constant for an epitope present in PD-Ll of, for example, 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-Ll antibodies disclosed herein can have a dissociation constant for an epitope present in PD-Ll of more than 0.500 nM. In aspects of this embodiment, the binding affinity of the modified anti-PD-Ll antibodies disclosed herein can have a dissociation constant for an epitope present in PD-Ll of, for example, more than 0.500 nM, more than 0.450 nM, more than 0.400 nM, more than 0.350 nM, more than 0.300 nM, more than 0.250 nM, more than 0.200 nM, more than 0.150 nM, more than 0.100 nM, or more than 0.050 nM.

[0176] Binding specificity is the ability of an antibody to distinguish between a molecule containing its epitope and a molecule not containing the epitope. One method of measuring binding specificity is to compare the antibody's on rate (Kon) for a molecule containing its epitope to the antibody's on rate for a molecule not containing the epitope. For example, the modified anti-PD-Ll antibodies disclosed herein are compared for their on rate constant (Ka) for selectively binding an epitope present in PD-Ll versus an epitope not present in PD-Ll. In aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein can have a binding rate constant (Ka) for an epitope not present in PD-Ll of, for example, less than 1 x 105M-1s-1, less than 1 x 104M-1s-1, less than 1 x 103M-1s-1, less than 1 x 102M-1s-1, less than 1 x 101M-1s-1, less than 1 x 100M-1s-1, less than 1 x 10-1M-1s-1, less than 1 x 10-2M-1s-1, less than 1 x 10-3M-1s-1, less than 1 x 10-4M-1s-1, less than 1 x 10-5M-1s-1, less than 1 x 10-6M-1s-1, less than 1 x 10-7M-1s-1, less than 1 x 10-8M-1s-1, less than 1 x 10-9M-1s-1, or less than 1 x 10-10M-1s-1. 0 M -1 s -1 , less than 1 x 10 1 M -1 s -1 , less than 1 x 10 2 M -1 s -1 , less than 1 x 10 3 M -1 s -1 , less than 1 x 10 4 M -1 s -1In other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein can have a binding rate constant (Ka) for an epitope present in PD-Ll that is, for example, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, or at least 9-fold greater than the binding rate constant (Ka) for an epitope not present in PD-Ll. In still other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein can have a binding rate constant (Ka) for an epitope present in PD-Ll that is, for example, at least 10-fold, at least 100-fold, at least 1,000-fold, or at least 10,000-fold greater than the binding rate constant (Ka) for an epitope not present in PD-Ll. 0 M -1 s -1 , at least 1 x 10 1 M - 1 s -1 , at least 1 x 10 2 M -1 s -1 , at least 1 x 10 3 M -1 s -1 , or at least 1 x 10 4 M -1 s -1 .

[0177] In other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein can have a binding rate constant (Ka) for an epitope present in PD-Ll that is, for example, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, or at least 9-fold greater than the binding rate constant (Ka) for an epitope not present in PD-Ll. In still other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein can have a binding rate constant (Ka) for an epitope present in PD-Ll that is, for example, at least 10-fold, at least 100-fold, at least 1,000-fold, or at least 10,000-fold greater than the binding rate constant (Ka) for an epitope not present in PD-Ll.

[0178] In other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein can have a binding rate constant (Ka) for an epitope present in PD-Ll that is, for example, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, or at least 9-fold greater than the binding rate constant (Ka) for an epitope not present in PD-Ll. In still other aspects of this embodiment, the modified anti-PD-Ll antibodies disclosed herein can have a binding rate constant (Ka) for an epitope present in PD-Ll that is, for example, at least 10-fold, at least 100-fold, at least 1,000-fold, or at least 10,000-fold greater than the binding rate constant (Ka) for an epitope not present in PD-Ll.

[0179] The binding specificity of the modified anti-PD-L1 antibodies disclosed herein can also be characterized as a ratio in that such modified anti-PD-L1 antibodies disclosed herein can distinguish their epitope relative to an epitope not present in PD-L1 in a ratio. In aspects of this embodiment, the modified anti-PD-L1 antibodies disclosed herein can have a binding specificity ratio for their epitope relative to an epitope not present in PD-L1 of, for example, at least 2: 1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6: 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.

