WO2022006555A2

WO2022006555A2 - BISPECIFIC ANTIGEN BINDING PROTEINS TARGETING PD-L1 AND TGF-β AND METHODS OF USE

Info

Publication number: WO2022006555A2
Application number: PCT/US2021/040373
Authority: WO
Inventors: David Scott Johnson; Adam Shultz ADLER; Rena Aviva MIZRAHI; Yoong Wearn LIM; Michael ASENSIO; Ellen Kathleen WAGNER; Eric Lyn STONE
Original assignee: Gigagen, Inc.
Priority date: 2020-07-02
Filing date: 2021-07-02
Publication date: 2022-01-06
Also published as: WO2022006555A3

Abstract

Provided herein are bispecific antigen-binding proteins (ABPs) that selectively bind to PD-L1 and TGF-β and its isoforms and homologs, and compositions comprising the ABPs. Also provided are methods of using the ABPs, such as therapeutic and diagnostic methods.

Description

Bispecific Antigen Binding Proteins Targeting PD-L1 and TGF-β and Methods of Use 1. CROSS REFERENCE TO RELATED APPLICATIONS [0001] The instant application claims priority to the US provisional application no. 63/047,791 filed on July 2, 2020, which is incorporated by reference in its entirety herein. 2. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing with 9287 sequences which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on July 2, 2021, is named 28152-49369_sequence_listing.txt, and is 841,125 bytes in size. 3. FIELD [0003] Provided herein are bispecific antigen-binding proteins (ABPs) with binding specificity for PD-L1 (programmed death-ligand 1) and TGF-β (transforming growth factor-β). Also provided are compositions comprising such ABPs, including pharmaceutical compositions, diagnostic compositions, and kits. Also provided are methods of making the ABPs, and methods of using the ABPs for, for example, therapeutic purposes, diagnostic purposes, and research purposes. 4. BACKGROUND [0004] PD-L1, also known as CD274 (cluster of differentiation 274) and B7 homolog 1 (B7-H1), is a cell surface receptor that suppresses T cell inflammatory activity. PD-L1 is a member of the B7 family of molecules involved in immune regulation and is over-expressed in certain types of T cells, many solid tumor cells, cancer stem-like cells, supporting vasculature, and stroma. The binding of PD-L1 to PD-1 or B7.1 transmits an inhibitory signal that reduces the proliferation of antigen-specific T-cells, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells). PD-L1 is therefore vitally important for downregulating the immune responses and promoting self-tolerance by suppressing T cell inflammatory activity. This activity prevents the immune system from killing cancer cells. [0005] Tumor cells hijack the PD-L1 pathway by up-regulating PD-L1 and thus suppress the anti-tumor immune response. Recently, it has been proposed that PD-L1 inhibitors could antagonize binding of PD-L1 to its ligands, thereby activating the immune system to attack tumors. PD-L1 antibodies could also be used to induce antibody-dependent cell-mediated cytotoxicity (ADCC) cells specific to the tumor microenvironment, thus directly killing the tumor. PD-L1 antibodies could therefore be used to treat some types of cancer. [0006] Though the biological function of PD-L1 is still being elucidated, the molecule is also a promising target for therapy of autoimmune disease. Because PD-L1 has both immune stimulatory and immune inhibitory properties, drugs that agonize or antagonize PD-L1 could be used to treat autoimmune diseases. [0007] International application no. PCT/US2019/068826 filed on December 27, 2019 discloses anti PD-L1 binding proteins. [0008] The cytokine transforming growth factor-β (TGF-β) has three known mammalian family members (TGF-β1, -β2, and -β3) that regulate multiple physiological processes. Binding of active TGF-β to its receptor complex triggers receptor serine/threonine kinase activity, allowing for the phosphorylation of downstream signaling targets. Nearly every cell type has the ability to secrete TGF-β, as well as the ability to respond to TGF-β via the presence of TGF-β receptors on the cell surface. [0009] A number of anti-TGF-β ABPs have been developed, including fresolimumab, developed by Genzyme and currently in clinical trials. [0010] The bifunctional molecule M7824 (Merck Serono), which is the anti-PD-L1 Avelumab (Merck Serono) plus a TGF-β trap (which is the extracellular domain of human TGF^RII), has been shown to have anti-tumor activity in early clinical trials (Lan et al. Enhanced Preclinical Antitumor Activity of M7824, a Bifunctional Fusion Protein Simultaneously Targeting PD-L1 and TGF-β. Sci Transl Med .2018 Jan 17;10(424)). 5. SUMMARY [0011] Provided herein are novel bi-specific anti-PD-L1 x anti-TGF-β antigen binding proteins (ABPs). [0012] The ABPs provided herein can induce various biological effects associated with inhibition or activation of PD-L1 and/or TGF-β. In some embodiments, an ABP provided herein prevents binding between PD-L1 and its ligands. In some embodiments, an ABP provided herein block PD-1/PD-L1 signaling. In some embodiments, an ABP provided herein block TGF-β signaling. For example, the ABP can block the TGF-β signaling by hindering binding of TGF-β to its receptor or by preventing activation of latent TGF-β. [0013] In some embodiments, the ABPs activate immune cells and enhance immune cell infiltration into the tumor microenvironment, providing, e.g., a durable response in late stage cancer. For example, the ABPs can enhance infiltration of immune cells into fibrotic tissues or other tissues where immune cells are excluded. In some embodiments, an ABP provided herein prevents inhibition of an effector T cell by a Treg. In some embodiments, the ABP directly kills tumor cells by ADCC, for example mediated by binding of NK cell-expressed CD16 to the ABP Fc domain. [0014] In some embodiments, the present disclosure provides an isolated bispecific antigen binding protein (ABP) comprising a first antigen binding domain that specifically binds a human programmed death-ligand 1 (PD-L1) and a second antigen binding domain that binds a human transforming growth factor-β (TGF-β), wherein the first antigen binding domain comprises a first CDR1-L, a first CDR2-L, a first CDR3-L, a first CDR1-H, a first CDR2-H and a first CDR3-H and the second antigen binding domain comprises a second CDR1-L, a second CDR2-L, a second CDR3-L, a second CDR1-H, a second CDR2-H and a second CDR3-H, wherein the six CDRs of the first antigen binding domain consist of the sequences of the six CDRs of A2, A5, A3, or A7. [0015] In some embodiments, the six CDRs of the second antigen binding domain consist of the sequences of the six CDRs of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. [0016] In some embodiments, the bispecific ABP comprises two first antigen binding domains and two second antigen binding domains. In some embodiments, the bispecific ABP comprises two first antigen binding domains and one second antigen binding domain. In some embodiments, the bispecific ABP comprises one first antigen binding domain and two second antigen binding domains. [0017] In some embodiments, the first antigen binding domain is a Fab format and the second antigen binding domain is an scFv format or the first antigen binding domain is an scFv format and the second antigen binding domain is a Fab format. In some embodiments, the bispecific ABP comprises a Fc region, optionally comprising a human IgG1, a human IgG2, or a human IgG4, and/or optionally the Fc region with a modified effector function, optionally comprising a LALAPG a N297A, aDANA, a LALA, or a N297Q mutation. [0018] In some embodiments, the first antigen binding domain comprises the first CDR1- L having a sequence selected from SEQ ID NO: 1002, 1003, 1005, and 1007, a first CDR2-L having a sequence selected from SEQ ID NO: 2002, 2003, 2005, and 2007, a first CDR3-L having a sequence selected from SEQ ID NO: 3002, 3003, 3005, and 3007, a first CDR1-H having a sequence selected from SEQ ID NO: 4002, 4003, 4005, and 4007, a first CDR2-H having a sequence selected from SEQ ID NO: 5002, 5003, 5005, and 5007 and a first CDR3-H having a sequence selected from SEQ ID NO: 6002, 6003, 6005, and 6007. [0019] In some embodiments, the first antigen binding domain comprises the first CDR1- L having the sequence of SEQ ID NO: 1002, a first CDR2-L having the sequence of SEQ ID NO: 2002, a first CDR3-L having the sequence of SEQ ID NO: 3002, a first CDR1-H having the sequence of SEQ ID NO: 4002, a first CDR2-H having the sequence of SEQ ID NO: 5002 and a first CDR3-H having the sequence of SEQ ID NO: 6002. In some embodiments, the first antigen binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1005, a first CDR2-L having the sequence of SEQ ID NO: 2005, a first CDR3-L having the sequence of SEQ ID NO: 3005, a first CDR1-H having the sequence of SEQ ID NO: 4005, a first CDR2-H having the sequence of SEQ ID NO: 5005 and a first CDR3-H having the sequence of SEQ ID NO: 6005. In some embodiments, the first antigen binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1003, a first CDR2-L having the sequence of SEQ ID NO: 2003, a first CDR3-L having the sequence of SEQ ID NO: 3003, a first CDR1-H having the sequence of SEQ ID NO: 4003, a first CDR2-H having the sequence of SEQ ID NO: 5003 and a first CDR3-H having the sequence of SEQ ID NO: 6003. In some embodiments, the first antigen binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1007, a first CDR2-L having the sequence of SEQ ID NO: 2007, a first CDR3-L having the sequence of SEQ ID NO: 3007, a first CDR1-H having the sequence of SEQ ID NO: 4007, a first CDR2-H having the sequence of SEQ ID NO: 5007 and a first CDR3-H having the sequence of SEQ ID NO: 6007. [0020] In some embodiments, the second antigen binding domain comprises a second CDR1-L having the sequence of SEQ ID NO: 9276, a second CDR2-L having the sequence of SEQ ID NO: 9277, a second CDR3-L having the sequence of SEQ ID NO: 9278, a second CDR1-H having the sequence of SEQ ID NO: 9279, a second CDR2-H having the sequence of SEQ ID NO: 9280 and a second CDR3-H having the sequence of SEQ ID NO: 9281. In some embodiments, the second antigen binding domain comprises a second CDR1-L having the sequence of SEQ ID NO: 9282, a second CDR2-L having the sequence of SEQ ID NO: 9283, a second CDR3-L having the sequence of SEQ ID NO: 9284, a second CDR1-H having the sequence of SEQ ID NO: 9285, a second CDR2-H having the sequence of SEQ ID NO: 9286 and a second CDR3-H having the sequence of SEQ ID NO: 9287. [0021] In another aspect, the present disclosure provides an isolated bispecific antigen binding protein (ABP) comprising a light chain having the sequence of SEQ ID NO: 9264 and a heavy chain having the sequence of SEQ ID NO: 9265. In yet another aspect, the present disclosure provides an isolated bispecific antigen binding protein (ABP) comprising a light chain having the sequence of SEQ ID NO: 9257 and a heavy chain having the sequence of SEQ ID NO: 9258. [0022] The present disclosure further provides an isolated bispecific antigen binding protein (ABP) comprising a first antigen binding domain that specifically binds a human programmed death-ligand 1 (PD-L1) and a second antigen binding domain that binds a human transforming growth factor-β (TGF-β), wherein the first antigen binding domain comprises a first CDR1-L having a sequence selected from SEQ ID NO: 8306-8458, a first CDR2-L having a sequence selected from SEQ ID NO: 8459-8611, a first CDR3-L having a sequence selected from SEQ ID NO: 8612-8764, a first CDR1-H having a sequence selected from SEQ ID NO: 8765-8917, a first CDR2-H having a sequence selected from SEQ ID NO: 8918-9070 and a first CDR3-H having a sequence selected from SEQ ID NO: 9071-9223, and the second antigen binding domain comprises a second CDR1-L having a sequence selected from SEQ ID NO: 9276 and 9282, a second CDR2-L having a sequence selected from SEQ ID NO: 9277 and 9283, a second CDR3-L having a sequence selected from SEQ ID NO: 9278 and 9284, a second CDR1- H having a sequence selected from SEQ ID NO: 9279 and 9285, a second CDR2-H having a sequence selected from SEQ ID NO: 9280 and 9286 and a second CDR3-H having a sequence selected from SEQ ID NO: 9281 and 9287. [0023] Also provided are kits comprising one or more of the pharmaceutical compositions comprising the ABPs, and instructions for use of the pharmaceutical composition. [0024] Also provided are isolated polynucleotides encoding the ABPs provided herein, and portions thereof. [0025] Also provided are vectors comprising such polynucleotides. [0026] Also provided are recombinant host cells comprising such polynucleotides and recombinant host cells comprising such vectors. [0027] Also provided are methods of producing the ABP using the polynucleotides, vectors, or host cells provided herein. [0028] Also provided are pharmaceutical compositions comprising the ABPs and a pharmaceutically acceptable excipient. [0029] Another aspect of the present disclosure provides a pharmaceutical composition comprising any one of the disclosed ABPs and an excipient. [0030] Another aspect of the present disclosure provides a method of treating a disease comprising the step of: administering to a subject in need thereof an effective amount an ABP as disclosed herein or a pharmaceutical composition as disclosed herein. In some embodiments, the disease is selected from the group consisting of cancer, AIDS, Alzheimer’s disease and viral or bacterial infection. In some embodiments, the method further comprises the step of administering one or more additional therapeutic agents to the subject. In some embodiments, the additional therapeutic agent is selected from CTLA-4 inhibitor, TIGIT inhibitor, a chemotherapy agent, an immune-stimulatory agent, radiation, a cytokine, a polynucleotide encoding a cytokine and a combination thereof. [0031] In one aspect, the present disclosure provides a mixture of a first isolated antigen binding protein (ABP) that specifically binds a human programmed death-ligand 1 (PD-L1) and a second ABP that binds a human transforming growth factor-β (TGF-β), wherein the six CDRs of the first ABP consist of the sequences of the six CDRs of A2, A5, A3, or A7. In another aspect, the present disclosure provides a kit comprising a first isolated antigen binding protein (ABP) that specifically binds a human programmed death-ligand 1 (PD-L1) and a second ABP that binds a human transforming growth factor-β (TGF-β), wherein the six CDRs of the first ABP consist of the sequences of the six CDRs of A2, A5, A3, or A7. In some embodiments, the six CDRs of the second ABP consist of the sequences of the six CDRs of fresolimumab or anti- TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. [0032] In yet another aspect, the present disclosure provides a method of treating a disease comprising the step of administering to a subject in need thereof an effective amount of the first isolated antigen binding protein (ABP) that specifically binds a human programmed death-ligand 1 (PD-L1) and the second ABP that binds a human transforming growth factor-β (TGF-β). In some embodiments, the first and second ABPs are not administered concurrently. [0033] In one aspect, the present disclosure provides an isolated antigen binding protein (ABP) comprises a heavy chain variable region having a sequence selected from SEQ ID NOs: 9268-9271 and a light chain variable region having a sequence selected from SEQ ID NO: 9272- 9275. In some embodiments, the ABP comprises a heavy chain variable region having a sequence of SEQ ID NO: 9268 and a light chain variable region having a sequence of SEQ ID NO: 9272. In some embodiments, the ABP comprises a heavy chain variable region having a sequence of SEQ ID NO: 9269 and a light chain variable region having a sequence of SEQ ID NO: 9273. In some embodiments, the ABP comprises a heavy chain variable region having a sequence of SEQ ID NO: 9270 and a light chain variable region having a sequence of SEQ ID NO: 9274. In some embodiments, the ABP comprises a heavy chain variable region having a sequence of SEQ ID NO: 9271 and a light chain variable region having a sequence of SEQ ID NO: 9275. [0034] In another aspect, the present disclosure provides a pharmaceutical composition comprising the ABP. In one aspect, the present disclosure provides a method of treating a disease comprising the step of administering to a subject in need thereof an effective amount of the ABP or the pharmaceutical composition. In yet another aspect, the present disclosure provides an isolated polynucleotide or set of isolated polynucleotides encoding the ABP as described herein. In one aspect, the present disclosure provides a vector or set of vectors comprising the isolated polynucleotide or set of isolated polynucleotides. Further provided includes a host cell comprising the isolated polynucleotide or the vector. 6. BRIEF DESCRIPTION OF THE DRAWINGS [0035] FIG.1 summarizes the method of generating scFv libraries from B cells isolated from fully human mice and selecting for yeast expressing an scFv having affinity to the antigen derived from a B cell expressing an antibody having high-affinity to the antigen. FIG.1 discloses SEQ ID NOS 9227-9254, respectively, in order of appearance. [0036] FIG.2 illustrates scFv amplification procedure. First, a mixture of primers directed against the IgK C region, the IgG C region, and all V regions is used to separately amplify IgK and IgH. Second, the V-H and C-K primers contain a region of complementarity that results in the formation of an overlap extension amplicon that is a fusion product between IgK and IgH. The region of complementarity comprises a DNA sequence that encodes a Gly-Ser rich scFv linker sequence. Third, semi-nested PCR is performed to add adapters for Illumina sequencing or yeast display. [0037] FIG.3 includes a plot from the PD-L1 blocking assay of anti-PD-L1 antibodies (A1, A2, A3, A5, A7, and Atezolizumab) described in Example 3. It plots the luminescence (RLU) against concentration of anti-PD-L1 treatment from the PD-L1 blocking assay. [0038] FIG.4 includes a schematic showing the monoclonal antibodies in their epitope bins (Bin “A” or Bin “B”) as identified from the epitope binning described in Example 3. [0039] FIG.5A through 5F provide results from in vivo testing of multiple anti-PD-L1 mAbs with or without anti-TGF-β in hPD-L1 knock-in mice bearing MC38 tumors expressing human PD-L1 as described in Example 6. FIG.5A shows tumor volume (mm³) measured after monotherapy with various anti-PD-L1 ABPs (atezolizumab, atezolizumab-mIgG2a-LALA-PG, aPD-L1.5-mIgG2a-LALA-PG, aPD-L1.30-mIgG2a-LALA-PG, aPD-L1.3.6-mIgG2a-LALA- PG). FIG.5B shows tumor volume (mm³) measured after administration of various anti-PD-L1 ABPs in combination with or without anti-TGF-β. FIG.5C shows a subset of data provided in FIG.5B, where combination with anti-TGF-β enhanced tumor growth inhibition (TGI). FIG.5D shows a subset of data provided in FIG.5B, where combination with anti-TGF-β did not enhance tumor growth inhibition (TGI). FIG.5E shows tumor volume (mm³) measured after a monotherapy with atezolizumab or anti-TGF-β, or a combination therapy with atezolizumab and anti-TGF-β at different frequencies and durations. FIG.5F shows body weight change (%) measured in the test animals from day 6 (day of randomization and dosing initiation) to day 31 (day 25 post randomization). For animals euthanized due to a tumor volume of >300 mm³, the last observation was carried forward until no animals survived in the group. [0040] FIG.6A and FIG 6B provide results from in vivo testing of the combination of anti-PD-L1 (Atezo) and anti-TGF-β in a mouse model bearing ortotopic EMT6 tumors as described in Example 8. FIG.6A shows changes in the tumor volume (mm³) and FIG.6B shows changes in the body weight (%) over time. [0041] FIG.7A and FIG 7B provide results from in vivo testing of the combination of anti-PD-L1 (Atezo) and anti-TGF-β in CT26 syngeneic tumor model mice as described in Example 9. FIG.7A shows changes in the tumor volume (mm³) and FIG.7B shows changes in the body