[0180] Binding avidity, also known as functional avidity, refers to the sum of the functional binding strengths between a multivalent antibody and its antigen. Antibody molecules can have more than one binding site (e.g., 2 for IgG), and many antigens comprise more than one antigenic site. While the binding avidity of an antibody depends on the binding affinity of the individual antibody binding sites, binding avidity is greater than binding affinity because all antibody-antigen interactions must be broken simultaneously for the antibody to fully dissociate. It is contemplated that the modified anti-PD-L1 antibodies disclosed herein can bind selectively with any and all epitopes of the antibody.

[0181] Aspects of the present specification disclose, in part, a therapeutic composition. The therapeutic compositions disclosed herein can comprise one or more of the anti-PD-L1 antibodies disclosed herein, and optionally can 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 untoward reaction or an undesirable reaction when administered to a subject. 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, for example, the modified anti-PD-L1 antibodies disclosed herein. The therapeutic compositions comprising the modified anti-PD-L1 antibodies disclosed herein are useful for medical and veterinary applications. The therapeutic compositions can be administered to a subject alone or in combination with other supplementary active ingredients, agents, drugs, or hormones. The therapeutic compositions can be manufactured using any of a variety of methods including, but not limited to, conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, and lyophilizing processes. The therapeutic compositions can take any of a variety of forms including, but not limited to, sterile solutions, suspensions, emulsions, lyophilizates, tablets, pills, pellets, capsules, powders, syrups, elixirs, or any other dosage form suitable for administration.

[0182] The amount of the modified anti-PD-Ll antibody disclosed herein included in a therapeutic composition is an amount sufficient to elicit an appropriate therapeutic response in an individual. Typically, this amount is also an amount that does not cause significant adverse side effects. Thus, the amount of the modified anti-PD-Ll antibody disclosed herein included in a therapeutic composition is an effective and safe amount of the modified anti-PD-Ll antibody disclosed herein. This amount will vary depending on the particular anti-PD-Ll antibody(s) employed. The optimal amount of a particular therapeutic composition can be determined by one of skill in the art using standard and routine research, including observation of antibody titers and other responses in an individual.

[0183] The therapeutic compositions disclosed herein can optionally include one or more pharmaceutically acceptable carriers, which facilitate processing of active ingredients into the therapeutic compositions. As used herein, the term "pharmacologically acceptable carrier" is synonymous with "pharmacological carrier" and means any compound, which is substantially non-detrimental to the recipient when administered in suitable quantities, and encompasses terms such as "pharmacologically acceptable vehicle, stabilizer, diluent, additive, adjuvant, or excipient." Such carriers are typically mixed with the active compound or allowed to dilute or encapsulate the active compound and can be solid, semi-solid, or liquid. It should be understood that an active ingredient can be soluble in, or can be delivered as a suspension in, the desired carrier. Any of a variety of pharmaceutically acceptable carriers can be used, including but not limited to, aqueous media such as, for example, water, saline, glycine, hyaluronic acid, etc.; solid carriers such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc.; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient. The choice of a pharmacologically acceptable carrier can depend on the mode of administration. Except insofar as any pharmacologically acceptable carrier is incompatible with the active ingredient, its use in the pharmaceutical composition is contemplated. Non-limiting examples of particular 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, 7thedition 1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R. Gennaro, ed., Lippincott, Williams & Wilkins, 20thedition 2000); GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10thedition 2001); and HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (Raymond C. Rowe et al., APhA Publications, 4thedition 2003). These schemes are routine procedures and any modification is well within the skill of the artisan and from the teachings herein.

[0184] The therapeutic compositions disclosed herein can optionally include, but are not limited to, other pharmaceutically acceptable components (or pharmaceutical components), including, but not limited to, buffers, preservatives, tonicity adjusting agents, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like. Various buffers and means of adjusting pH can be used in the preparation of the therapeutic compositions disclosed herein, provided that the resulting formulation is pharmaceutically acceptable. Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, neutral buffered saline, phosphate buffered saline, and borate buffers. It will be appreciated that acids or bases can be used as needed to adjust the pH of the composition. 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 composition, and chelators such as, for example, DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjusting agents that can be used in pharmaceutical compositions include, but are not limited to, salts such as, for example, sodium chloride, potassium chloride, mannitol, or glycerin, and other pharmaceutically acceptable tonicity adjusting agents. Active ingredients, such as, for example, the modified anti-PD-Ll antibodies disclosed herein, can be provided as salts and can be formed with a variety of acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts are more soluble in water or other protonic solvents than are the corresponding free base forms. It will be appreciated that these and other substances known in the pharmacological arts can be included in the therapeutic compositions.

[0185] Aspects of the present description disclose, in part, pharmaceutical kits. The kits disclosed herein can comprise one or more containers comprising a modified anti-PD-Ll antibody or therapeutic composition disclosed herein. The kits disclosed herein can also comprise a label or package insert providing useful information, including but not limited to, details of the modified anti-PD-Ll antibody or therapeutic composition disclosed herein, a description of how to prepare and use the modified anti-PD-Ll antibody or therapeutic composition disclosed herein to treat and / or prevent a neurodegenerative disease disclosed herein, a description of how to detect serum levels of the modified anti-PD-Ll antibody disclosed herein in an individual after administration of the modified anti-PD-Ll antibody or therapeutic composition disclosed herein, and / or a marketing authorization number (e.g., FDA or EMA authorization number). The kits disclosed herein can also comprise a delivery system useful for administering the modified anti-PD-Ll antibody or therapeutic composition disclosed herein, such as, for example, an injection device. The kits disclosed herein can also comprise one or more containers comprising another pharmaceutical composition used as an adjunct therapy to the modified anti-PD-Ll antibody or therapeutic composition disclosed herein. The contents of the kits can be enclosed in an outer casing. The outer casing can be a box, a sealed pouch, a foil pouch, or the like. In certain embodiments, the contents of the kits disclosed herein are enclosed in a box.

[0186] Aspects of the present description disclose, in part, methods of treating a neurodegenerative disease. In another aspect, the present description discloses, in part, methods for reducing the Ab plaque burden in an individual diagnosed with Alzheimer's disease. In another aspect, the present description discloses, in part, methods for reducing hippocampal gliosis in a patient diagnosed with Alzheimer's disease.

[0187] Such methods include therapeutic (post-disease onset) and prophylactic (pre-disease onset or pathology). For example, therapeutic and prophylactic methods of treating a neurodegenerative disease in an individual include methods of treating an individual having a neurodegenerative disease or pathology or at risk of developing a neurodegenerative disease or pathology, treating an individual having a neurodegenerative disease, and protecting an individual from a neurodegenerative disease to reduce or decrease the probability of a neurodegenerative disease in an individual, reduce or decrease the susceptibility of an individual to a neurodegenerative disease, or inhibit or prevent a neurodegenerative disease in an individual. Such methods include administering an immunogenic composition disclosed herein to therapeutically or prophylactically treat an individual having a neurodegenerative disease or pathology or at risk of developing a neurodegenerative disease or pathology. Thus, the methods can treat a neurodegenerative disease or pathology or provide protection (e.g., prophylactic protection) from a neurodegenerative disease to an individual.

[0188] In an embodiment, the method of treating a neurodegenerative disease comprises administering to an individual in need thereof an amount of a modified anti-PD-Ll antibody disclosed herein or a therapeutic composition disclosed herein sufficient to reduce one or more physiological conditions or symptoms associated with the neurodegenerative disease or pathology, thereby treating the neurodegenerative disease. In aspects of this embodiment, the therapeutic composition comprises one or more anti-PD-Ll antibodies disclosed herein.