weight (%) over time. [0042] FIG.8 illustrates exemplary structures of anti-PD-L1 and anti-TGF-β bispecific ABPs in the 2:2 or 2:1 format as described herein. [0043] FIG.9 illustrates ELISA developed to examine concurrent binding of bispecific ABPs against TGF-β and PD-L1. [0044] FIG.10 provides ELISA results demonstrating the ability of bi-specific ABPs to bind both TGF-β1 and PD-L1. [0045] FIG.11 provides ELISA results demonstrating the ability of bi-specific ABPs to block the PD-L1 and CD80 interaction. [0046] FIG.12 provides FACS results demonstrating the ability of bi-specific ABPs to bind PD-L1 on the mammalian cell membrane. [0047] FIG.13 provides experimental results demonstrating the ability of bi-specific ABPs to block TGF-β signaling. [0048] FIG.14 provides experimental results demonstrating the ability of bi-specific ABPs to block the PD-1 and PD-L1 signaling pathway. [0049] FIG.15 provides experimental results demonstrating the ability of humanized 1D11 ABPs to block the TGF-β1 and TGF-βR signaling pathway. [0050] FIG.16 provides concentration of human IgG antibodies measured from animals administered with bispecific ABPs, for testing maintenance of bispecific ABPs in vivo. [0051] FIG.17 provides ELISA results demonstrating the ability of bispecific ABPs obtained from animal serum samples to concurrently bind TGF-β and PD-L1. [0052] FIG.18A-18C show data from two sets of in vivo testing of anti-PD-L1 (Atezo) or anti-TGF-β (Freso or 1D11), the combination (Atezo+Freso or Atezo+1D11) or anti-PD-L1 and anti-TGF-β bispecific ABPs (AtezoxFreso or Atezox1D11) in CT26 syngeneic tumor model mice as described in Example 11. FIG.18A, 18B and 18C show changes in the tumor volume (mm³) and FIG.18D shows changes in the body weight (%) over time. 7. DETAILED DESCRIPTION 7.1. Definitions [0053] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art. The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and Lane Antibodies: A Laboratory Manual Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1990), which are incorporated herein by reference. Enzymatic reactions and purification techniques are performed according to manufacturer’s specifications, as commonly accomplished in the art or as described herein. The terminology used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. [0054] The following terms, unless otherwise indicated, shall be understood to have the following meanings: [0055] The terms “PD-L1,” “PD-L1 protein,” and “PD-L1 antigen” are used interchangeably herein to refer to human PD-L1, or any variants (e.g., splice variants and allelic variants), isoforms, and species homologs of human PD-L1 that are naturally expressed by cells, or that are expressed by cells transfected with a pd-l1 gene (a.k.a. CD274). In some aspects, the PD-L1 protein is a PD-L1 protein naturally expressed by a primate (e.g., a monkey or a human), a rodent (e.g., a mouse or a rat), a dog, a camel, a cat, a cow, a goat, a horse, or a sheep. In some embodiments, the PD-L1 protein is human PD-L1 (hPD-L1; SEQ ID NO: 7001). [0056] The term “TGF-β” or transforming growth factor-β refers to TGF-β, or any variants (e.g., splice variants and allelic variants), isoforms, and species homologs of human TGF-β that are naturally expressed by cells. TGF-β can be in an activated or latent form. In some aspects, the TGF-β protein is a TGF-β protein naturally expressed by a primate (e.g., a monkey or a human), a rodent (e.g., a mouse or a rat), a dog, a camel, a cat, a cow, a goat, a horse, or a sheep. In some embodiments, the TGF-β protein is human TGF-β. [0057] The term antigen-binding protein (ABP) refers to a protein comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. In some embodiments, the antigen-binding domain binds the antigen or epitope with specificity and affinity similar to that of naturally occurring antibodies. In some embodiments, the ABP comprises an antibody. In some embodiments, the ABP consists of an antibody. In some embodiments, the ABP consists essentially of an antibody. In some embodiments, the ABP comprises an alternative scaffold. In some embodiments, the ABP consists of an alternative scaffold. In some embodiments, the ABP consists essentially of an alternative scaffold. In some embodiments, the ABP comprises an antibody fragment. In some embodiments, the ABP consists of an antibody fragment. In some embodiments, the ABP consists essentially of an antibody fragment. A “PD-L1 ABP,” “anti-PD-L1 ABP,” or “PD-L1-specific ABP” is an ABP, as provided herein, which specifically binds to the antigen PD-L1. In some embodiments, the ABP binds the extracellular domain of PD-L1. In certain embodiments, a PD-L1 ABP provided herein binds to an epitope of PD-L1 that is conserved between or among PD-L1 proteins from different species. A “TGF-β ABP,” “anti-TGF-β ABP,” or “TGF-β-specific ABP” is an ABP, as provided herein, which specifically binds to the antigen TGF-β. In certain embodiments, a ABP provided herein binds to an epitope of TGF-β that is conserved between or among TGF-β proteins from different species. [0058] The term “bispecific ABP” refers to an ABP, e.g., an antibody, with at least two different antigen binding domains that each specifically bind a different antigen, e.g., PD-L1 and TGF-β. A bispecific ABP can be of any number of valencies, e.g., bivalent, trivalent, tetravalent, and the like. [0059] The term “antibody” as used herein in its broadest sense and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multi-specific antibodies. One example of an antigen-binding domain is an antigen-binding domain formed by a V_H -V_L dimer. An antibody is one type of ABP. [0060] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch.5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (V_H) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, abbreviated C_H1, C_H2, and C_H3. Each light chain typically comprises a light chain variable region (V_L) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated C_L. [0061] The term “alternative scaffold” refers to a molecule in which one or more regions may be diversified to produce one or more antigen-binding domains that specifically bind to an antigen or epitope. In some embodiments, the antigen-binding domain binds the antigen or epitope with specificity and affinity similar to that of naturally occurring antibodies. Exemplary alternative scaffolds include those derived from fibronectin (e.g., Adnectins^TM), the β-sandwich (e.g., iMab), lipocalin (e.g., Anticalins^®), EETI-II/AGRP, BPTI/LACI-D1/ITI-D2 (e.g., Kunitz domains), thioredoxin peptide aptamers, protein A (e.g., Affibody^®), ankyrin repeats (e.g., DARPins), gamma-B-crystallin/ubiquitin (e.g., Affilins), CTLD3 (e.g., Tetranectins), Fynomers, and (LDLR-A module) (e.g., Avimers). Additional information on alternative scaffolds is provided in Binz et al., Nat. Biotechnol., 200523:1257-1268; Skerra, Current Opin. in Biotech., 200718:295-304; and Silacci et al., J. Biol. Chem., 2014, 289:14392-14398; each of which is incorporated by reference in its entirety. An alternative scaffold is one type of ABP. [0062] The term “antigen-binding domain” means the portion of an ABP that is capable of specifically binding to an antigen or epitope. [0063] The terms “full length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a naturally occurring antibody structure and having heavy chains that comprise an Fc region. [0064] The term “Fc region” means the C-terminal region of an immunoglobulin heavy chain that, in naturally occurring antibodies, interacts with Fc receptors and certain proteins of the complement system. The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art. See Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125:S41-52, incorporated by reference in its entirety. The Fc region may be a naturally occurring Fc region, or an Fc region modified as described elsewhere in this disclosure. For example, the Fc region can comprise a mutation that prevent its interaction with an Fc receptor. [0065] The V_H and V_L regions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs)”) also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each V_H and V_L generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding, and influence antigen specificity and binding affinity of the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety. [0066] The light chain from any vertebrate species can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the sequence of its constant domain. [0067] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated α, δ, ε, γ, and µ, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. [0068] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol.262:732-745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme); each of which is incorporated by reference in its entirety. [0069] Table 1 provides the positions of CDR1-L (CDR1 of V_L), CDR2-L (CDR2 of V_L), CDR3-L (CDR3 of V_L), CDR1-H (CDR1 of V_H), CDR2-H (CDR2 of V_H), and CDR3-H (CDR3 of V_H), as identified by the Kabat and Chothia schemes. For CDR1-H, residue numbering is provided using both the Kabat and Chothia numbering schemes. [0070] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk/abs/abnum/, and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety.

* The C-terminus of CDR1-H, when numbered using the Kabat numbering convention, varies between 32 and 34, depending on the length of the CDR. [0071] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). [0072] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)₂ fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments. [0073] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain. [0074] “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (C_H1) of the heavy chain. Fab fragments may be generated, for example, by recombinant methods or by papain digestion of a full-length antibody. [0075] “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds. F(ab’)2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab’) fragments can be dissociated, for example, by treatment with ß-mercaptoethanol. [0076] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a V_H domain and a V_L domain in a single polypeptide chain. The V_H and V_L are generally linked by a peptide linker. See Plückthun A. (1994). In some embodiments, the linker is a (GGGGS)_n (SEQ ID NO: 9224). In some embodiments, n = 1, 2, 3, 4, 5, or 6. See Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol.113 (pp. 269-315). Springer-Verlag, New York, incorporated by reference in its entirety. [0077] “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the V_H or V_L, depending on the orientation of the variable domains in the scFv (i.e., V_H -V_L or V_L -V_H ). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG4 Fc domain. [0078] The term “single domain antibody” refers to a molecule in which one variable domain of an antibody specifically binds to an antigen without the presence of the other variable domain. Single domain antibodies, and fragments thereof, are described in Arabi Ghahroudi et al., FEBS Letters, 1998, 414:521-526 and Muyldermans et al., Trends in Biochem. Sci., 2001, 26:230-245, each of which is incorporated by reference in its entirety. [0079] A “monospecific ABP” is an ABP that comprises a binding site that specifically binds to a single epitope. An example of a monospecific ABP is a naturally occurring IgG molecule which, while divalent, recognizes the same epitope at each antigen-binding domain. The binding specificity may be present in any suitable valency. [0080] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and/or to reduce its immunogenicity in a subject. [0081] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species. [0082] Humanized forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human antibody (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody. Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety. [0083] A “human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies. In some embodiments, rodents are genetically engineered to replace their rodent antibody sequences with human antibody sequences. [0084] An “isolated ABP” or “isolated nucleic acid” is an ABP or nucleic acid that has been separated and/or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous materials. In some embodiments, an isolated ABP is purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example by use of a spinning cup sequenator. In some embodiments, an isolated ABP is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain. An isolated ABP includes an ABP in situ within recombinant cells, since at least one component of the ABP’s natural environment is not present. In some embodiments, an isolated ABP or isolated nucleic acid is prepared by at least one purification step. In some embodiments, an isolated ABP or isolated nucleic acid is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, an isolated ABP or isolated nucleic acid is purified to at least 80%, 85%, 90%, 95%, or 99% by volume. In some embodiments, an isolated ABP or isolated nucleic acid is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% ABP or nucleic acid by weight. In some embodiments, an isolated ABP or isolated nucleic acid is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% ABP or nucleic acid by volume. [0085] “Affinity” refers to the strength of the total non-covalent interactions between a single binding site of a molecule (e.g., an ABP) and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., ABP and antigen or epitope). The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (K_D). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology (e.g., BIACORE^®) or biolayer interferometry (e.g., FORTEBIO^®). [0086] With regard to the binding of an ABP to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non- target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the ABP to the target molecule is competitively inhibited by the control molecule. In some embodiments, the affinity of anti-PD-L1 and/or anti-TGF-β ABP for a non-target molecule is less than about 50% of the affinity for PD-L1 and/or TGF-β. In some embodiments, the affinity of anti-PD-L1 and/or anti- TGF-β ABP for a non-target molecule is less than about 40% of the affinity for PD-L1 and/or TGF-β. In some embodiments, the affinity of anti-PD-L1 and/or anti-TGF-β ABP for a non- target molecule is less than about 30% of the affinity for PD-L1 and/or TGF-β. In some embodiments, the affinity of anti-PD-L1 and/or anti-TGF-β ABP for a non-target molecule is less than about 20% of the affinity for PD-L1 and/or anti-TGF-β. In some embodiments, the affinity of anti-PD-L1 and/or anti-TGF-β ABP for a non-target molecule is less than about 10% of the affinity for PD-L1 and/or TGF-β. In some embodiments, the affinity of anti-PD-L1 and/or anti-TGF-β ABP for a non-target molecule is less than about 1% of the affinity for PD-L1 and/or TGF-β. In some embodiments, the affinity of anti-PD-L1 and/or anti-TGF-β ABP for a non- target molecule is less than about 0.1% of the affinity for PD-L1 and/or TGF-β. [0087] The term “kd” (sec^-1), as used herein, refers to the dissociation rate constant of a particular ABP -antigen interaction. This value is also referred to as the k_off value. [0088] The term “k_a” (M^-1×sec^-1), as used herein, refers to the association rate constant of a particular ABP -antigen interaction. This value is also referred to as the kon value. [0089] The term “K_D” (M), as used herein, refers to the dissociation equilibrium constant of a particular ABP -antigen interaction. K_D = k_d/k_a. [0090] The term “KA” (M^-1), as used herein, refers to the association equilibrium constant of a particular ABP -antigen interaction. KA = ka/kd. [0091] An “affinity matured” ABP is one with one or more alterations (e.g., in one or more CDRs or FRs) that result in an improvement (decrease or increase) in the affinity of the ABP for its antigen, compared to a parent ABP which does not possess the alteration(s). In one embodiment, an affinity matured ABP has nanomolar or picomolar affinity for the target antigen. Affinity matured ABPs may be produced using a variety of methods known in the art. For example, Marks et al. (Bio/Technology, 1992, 10:779-783, incorporated by reference in its entirety) describes affinity maturation by V_H and V_L domain shuffling. Random mutagenesis of CDR and/or framework residues is described by, for example, Barbas et al. (Proc. Nat. Acad. Sci. U.S.A., 1994, 91:3809-3813); Schier et al., Gene, 1995, 169:147-155; Yelton et al., J. Immunol., 1995, 155:1994-2004; Jackson et al., J. Immunol., 1995, 154:3310-33199; and Hawkins et al, J. Mol. Biol., 1992, 226:889-896; each of which is incorporated by reference in its entirety. [0092] An “immunoconjugate” is an ABP conjugated to one or more heterologous molecule(s). [0093] “Effector functions” refer to those biological activities mediated by the Fc region of an antibody, which activities may vary depending on the antibody isotype. Examples of antibody effector functions include C1q binding to activate complement dependent cytotoxicity (CDC), Fc receptor binding to activate antibody-dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP). [0094] When used herein in the context of two or more ABPs, the term competes with or “cross-competes with” indicates that the two or more ABPs compete for binding to an antigen (e.g., PD-L1 or TGF-β). In one exemplary assay, PD-L1 or TGF-β is coated on a surface and contacted with a first PD-L1 or TGF-β ABP, after which a second PD-L1 or TGF-β ABP is added. In another exemplary assay, a first PD-L1 or TGF-β ABP is coated on a surface and contacted with PD-L1 or TGF-β, and then a second PD-L1 or TGF-β ABP is added. If the presence of the first PD-L1 or TGF-β ABP reduces binding of the second PD-L1 or TGF-β ABP, in either assay, then the ABPs compete. The term “competes with” also includes combinations of ABPs where one ABP reduces binding of another ABP, but where no competition is observed when the ABPs are added in the reverse order. However, in some embodiments, the first and second ABPs inhibit binding of each other, regardless of the order in which they are added. In some embodiments, one ABP reduces binding of another ABP to its antigen by at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%. A skilled artisan can select the concentrations of the antibodies used in the competition assays based on the affinities of the ABPs for PD-L1 or TGF-β and the valency of the ABPs. The assays described in this definition are illustrative, and a skilled artisan can utilize any suitable assay to determine if antibodies compete with each other. Suitable assays are described, for example, in Cox et al., “Immunoassay Methods,” in Assay Guidance Manual [Internet], Updated December 24, 2014 (www.ncbi.nlm.nih.gov/books/NBK92434/; accessed September 29, 2015); Silman et al., Cytometry, 2001, 44:30-37; and Finco et al., J. Pharm. Biomed. Anal., 2011, 54:351-358; each of which is incorporated by reference in its entirety. [0095] The term “epitope” means a portion of an antigen the specifically binds to an ABP. Epitopes frequently consist of surface-accessible amino acid residues and/or sugar side chains and may have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an ABP binds can be determined using known techniques for epitope determination such as, for example, testing for ABP binding to PD-L1 or TGF-β variants with different point-mutations, or to chimeric PD-L1 or TGF-β variants. [0096] Percent identity between a polypeptide sequence and a reference sequence, is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. [0097] A “conservative substitution” or a “conservative amino acid substitution,” refers to the substitution an amino acid with a chemically or functionally similar amino acid. Conservative substitution tables providing similar amino acids are well known in the art. By way of example, the groups of amino acids provided in TABLES 2-4 are, in some embodiments, considered conservative substitutions for one another.