[0189] In an embodiment, a modified anti-PD-Ll antibody disclosed herein or a therapeutic composition disclosed herein is used to treat a neurodegenerative disease. The use of a modified anti-PD-Ll antibody disclosed herein or a therapeutic composition disclosed herein treats a neurodegenerative disease by reducing one or more physiological conditions or symptoms associated with the neurodegenerative disease or pathology. In aspects of this embodiment, the anti-PD-Ll or therapeutic composition is administered in an amount sufficient to reduce one or more physiological conditions or symptoms associated with the neurodegenerative disease or pathology, thereby treating the neurodegenerative disease.

[0190] A neurodegenerative disease refers to any condition, disease, or disorder that results in pathophysiological effects due to a gradual loss of structure or function of neurons, including neuron 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 degeneration disorder; anterior ischemic optic neuropathy; glaucoma; uveitis; depression; trauma-related stress or post-traumatic stress disorder, frontotemporal dementia, Lewy body dementia, mild cognitive impairment, posterior cortical atrophy, primary progressive aphasia, progressive supranuclear palsy, or CNS injury.

[0191] Tauopathies are a class of neurodegenerative diseases that are clinically, morphologically, and biochemically heterogeneous, characterized by pathological aggregation of tau protein in neurofibrillary or glial fibrillary tangles in the human brain. Tau is a microtubule-associated protein (MAP) that binds to microtubules and promotes their polymerization. It plays an important role in maintaining axonal transport and neuronal integrity, but has a physiological role in dendrites, and it is expressed at low levels in glial cells. In tauopathies, tau aggregates in insoluble forms due to hyperphosphorylation of tau, resulting in tangles. Non-limiting examples of tauopathies include Alzheimer's disease, argyrophilic grain disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia pugilistica, frontotemporal lobar dementia, frontotemporal lobar degeneration, Hallervorden-Spatz disease, Huntington's disease, ganglioglioma, ganglionocell tumor, globular glial tauopathy, lead encephalopathy, lipofuscinosis, Lytico-boding disease (Parkinson-dementia complex of Guam), meningioangiomatosis, Parkinson's disease linked to chromosome 17, Pick's disease, primary age-related tauopathy (PART), previously known as neurofibrillary tangle-only dementia (NFT dementia), postencephalitic parkinsonism, progressive supranuclear palsy, subacute sclerosing panencephalitis, and tuberous sclerosis.

[0192] Retinal degeneration disorders are diseases that result from the death of photoreceptor cells leading to the degeneration of the retina. There are several causes of retinal degeneration, including arterial or venous occlusion, diabetic retinopathy, retrolental fibroplasia / retinopathy of prematurity or a disease (often genetic). Symptoms include, but are not limited to, impaired 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 loss of vision altogether. Retinal degeneration disorders include, but are not limited to, age-related macular degeneration (wet and dry), retinitis pigmentosa, choroideremia, cone-rod dystrophy, Gyrate Atrophy, juvenile retinoschisis, vitelliform macular dystrophy (Best disease), Abetalipoproteinemia (Bassen-Kornzweig disease), Bardet-Biedl syndrome, Blue Cone Monochromatism Disease, dominant Drusen, Goldman-Favre vitreoretinal dystrophy (enhanced S-cone syndrome), Kearns-Sayre syndrome, Laurence-Moon syndrome, Leber congenital amaurosis, Leber’s Refsum disease, Oguchi disease, peripheral (pericentral) chorioretinal dystrophy, Pigment Pattern Dystrophy, Sorsby macular dystrophy, Stargardt disease, Stickler syndrome, Usher syndrome, and Wagner vitreoretinal dystrophy.

[0193] CNS injuries include, but are not limited to, spinal cord injury, closed head injury, blunt trauma, penetrating trauma, hemorrhagic stroke, ischemic stroke, cerebral ischemia, optic nerve injury, myocardial infarction, organophosphate poisoning, and injury caused by tumor resection.

[0194] Aspects of the present specification provide, in part, individuals. Individuals include any mammal, including humans, and the human can be a patient.

[0195] The methods disclosed herein include treatment of a neurodegenerative disease. Treatment includes any therapeutic effect or beneficial effect, including any objective or individual measurable or detectable improvement or benefit provided to a particular individual. The therapeutic effect or beneficial effect can, but need not, be complete eradication of all or any particular adverse condition, symptom, disorder, illness, disease, or complication caused by or associated with a neurodegenerative disease or pathology. Thus, a satisfactory clinical endpoint is achieved when there is an incremental improvement or partial reduction in an adverse condition, symptom, disorder, illness, disease, or complication caused by or associated with a neurodegenerative disease or pathology, or inhibition, reduction, decrease, containment, prevention, limitation, 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 pathology, for a short duration or for a long duration.

[0196] In aspects of this embodiment, the treatment methods or uses disclosed herein can reduce, decrease, inhibit, limit, delay, or prevent a neurodegenerative disease or pathology. In other aspects of this embodiment, the treatment methods or uses disclosed herein can reduce, decrease, 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 pathology. In yet other aspects of this embodiment, the treatment methods or uses disclosed herein can improve, accelerate, promote, enhance, strengthen, or expedite recovery of an individual from a neurodegenerative disease or pathology, or one or more adverse symptoms, disorders, illnesses, diseases, or complications caused by or associated with a neurodegenerative disease or pathology.

[0197] In other aspects of this embodiment, the treatment methods or uses disclosed herein can stabilize a neurodegenerative disease, pathology, or adverse condition, symptom, disorder, illness, disease, or complication caused by or associated with a neurodegenerative disease or pathology. In yet other aspects of this embodiment, the treatment or use methods disclosed herein can reduce or eliminate the need for, dose frequency, or amount of a concurrent or subsequent treatment, such as another drug or other agent for treating an individual having a neurodegenerative disease or pathology or at risk of developing a neurodegenerative disease or pathology. For example, reducing the amount of adjunct therapy, e.g., reducing or decreasing treatment of a neurodegenerative disease or pathology.

[0198] One or more physiological conditions or symptoms associated with a neurodegenerative disease or pathology will be responsive to the treatment methods disclosed herein. Symptoms of a neurodegenerative disease or pathology vary depending on the stage of the disease, but include, without limitation, improved CNS function, cognition, learning, memory, and plasticity.

[0199] The term "CNS function" as used herein refers, inter alia, to the reception and processing of sensory information, thinking, learning, memory, perception, production and comprehension of language, control of voluntary motor function, and auditory and visual responses, maintenance of balance and equilibrium, motor coordination, conduction of sensory information, and control of autonomic functions such as respiration, heart rate, and digestion.

[0200] The terms "cognition", "cognitive function" and "cognitive performance" are used interchangeably herein and relate to any mental process or state related to, but not limited to, learning, memory, image creation, thinking, consciousness, reasoning, spatial abilities, verbal and language skills, language acquisition, and attentional capacity for judgment. Cognition is formed in multiple regions of the brain, such as the hippocampus, cortex, and other brain structures. However, long-term memory is hypothesized to be stored at least in part in the cortex, and sensory information is known to be acquired, consolidated, and retrieved by specific cortical structures, namely the gustatory cortex located within the insular cortex.

[0201] In humans, cognitive function can be measured by any known method, for example, but not limited to, by the Clinical Global Impression of Change scale (CIBIC-plus scale); the Mini Mental State Exam (MMSE); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating scale (CDR); the Cambridge Neuropsychological Test Automated Battery (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 technique that allows one to measure brain function.

[0202] Improvement of one or more processes affecting cognition of a patient will mean improvement of cognitive function of said patient, and thus in certain embodiments, improving cognition includes improving learning, plasticity, and / or long-term memory. The terms "improving" and "enhancing" can be used interchangeably. The term "learning" relates to acquiring or obtaining new, or modifying and strengthening existing, knowledge, behavior, skills, values, or preferences. The term "memory" relates to the process by which information is encoded, stored, and retrieved. Memory has three distinguishable categories: sensory memory, short-term memory, and long-term memory.