[0098] Additional conservative substitutions may be found, for example, in Creighton, Proteins: Structures and Molecular Properties 2nd ed. (1993) W. H. Freeman & Co., New York, NY. An ABP generated by making one or more conservative substitutions of amino acid residues in a parent ABP is referred to as a “conservatively modified variant.” [0099] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed both for prophylaxis and during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminish of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. [00100] As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount of an ABP or pharmaceutical composition provided herein that, when administered to a subject, is effective to treat a disease or disorder. The exact dose or amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding). A therapeutically effective amount can be a “prophylactically effective amount” as prophylaxis can be considered therapy. [00101] As used herein, the term “subject” means a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In certain embodiments, the subject is a human. In some embodiments the subject has a disease or condition that can be treated with an ABP provided herein. In some embodiments, the disease or condition is a cancer. In some embodiments, the disease or condition is AIDS, Alzheimer’s disease. fibrosis, wound healing, a viral infection, and a bacterial infection, a viral infection. [00102] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic or diagnostic products (e.g., kits) that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic or diagnostic products. [00103] The term cytotoxic agent, as used herein, refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. [00104] A “chemotherapeutic agent” refers to a chemical compound useful in the treatment of cancer. Chemotherapeutic agents include “anti-hormonal agents” or “endocrine therapeutics” which act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer. [00105] The term “tumor” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “cell proliferative disorder,” “proliferative disorder” and “tumor” are not mutually exclusive as referred to herein. The terms “cell proliferative disorder” and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation. In some embodiments, the cell proliferative disorder is a cancer. [00106] The term “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject. [00107] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable. [00108] The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20- fold, 50-fold, 100-fold, or greater in a recited variable. [00109] The terms “reduce” and “inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50- fold, 100-fold, or greater in a recited variable. [00110] The term “agonize” refers to the activation of receptor signaling to induce a biological response associated with activation of the receptor. An “agonist” is an entity that binds to and agonizes a receptor. [00111] The term “antagonize” refers to the inhibition of receptor signaling to inhibit a biological response associated with activation of the receptor. An “antagonist” is an entity that binds to and antagonizes a receptor. [00112] The term effector T cell includes T helper (i.e., CD4+) cells, cytotoxic (i.e., CD8+) T cells, Natural Killer T cells (NKT cells), and gamma delta T cells. CD4+ effector T cells contribute to the development of several immunologic processes, including maturation of B cells into plasma cells and memory B cells, and activation of cytotoxic T cells and macrophages. CD8+ effector T cells destroy virus-infected cells and tumor cells. See Seder and Ahmed, Nature Immunol., 2003, 4:835-842, incorporated by reference in its entirety, for additional information on effector T cells. [00113] The term “regulatory T cell” includes cells that regulate immunological tolerance, for example, by suppressing effector T cells. In some embodiments, the regulatory T cell has a CD4+CD25+Foxp3+ phenotype. In some embodiments, the regulatory T cell has a CD8+CD25+ phenotype. In some embodiments, the regulatory T cell has a CD4+Foxp3+CD127Lo phenotype. In some embodiments the regulatory T cell has a CD8+Foxp3+ phenotype. See Nocentini et al., Br. J. Pharmacol., 2012, 165:2089-2099, incorporated by reference in its entirety, for additional information on regulatory T cells. [00114] The term “dendritic cell” refers to a professional antigen-presenting cell capable of activating a naïve T cell and stimulating growth and differentiation of a B cell. [00115] A “variant” of a polypeptide (e.g., an antibody) comprises an amino acid sequence wherein one or more amino acid residues are inserted into, deleted from and/or substituted into the amino acid sequence relative to the native polypeptide sequence, and retains essentially the same biological activity as the native polypeptide. The biological activity of the polypeptide can be measured using standard techniques in the art (for example, if the variant is an antibody, its activity may be tested by binding assays, as described herein). Variants of the present disclosure include fragments, analogs, recombinant polypeptides, synthetic polypeptides, and/or fusion proteins. [00116] A “derivative” of a polypeptide is a polypeptide (e.g., an antibody) that has been chemically modified, e.g., via conjugation to another chemical moiety such as, for example, polyethylene glycol, albumin (e.g., human serum albumin), phosphorylation, and glycosylation. Unless otherwise indicated, the term “antibody” includes, in addition to antibodies comprising two full-length heavy chains and two full-length light chains, derivatives, variants, fragments, and muteins thereof, examples of which are described below. [00117] A nucleotide sequence is operably linked to a regulatory sequence if the regulatory sequence affects the expression (e.g., the level, timing, or location of expression) of the nucleotide sequence. A “regulatory sequence” is a nucleic acid that affects the expression (e.g., the level, timing, or location of expression) of a nucleic acid to which it is operably linked. The regulatory sequence can, for example, exert its effects directly on the regulated nucleic acid, or through the action of one or more other molecules (e.g., polypeptides that bind to the regulatory sequence and/or the nucleic acid). Examples of regulatory sequences include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Further examples of regulatory sequences are described in, for example, Goeddel, 1990, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA and Baron et al., 1995, Nucleic Acids Res.23:3605–06. [00118] A “host cell” is a cell that can be used to express a nucleic acid, e.g., a nucleic acid of the present disclosure. A host cell can be a prokaryote, for example, E. coli, or it can be a eukaryote, for example, a single-celled eukaryote (e.g., a yeast or other fungus), a plant cell (e.g., a tobacco or tomato plant cell), an animal cell (e.g., a human cell, a monkey cell, a hamster cell, a rat cell, a mouse cell, or an insect cell) or a hybridoma. Examples of host cells include CS-9 cells, the COS-7 line of monkey kidney cells (ATCC CRL 1651) (see Gluzman et al., 1981, Cell 23:175), L cells, C127 cells, 3T3 cells (ATCC CCL 163), Chinese hamster ovary (CHO) cells or their derivatives such as Veggie CHO and related cell lines which grow in serum-free media (see Rasmussen et al., 1998, Cytotechnology 28:31), HeLa cells, BHK (ATCC CRL 10) cell lines, the CV1/EBNA cell line derived from the African green monkey kidney cell line CV1 (ATCC CCL 70) (see McMahan et al., 1991, EMBO J.10:2821), human embryonic kidney cells such as 293, 293 EBNA or MSR 293, human epidermal A431 cells, human Colo205 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HL-60, U937, HaK or Jurkat cells. Typically, a host cell is a cultured cell that can be transformed or transfected with a polypeptide-encoding nucleic acid, which can then be expressed in the host cell. [00119] The phrase “recombinant host cell” can be used to denote a host cell that has been transformed or transfected with a nucleic acid to be expressed. A host cell can also be a cell that comprises the nucleic acid but does not express it at a desired level unless a regulatory sequence is introduced into the host cell such that it becomes operably linked with the nucleic acid. It is understood that the term host cell refers not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to, e.g., mutation or environmental influence, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. 7.2. Other interpretational conventions [00120] Ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50. [00121] Unless otherwise indicated, reference to a compound that has one or more stereocenters intends each stereoisomer, and all combinations of stereoisomers, thereof. 7.3. Antigen binding protein [00122] In one aspect, the present disclosure provides antigen binding proteins (ABPs) (e.g., antibodies, antibody fragments, antibody derivatives, antibody muteins, and antibody variants), that bind to PD-L1 and/or TGF-β. In some embodiments, the ABPs are bispecific and bind both PD-L1 and TGF-β. [00123] In some embodiments, the ABP comprises a first antigen binding domain that specifically binds a human programmed death-ligand 1 (PD-L1 binding domain) and a second antigen binding domain that binds a human transforming growth factor-β (TGF-β binding domain). [00124] The ABPs can comprise one or more PD-L1 binding domains and one or more TGF-β binding domains. In some embodiments, the ABP comprises two PD-L1 binding domains and one TGF-β binding domain (e.g., 2:1 format in FIG.8). In some embodiments, the ABP comprises one PD-L1 binding domain and two TGF-β binding domains. In some embodiments, the ABP comprises one PD-L1 binding domain and one TGF-β binding domain. In some embodiments, the ABP comprises two PD-L1 binding domains and two TGF-β binding domains (e.g., 2:2 format in FIG.8). [00125] The PD-L1 binding domain and the TGF-β binding domain comprise one or more CDR sequences. In some embodiments, the PD-L1 binding domain comprises one, two, three, four, five or six CDRs. In some embodiments, the TGF-β binding domain comprises one, two, three, four, five or six CDRs. [00126] In some embodiments, the PD-L1 binding domain comprises a first CDR1-L, a first CDR2-L, a first CDR3-L, a first CDR1-H, a first CDR2-H and a first CDR3-H and the TGF- β binding domain comprises a second CDR1-L, a second CDR2-L, a second CDR3-L, a second CDR1-H, a second CDR2-H and a second CDR3-H. [00127] In some embodiments, the PD-L1 binding domain comprises an antigen binding domain of A2, A5, A3, or A7 as described in TABLE 5. In some embodiments, the PD-L1 binding domain comprises an antigen binding domain of A1-A25 as described in TABLE 5. In some embodiments, the PD-L1 binding domain comprises one or more CDR sequences from A2, A5, A3, or A7 as described in TABLE 5. In some embodiments, the PD-L1 binding domain comprises one or more light chain CDR sequences from A2, A5, A3, or A7 as described in TABLE 5. In some embodiments, the PD-L1 binding domain comprises one or more heavy chain CDR sequences from A2, A5, A3, or A7 as described in TABLE 5. [00128] An ABP can have, for example, the structure of a naturally occurring immunoglobulin. An “immunoglobulin” is a tetrameric molecule. In a naturally occurring immunoglobulin, each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The amino- terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody’s isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. See generally, Fundamental Immunology Ch.7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)) (incorporated by reference in its entirety for all purposes). The variable regions of each light/heavy chain pair form the antibody binding site such that an intact immunoglobulin has two binding sites. [00129] In some embodiments, the ABP can inhibit a biological activity of PD-L1 and/or TGF-β. [00130] In some embodiments, different PD-L1 binding domains can bind to different domains of PD-L1 or act by different mechanisms of action. As indicated herein inter alia, the domain regions are designated such as to be inclusive of the group, unless otherwise indicated. For example, amino acids 4-12 refers to nine amino acids: amino acids at positions 4, and 12, as well as the seven intervening amino acids in the sequence. Other examples include antigen binding proteins that inhibit binding of PD-L1 to its ligands. A PD-L1 binding domain needs not completely inhibit a PD-L1-induced activity to find use in the present disclosure; rather, PD-L1 binding domains that reduce a particular activity of PD-L1 are contemplated for use as well. (Discussions herein of particular mechanisms of action for PD-L1-binding antigen binding proteins in treating particular diseases are illustrative only, and the methods presented herein are not bound thereby.) [00131] In some embodiments, an ABP provided herein prevents binding between PD-L1 and its ligands. In some embodiments, an ABP provided herein block PD-1/PD-L1 signaling. In some embodiments, an ABP provided herein block TGF-β signaling. For example, the ABP can block the TGF-β signaling by hindering binding of TGF-β to its receptor or by preventing activation of latent TGF-β. [00132] In some embodiments, the ABPs activate immune cells and enhance immune cell infiltration into the tumor microenvironment, providing, e.g., a durable response in late stage cancer. For example, the ABPs can enhance infiltration of immune cells into fibrotic tissues or other tissues where immune cells are excluded. In some embodiments, an ABP provided herein prevents inhibition of an effector T cell by a Treg. In some embodiments, the ABP directly kills target cells by ADCC, for example mediated by binding of NK cell-expressed CD16 to the ABP Fc domain. [00133] In some embodiments, the present disclosure provides PD-L1 binding domains that comprise a light chain variable region selected from the group consisting of A1LC-A25LC or a heavy chain variable region selected from the group consisting of A1HC-A25HC, and fragments, derivatives, muteins, and variants thereof. Such a PD-L1 binding domain can be denoted using the nomenclature “LxHy,” wherein “x” corresponds to the number of the light chain variable region and “y” corresponds to the number of the heavy chain variable region as they are labeled in the sequences below. That is to say, for example, that “A1HC” denotes the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101; “A1LC” denotes the light chain variable region comprising the amino acid sequence of SEQ ID NO:1, and so forth. More generally speaking, “L2H1” refers to an antigen binding protein with a light chain variable region comprising the amino acid sequence of L2 (SEQ ID NO:2) and a heavy chain variable region comprising the amino acid sequence of H1 (SEQ ID NO:101). For clarity, all ranges denoted by at least two members of a group include all members of the group between and including the end range members. Thus, the group range A1-A25, includes all members between A1 and A25, as well as members A1 and A25 themselves. The group range A4-A6 includes members A4, A5, and A6, etc. [00134] In some embodiments, PD-L1 binding domains comprise variable (V(D)J) regions of both heavy and light chain sequences identical to one of the clones in the library of PD-L1 binding clones, deposited under ATCC Accession NO. PTA-125513. In some embodiments, PD- L1 binding domains comprise variable (V(D)J) regions of either heavy or light chain sequence identical to one of the clones in the library of PD-L1 binding clones, deposited under ATCC Accession NO. PTA-125513. In some embodiments, antigen binding proteins are expressed from the expression vector in one of the clones in the library of PD-L1 binding clones, deposited under ATCC Accession NO. PTA-125513. [00135] Also shown below are the locations of the CDRs (underlined) that create part of the antigen-binding site, while the Framework Regions (FRs) are the intervening segments of these variable domain sequences. In both light chain variable regions and heavy chain variable regions there are three CDRs (CDR1-3) and four FRs (FR 1-4). The CDR regions of each light and heavy chain also are grouped by antibody type (A1, A2, A3, etc.). Antigen binding proteins of the present disclosure include, for example, antigen binding proteins having a combination of light chain and heavy chain variable domains selected from the group of combinations consisting of L1H1 (antibody A1), L2H2 (antibody A2), L3H3 (antibody A3), L4H4 (antibody A4), L5H5 (antibody A5), L6H6 (antibody A6), L7H7 (antibody A7), L8H8 (antibody A8), L9H9 (antibody A9), L10H10 (antibody A10), L11H11 (antibody A11), L12H12 (antibody A12), L13H13 (antibody A13), … and L25H25 (antibody A25). [00136] In some embodiments, antigen binding proteins comprise one or more CDR sequences identical to one of the clones in the library of PD-L1 binding clones, deposited under ATCC Accession NO. PTA-125513. In some embodiments, antigen binding proteins comprise a light chain CDR3 and a heavy chain CDR3 of one of the clones in the library. [00137] In some embodiments, antigen binding proteins comprise all six CDR sequences (three CDRs of light chain and three CDRs of heavy chain) identical to one of the clones in the library of PD-L1 binding clones, deposited under ATCC Accession NO. PTA-125513. In some embodiments, antigen binding proteins comprise three out of six CDR sequences (three CDRs of light chain or three CDRs of heavy chain) identical to one of the clones in the library of PD-L1 binding clones, deposited under ATCC Accession NO. PTA-125513. In some embodiments, antigen binding proteins comprise one, two, three, four, or five out of six CDR sequences identical to one of the clones in the library of PD-L1 binding clones, deposited under ATCC Accession NO. PTA-125513. [00138] In one embodiment, the present disclosure provides an antigen binding protein comprising a light chain variable domain comprising a sequence of amino acids that differs from the sequence of a light chain variable domain selected from the group consisting of L1 through L25 only at 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 residues, wherein each such sequence difference is independently either a deletion, insertion, or substitution of one amino acid residue. In another embodiment, the light-chain variable domain comprises a sequence of amino acids that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of a light chain variable domain selected from the group consisting of L1-L25. In another embodiment, the light chain variable domain comprises a sequence of amino acids that is encoded by a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a nucleotide sequence that encodes a light chain variable domain selected from the group consisting of L1-L25 (which includes L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, … and L25). In another embodiment, the light chain variable domain comprises a sequence of amino acids that is encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide that encodes a light chain variable domain selected from the group consisting of L1-L25. In another embodiment, the light chain variable domain comprises a sequence of amino acids that is encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide that encodes a light chain variable domain selected from the group consisting of L1-L25. In another embodiment, the light chain variable domain comprises a sequence of amino acids that is encoded by a polynucleotide that hybridizes under moderately stringent conditions to a complement of a light chain polynucleotide of L1-L25. [00139] In one embodiment, the present disclosure provides an antigen binding protein comprising a light chain variable domain comprising a sequence of amino acids that differs from the sequence of a light chain variable domain encoded by one of the clones of the library of PD- L1 binding clones, deposited under ATCC Accession No. PTA-125513, only at 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 residues, wherein each such sequence difference is independently either a deletion, insertion, or substitution of one amino acid residue. In another embodiment, the light-chain variable domain comprises a sequence of amino acids that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of a light chain variable domain encoded by one of the clones of the library of PD-L1 binding clones, deposited under ATCC Accession No. PTA-125513. In another embodiment, the light chain variable domain comprises a sequence of amino acids that is encoded by a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a nucleotide sequence of one of the clones of the library of PD-L1 binding clones, deposited under ATCC Accession No. PTA-125513. [00140] In another embodiment, the present disclosure provides an antigen binding protein comprising a heavy chain variable domain comprising a sequence of amino acids that differs from the sequence of a heavy chain variable domain selected from the group consisting of H1- H24 only at 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 residue(s), wherein each such sequence difference is independently either a deletion, insertion, or substitution of one amino acid residue. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identical to the sequence of a heavy chain variable domain selected from the group consisting of H1-H24. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is encoded by a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identical to a nucleotide sequence that encodes a heavy chain variable domain selected from the group consisting of H1-H24. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide that encodes a heavy chain variable domain selected from the group consisting of H1-H24. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide that encodes a heavy chain variable domain selected from the group consisting of H1-H24. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is encoded by a polynucleotide that hybridizes under moderately stringent conditions to a complement of a heavy chain polynucleotide disclosed herein. [00141] In one embodiment, the present disclosure provides an antigen binding protein comprising a heavy chain variable domain comprising a sequence of amino acids that differs from the sequence of a heavy chain variable domain encoded by one of the clones of the library of PD-L1 binding clones, deposited under ATCC Accession NO. PTA-125513, only at 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 residues, wherein each such sequence difference is independently either a deletion, insertion, or substitution of one amino acid residue. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of a heavy chain variable domain encoded by one of the clones of the library of PD-L1 binding clones, deposited under ATCC Accession NO. PTA-125513. In another embodiment, the heavy chain variable domain comprises a sequence of amino acids that is encoded by a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a nucleotide sequence of one of the clones of the library of PD-L1 binding clones, deposited under ATCC Accession NO. PTA-125513. [00142] Particular embodiments of antigen binding proteins of the present disclosure comprise one or more amino acid sequences that are identical to the amino acid sequences of one or more of the CDRs and/or FRs referenced herein. In one embodiment, the antigen binding protein comprises a light chain CDR1 sequence illustrated above. In another embodiment, the antigen binding protein comprises a light chain CDR2 sequence illustrated above. In another embodiment, the antigen binding protein comprises a light chain CDR3 sequence illustrated above. In another embodiment, the antigen binding protein comprises a heavy chain CDR1 sequence illustrated above. In another embodiment, the antigen binding protein comprises a heavy chain CDR2 sequence illustrated above. In another embodiment, the antigen binding protein comprises a heavy chain CDR3 sequence illustrated above. [00143] In one embodiment, the present disclosure provides an antigen binding protein that comprises one or more CDR sequences that differ from a CDR sequence shown above by no more than 5, 4, 3, 2, or 1 amino acid residues. [00144] In some embodiments, at least one of the antigen binding protein’s CDR1 sequences is a CDR1 sequence from A1-A25, CDR1-L1 to 25, or CDR1-H1 to 25 as shown in TABLE 5. In some embodiments, at least one of the antigen binding protein s CDR2 sequences is a CDR2 sequence from A1-A25, CDR2-L1 to 25, or CDR2-H1 to 25 as shown in TABLE 5. In some embodiments, at least one of the antigen binding protein’s CDR3 sequences is a CDR3 sequence from A1-A25, CDR3-L1 to 25, or CDR3-H1 to 25 as shown in TABLE 5. [00145] In another embodiment, the antigen binding protein’s light chain CDR3 sequence is a light chain CDR3 sequence from A1-A25 or CDR3-L1 to 25, as shown in TABLE 5, and the antigen binding protein’s heavy chain CDR3 sequence is a heavy chain sequence from A1-A25 or CDR-H1 to 25, as shown in TABLE 5. [00146] In another embodiment, the antigen binding protein comprises 1, 2, 3, 4, or 5 CDR sequence(s) that each independently differs by 6, 5, 4, 3, 2, 1, or 0 single amino acid additions, substitutions, and/or deletions from a CDR sequence of A1-A25, and the antigen binding protein further comprises 1, 2, 3, 4, or 5 CDR sequence(s) that each independently differs by 6, 5, 4, 3, 2, 1, or 0 single amino acid additions, substitutions, and/or deletions from a CDR sequence. In some embodiments, the antigen binding protein comprises 1, 2, 3, 4, or 5 CDR sequence(s) that each has at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to a CDR sequence of A1-A25. [00147] The nucleotide sequences of A1-A25, or the amino acid sequences of A1-A25, can be altered, for example, by random mutagenesis or by site-directed mutagenesis (e.g., oligonucleotide-directed site-specific mutagenesis) to create an altered polynucleotide comprising one or more particular nucleotide substitutions, deletions, or insertions as compared to the non-mutated polynucleotide. Examples of techniques for making such alterations are described in Walder et al., 1986, Gene 42:133; Bauer et al.1985, Gene 37:73; Craik, BioTechniques, January 1985, 12-19; Smith et al., 1981, Genetic Engineering: Principles and Methods, Plenum Press; and U.S. Patent Nos.4,518,584 and 4,737,462. These and other methods can be used to make, for example, derivatives of anti-PD-L1 antibodies that have a desired property, for example, increased affinity, avidity, or specificity for PD-L1, increased activity or stability in vivo or in vitro, or reduced in vivo side-effects as compared to the underivatized antibody. [00148] In some embodiments, the PD-L1 binding domain comprises the first CDR1-L having a sequence selected from SEQ ID NO: 1002, 1003, 1005, and 1007, a first CDR2-L having a sequence selected from SEQ ID NO: 2002, 2003, 2005, and 2007, a first CDR3-L having a sequence selected from SEQ ID NO: 3002, 3003, 3005, and 3007, a first CDR1-H having a sequence selected from SEQ ID NO: 4002, 4003, 4005, and 4007, a first CDR2-H having a sequence selected from SEQ ID NO: 5002, 5003, 5005, and 5007 and a first CDR3-H having a sequence selected from SEQ ID NO: 6002, 6003, 6005, and 6007. [00149] In some embodiments, the PD-L1 binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1002, a first CDR2-L having the sequence of SEQ ID NO: 2002, a first CDR3-L having the sequence of SEQ ID NO: 3002, a first CDR1-H having the sequence of SEQ ID NO: 4002, a first CDR2-H having the sequence of SEQ ID NO: 5002 and a first CDR3-H having the sequence of SEQ ID NO: 6002. [00150] In some embodiments, the PD-L1 binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1005, a first CDR2-L having the sequence of SEQ ID NO: 2005, a first CDR3-L having the sequence of SEQ ID NO: 3005, a first CDR1-H having the sequence of SEQ ID NO: 4005, a first CDR2-H having the sequence of SEQ ID NO: 5005 and a first CDR3-H having the sequence of SEQ ID NO: 6005. [00151] In some embodiments, the PD-L1 binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1003, a first CDR2-L having the sequence of SEQ ID NO: 2003, a first CDR3-L having the sequence of SEQ ID NO: 3003, a first CDR1-H having the sequence of SEQ ID NO: 4003, a first CDR2-H having the sequence of SEQ ID NO: 5003 and a first CDR3-H having the sequence of SEQ ID NO: 6003. [00152] In some embodiments, the PD-L1 binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1007, a first CDR2-L having the sequence of SEQ ID NO: 2007, a first CDR3-L having the sequence of SEQ ID NO: 3007, a first CDR1-H having the sequence of SEQ ID NO: 4007, a first CDR2-H having the sequence of SEQ ID NO: 5007 and a first CDR3-H having the sequence of SEQ ID NO: 6007. [00153] In some embodiments, the TGF-β binding domain comprises a second CDR1-L, a second CDR2-L, a second CDR3-L, a second CDR1-H, a second CDR2-H and a second CDR3- H. In some embodiments, the TGF-β binding domain comprises the heavy chain and light chain sequences of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF-β binding domain comprises six CDRs of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. [00154] In some embodiments, the TGF-β binding domain comprises a light chain having at least 95% sequence identity to a light chain sequence of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF-β binding domain comprises a light chain having at least 96% sequence identity to a light chain sequence of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF-β binding domain comprises a light chain having at least 97% sequence identity to a light chain sequence sequences of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF- β binding domain comprises a light chain having at least 98% sequence identity to a light chain sequence of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF-β binding domain comprises a light chain having at least 99% sequence identity to a light chain sequence of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. [00155] In some embodiments, the TGF-β binding domain comprises a heavy chain having at least 95% sequence identity to a heavy chain sequence of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF- β binding domain comprises a heavy chain having at least 96% sequence identity to a heavy chain sequence of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF- β clone 1D11. In some embodiments, the TGF-β binding domain comprises a heavy chain having at least 97% sequence identity to a heavy chain sequence sequences of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF-β binding domain comprises a heavy chain having at least 98% sequence identity to a light heavy sequence of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF-β binding domain comprises a heavy chain having at least 99% sequence identity to a heavy chain sequence of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. [00156] In some embodiments, the TGF-β binding domain comprises six CDRs having at least 95% sequence identity to corresponding CDR sequences of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF- β binding domain comprises six CDRs having at least 96% sequence identity to corresponding CDR sequences of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti- TGF-β clone 1D11. In some embodiments, the TGF-β binding domain comprises six CDRs having at least 97% sequence identity to corresponding CDR sequences of fresolimumab or anti- TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF-β binding domain comprises six CDRs having at least 98% sequence identity to corresponding CDR sequences of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. In some embodiments, the TGF-β binding domain comprises six CDRs having at least 99% sequence identity to corresponding CDR sequences of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. [00157] In some embodiments, the TGF-β binding domain comprises a second CDR1-L having the sequence of SEQ ID NO: 9276, a second CDR2-L having the sequence of SEQ ID NO: 9277, a second CDR3-L having the sequence of SEQ ID NO: 9278, a second CDR1-H having the sequence of SEQ ID NO: 9279, a second CDR2-H having the sequence of SEQ ID NO: 9280 and a second CDR3-H having the sequence of SEQ ID NO: 9281. [00158] In some embodiments, the TGF-β binding domain comprises a second CDR1-L having the sequence of SEQ ID NO: 9282, a second CDR2-L having the sequence of SEQ ID NO: 9283, a second CDR3-L having the sequence of SEQ ID NO: 9284, a second CDR1-H having the sequence of SEQ ID NO: 9285, a second CDR2-H having the sequence of SEQ ID NO: 9286 and a second CDR3-H having the sequence of SEQ ID NO: 9287. [00159] Some embodiments provide an ABP comprising a light chain having the sequence of SEQ ID NO: 9264 and a heavy chain having the sequence of SEQ ID NO: 9265. In some embodiments, an ABP comprises a light chain having the sequence of SEQ ID NO: 9257 and a heavy chain having the sequence of SEQ ID NO: 9258. [00160] In some embodiments, the bispecific ABP comprises a first antigen binding domain comprising a first CDR1-L having a sequence selected from SEQ ID NO: 8306-8458, a first CDR2-L having a sequence selected from SEQ ID NO: 8459-8611, a first CDR3-L having a sequence selected from SEQ ID NO: 8612-8764, a first CDR1-H having a sequence selected from SEQ ID NO: 8765-8917, a first CDR2-H having a sequence selected from SEQ ID NO: 8918-9070 and a first CDR3-H having a sequence selected from SEQ ID NO: 9071-9223, and a second antigen binding domain comprises a second CDR1-L having a sequence selected from SEQ ID NO: 9276 and 9282, a second CDR2-L having a sequence selected from SEQ ID NO: 9277 and 9283, a second CDR3-L having a sequence selected from SEQ ID NO: 9278 and 9284, a second CDR1-H having a sequence selected from SEQ ID NO: 9279 and 9285, a second CDR2-H having a sequence selected from SEQ ID NO: 9280 and 9286 and a second CDR3-H having a sequence selected from SEQ ID NO: 9281 and 9287. [00161] In some embodiments, the ABP comprises a light chain having the sequence of SEQ ID NO: 9264 and a heavy chain having the sequence of SEQ ID NO: 9265. In some embodiments, the ABP comprises a light chain having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 9264 and a heavy chain having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 9265. [00162] In some embodiments, the ABP comprises a light chain having the sequence of SEQ ID NO: 9257 and a heavy chain having the sequence of SEQ ID NO: 9258. In some embodiments, the ABP comprises a light chain having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 9257 and a heavy chain having at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 9258. [00163] In one aspect, the present disclosure provides an isolated antigen binding protein (ABP) comprising a first antigen binding domain that specifically binds a human programmed death-ligand 1 (PD-L1) and a second antigen binding domain that binds a human transforming growth factor-β (TGF-β), wherein the first antigen binding domain comprises a first CDR1-L having a sequence selected from SEQ ID NO: 8306-8458, a first CDR2-L having a sequence selected from SEQ ID NO: 8459-8611, a first CDR3-L having a sequence selected from SEQ ID NO: 8612-8764, a first CDR1-H having a sequence selected from SEQ ID NO: 8765-8917, a first CDR2-H having a sequence selected from SEQ ID NO: 8918-9070 and a first CDR3-H having a sequence selected from SEQ ID NO: 9071-9223, and the second antigen binding domain comprises a second CDR1-L having a sequence selected from SEQ ID NO: 9276 and 9282, a second CDR2-L having a sequence selected from SEQ ID NO: 9277 and 9283, a second CDR3-L having a sequence selected from SEQ ID NO: 9278 and 9284, a second CDR1-H having a sequence selected from SEQ ID NO: 9279 and 9285, a second CDR2-H having a sequence selected from SEQ ID NO: 9280 and 9286 and a second CDR3-H having a sequence selected from SEQ ID NO: 9281 and 9287. [00164] Other derivatives of anti-PD-L1 and anti-TGFβ ABPs within the scope of this disclosure include covalent or aggregative conjugates of anti-PD-L1 antibodies and/or anti-TGFβ antibodies, or fragments thereof, with other proteins or polypeptides, such as by expression of recombinant fusion proteins comprising heterologous polypeptides fused to the N-terminus or C- terminus of the ABPs. For example, the conjugated peptide may be a heterologous signal (or leader) polypeptide, e.g., the yeast alpha-factor leader, or a peptide such as an epitope tag. Antigen binding protein-containing fusion proteins can comprise peptides added to facilitate purification or identification of antigen binding protein (e.g., poly-His). An antigen binding protein also can be linked to the FLAG peptide Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys (DYKDDDDK) (SEQ ID NO: 7002) as described in Hopp et al., Bio/Technology 6:1204, 1988, and U.S. Patent 5,011,912. The FLAG peptide is highly antigenic and provides an epitope reversibly bound by a specific monoclonal antibody (mAb), enabling rapid assay and facile purification of expressed recombinant protein. Reagents useful for preparing fusion proteins in which the FLAG peptide is fused to a given polypeptide are commercially available (Sigma, St. Louis, MO). [00165] One suitable Fc polypeptide, described in PCT application WO 93/10151 (hereby incorporated by reference), is a single chain polypeptide extending from the N-terminal hinge region to the native C-terminus of the Fc region of a human IgG1 antibody. Another useful Fc polypeptide is the Fc mutein described in U.S. Patent 5,457,035 and in Baum et al., 1994, EMBO J.13:3992-4001. The amino acid sequence of this mutein is identical to that of the native Fc sequence presented in WO 93/10151, except that amino acid 19 has been changed from Leu to Ala, amino acid 20 has been changed from Leu to Glu, and amino acid 22 has been changed from Gly to Ala. The mutein exhibits reduced affinity for Fc receptors. [00166] In some embodiments, the Fc region comprises a human IgG1, a human IgG2, a human IgG4 or a variant thereof. In some embodiments, the Fc region comprises a modification that affects an effector function. In some embodiments, the Fc region comprises a LALAPG a N297A, a DANA, a LALA, or a N297Q mutation. The LALAPG mutation can refer to L234A, L235A, and P329G mutations in the Fc region. The DANA mutation can refer to D265A and N297A mutations in the Fc region. The LALA mutation can refer to L234A and L235A mutation in the Fc region. [00167] In some embodiments, the PD-L1 binding domain is a Fab format and the TGF-β binding domain is an scFv format or the PD-L1 bidning domain is an scFv format and the TGF-β binding domain is a Fab format. [00168] In other embodiments, the variable portion of the heavy and/or light chains of the ABPs may be substituted for the variable portion of an antibody heavy and/or light chain. [00169] Oligomers that contain one or more antigen binding proteins may be employed. Oligomers may be in the form of covalently-linked or non-covalently-linked dimers, trimers, or higher oligomers. Oligomers comprising two or more antigen binding proteins are contemplated for use, with one example being a homodimer. Other oligomers include heterodimers, homotrimers, heterotrimers, homotetramers, heterotetramers, etc. [00170] One embodiment is directed to oligomers comprising multiple antigen binding proteins joined via covalent or non-covalent interactions between peptide moieties fused to the antigen binding proteins. Such peptides may be peptide linkers (spacers), or peptides that have the property of promoting oligomerization. Leucine zippers and certain polypeptides derived from antibodies are among the peptides that can promote oligomerization of antigen binding proteins attached thereto, as described in more detail below. [00171] In particular embodiments, the oligomers comprise from two to four antigen binding proteins. The antigen binding proteins of the oligomer may be in any form, such as any of the forms described above, e.g., variants or fragments. Preferably, the oligomers comprise antigen binding proteins that have PD-L1 and/or TGF-β binding activity. [00172] In one embodiment, an oligomer is prepared using polypeptides derived from immunoglobulins. Preparation of fusion proteins comprising certain heterologous polypeptides fused to various portions of antibody-derived polypeptides (including the Fc domain) has been described, e.g., by Ashkenazi et al., 1991, PNAS USA 88:10535; Byrn et al., 1990, Nature 344:677; and Hollenbaugh et al., 1992 Curr. Prot.s in Immunol., Suppl.4, pages 10.19.1 - 10.19.11. [00173] One embodiment of the present disclosure is directed to a dimer comprising two fusion proteins created by fusing a PD-L1 binding fragment of an anti-PD-L1 antibody to a TGF- β binding domain of an anti-TGF-β antibody. The dimer can be made by, for example, inserting a gene fusion encoding the fusion protein into an appropriate expression vector, expressing the gene fusion in host cells transformed with the recombinant expression vector, and allowing the expressed fusion protein to assemble much like antibody molecules, whereupon interchain disulfide bonds form between the Fc moieties to yield the dimer. [00174] Alternatively, the oligomer is a fusion protein comprising multiple antigen binding proteins, with or without peptide linkers (spacer peptides). Among the suitable peptide linkers are those described in U.S. Patents 4,751,180 and 4,935,233. [00175] Another method for preparing oligomeric antigen binding proteins involves use of a leucine zipper. Leucine zipper domains are peptides that promote oligomerization of the proteins in which they are found. Leucine zippers were originally identified in several DNA- binding proteins (Landschulz et al., 1988, Science 240:1759), and have since been found in a variety of different proteins. Among the known leucine zippers are naturally occurring peptides and derivatives thereof that dimerize or trimerize. Examples of leucine zipper domains suitable for producing soluble oligomeric proteins are described in PCT application WO 94/10308, and the leucine zipper derived from lung surfactant protein D (SPD) described in Hoppe et al., 1994, FEBS Letters 344:191, hereby incorporated by reference. The use of a modified leucine zipper that allows for stable trimerization of a heterologous protein fused thereto is described in Fanslow et al., 1994, Semin. Immunol.6:267-78. In one approach, recombinant fusion proteins comprising an anti-PD-L1 antibody fragment or derivative or an anti-TGF-β antibody fragment or derivative fused to a leucine zipper peptide are expressed in suitable host cells, and the soluble oligomeric anti-PD-L1 antibody fragments or derivatives or an anti-TGF-β antibody fragment or derivative that form are recovered from the culture supernatant. [00176] In one aspect, the present disclosure provides antigen binding proteins that interfere with the binding of PD-L1 to its ligands. Such antigen binding proteins can be made against PD-L1, or a fragment, variant or derivative thereof, and screened in conventional assays for the ability to interfere with binding of PD-L1 to its ligands. Examples of suitable assays are assays that test the antigen binding proteins for the ability to inhibit binding of PD-L1 ligands to cells expressing PD-L1, or that test antigen binding proteins for the ability to reduce a biological or cellular response that results from the binding of PD-L1 ligands to cell surface PD-L1. For example, antibodies can be screened according to their ability to bind to immobilized antibody surfaces (PD-L1). Antigen binding proteins that block the binding of PD-L1 to a ligand can be employed in treating any PD-L1-related condition, including but not limited to cancer or autoimmune disease. In an embodiment, a human anti-PD-L1 monoclonal antibody generated by procedures involving immunization of transgenic mice is employed in treating such conditions. [00177] In one aspect, the present disclosure provides antigen binding proteins that interfere with the TGF-β signaling or prevent activation of latent TGF-β. [00178] In some embodiments, the ABPs comprise a TGF-β binding domain but lack a PD-L1 binding domain. In some embodiments, the ABPs are anti-TGF-β antibody. In some embodiments, the ABP comprises a heavy chain variable region having a sequence selected from SEQ ID NOs: 9268-9271 and a light chain variable region having a sequence selected from SEQ ID NO: 9272-9275. In some embodiments, the ABP comprises a heavy chain variable region having a sequence of SEQ ID NO: 9268 and a light chain variable region having a sequence of SEQ ID NO: 9272. In some embodiments, the ABP comprises a heavy chain variable region having a sequence of SEQ ID NO: 9269 and a light chain variable region having a sequence of SEQ ID NO: 9273. In some embodiments, the ABP comprises a heavy chain variable region having a sequence of SEQ ID NO: 9270 and a light chain variable region having a sequence of SEQ ID NO: 9274. In some embodiments, the ABP comprises a heavy chain variable region having a sequence of SEQ ID NO: 9271 and a light chain variable region having a sequence of SEQ ID NO: 9275 [00179] Antigen-binding domains of antigen binding proteins of the present disclosure can be produced by conventional techniques. Examples of such fragments include, but are not limited to, Fab and F(ab’)₂ fragments. Antibody fragments and derivatives produced by genetic engineering techniques also are contemplated. [00180] Additional embodiments include chimeric antibodies, e.g., humanized versions of non-human (e.g., murine) monoclonal antibodies. Such humanized antibodies may be prepared by known techniques, and offer the advantage of reduced immunogenicity when the antibodies are administered to humans. In one embodiment, a humanized monoclonal antibody comprises the variable domain of a murine antibody (or all or part of the antigen binding site thereof) and a constant domain derived from a human antibody. Alternatively, a humanized antibody fragment may comprise the antigen binding site of a murine monoclonal antibody and a variable domain fragment (lacking the antigen-binding site) derived from a human antibody. Procedures for the production of chimeric and further engineered monoclonal antibodies include those described in Riechmann et al., 1988, Nature 332:323, Liu et al., 1987, Proc. Nat. Acad. Sci. USA 84:3439, Larrick et al., 1989, Bio/Technology 7:934, and Winter et al., 1993, TIPS 14:139. In one embodiment, the chimeric antibody is a CDR grafted antibody. Techniques for humanizing antibodies are discussed in, e.g., U.S. Pat. Nos.5,869,619, 5,225,539, 5,821,337, 5,859,205, 6,881,557, Padlan et al., 1995, FASEB J.9:133-39, and Tamura et al., 2000, J. Immunol. 