[0203] The term "long-term memory" refers to the ability to retain information for a long or indefinite period of time. Long-term memory includes two main components: explicit memory (declarative memory) and implicit memory (non-declarative memory). Long-term memory is achieved through memory consolidation, which is a class of processes that stabilize memory traces after their initial acquisition. Consolidation is divided into two specific processes, synaptic consolidation and systems consolidation, synaptic consolidation occurs within the first few hours after learning, and in systems consolidation, hippocampus-dependent memories become independent of the hippocampus over a period of weeks to years.

[0204] The term "plasticity" relates to synaptic plasticity, brain plasticity, or neural plasticity associated with the ability of the brain to change with learning and to change already acquired memories. One measurable parameter that reflects plasticity is memory extinction.

[0205] Aspects of the present specification provide, in part, for administering the modified anti-PD-Ll antibodies disclosed herein or the therapeutic compositions disclosed herein. As used herein, the term "administering" refers to any delivery mechanism that provides the immunogenic compositions or therapeutic compositions disclosed herein to an individual with the potential to result in a clinically, therapeutically, or experimentally beneficial outcome. The actual delivery mechanism used to administer the compositions disclosed herein to an individual can be determined by one of ordinary skill in the art by taking into account a variety of factors including, 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 degree of relief from the neurodegenerative disease that is desired, the duration of relief from the neurodegenerative disease that is desired, the particular anti-PD-Ll antibody and / or therapeutic composition used, the excretion rate of the particular anti-PD-Ll antibody and / or therapeutic composition used, the pharmacodynamics of the particular anti-PD-Ll antibody and / or therapeutic composition used, the properties of other compounds included in the therapeutic composition, the particular route of administration, the particular characteristics, medical history, and risk factors of the individual, such as, for example, age, body weight, general health, and the like, or any combination thereof.

[0206] The compositions disclosed herein can be administered to an individual using a cell uptake method. Administration of the compositions disclosed herein using a cell uptake method includes various enteral or parenteral methods, including but not limited to, oral administration in any acceptable form, such as, for example, tablets, liquids, capsules, powders, and the like; topical administration in any acceptable form, such as, for example, drops, sprays, creams, gels, or ointments; intravascular administration in any acceptable form, such as, for example, intravenous injection, intravenous infusion, intraarterial injection, intraarterial infusion, and catheter drip into the vasculature; peri- and intra-tissue administration in any acceptable form, such as, for example, intraperitoneal injection, intramuscular injection, subcutaneous injection, subcutaneous infusion, intraocular injection, retinal injection, or subretinal injection, or epidural injection; intravesicular administration in any acceptable form, such as, for example, catheter drip; and by placement of a device, such as, for example, an implant, a patch, a pellet, a catheter, an osmotic pump, a suppository, a biologically erodible delivery system, a non-biologically erodible delivery system, or other implanted extended or slow release system. An exemplary list of biodegradable polymers and methods of use are described in, for example, Handbook of Biodegradable Polymers (Abraham J. Domb et al., eds., Overseas Publishers Association, 1997).

[0207] The modified anti-PD-Ll antibodies disclosed herein and / or the therapeutic compositions disclosed herein are administered in an amount sufficient to treat a neurodegenerative disease. In aspects of this embodiment, the anti-PD-Ll antibodies and / or therapeutic compositions are administered in an amount sufficient to reduce one or more physiological conditions or symptoms associated with a neurodegenerative disease or pathology, or in an amount sufficient to protect an individual from a neurodegenerative disease or pathology. As used herein, the term "sufficient amount" includes "effective amount," "effective dose," "therapeutically effective amount," or "therapeutically effective dose," and refers to the minimum amount of the modified anti-PD-Ll antibodies and / or therapeutic compositions disclosed herein necessary to achieve the desired therapeutic effect, and includes an amount sufficient to reduce or inhibit one or more physiological conditions or symptoms associated with a neurodegenerative disease or pathology.

[0208] In aspects of this embodiment, an effective amount of the modified anti-PD-Ll antibody disclosed herein and / or the therapeutic composition disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with the neurodegenerative disease ...