164:1432-41. [00181] Procedures have been developed for generating human or partially human antibodies in non-human animals. For example, mice in which one or more endogenous immunoglobulin genes have been inactivated by various means have been prepared. Human immunoglobulin genes have been introduced into the mice to replace the inactivated mouse genes. Antibodies produced in the animal incorporate human immunoglobulin polypeptide chains encoded by the human genetic material introduced into the animal. In one embodiment, a non-human animal, such as a transgenic mouse, is immunized with a PD-L1 polypeptide, such that antibodies directed against the PD-L1 polypeptide are generated in the animal. In one embodiment, a non-human animal, such as a transgenic mouse, is immunized with a TGF-β polypeptide, such that antibodies directed against the TGF-β polypeptide are generated in the animal. The TGF-β polypeptide can be administered to the animal or expressed from a polynucleotide delivered to the animal to induce immunization. [00182] One example of a suitable immunogen is a soluble human PD-L1, such as a polypeptide comprising the extracellular domain of the protein having the following sequence: SEQ ID: 7001, TGF-β or other immunogenic fragment of the protein. Examples of techniques for production and use of transgenic animals for the production of human or partially human antibodies are described in U.S. Patents 5,814,318, 5,569,825, and 5,545,806, Davis et al., 2003, Production of human antibodies from transgenic mice in Lo, ed. Antibody Engineering: Methods and Protocols, Humana Press, NJ:191-200, Kellermann et al., 2002, Curr Opin Biotechnol. 13:593-97, Russel et al., 2000, Infect Immun.68:1820-26, Gallo et al., 2000, Eur J Immun. 30:534-40, Davis et al., 1999, Cancer Metastasis Rev.18:421-25, Green, 1999, J Immunol Methods.231:11-23, Jakobovits, 1998, Advanced Drug Delivery Reviews 31:33-42, Green et al., 1998, J Exp Med.188:483-95, Jakobovits A, 1998, Exp. Opin. Invest. Drugs.7:607-14, Tsuda et al., 1997, Genomics.42:413-21, Mendez et al., 1997, Nat Genet.15:146-56, Jakobovits, 1994, Curr Biol.4:761-63, Arbones et al., 1994, Immunity.1:247-60, Green et al., 1994, Nat Genet. 7:13-21, Jakobovits et al., 1993, Nature.362:255-58, Jakobovits et al., 1993, Proc Natl Acad Sci U S A.90:2551-55. Chen, J., M. Trounstine, F. W. Alt, F. Young, C. Kurahara, J. Loring, D. Huszar. Inter’l Immunol.5 (1993): 647-656, Choi et al., 1993, Nature Genetics 4: 117-23, Fishwild et al., 1996, Nature Biotech.14: 845-51, Harding et al., 1995, Annals of the New York Academy of Sciences, Lonberg et al., 1994, Nature 368: 856-59, Lonberg, 1994, Transgenic Approaches to Human Monoclonal Antibodies in Handbook of Experimental Pharmacology 113: 49-101, Lonberg et al., 1995, Internal Review of Immunology 13: 65-93, Neuberger, 1996, Nature Biotechnology 14: 826, Taylor et al., 1992, Nucleic Acids Res.20: 6287-95, Taylor et al., 1994, Inter’l Immunol.6: 579-91, Tomizuka et al., 1997, Nature Genetics 16: 133-43, Tomizuka et al., 2000, Pro. Nat’lAcad. Sci. USA 97: 722-27, Tuaillon et al., 1993, Pro.Nat’lAcad.Sci. USA 90: 3720-24, and Tuaillon et al., 1994, J.Immunol.152: 2912-20. [00183] Antigen binding proteins (e.g., antibodies, antibody fragments, and antibody derivatives) of the present disclosure can comprise any constant region known in the art. The light chain constant region can be, for example, a kappa- or lambda-type light chain constant region, e.g., a human kappa- or lambda-type light chain constant region. The heavy chain constant region can be, for example, an alpha-, delta-, epsilon-, gamma-, or mu-type heavy chain constant regions, e.g., a human alpha-, delta-, epsilon-, gamma-, or mu-type heavy chain constant region. In one embodiment, the light or heavy chain constant region is a fragment, derivative, variant, or mutein of a naturally occurring constant region. [00184] Techniques are known for deriving an antibody of a different subclass or isotype from an antibody of interest, i.e., subclass switching. Thus, IgG antibodies may be derived from an IgM antibody, for example, and vice versa. Such techniques allow the preparation of new antibodies that possess the antigen-binding properties of a given antibody (the parent antibody), but also exhibit biological properties associated with an antibody isotype or subclass different from that of the parent antibody. Recombinant DNA techniques may be employed. Cloned DNA encoding particular antibody polypeptides may be employed in such procedures, e.g., DNA encoding the constant domain of an antibody of the desired isotype. See also Lantto et al., 2002, Methods Mol. Biol.178:303-16. [00185] In one embodiment, an antigen binding protein of the present disclosure comprises the IgG1 heavy chain domain of any of A1-A25 (H1-H25) or a fragment of the IgG1 heavy chain domain of any of A1-A25 (H1-H25). In another embodiment, an antigen binding protein of the present disclosure comprises the kappa light chain constant chain region of A1- A25 (L1-L25), or a fragment of the kappa light chain constant region of A1-A25 (L1-L25). In another embodiment, an antigen binding protein of the present disclosure comprises both the IgG1 heavy chain domain, or a fragment thereof, of A1-A25 (L1-L25) and the kappa light chain domain, or a fragment thereof, of A1-A25 (L1-L25). [00186] Accordingly, the antigen binding proteins of the present disclosure include those comprising, for example, the variable domain combinations L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, … L23H23, L24H24, and L25H25, having a desired isotype (for example, IgA, IgG1, IgG2, IgG3, IgG4, IgM, IgE, and IgD) as well as Fab or F(ab’)₂ fragments thereof. Moreover, if an IgG4 is desired, it may also be desired to introduce a point mutation (CPSCP (SEQ ID NO: 9225) -> CPPCP (SEQ ID NO: 9226)) in the hinge region as described in Bloom et al., 1997, Protein Science 6:407, incorporated by reference herein) to alleviate a tendency to form intra-H chain disulfide bonds that can lead to heterogeneity in the IgG4 antibodies. [00187] In one embodiment, the antigen binding protein has a K_off of 1x10^-4 s^-1 or lower. In another embodiment, the K_off is 5x10^-5 s^-1 or lower. In another embodiment, the K_off is substantially the same as an antibody having a combination of light chain and heavy chain variable domain sequences selected from the group of combinations consisting of L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, … and L25H25. In another embodiment, the antigen binding protein binds to PD-L1 with substantially the same K_off as an antibody that comprises one or more CDRs from an antibody having a combination of light chain and heavy chain variable domain sequences selected from the group of combinations consisting of L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, … and L25H25. In another embodiment, the antigen binding protein binds to PD- L1 with substantially the same K_off as an antibody that comprises one of the amino acid sequences illustrated above. In another embodiment, the antigen binding protein binds to PD-L1 with substantially the same K_off as an antibody that comprises one or more CDRs from an antibody that comprises one of the amino acid sequences illustrated above. [00188] In one aspect, the present disclosure provides antigen-binding fragments of an anti-PD-L1 antibody of the present disclosure. Such fragments can consist entirely of antibody- derived sequences or can comprise additional sequences. Examples of antigen-binding fragments include Fab, F(ab’)2, single chain antibodies, diabodies, triabodies, tetrabodies, and domain antibodies. Other examples are provided in Lunde et al., 2002, Biochem. Soc. Trans. 30:500-06. [00189] Single chain antibodies (scFv) may be formed by linking heavy and light chain variable domain (Fv region) fragments via an amino acid bridge (short peptide linker, e.g., a synthetic sequence of amino acid residues), resulting in a single polypeptide chain. Such single- chain Fvs (scFvs) have been prepared by fusing DNA encoding a peptide linker between DNAs encoding the two variable domain polypeptides (V_L and V_H). The resulting polypeptides can fold back on themselves to form antigen-binding monomers, or they can form multimers (e.g., dimers, trimers, or tetramers), depending on the length of a flexible linker between the two variable domains (Kortt et al., 1997, Prot. Eng.10:423; Kortt et al., 2001, Biomol. Eng.18:95- 108, Bird et al., 1988, Science 242:423-26 and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-83). By combining different V_L and V_H-comprising polypeptides, one can form multimeric scFvs that bind to different epitopes (Kriangkum et al., 2001, Biomol. Eng.18:31- 40). Techniques developed for the production of single chain antibodies include those described in U.S. Patent No.4,946,778; Bird, 1988, Science 242:423; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879; Ward et al., 1989, Nature 334:544, de Graaf et al., 2002, Methods Mol Biol.178:379-87. ScFvs comprising the variable domain combinations L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, …, and L25H25 are encompassed by the present disclosure. [00190] The ABPs can be purified from host cells that have been transfected by a gene encoding the ABPs by elution of filtered supernatant of host cell culture fluid using a Heparin HP column, using a salt gradient. [00191] A Fab fragment is a monovalent fragment having the V_L, V_H, C_L and C_H1 domains; a F(ab’)2 fragment is a bivalent fragment having two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment has the V_H and C_H1 domains; an Fv fragment has the V_L and V_H domains of a single arm of an antibody; and a dAb fragment has a V_H domain, a V_L domain, or an antigen-binding fragment of a V_H or V_L domain (US Pat. No.6,846,634, 6,696,245, US App. Pub. No.05/0202512, 04/0202995, 04/0038291, 04/0009507, 03/0039958, Ward et al., Nature 341:544-546, 1989). [00192] Polynucleotide and polypeptide sequences of particular light and heavy chain variable domains are described below. Antibodies comprising a light chain and heavy chain are designated by combining the name of the light chain and the name of the heavy chain variable domains. For example, “L4H7,” indicates an antibody comprising the light chain variable domain of L4 (comprising a sequence of SEQ ID NO:4) and the heavy chain variable domain of H7 (comprising a sequence of SEQ ID NO:507). Light chain variable sequences are provided in SEQ ID Nos: 1-25, and heavy chain variable sequences are provided in SEQ ID Nos:101-124. In some embodiments, the ABPs comprise sequences of anti-PD-L1 antibodies and their light chain and heavy chain sequences and CDR sequences disclosed in PCT/US2019/0068826 which has been incorporated by reference in its entirety herein. [00193] In other embodiments, an antibody may comprise a specific heavy or light chain, while the complementary light or heavy chain variable domain remains unspecified. In particular, certain embodiments herein include antibodies that bind a specific antigen (such as PD-L1 and/or TGF-β) by way of a specific light or heavy chain, such that the complementary heavy or light chain may be promiscuous, or even irrelevant, but may be determined by, for example, screening combinatorial libraries. Portolano et al., J. Immunol. V.150 (3), pp.880-887 (1993); Clackson et al., Nature v.352 pp.624-628 (1991); Adler et al., A natively paired antibody library yields drug leads with higher sensitivity and specificity than a randomly paired antibody library, MAbs (2018)); Adler et al., Rare, high-affinity mouse anti-PD-L1 antibodies that function in checkpoint blockade, discovered using microfluidics and molecular genomics, MAbs (2017). [00194] Naturally occurring immunoglobulin chains exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. From N-terminus to C-terminus, both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each domain is in accordance with the definitions of Kabat et al. in Sequences of Proteins of Immunological Interest, 5th Ed., US Dept. of Health and Human Services, PHS, NIH, NIH Publication no.91-3242, 1991. [00195] The term “chimeric antibody” refers to an antibody that contains one or more regions from one antibody and one or more regions from one or more other antibodies. In one embodiment, one or more of the CDRs are derived from a human anti-PD-L1 or anti-TGF-β antibody. In another embodiment, all of the CDRs are derived from a human anti-PD-L1 or anti- TGF-β antibody. In another embodiment, the CDRs from more than one human anti-PD-L1 antibodies are mixed and matched in a chimeric antibody. For instance, a chimeric antibody may comprise a CDR1 from the light chain of a first human anti-PD-L1 antibody, a CDR2 and a CDR3 from the light chain of a second human anti-PD-L1 antibody, and the CDRs from the heavy chain from a third anti-PD-L1 antibody. Further, the framework regions may be derived from one of the same anti-PD-L1 antibodies, from one or more different antibodies, such as a human antibody, or from a humanized antibody. In one example of a chimeric antibody, a portion of the heavy and/or light chain is identical with, homologous to, or derived from an antibody from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is/are identical with, homologous to, or derived from an antibody (- ies) from another species or belonging to another antibody class or subclass. Also included are fragments of such antibodies that exhibit the desired biological activity (i.e., the ability to specifically bind PD-L1 and TGF-β). [00196] Fragments or analogs of antibodies can be readily prepared by those of ordinary skill in the art following the teachings of this specification and using techniques well-known in the art. Preferred amino- and carboxy-termini of fragments or analogs occur near boundaries of functional domains. Structural and functional domains can be identified by comparison of the nucleotide and/or amino acid sequence data to public or proprietary sequence databases. Computerized comparison methods can be used to identify sequence motifs or predicted protein conformation domains that occur in other proteins of known structure and/or function. Methods to identify protein sequences that fold into a known three-dimensional structure are known. See, e.g., Bowie et al., 1991, Science 253:164. [00197] Antigen binding fragments derived from an antibody can be obtained, for example, by proteolytic hydrolysis of the antibody, for example, pepsin or papain digestion of whole antibodies according to conventional methods. By way of example, antibody fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment termed F(ab’)2. This fragment can be further cleaved using a thiol reducing agent to produce 3.5S Fab’ monovalent fragments. Optionally, the cleavage reaction can be performed using a blocking group for the sulfhydryl groups that result from cleavage of disulfide linkages. As an alternative, an enzymatic cleavage using papain produces two monovalent Fab fragments and an Fc fragment directly. These methods are described, for example, by Goldenberg, U.S. Patent No.4,331,647, Nisonoff et al., Arch. Biochem. Biophys.89:230, 1960; Porter, Biochem. J. 73:119, 1959; Edelman et al., in Methods in Enzymology 1:422 (Academic Press 1967); and by Andrews, S.M. and Titus, J.A. in Current Protocols in Immunology (Coligan J.E., et al., eds), John Wiley & Sons, New York (2003), pages 2.8.12.8.10 and 2.10A.12.10A.5. Other methods for cleaving antibodies, such as separating heavy chains to form monovalent light heavy chain fragments (Fd), further cleaving of fragments, or other enzymatic, chemical, or genetic techniques may also be used, so long as the fragments bind to the antigen that is recognized by the intact antibody. [00198] An antibody fragment may also be any synthetic or genetically engineered protein. For example, antibody fragments include isolated fragments consisting of the light chain variable region, “Fv” fragments consisting of the variable regions of the heavy and light chains, recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (scFv proteins). [00199] Another form of an antibody fragment is a peptide comprising one or more complementarity determining regions (CDRs) of an antibody. CDRs (also termed “minimal recognition units”, or “hypervariable region”) can be incorporated into a molecule either covalently or noncovalently to make it an antigen binding protein. CDRs can be obtained by constructing polynucleotides that encode the CDR of interest. Such polynucleotides are prepared, for example, by using the polymerase chain reaction to synthesize the variable region using mRNA of antibody producing cells as a template (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology 2:106, 1991; Courtenay Luck, “Genetic Manipulation of Monoclonal Antibodies,” in Monoclonal Antibodies: Production, Engineering and Clinical Application, Ritter et al. (eds.), page 166 (Cambridge University Press 1995); and Ward et al., “Genetic Manipulation and Expression of Antibodies,” in Monoclonal Antibodies: Principles and Applications, Birch et al., (eds.), page 137 (Wiley Liss, Inc.1995). [00200] Thus, in one embodiment, the binding agent comprises at least one CDR as described herein. The binding agent may comprise at least two, three, four, five or six CDR’s as described herein. The binding agent may further comprise at least one variable region domain of an antibody described herein. The variable region domain may be of any size or amino acid composition and will generally comprise at least one CDR sequence responsible for binding to human PD-L1 or TGF-β, for example CDR1-H, CDR2-H, CDR3-H, CDR1-L, CDR2-L, and CDR3-L, specifically described herein and which is adjacent to or in frame with one or more framework sequences. In general terms, the variable (V) region domain may be any suitable arrangement of immunoglobulin heavy (V_H) and/or light (V_L) chain variable domains. Thus, for example, the V region domain may be monomeric and be a V_H or V_L domain, which is capable of independently binding human PD-L1 or TGF-β with an affinity at least equal to 1 x 10⁷M or less as described below. Alternatively, the V region domain may be dimeric and contain V_H, V_H V_L, or V_L, dimers. The V region dimer comprises at least one V_H and at least one V_L chain that may be non-covalently associated (hereinafter referred to as FV). If desired, the chains may be covalently coupled either directly, for example via a disulfide bond between the two variable domains, or through a linker, for example a peptide linker, to form a single chain Fv (scFv). [00201] The variable region domain may be any naturally occurring variable domain or an engineered version thereof. By engineered version is meant a variable region domain that has been created using recombinant DNA engineering techniques. Such engineered versions include those created, for example, from a specific antibody variable region by insertions, deletions, or changes in or to the amino acid sequences of the specific antibody. Particular examples include engineered variable region domains containing at least one CDR and optionally one or more framework amino acids from a first antibody and the remainder of the variable region domain from a second antibody. [00202] The variable region domain may be covalently attached at a C terminal amino acid to at least one other antibody domain or a fragment thereof. Thus, for example, a V_H domain that is present in the variable region domain may be linked to an immunoglobulin CH1 domain, or a fragment thereof. Similarly a V_L domain may be linked to a CK domain or a fragment thereof. In this way, for example, the antibody may be a Fab fragment wherein the antigen binding domain contains associated V_H and V_L domains covalently linked at their C termini to a CH1 and CK domain, respectively. The CH1 domain may be extended with further amino acids, for example to provide a hinge region or a portion of a hinge region domain as found in a Fab’ fragment, or to provide further domains, such as antibody CH2 and CH3 domains. [00203] As described herein, antibodies comprise at least one of these CDRs. For example, one or more CDR may be incorporated into known antibody framework regions (IgG1, IgG2, etc.), or conjugated to a suitable vehicle to enhance the half-life thereof. Suitable vehicles include, but are not limited to Fc, polyethylene glycol (PEG), albumin, transferrin, and the like. These and other suitable vehicles are known in the art. Such conjugated CDR peptides may be in monomeric, dimeric, tetrameric, or other form. In one embodiment, one or more water-soluble polymer is bonded at one or more specific position, for example at the amino terminus, of a binding agent. [00204] In another example, individual V_L or V_H chains from an antibody (i.e. PD-L1 or TGF-β antibody) can be used to search for other V_H or V_L chains that could form antigen-binding fragments (or Fab), with the same specificity. Thus, random combinations of V_H and V_L chain Ig genes can be expressed as antigen-binding fragments in a bacteriophage library (such as fd or lambda phage). For instance, a combinatorial library may be generated by utilizing the parent V_L or V_H chain library combined with antigen-binding specific V_L or V_H chain libraries, respectively. The combinatorial libraries may then be screened by conventional techniques, for example by using radioactively labeled probe (such as radioactively labeled PD-L1). See, for example, Portolano et al., J. Immunol. V.150 (3) pp.880-887 (1993). [00205] Diabodies are bivalent antibodies comprising two polypeptide chains, wherein each polypeptide chain comprises V_H and V_L domains joined by a linker that is too short to allow for pairing between two domains on the same chain, thus allowing each domain to pair with a complementary domain on another polypeptide chain (see, e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-48, and Poljak et al., 1994, Structure 2:1121-23). If the two polypeptide chains of a diabody are identical, then a diabody resulting from their pairing will have two identical antigen binding sites. Polypeptide chains having different sequences can be used to make a diabody with two different antigen binding sites. Similarly, tribodies and tetrabodies are antibodies comprising three and four polypeptide chains, respectively, and forming three and four antigen binding sites, respectively, which can be the same or different. [00206] Antibody polypeptides are also disclosed in U. S. Patent No.6,703,199, including fibronectin polypeptide monobodies. Other antibody polypeptides are disclosed in U.S. Patent Publication 2005/0238646, which are single-chain polypeptides. [00207] In certain embodiments, an antibody comprises one or more water soluble polymer attachments, including, but not limited to, polyethylene glycol, polyoxyethylene glycol, or polypropylene glycol. See, e.g., U.S. Pat. Nos.4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and 4,179,337. In certain embodiments, a derivative binding agent comprises one or more of monomethoxy-polyethylene glycol, dextran, cellulose, or other carbohydrate based polymers, poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of such polymers. In certain embodiments, one or more water-soluble polymer is randomly attached to one or more side chains. In certain embodiments, PEG can act to improve the therapeutic capacity for a binding agent, such as an antibody. Certain such methods are discussed, for example, in U.S. Pat. No.6,133,426, which is hereby incorporated by reference for any purpose. 