Claims

1. A modified anti-programmed death-ligand 1 (PD-L1) antibody, wherein the modified anti-programmed death-ligand 1 (PD-L1) antibody comprises: A) A heavy chain comprising a heavy chain variable region comprising CDR1 of SEQ ID NO: 3, CDR2 of SEQ ID NO: 5, and CDR3 of SEQ ID NO: 7; The heavy chain constant region of SEQ ID NO: 55, SEQ ID NO: 56 or SEQ ID NO: 57; and A light chain, the light chain comprising a light chain variable region, the light chain variable region comprising CDR1 of SEQ ID NO: 10, CDR2 of SEQ ID NO: 12 and CDR3 of SEQ ID NO: 14; or, B) A heavy chain comprising a heavy chain variable region comprising CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 6, and CDR3 of SEQ ID NO: 8; The 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.

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

2.

3. The modified anti-PD-L1 antibody according to claim 1, wherein the heavy chain constant region is SEQ ID NO:

55.

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

42.

5. The modified anti-PD-L1 antibody according to claim 1, wherein the heavy chain constant region is SEQ ID NO:

56.

6. The modified anti-PD-L1 antibody according to claim 5, wherein the heavy chain is SEQ ID NO:

43.

7. The modified anti-PD-L1 antibody according to claim 1, wherein the heavy chain constant region is SEQ ID NO:

57.

8. The modified anti-PD-L1 antibody according to claim 7, wherein the heavy chain is SEQ ID NO:

44.

9. The modified anti-PD-L1 antibody according to any one of claims 1-8, wherein the light chain further comprises a light chain constant region.

10. The modified anti-PD-L1 antibody according to claim 9, wherein the light chain constant region is a κ light chain constant region or a λ light chain constant region.

11. The modified anti-PD-L1 antibody according to any one of claims 1-8, wherein the light chain variable region is SEQ ID NO:

9.

12. The modified anti-PD-L1 antibody according to any one of claims 1-8, wherein the light chain is 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.

13. A modified anti-programmed death-ligand 1 (PD-L1) antibody, said modified anti-programmed death-ligand 1 (PD-L1) antibody comprising the heavy chain of SEQ ID NO: 42, SEQ ID NO: 43 or SEQ ID NO: 44 and the light chain of SEQ ID NO:

21.

14. A pharmaceutical composition comprising a modified anti-PD-L1 antibody as defined in any one of claims 1-8, 12 or 13.

15. A pharmaceutical kit comprising a modified anti-PD-L1 antibody as defined in any one of claims 1-8, 12 or 13.

16. Use of the modified antiPD-L1 antibody as defined in any one of claims 1-8, 12 or 13 in the preparation of a medicament for the treatment of Alzheimer's disease or frontotemporal dementia.

17. A polynucleotide comprising a nucleic acid sequence encoding a heavy chain of a modified anti-PD-L1 antibody as defined in any one of claims 1-8, 12 or 13 and a nucleic acid sequence encoding a light chain of a modified anti-PD-L1 antibody as defined in any one of claims 1-8, 12 or 13.

18. The polynucleotide of claim 17, wherein the nucleic acid sequence encoding the heavy chain is SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:80 or SEQ ID NO:

81.

19. The polynucleotide of claim 17, wherein the nucleic acid sequence encoding the light chain is SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:86 or SEQ ID NO:

87.

20. An expression construct, said expression construct comprising: A) An expression construct comprising a nucleic acid sequence encoding a heavy chain of an anti-PD-L1 antibody modified according to any one of claims 1-8, 12 or 13; and B) An expression construct comprising a nucleic acid sequence encoding a light chain of an anti-PD-L1 antibody modified as defined in any one of claims 1-8, 12 or 13.

21. The expression construct of claim 20, wherein the nucleic acid sequence encoding the heavy chain is SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:80 or SEQ ID NO:

81.

22. The expression construct of claim 20, wherein the nucleic acid sequence encoding the light chain is SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:86 or SEQ ID NO:

87.

23. A method for preparing a modified anti-programmed death-ligand 1 (PD-L1) antibody, the method comprising expressing an expression construct according to any one of claims 20-22 in a host cell.

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