7.3.1. Monoclonal antibody [00208] In another aspect, the present disclosure provides monoclonal antibodies that bind to PD-L1 and/or TGF-β. Monoclonal antibodies of the present disclosure may be generated using a variety of known techniques. In general, monoclonal antibodies that bind to specific antigens may be obtained by methods known to those skilled in the art (see, for example, Kohler et al., Nature 256:495, 1975; Coligan et al. (eds.), Current Protocols in Immunology, 1:2.5.12.6.7 (John Wiley & Sons 1991); U.S. Patent Nos. RE 32,011, 4,902,614, 4,543,439, and 4,411,993; Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Plenum Press, Kennett, McKearn, and Bechtol (eds.) (1980); and Antibodies: A Laboratory Manual, Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press (1988); Picksley et al., “Production of monoclonal antibodies against proteins expressed in E. coli,” in DNA Cloning 2: Expression Systems, 2nd Edition, Glover et al. (eds.), page 93 (Oxford University Press 1995)). Antibody fragments may be derived therefrom using any suitable standard technique such as proteolytic digestion, or optionally, by proteolytic digestion (for example, using papain or pepsin) followed by mild reduction of disulfide bonds and alkylation. Alternatively, such fragments may also be generated by recombinant genetic engineering techniques as described herein. [00209] Monoclonal antibodies can be obtained by injecting an animal, for example, a rat, hamster, a rabbit, or preferably a mouse, including for example a transgenic or a knock-out, as known in the art, with an immunogen comprising human PD-L1 [sequence SEQ ID 7001], TGF- β, a fragment thereof, or a vector expressing the immunogen according to methods known in the art and described herein. The presence of specific antibody production may be monitored after the initial injection and/or after a booster injection by obtaining a serum sample and detecting the presence of an antibody that binds to human PD-L1, TGF-β, or peptide using any one of several immunodetection methods known in the art and described herein. From animals producing the desired antibodies, lymphoid cells, most commonly cells from the spleen or lymph node, are removed to obtain B-lymphocytes. The B lymphocytes are then fused with a drug-sensitized myeloma cell fusion partner, preferably one that is syngeneic with the immunized animal and that optionally has other desirable properties (e.g., inability to express endogenous Ig gene products, e.g., P3X63 - Ag 8.653 (ATCC No. CRL 1580); NSO, SP20) to produce hybridomas, which are immortal eukaryotic cell lines. [00210] The lymphoid (e.g., spleen) cells and the myeloma cells may be combined for a few minutes with a membrane fusion-promoting agent, such as polyethylene glycol or a nonionic detergent, and then plated at low density on a selective medium that supports the growth of hybridoma cells but not unfused myeloma cells. A preferred selection media is HAT (hypoxanthine, aminopterin, thymidine). After a sufficient time, usually about one to two weeks, colonies of cells are observed. Single colonies are isolated, and antibodies produced by the cells may be tested for binding activity to human PD-L1 or TGF-β, using any one of a variety of immunoassays known in the art and described herein. The hybridomas are cloned (e.g., by limited dilution cloning or by soft agar plaque isolation) and positive clones that produce an antibody specific to PD-L1 are selected and cultured. The monoclonal antibodies from the hybridoma cultures may be isolated from the supernatants of hybridoma cultures. [00211] An alternative method for production of a murine monoclonal antibody is to inject the hybridoma cells into the peritoneal cavity of a syngeneic mouse, for example, a mouse that has been treated (e.g., pristane-primed) to promote formation of ascites fluid containing the monoclonal antibody. Monoclonal antibodies can be isolated and purified by a variety of well-established techniques. Such isolation techniques include affinity chromatography with Protein-A Sepharose, size-exclusion chromatography, and ion-exchange chromatography (see, for example, Coligan at pages 2.7.1-2.7.12 and pages 2.9.1-2.9.3; Baines et al., “Purification of Immunoglobulin G (IgG),” in Methods in Molecular Biology, Vol.10, pages 79-104 (The Humana Press, Inc.1992)). Monoclonal antibodies may be purified by affinity chromatography using an appropriate ligand selected based on particular properties of the antibody (e.g., heavy or light chain isotype, binding specificity, etc.). Examples of a suitable ligand, immobilized on a solid support, include Protein A, Protein G, an anticonstant region (light chain or heavy chain) antibody, an anti-idiotype antibody, and a TGF-beta binding protein, or fragment or variant thereof. [00212] Monoclonal antibodies may be produced using any technique known in the art, e.g., by immortalizing spleen cells harvested from the transgenic animal after completion of the immunization schedule. The spleen cells can be immortalized using any technique known in the art, e.g., by fusing them with myeloma cells to produce hybridomas. Hybridoma cell lines are identified that produce an antibody that binds a PD-L1 or TGF-β polypeptide. Such hybridoma cell lines, and anti-PD-L1 or TGF-β monoclonal antibodies produced by them, are encompassed by the present disclosure. Myeloma cells for use in hybridoma-producing fusion procedures preferably are non-antibody-producing, have high fusion efficiency, and enzyme deficiencies that render them incapable of growing in certain selective media which support the growth of only the desired fused cells (hybridomas). Examples of suitable cell lines for use in mouse fusions include Sp-20, P3-X63/Ag8, P3-X63-Ag8.653, NS1/1.Ag 41, Sp210-Ag14, FO, NSO/U, MPC-11, MPC11-X45-GTG 1.7 and S194/5XX0 Bul; examples of cell lines used in rat fusions include R210.RCY3, Y3-Ag 1.2.3, IR983F and 4B210. Other cell lines useful for cell fusions are U-266, GM1500-GRG2, LICR-LON-HMy2 and UC729-6. Hybridomas or mAbs may be further screened to identify mAbs with particular properties, such as the ability to block a PD-L1 or TGF-β-induced activity. [00213] The ABP of the present disclosure can be a fully human monoclonal antibody. In some embodiments, the ABP of the present disclosure is a humanized antibody. In some embodiments, the ABP of the present disclosure is a chimeric antibody. The ABP specifically binds to the PD-L1 or TGF-β and possesses at least one in vivo biological activity of a human anti-PD-L1 or anti-TGF-β antibody. 7.4. Nucleic acids [00214] In one aspect, the present disclosure provides isolated nucleic acid molecules. The nucleic acids comprise, for example, polynucleotides that encode all or part of an antigen binding protein, for example, one or both chains of an antibody of the present disclosure, or a fragment, derivative, mutein, or variant thereof, polynucleotides sufficient for use as hybridization probes, PCR primers or sequencing primers for identifying, analyzing, mutating or amplifying a polynucleotide encoding a polypeptide, anti-sense nucleic acids for inhibiting expression of a polynucleotide, and complementary sequences of the foregoing. The nucleic acids can be any length. They can be, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 750, 1,000, 1,500, 3,000, 5,000 or more nucleotides in length, and/or can comprise one or more additional sequences, for example, regulatory sequences, and/or be part of a larger nucleic acid, for example, a vector. The nucleic acids can be single-stranded or double-stranded and can comprise RNA and/or DNA nucleotides, and artificial variants thereof (e.g., peptide nucleic acids). [00215] Nucleic acids encoding antibody polypeptides (e.g., heavy or light chain, variable domain only, or full length) can be isolated from B-cells of mice that have been immunized with PD-L1 or TGF-β. The nucleic acid can be isolated by conventional procedures such as polymerase chain reaction (PCR). In some embodiments, the nucleic acid can be isolated by the method illustrated in FIG.1. [00216] Nucleic acid sequences encoding the variable regions of the heavy and light chain variable regions are shown herein. The skilled artisan will appreciate that, due to the degeneracy of the genetic code, each of the polypeptide sequences disclosed herein is encoded by a large number of other nucleic acid sequences. The present disclosure provides each degenerate nucleotide sequence encoding each antigen binding protein of the present disclosure. [00217] The present disclosure further provides nucleic acids that hybridize to other nucleic acids (e.g., nucleic acids comprising a nucleotide sequence of any PD-L1 or TGF-β gene) under particular hybridization conditions. Methods for hybridizing nucleic acids are well-known in the art. See, e.g., Curr. Prot. in Mol. Biol., John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. As defined herein, a moderately stringent hybridization condition uses a prewashing solution containing 5x sodium chloride/sodium citrate (SSC), 0.5% SDS, 1.0 mM EDTA (pH 8.0), hybridization buffer of about 50% formamide, 6X SSC, and a hybridization temperature of 55° C (or other similar hybridization solutions, such as one containing about 50% formamide, with a hybridization temperature of 42° C), and washing conditions of 60° C, in 0.5X SSC, 0.1% SDS. A stringent hybridization condition hybridizes in 6X SSC at 45° C, followed by one or more washes in 0.1x SSC, 0.2% SDS at 68° C. Furthermore, one of skill in the art can manipulate the hybridization and/or washing conditions to increase or decrease the stringency of hybridization such that nucleic acids comprising nucleotide sequences that are at least 65, 70, 75, 80, 85, 90, 95, 98, or 99% identical to each other typically remain hybridized to each other. The basic parameters affecting the choice of hybridization conditions and guidance for devising suitable conditions are set forth by, for example, Sambrook, Fritsch, and Maniatis (1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., chapters 9 and 11; and Curr. Prot. in Mol. Biol.1995, Ausubel et al., eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4), and can be readily determined by those having ordinary skill in the art based on, for example, the length and/or base composition of the DNA. [00218] Changes can be introduced by mutation into a nucleic acid, thereby leading to changes in the amino acid sequence of a polypeptide (e.g., an antigen binding protein) that it encodes. Mutations can be introduced using any technique known in the art. In one embodiment, one or more particular amino acid residues are changed using, for example, a site- directed mutagenesis protocol. In another embodiment, one or more randomly selected residues are changed using, for example, a random mutagenesis protocol. A mutant polypeptide can be expressed and screened for a desired property (e.g., binding to PD-L1). [00219] Mutations can be introduced into a nucleic acid without significantly altering the biological activity of a polypeptide that it encodes. For example, one can make nucleotide substitutions leading to amino acid substitutions at non-essential amino acid residues. In one embodiment, a nucleotide sequence provided herein for PD-L1 binding domain or TGF-β binding domain, or a desired fragment, variant, or derivative thereof, is mutated such that it encodes an amino acid sequence comprising one or more deletions or substitutions of amino acid residues that are shown herein for PD-L1 binding domain or TGF-β binding domain to be residues where two or more sequences differ. Alternatively, one or more mutations can be introduced into a nucleic acid that selectively change the biological activity (e.g., binding of PD- L1 or TGF-β) of a polypeptide that it encodes. For example, the mutation can quantitatively or qualitatively change the biological activity. Examples of quantitative changes include increasing, reducing or eliminating the activity. Examples of qualitative changes include changing the antigen specificity of an antigen binding protein. [00220] In another aspect, the present disclosure provides nucleic acid molecules that are suitable for use as primers or hybridization probes for the detection of nucleic acid sequences of the present disclosure. A nucleic acid molecule of the present disclosure can comprise only a portion of a nucleic acid sequence encoding a full-length polypeptide of the present disclosure, for example, a fragment that can be used as a probe or primer or a fragment encoding an active portion (e.g., a PD-L1 or TGF-β binding portion) of a polypeptide of the present disclosure. [00221] Probes based on the sequence of a nucleic acid of the present disclosure can be used to detect the nucleic acid or similar nucleic acids, for example, transcripts encoding a polypeptide of the present disclosure. The probe can comprise a label group, e.g., a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used to identify a cell that expresses the polypeptide 7.5. Expression vectors [00222] The present disclosure provides vectors comprising a nucleic acid encoding a polypeptide of the present disclosure or a portion thereof. Examples of vectors include, but are not limited to, plasmids, viral vectors, non-episomal mammalian vectors and expression vectors, for example, recombinant expression vectors. [00223] In another aspect of the present disclosure, expression vectors containing the nucleic acid molecules and polynucleotides of the present disclosure are also provided, and host cells transformed with such vectors, and methods of producing the polypeptides are also provided. The term “expression vector” refers to a plasmid, phage, virus or vector for expressing a polypeptide from a polynucleotide sequence. Vectors for the expression of the polypeptides contain at minimum sequences required for vector propagation and for expression of the cloned insert. An expression vector comprises a transcriptional unit comprising an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers, (2) a sequence that encodes polypeptides and proteins to be transcribed into mRNA and translated into protein, and (3) appropriate transcription initiation and termination sequences. These sequences may further include a selection marker. Vectors suitable for expression in host cells are readily available and the nucleic acid molecules are inserted into the vectors using standard recombinant DNA techniques. Such vectors can include promoters which function in specific tissues, and viral vectors for the expression of polypeptides in targeted human or animal cells. [00224] The recombinant expression vectors of the present disclosure can comprise a nucleic acid of the present disclosure in a form suitable for expression of the nucleic acid in a host cell. The recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operably linked to the nucleic acid sequence to be expressed. Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cells (e.g., SV40 early gene enhancer, Rous sarcoma virus promoter and cytomegalovirus promoter), those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences, see Voss et al., 1986, Trends Biochem. Sci.11:287, Maniatis et al., 1987, Science 236:1237, incorporated by reference herein in their entireties), and those that direct inducible expression of a nucleotide sequence in response to particular treatment or condition (e.g., the metallothionin promoter in mammalian cells and the tet-responsive and/or streptomycin responsive promoter in both prokaryotic and eukaryotic systems (see id.). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the present disclosure can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein. [00225] In some embodiments, the expression vector is an expression vector purified from one of the clones of the library of PD-L1 binding clones deposited under ATCC Accession No. PTA-125513. In some embodiments, the expression vector is generated by genetic modification of one of an expression vector in one of the clones purified from the library of PD-L1 binding clones deposited under ATCC Accession No. PTA-125513. In some embodiments, the expression vector is generated by using variable region sequences of heavy and light chains of one of the clones of the library of PD-L1 binding clones deposited under ATCC Accession No. PTA-125513. [00226] The present disclosure further provides methods of making polypeptides. A variety of other expression/host systems may be utilized. Vector DNA can be introduced into prokaryotic or eukaryotic systems via conventional transformation or transfection techniques. These systems include but are not limited to microorganisms such as bacteria (for example, E. coli) transformed with recombinant bacteriophage, plasmid or cosmid DNA expression vectors; yeast transformed with yeast expression vectors; insect cell systems infected with virus expression vectors (e.g., baculovirus); plant cell systems transfected with virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with bacterial expression vectors (e.g., Ti or pBR322 plasmid); or animal cell systems. Mammalian cells useful in recombinant protein production include but are not limited to VERO cells, HeLa cells, Chinese hamster ovary (CHO) cell lines, or their derivatives such as Veggie CHO and related cell lines which grow in serum-free media (see Rasmussen et al., 1998, Cytotechnology 28:31) or CHO strain DX-B11, which is deficient in DHFR (see Urlaub et al., 1980, Proc. Natl. Acad. Sci. USA 77:4216-20) COS cells such as the COS-7 line of monkey kidney cells (ATCC CRL 1651) (see Gluzman et al., 1981, Cell 23:175), W138, BHK, HepG2, 3T3 (ATCC CCL 163), RIN, MDCK, A549, PC12, K562, L cells, C127 cells, BHK (ATCC CRL 10) cell lines, the CV1/EBNA cell line derived from the African green monkey kidney cell line CV1 (ATCC CCL 70) (see McMahan et al., 1991, EMBO J.10:2821), human embryonic kidney cells such as 293, 293 EBNA or MSR 293, human epidermal A431 cells, human Colo205 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HL-60, U937, HaK or Jurkat cells. Mammalian expression allows for the production of secreted or soluble polypeptides which may be recovered from the growth medium. [00227] For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., for resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Once such cells are transformed with vectors that contain selectable markers as well as the desired expression cassette, the cells can be allowed to grow in an enriched media before they are switched to selective media, for example. The selectable marker is designed to allow growth and recovery of cells that successfully express the introduced sequences. Resistant clumps of stably transformed cells can be proliferated using tissue culture techniques appropriate to the cell line employed. An overview of expression of recombinant proteins is found in Methods of Enzymology, v.185, Goeddell, D.V., ed., Academic Press (1990). Preferred selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methotrexate. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die), among other methods. [00228] The transformed cells can be cultured under conditions that promote expression of the polypeptide, and the polypeptide recovered by conventional protein purification procedures (as defined above). One such purification procedure includes the use of affinity chromatography, e.g., over a matrix having all or a portion (e.g., the extracellular domain) of PD- L1 bound thereto. Polypeptides contemplated for use herein include substantially homogeneous recombinant mammalian anti-PD-L1 and anti-TGFβ bispecific ABPs substantially free of contaminating endogenous materials. [00229] In some cases, such as in expression using prokaryotic systems, the expressed polypeptides of this disclosure may need to be “refolded” and oxidized into a proper tertiary structure and disulfide linkages generated in order to be biologically active. Refolding can be accomplished using a number of procedures well known in the art. Such methods include, for example, exposing the solubilized polypeptide to a pH usually above 7 in the presence of a chaotropic agent. The selection of chaotrope is similar to the choices used for inclusion body solubilization; however, a chaotrope is typically used at a lower concentration. Exemplary chaotropic agents are guanidine and urea. In most cases, the refolding/oxidation solution will also contain a reducing agent plus its oxidized form in a specific ratio to generate a particular redox potential which allows for disulfide shuffling to occur for the formation of cysteine bridges. Some commonly used redox couples include cysteine/cystamine, glutathione/dithiobisGSH, cupric chloride, dithiothreitol DTT/dithiane DTT, and 2- mercaptoethanol (bME)/dithio-bME. In many instances, a co-solvent may be used to increase the efficiency of the refolding. Commonly used cosolvents include glycerol, polyethylene glycol of various molecular weights, and arginine. [00230] In addition, the polypeptides can be synthesized in solution or on a solid support in accordance with conventional techniques. Various automatic synthesizers are commercially available and can be used in accordance with known protocols. See, for example, Stewart and Young, Solid Phase Peptide Synthesis, 2d.Ed., Pierce Chemical Co. (1984); Tam et al., J Am Chem Soc, 105:6442, (1983); Merrifield, Science 232:341-347 (1986); Barany and Merrifield, The Peptides, Gross and Meienhofer, eds, Academic Press, New York, 1-284; Barany et al., Int J Pep Protein Res, 30:705-739 (1987). [00231] The polypeptides and proteins of the present disclosure can be purified according to protein purification techniques well known to those of skill in the art. These techniques involve, at one level, the crude fractionation of the proteinaceous and non-proteinaceous fractions. Having separated the peptide polypeptides from other proteins, the peptide or polypeptide of interest can be further purified using chromatographic and electrophoretic techniques to achieve partial or complete purification (or purification to homogeneity). The term “purified polypeptide” as used herein, is intended to refer to a composition, isolatable from other components, wherein the polypeptide is purified to any degree relative to its naturally-obtainable state. A purified polypeptide therefore also refers to a polypeptide that is free from the environment in which it may naturally occur. Generally, “purified” will refer to a polypeptide composition that has been subjected to fractionation to remove various other components, and which composition substantially retains its expressed biological activity. Where the term “substantially purified” is used, this designation will refer to a peptide or polypeptide composition in which the polypeptide or peptide forms the major component of the composition, such as constituting about 50 %, about 60 %, about 70 %, about 80 %, about 85 %, or about 90 % or more of the proteins in the composition. [00232] Various techniques suitable for use in purification will be well known to those of skill in the art. These include, for example, precipitation with ammonium sulphate, PEG, antibodies (immunoprecipitation) and the like or by heat denaturation, followed by centrifugation; chromatography such as affinity chromatography (Protein-A columns), ion exchange, gel filtration, reverse phase, hydroxylapatite, hydrophobic interaction chromatography, isoelectric focusing, gel electrophoresis, and combinations of these techniques. As is generally known in the art, it is believed that the order of conducting the various purification steps may be changed, or that certain steps may be omitted, and still result in a suitable method for the preparation of a substantially purified polypeptide. Exemplary purification steps are provided in the Examples below. [00233] Various methods for quantifying the degree of purification of polypeptide will be known to those of skill in the art in light of the present disclosure. These include, for example, determining the specific binding activity of an active fraction, or assessing the amount of peptide or polypeptide within a fraction by SDS/PAGE analysis. A preferred method for assessing the purity of a polypeptide fraction is to calculate the binding activity of the fraction, to compare it to the binding activity of the initial extract, and to thus calculate the degree of purification, herein assessed by a “-fold purification number.” The actual units used to represent the amount of binding activity will, of course, be dependent upon the particular assay technique chosen to follow the purification and whether or not the polypeptide or peptide exhibits a detectable binding activity. 7.6. Method of generating ABPs [00234] ABPs disclosed herein can be generated by any number of techniques with which those having ordinary skill in the art will be familiar. Such methods include, but are not limited to, Epstein Barr Virus (EBV) transformation of human peripheral blood cells (e.g., containing B lymphocytes), in vitro immunization of human B-cells, fusion of spleen cells from immunized transgenic mice carrying inserted human immunoglobulin genes, isolation from human immunoglobulin V region phage libraries, or other procedures as known in the art and based on the disclosure herein. For example, fully human monoclonal antibodies may be obtained from transgenic mice that have been engineered to produce specific human antibodies in response to antigenic challenge. Methods for obtaining fully human antibodies from transgenic mice are described, for example, by Green et al., Nature Genet.7:13, 1994; Lonberg et al., Nature 368:856, 1994; Taylor et al., Int. Immun.6:579, 1994; U.S. Patent No.5,877,397; Bruggemann et al., 1997 Curr. Opin. Biotechnol.8:455-58; Jakobovits et al., 1995 Ann. N. Y. Acad. Sci. 764:525-35. In this technique, elements of the human heavy and light chain locus are introduced into strains of mice derived from embryonic stem cell lines that contain targeted disruptions of the endogenous heavy chain and light chain loci (see also Bruggemann et al., Curr. Opin. Biotechnol.8:455-58 (1997)). For example, human immunoglobulin transgenes may be mini-gene constructs, or transloci on yeast artificial chromosomes, which undergo B-cell-specific DNA rearrangement and hypermutation in the mouse lymphoid tissue. Fully human monoclonal antibodies may be obtained by immunizing the transgenic mice, which may then produce human antibodies specific for an antigen (e.g., PD-L1, TGF-β). Lymphoid cells of the immunized transgenic mice can be used to produce human antibody-secreting hybridomas according to the methods described herein. Polyclonal sera containing fully human antibodies may also be obtained from the blood of the immunized animals. [00235] Another method for generating human antibodies of the present disclosure includes immortalizing human peripheral blood cells by EBV transformation. See, e.g., U.S. Patent No.4,464,456. Such an immortalized B-cell line (or lymphoblastoid cell line) producing a monoclonal antibody that specifically binds to PD-L1 or TGF-β can be identified by immunodetection methods as provided herein, for example, an ELISA, and then isolated by standard cloning techniques. The stability of the lymphoblastoid cell line producing an anti-PD- L1 or anti- TGF-β antibody may be improved by fusing the transformed cell line with a murine myeloma to produce a mouse-human hybrid cell line according to methods known in the art (see, e.g., Glasky et al., Hybridoma 8:377-89 (1989)). Still another method to generate human monoclonal antibodies is in vitro immunization, which includes priming human splenic B-cells with human PD-L1 or TGF-β, followed by fusion of primed B-cells with a heterohybrid fusion partner. See, e.g., Boerner et al., 1991 J. Immunol.147:86-95. [00236] In certain embodiments, a B-cell that is producing an anti-human PD-L1 antibody is selected and the light chain and heavy chain variable regions are cloned from the B-cell according to molecular biology techniques known in the art (WO 92/02551; U.S. Patent 5,627,052; Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-48 (1996)) and described herein. B-cells from an immunized animal may be isolated from the spleen, lymph node, or peripheral blood sample by selecting a cell that is producing an antibody that specifically binds to PD-L1. B-cells may also be isolated from humans, for example, from a peripheral blood sample. [00237] Methods for detecting single B-cells that are producing an antibody with the desired specificity are well known in the art, for example, by plaque formation, fluorescence-activated cell sorting, in vitro stimulation followed by detection of specific antibody, and the like. Methods for selection of specific antibody-producing B-cells include, for example, preparing a single cell suspension of B-cells in soft agar that contains human PD-L1 or TGF-β. Binding of the specific antibody produced by the B-cell to the antigen results in the formation of a complex, which may be visible as an immunoprecipitate. [00238] In some embodiments, specific antibody-producing B-cells are selected by using a method that allows identification natively paired antibodies. For example, a method described in Adler et al., A natively paired antibody library yields drug leads with higher sensitivity and specificity than a randomly paired antibody library, MAbs (2018), which is incorporated by reference in its entirety herein, can be employed. The method combines microfluidic technology, molecular genomics, yeast single-chain variable fragment (scFv) display, fluorescence-activated cell sorting (FACS) and deep sequencing as summarized in FIG.1 adapted from Adler et al. In short, B cells can be isolated from immunized animals and then pooled. The B cells are encapsulated into droplets with oligo-dT beads and a lysis solution, and mRNA-bound beads are purified from the droplets, and then injected into a second emulsion with an OE-RT-PCR amplification mix that generates DNA amplicons that encode scFv with native pairing of heavy and light chain Ig. Libraries of natively paired amplicons are then electroporated into yeast for scFv display. FACS is used to identify high affinity scFv. Finally, deep antibody sequencing can be used to identify all clones in the pre- and post-sort scFv libraries. [00239] After the yeast cells expressing the desired scFvs are selected, the specific antibody genes may be cloned by isolating and amplifying DNA or mRNA according to methods known in the art and described herein. [00240] The methods for obtaining antibodies of the present disclosure can also adopt various phage display technologies known in the art. See, e.g., Winter et al., 1994 Annu. Rev. Immunol.12:433-55; Burton et al., 1994 Adv. Immunol.57:191-280. Human or murine immunoglobulin variable region gene combinatorial libraries may be created in phage vectors that can be screened to select Ig fragments (Fab, Fv, sFv, or multimers thereof) that bind specifically to PD-L1 or TGF-β binding protein or variant or fragment thereof. See, e.g., U.S. Patent No.5,223,409; Huse et al., 1989 Science 246:1275-81; Sastry et al., Proc. Natl. Acad. Sci. USA 86:5728-32 (1989); Alting-Mees et al., Strategies in Molecular Biology 3:1-9 (1990); Kang et al., 1991 Proc. Natl. Acad. Sci. USA 88:4363-66; Hoogenboom et al., 1992 J. Molec. Biol. 227:381-388; Schlebusch et al., 1997 Hybridoma 16:47-52 and references cited therein. For example, a library containing a plurality of polynucleotide sequences encoding Ig variable region fragments may be inserted into the genome of a filamentous bacteriophage, such as M13 or a variant thereof, in frame with the sequence encoding a phage coat protein. A fusion protein may be a fusion of the coat protein with the light chain variable region domain and/or with the heavy chain variable region domain. According to certain embodiments, immunoglobulin Fab fragments may also be displayed on a phage particle (see, e.g., U.S. Patent No.5,698,426). [00241] Antibody fragments fused to another protein, such as a minor coat protein, can be also used to enrich phage with antigen. Then, using a random combinatorial library of rearranged heavy (V_H) and light (V_L) chains from mice immune to the antigen (e.g. PD-L1, TGF- β), diverse libraries of antibody fragments are displayed on the surface of the phage. These libraries can be screened for complementary variable domains, and the domains purified by, for example, affinity column. See Clackson et al., Nature, V.352 pp.624-628 (1991). [00242] Heavy and light chain immunoglobulin cDNA expression libraries may also be prepared in lambda phage, for example, using λlmmunoZap^TM(H) and λImmunoZap^TM(L) vectors (Stratagene, La Jolla, California). Briefly, mRNA is isolated from a B-cell population, and used to create heavy and light chain immunoglobulin cDNA expression libraries in the λImmunoZap(H) and λImmunoZap(L) vectors. These vectors may be screened individually or co-expressed to form Fab fragments or antibodies (see Huse et al., supra; see also Sastry et al., supra). Positive plaques may subsequently be converted to a non-lytic plasmid that allows high level expression of monoclonal antibody fragments from E. coli. [00243] In one embodiment, in a hybridoma the variable regions of a gene expressing a monoclonal antibody of interest are amplified using nucleotide primers. These primers may be synthesized by one of ordinary skill in the art, or may be purchased from commercially available sources. (See, e.g., Stratagene (La Jolla, California), which sells primers for mouse and human variable regions including, among others, primers for V_Ha, V_Hb, V_Hc, V_Hd, C_H1, V_L and C_L regions.) These primers may be used to amplify heavy or light chain variable regions, which may then be inserted into vectors such as ImmunoZAP^TMH or ImmunoZAP^TML (Stratagene), respectively. These vectors may then be introduced into E. coli, yeast, or mammalian-based systems for expression. Large amounts of a single-chain protein containing a fusion of the V_H and V_L domains may be produced using these methods (see Bird et al., Science 242:423-426, 1988). [00244] Once cells producing antibodies according to the disclosure have been obtained using any of the above-described immunization and other techniques, the specific antibody genes may be cloned by isolating and amplifying DNA or mRNA therefrom according to standard procedures as described herein. The antibodies produced therefrom may be sequenced and the CDRs identified and the DNA coding for the CDRs may be manipulated as described previously to generate other antibodies (e.g., bispecific ABPs) according to the disclosure. [00245] PD-L1 and/or TGF-β binding agent of the present disclosure preferably modulate PD-L1 and/or TGF-β function in the cell-based assay described herein and/or the in vivo assay described herein and/or bind to one or more of the domains described herein and/or cross-block the binding of one of the antibodies described in this application and/or are cross-blocked from binding PD-L1 and/or TGF-β by one of the antibodies described in this application. Accordingly such binding agents can be identified using the assays described herein. [00246] In certain embodiments, antibodies are generated by first identifying antibodies that bind to one or more of the domains provided herein and/or neutralize in the cell-based and/or in vivo assays described herein and/or cross-block the antibodies described in this application and/or are cross-blocked from binding PD-L1 and/or TGF-β by one of the antibodies described in this application. The CDR regions from these antibodies are then used to insert into appropriate biocompatible frameworks to generate PD-L1 and/or TGF-β binding agents. The non-CDR portion of the binding agent may be composed of amino acids, or may be a non- protein molecule. The assays described herein allow the characterization of binding agents. Preferably the binding agents of the present disclosure are antibodies as defined herein. [00247] Other antibodies according to the disclosure may be obtained by conventional immunization and cell fusion procedures as described herein and known in the art. [00248] Molecular evolution of the complementarity determining regions (CDRs) in the center of the antibody binding site also has been used to isolate antibodies with increased affinity, for example, antibodies having increased affinity for c-erbB-2, as described by Schier et al., 1996, J. Mol. Biol.263:551. Accordingly, such techniques are useful in preparing antibodies to PD-L1. Antigen binding proteins directed against a PD-L1 and/or TGF-β can be used, for example, in assays to detect the presence of PD-L1 and/or TGF-β polypeptides, either in vitro or in vivo. The antigen binding proteins also may be employed in purifying PD-L1 and/or TGF-β proteins by immunoaffinity chromatography. [00249] Although human, partially human, or humanized antibodies will be suitable for many applications, particularly those involving administration of the antibody to a human subject, other types of antigen binding proteins will be suitable for certain applications. Non- human antibodies can be derived from any antibody-producing animal, such as mouse, rat, rabbit, goat, donkey, or non-human primate (such as monkey (e.g., cynomolgus or rhesus monkey) or ape (e.g., chimpanzee)). An antibody from a particular species can be made by, for example, immunizing an animal of that species with the desired immunogen (e.g., a PD-L1 polypeptide, TGF-β) or using an artificial system for generating antibodies of that species (e.g., a bacterial or phage display-based system for generating antibodies of a particular species), or by converting an antibody from one species into an antibody from another species by replacing, e.g., the constant region of the antibody with a constant region from the other species, or by replacing one or more amino acid residues of the antibody so that it more closely resembles the sequence of an antibody from the other species. In one embodiment, the antibody is a chimeric antibody comprising amino acid sequences derived from antibodies from two or more different species. [00250] Antigen binding proteins may be prepared, and screened for desired properties, by any of a number of conventional techniques. Certain of the techniques involve isolating a nucleic acid encoding a polypeptide chain (or portion thereof) of an antigen binding protein of interest (e.g., an anti- PD-L1 antibody), and manipulating the nucleic acid through recombinant DNA technology. The nucleic acid may be fused to another nucleic acid of interest, or altered (e.g., by mutagenesis or other conventional techniques) to add, delete, or substitute one or more amino acid residues, for example. Furthermore, the antigen binding proteins may be purified from cells that naturally express them (e.g., an antibody can be purified from a hybridoma that produces it), or produced in recombinant expression systems, using any technique known in the art. See, for example, Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Kennet et al. (eds.), Plenum Press, New York (1980); and Antibodies: A Laboratory Manual, Harlow and Land (eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, (1988). [00251] Any expression system known in the art can be used to make the recombinant polypeptides of the present disclosure. Expression systems are detailed comprehensively above. In general, host cells are transformed with a recombinant expression vector that comprises DNA encoding a desired polypeptide. Among the host cells that may be employed are prokaryotes, yeast or higher eukaryotic cells. Prokaryotes include gram negative or gram positive organisms, for example E. coli or Bacilli. Higher eukaryotic cells include insect cells and established cell lines of mammalian origin. Examples of suitable mammalian host cell lines include the COS-7 line of monkey kidney cells (ATCC CRL 1651) (Gluzman et al., 1981, Cell 23:175), L cells, 293 cells, C127 cells, 3T3 cells (ATCC CCL 163), Chinese hamster ovary (CHO) cells, HeLa cells, BHK (ATCC CRL 10) cell lines, and the CVI/EBNA cell line derived from the African green monkey kidney cell line CVI (ATCC CCL 70) as described by McMahan et al., 1991, EMBO J. 10: 2821. Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts are described by Pouwels et al. (Cloning Vectors: A Laboratory Manual, Elsevier, New York, 1985). [00252] It will be appreciated that an ABP of the present disclosure may have at least one amino acid substitution, providing that the antibody retains binding specificity. Therefore, modifications to the antibody structures are encompassed within the scope of the present disclosure. These may include amino acid substitutions, which may be conservative or non- conservative that do not destroy the PD-L1 and/or TGF-β binding capability of an ABP. Conservative amino acid substitutions may encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics and other reversed or inverted forms of amino acid moieties. A conservative amino acid substitution may also involve a substitution of a native amino acid residue with a normative residue such that there is little or no effect on the polarity or charge of the amino acid residue at that position. [00253] Non-conservative substitutions may involve the exchange of a member of one class of amino acids or amino acid mimetics for a member from another class with different physical properties (e.g. size, polarity, hydrophobicity, charge). Such substituted residues may be introduced into regions of the human antibody that are homologous with non-human antibodies, or into the non-homologous regions of the molecule. [00254] Moreover, one skilled in the art may generate test variants containing a single amino acid substitution at each desired amino acid residue. The variants can then be screened using activity assays known to those skilled in the art. Such variants could be used to gather information about suitable variants. For example, if one discovered that a change to a particular amino acid residue resulted in destroyed, undesirably reduced, or unsuitable activity, variants with such a change may be avoided. In other words, based on information gathered from such routine experiments, one skilled in the art can readily determine the amino acids where further substitutions should be avoided either alone or in combination with other mutations. [00255] A skilled artisan will be able to determine suitable variants of the polypeptide as set forth herein using well-known techniques. In certain embodiments, one skilled in the art may identify suitable areas of the molecule that may be changed without destroying activity by targeting regions not believed to be important for activity. In certain embodiments, one can identify residues and portions of the molecules that are conserved among similar polypeptides. In certain embodiments, even areas that may be important for biological activity or for structure may be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure. [00256] Additionally, one skilled in the art can review structure-function studies identifying residues in similar polypeptides that are important for activity or structure. In view of such a comparison, one can predict the importance of amino acid residues in a protein that correspond to amino acid residues which are important for activity or structure in similar proteins. One skilled in the art may opt for chemically similar amino acid substitutions for such predicted important amino acid residues. [00257] One skilled in the art can also analyze the three-dimensional structure and amino acid sequence in relation to that structure in similar polypeptides. In view of such information, one skilled in the art may predict the alignment of amino acid residues of an antibody with respect to its three dimensional structure. In certain embodiments, one skilled in the art may choose not to make radical changes to amino acid residues predicted to be on the surface of the protein, since such residues may be involved in important interactions with other molecules. [00258] A number of scientific publications have been devoted to the prediction of secondary structure. See Moult J., Curr. Op. in Biotech., 7(4):422-427 (1996), Chou et al., Biochem., 13(2):222-245 (1974); Chou et al., Biochem., 113(2):211-222 (1974); Chou et al., Adv. Enzymol. Relat. Areas Mol. Biol., 47:45-148 (1978); Chou et al., Ann. Rev. Biochem., 47:251-276 and Chou et al., Biophys. J., 26:367-384 (1979). Moreover, computer programs are currently available to assist with predicting secondary structure. One method of predicting secondary structure is based upon homology modeling. For example, two polypeptides or proteins which have a sequence identity of greater than 30%, or similarity greater than 40% often have similar structural topologies. The recent growth of the protein structural database (PDB) has provided enhanced predictability of secondary structure, including the potential number of folds within a polypeptide’s or protein’s structure. See Holm et al., Nucl. Acid. Res., 27(1):244-247 (1999). It has been suggested (Brenner et al., Curr. Op. Struct. Biol., 7(3):369-376 (1997)) that there are a limited number of folds in a given polypeptide or protein and that once a critical number of structures have been resolved, structural prediction will become dramatically more accurate. [00259] Additional methods of predicting secondary structure include “threading” (Jones, D., Curr. Opin. Struct. Biol., 7(3):377-87 (1997); Sippl et al., Structure, 4(1):15-19 (1996)), “profile analysis” (Bowie et al., Science, 253:164-170 (1991); Gribskov et al., Meth. Enzym., 183:146-159 (1990); Gribskov et al., Proc. Nat. Acad. Sci., 84(13):4355-4358 (1987)), and “evolutionary linkage” (See Holm, supra (1999), and Brenner, supra (1997)). [00260] In certain embodiments, variants of antibodies include glycosylation variants wherein the number and/or type of glycosylation site has been altered compared to the amino acid sequences of a parent polypeptide. In certain embodiments, variants comprise a greater or a lesser number of N-linked glycosylation sites than the native protein. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X can be any amino acid residue except proline. The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions which eliminate this sequence will remove an existing N-linked carbohydrate chain. Also provided is a rearrangement of N-linked carbohydrate chains wherein one or more N-linked glycosylation sites (typically those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Additional preferred antibody variants include cysteine variants wherein one or more cysteine residues are deleted from or substituted for another amino acid (e.g., serine) as compared to the parent amino acid sequence. Cysteine variants can be useful when antibodies must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. Cysteine variants generally have fewer cysteine residues than the native protein, and typically have an even number to minimize interactions resulting from unpaired cysteines. [00261] Desired amino acid substitutions (whether conservative or non-conservative) can be determined by those skilled in the art at the time such substitutions are desired. In certain embodiments, amino acid substitutions can be used to identify important residues of antibodies to PD-L1, or to increase or decrease the affinity of the antibodies to PD-L1 described herein. [00262] According to certain embodiments, preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and/or (4) confer or modify other physiochemical or functional properties on such polypeptides. According to certain embodiments, single or multiple amino acid substitutions (in certain embodiments, conservative amino acid substitutions) may be made in the naturally-occurring sequence (in certain embodiments, in the portion of the polypeptide outside the domain(s) forming intermolecular contacts). In certain embodiments, a conservative amino acid substitution typically may not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et al. Nature 354:105 (1991), which are each incorporated herein by reference. [00263] In certain embodiments, ABPs of the present disclosure may be chemically bonded with polymers, lipids, or other moieties. [00264] The binding agents may comprise at least one of the CDRs described herein incorporated into a biocompatible framework structure. In one example, the biocompatible framework structure comprises a polypeptide or portion thereof that is sufficient to form a conformationally stable structural support, or framework, or scaffold, which is able to display one or more sequences of amino acids that bind to an antigen (e.g., CDRs, a variable region, etc.) in a localized surface region. Such structures can be a naturally occurring polypeptide or polypeptide “fold” (a structural motif), or can have one or more modifications, such as additions, deletions or substitutions of amino acids, relative to a naturally occurring polypeptide or fold. These scaffolds can be derived from a polypeptide of any species (or of more than one species), such as a human, other mammal, other vertebrate, invertebrate, plant, bacteria or virus. [00265] Typically the biocompatible framework structures are based on protein scaffolds or skeletons other than immunoglobulin domains. For example, those based on fibronectin, ankyrin, lipocalin, neocarzinostain, cytochrome b, CP1 zinc finger, PST1, coiled coil, LACI-D1, Z domain and tendamistat domains may be used (See e.g., Nygren and Uhlen, 1997, Curr. Opin. in Struct. Biol., 7, 463-469). [00266] Humanized antibodies can be produced using techniques known to those skilled in the art (Zhang, W., et al., Molecular Immunology.42(12):1445-1451, 2005; Hwang W. et al., Methods.36(1):35-42, 2005; Dall’Acqua WF, et al., Methods 36(1):43-60, 2005; and Clark, M., Immunology Today.21(8):397-402, 2000). [00267] Additionally, one skilled in the art will recognize that suitable PD-L1 binding agents include portions of these antibodies, such as one or more of CDR1-L1 to 25 with SEQ ID NOS 1001-1025; CDR2-L1 to 25 with SEQ ID NOS 2001-2025; CDR3-L1 to 25 with SEQ ID NOS 3001-3025; CDR1-H1to 25 with SEQ ID NOS 4001-4025; CDR2-H1to 25 with SEQ ID NOS 5001-5025; and CDR3-H1to 25 with SEQ ID NOS 6001-6025, as specifically disclosed herein. At least one of the CDR regions may have at least one amino acid substitution from the sequences provided here, provided that the antibody retains the binding specificity of the non- substituted CDR. The non-CDR portion of the antibody may be a non-protein molecule, wherein the binding agent cross-blocks the binding of an antibody disclosed herein to PD-L1 and/or neutralizes PD-L1. The non-CDR portion of the antibody may be a non-protein molecule in which the antibody exhibits a similar binding pattern to human PD-L1 peptides in a competition binding assay as that exhibited by at least one of antibodies A1-A25, and/or neutralizes PD-L1. The non-CDR portion of the antibody may be composed of amino acids, wherein the antibody is a recombinant binding protein or a synthetic peptide, and the recombinant binding protein cross- blocks the binding of an antibody disclosed herein to PD-L1 and/or neutralizes PD-L1. The non- CDR portion of the antibody may be composed of amino acids, wherein the antibody is a recombinant antibody, and the recombinant antibody exhibits a similar binding pattern to human PD-L1 peptides in the human PD-L1 peptide epitope competition binding assay (described hereinbelow) as that exhibited by at least one of the antibodies A1-A25, and/or neutralizes PD- L1. [00268] Further, one skilled in the art will recognize that suitable TGF-β binding agents include portions of these antibodies, such as fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. The antibodies can comprise a CDR1-L having the sequence of SEQ ID NO: 9276, 9282, a CDR2-L having the sequence of SEQ ID NO: 9277 or 9283, a CDR3-L having the sequence of SEQ ID NO: 9278 or 9284, a CDR1-H having the sequence of SEQ ID NO: 9279 or 9285, a CDR2-H having the sequence of SEQ ID NO: 9280 or 9286 and a CDR3-H having the sequence of SEQ ID NO: 9281 or 9287. At least one of the CDR regions may have at least one amino acid substitution from the sequences provided here, provided that the antibody retains the binding specificity of the non-substituted CDR. The non- CDR portion of the antibody may be a non-protein molecule, wherein the binding agent cross- blocks the binding of an antibody disclosed herein to TGF-β and/or neutralizes TGF-β. The non- CDR portion of the antibody may be a non-protein molecule in which the antibody exhibits a similar binding pattern to TGF-β peptides in a competition binding assay as that exhibited by fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. The non-CDR portion of the antibody may be composed of amino acids, wherein the antibody is a recombinant binding protein or a synthetic peptide, and the recombinant binding protein cross- blocks the binding of an antibody disclosed herein to TGF-β and/or neutralizes TGF-β. The non- CDR portion of the antibody may be composed of amino acids, wherein the antibody is a recombinant antibody, and the recombinant antibody exhibits a similar binding pattern to TGF-β peptides in the TGF-β epitope competition binding assay (described hereinbelow) as that exhibited by fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11. [00269] Where an ABP comprises one or more of CDR1-H, CDR2-H, CDR3-H, CDR1-L, CDR2-L and CDR3-L as described above, it may be obtained by expression from a host cell containing DNA coding for these sequences. A DNA coding for each CDR sequence may be determined on the basis of the amino acid sequence of the CDR and synthesized together with any desired antibody variable region framework and constant region DNA sequences using oligonucleotide synthesis techniques, site-directed mutagenesis and polymerase chain reaction (PCR) techniques as appropriate. DNA coding for variable region frameworks and constant regions is widely available to those skilled in the art from genetic sequences databases such as GenBank®. [00270] Once synthesized, the DNA encoding an ABP of the present disclosure or fragment thereof may be propagated and expressed according to any of a variety of well-known procedures for nucleic acid excision, ligation, transformation, and transfection using any number of known expression vectors. Thus, in certain embodiments expression of an antibody fragment may be preferred in a prokaryotic host, such as Escherichia coli (see, e.g., Pluckthun et al., 1989 Methods Enzymol.178:497-515). In certain other embodiments, expression of the ABP or a fragment thereof may be preferred in a eukaryotic host cell, including yeast (e.g., Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Pichia pastoris), animal cells (including mammalian cells) or plant cells. Examples of suitable animal cells include, but are not limited to, myeloma (such as a mouse NSO line), COS, CHO, or hybridoma cells. Examples of plant cells include tobacco, corn, soybean, and rice cells. [00271] One or more replicable expression vectors containing DNA encoding an antibody variable and/or constant region may be prepared and used to transform an appropriate cell line, for example, a non-producing myeloma cell line, such as a mouse NSO line or a bacteria, such as E. coli, in which production of the antibody will occur. In order to obtain efficient transcription and translation, the DNA sequence in each vector should include appropriate regulatory sequences, particularly a promoter and leader sequence operatively linked to the variable domain sequence. Particular methods for producing antibodies in this way are generally well-known and routinely used. For example, basic molecular biology procedures are described by Maniatis et al. (Molecular Cloning, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, New York, 1989; see also Maniatis et al, 3rd ed., Cold Spring Harbor Laboratory, New York, (2001)). DNA sequencing can be performed as described in Sanger et al. (PNAS 74:5463, (1977)) and the Amersham International plc sequencing handbook, and site directed mutagenesis can be carried out according to methods known in the art (Kramer et al., Nucleic Acids Res.12:9441, (1984); Kunkel Proc. Natl. Acad. Sci. USA 82:488-92 (1985); Kunkel et al., Methods in Enzymol. 154:367-82 (1987); the Anglian Biotechnology Ltd. handbook). Additionally, numerous publications describe techniques suitable for the preparation of antibodies by manipulation of DNA, creation of expression vectors, and transformation and culture of appropriate cells (Mountain A and Adair, J R in Biotechnology and Genetic Engineering Reviews (ed. Tombs, M P, 10, Chapter 1, 1992, Intercept, Andover, UK); “Current Protocols in Molecular Biology”, 1999, F.M. Ausubel (ed.), Wiley Interscience, New York). [00272] Where it is desired to improve the affinity of antibodies according to the disclosure containing one or more of the above-mentioned CDRs can be obtained by a number of affinity maturation protocols including maintaining the CDRs (Yang et al., J. Mol. Biol., 254, 392-403, 1995), chain shuffling (Marks et al., Bio/Technology, 10, 779-783, 1992), use of mutation strains of E. coli. (Low et al., J. Mol. Biol., 250, 350-368, 1996), DNA shuffling (Patten et al., Curr. Opin. Biotechnol., 8, 724-733, 1997), phage display (Thompson et al., J. Mol. Biol., 256, 7-88, 1996) and sexual PCR (Crameri, et al., Nature, 391, 288-291, 1998). All of these methods of affinity maturation are discussed by Vaughan et al. (Nature Biotech., 16, 535-539, 1998). [00273] It will be understood by one skilled in the art that some proteins, such as antibodies, may undergo a variety of posttranslational modifications. The type and extent of these modifications often depends on the host cell line used to express the protein as well as the culture conditions. Such modifications may include variations in glycosylation, methionine oxidation, diketopiperizine formation, aspartate isomerization and asparagine deamidation. A frequent modification is the loss of a carboxy-terminal basic residue (such as lysine or arginine) due to the action of carboxypeptidases (as described in Harris, R.J. Journal of Chromatography 705:129-134, 1995). 7.7. Sequences PD-L1 binding domains [00274] In some embodiments, anti-PD-L1 and anti-TGF-β ABPs provided herein include PD-L1 binding domains from antibodies A1-A25 or modifications thereof. A1-A25 are anti-PD- L1 antibodies comprising heavy and light chain V(J)D polypeptides (also referred to herein as L1-L25 and H1-H25, respectively). Antibodies A1-A25 comprise the sequences listed in TABLE 5. For example, antibody A1 comprises light chain L1 (SEQ ID NO:1) and heavy chain H1 (SEQ ID NO:101). CDR sequences in the light chain (L1-L25) and heavy chain (H1-H25) are also provided with a specific SEQ ID NOs. For example, three CDR sequences (CDR1, CDR 2 and CDR3) for L1 are CDR1-L1 (SEQ ID NO:1001), CDR2-L1 (SEQ ID NO:2001) and CDR3-L1 (SEQ ID NO:3001), respectively and three CDR sequences (CDR1, CDR 2 and CDR3) for H1 are CDR1-H1 (SEQ ID NO:4001), CDR2-H1 (SEQ ID NO:5001) and CDR3-H1 (SEQ ID NO:6001).

[00275] In some embodiments, anti-PD-L1 and anti-TGF-β ABPs provided herein include PD-L1 binding domains from atezolizumab or avelumab. In some embodiments, the PD-L1 binding domain comprises a light chain sequence of atezolizumab or avelumab. In some embodiments, the PD-L1 binding domain comprises a heavy chain sequence of atezolizumab or avelumab. In some embodiments, the PD-L1 binding domain comprises one or more CDR sequences of atezolizumab or avelumab. TGF-β binding domains [00276] Anti-PD-L1 and anti-TGF-β ABPs provided herein include TGF-β binding domains from anti-TGF-β monoclonal antibody fresolimumab (freso), anti-TGF-β clone 1D11, or a modification thereof. [00277] Fresolimumab comprises a heavy chain having the sequence of SEQ ID NO: 9261 and a light chain having the sequence of SEQ ID NO: 9262. Fresolimumab comprises CDR1-L having the sequence of SEQ ID NO: 9282, CDR2-L having the sequence of SEQ ID NO: 9283, CDR3-L having the sequence of SEQ ID NO: 9284, CDR1-H having the sequence of SEQ ID NO: 9285, CDR2-H having the sequence of SEQ ID NO: 9286, and CDR3-H having the sequence of SEQ ID NO: 9287. [00278] The anti-TGF-β clone 1D11 comprises a heavy chain having the sequence of SEQ ID NO: 9260 and a light chain having the sequence of SEQ ID NO: 9259. The anti-TGF-β clone 1D11 comprises CDR1-L having the sequence of SEQ ID NO: 9276, CDR2-L having the sequence of SEQ ID NO: 9277, CDR3-L having the sequence of SEQ ID NO: 9278, CDR1-H having the sequence of SEQ ID NO: 9279, CDR2-H having the sequence of SEQ ID NO: 9280, and CDR3-H having the sequence of SEQ ID NO: 9281. [00279] In some embodiments, a modification of the anti-TGF-β clone 1D11 is used. The modification can comprise a heavy chain having the sequence selected from SEQ ID NO: 9268- 9271. In some embodiments, the modification comprises a light chain having the sequence selected from SEQ ID NO: 9272-9275. 7.8. Pharmaceutical compositions [00280] Pharmaceutical compositions containing the proteins and polypeptides of the present disclosure are also provided. Such compositions comprise a therapeutically or prophylactically effective amount of the polypeptide or protein in a mixture with pharmaceutically acceptable materials, and physiologically acceptable formulation materials. [00281] The pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. [00282] Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates, other organic acids); bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides and other carbohydrates (such as glucose, mannose, or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring; flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides (preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and/or pharmaceutical adjuvants. Neutral buffered saline or saline mixed with conspecific serum albumin are examples of appropriate diluents. In accordance with appropriate industry standards, preservatives such as benzyl alcohol may also be added. The composition may be formulated as a lyophilizate using appropriate excipient solutions (e.g., sucrose) as diluents. Suitable components are nontoxic to recipients at the dosages and concentrations employed. Further examples of components that may be employed in pharmaceutical formulations are presented in Remington’s Pharmaceutical Sciences, 16^th Ed. (1980) and 20^th Ed. (2000), Mack Publishing Company, Easton, PA. [00283] Optionally, the composition additionally comprises one or more physiologically active agents, for example, an anti-angiogenic substance, a chemotherapeutic substance (such as capecitabine, 5-fluorouracil, or doxorubicin), an analgesic substance, etc., non-exclusive examples of which are provided herein. In various particular embodiments, the composition comprises one, two, three, four, five, or six physiologically active agents in addition to a PD-L1- binding protein. [00284] In another embodiment of the present disclosure, the compositions disclosed herein may be formulated in a neutral or salt form. Illustrative pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. [00285] The carriers can further comprise any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. The phrase “pharmaceutically-acceptable” refers to molecular entities and compositions that do not produce an allergic or similar untoward reaction when administered to a human. [00286] The optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format, and desired dosage. See for example, Remington’s Pharmaceutical Sciences, supra. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the polypeptide. For example, suitable compositions may be water for injection, physiological saline solution for parenteral administration. 7.8.1. Content of pharmaceutically active ingredient [00287] In typical embodiments, the active ingredient (i.e., the proteins and polypeptides of the present disclosure) is present in the pharmaceutical composition at a concentration of at least 0.01mg/ml, at least 0.1mg/ml, at least 0.5mg/ml, or at least 1mg/ml. In certain embodiments, the active ingredient is present in the pharmaceutical composition at a concentration of at least 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, or 25 mg/ml. In certain embodiments, the active ingredient is present in the pharmaceutical composition at a concentration of at least 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml or 50 mg/ml. [00288] In some embodiments, the pharmaceutical composition comprises one or more additional active ingredients in addition to the proteins or polypeptides of the present disclosure. The one or more additional active ingredients can be a drug targeting a different check point receptor, such as PD-1 inhibitor (e.g., anti-PD-1 antibody), TIGIT inhibitor (e.g., anti-TIGIT antibody) or CTLA-4 inhibitor (e.g., anti-CTLA-4 antibody). 7.8.2. Formulation Generally [00289] The pharmaceutical composition can be in any form appropriate for human or veterinary medicine, including a liquid, an oil, an emulsion, a gel, a colloid, an aerosol or a solid. [00290] The pharmaceutical composition can be formulated for administration by any route of administration appropriate for human or veterinary medicine, including enteral and parenteral routes of administration. [00291] In various embodiments, the pharmaceutical composition is formulated for oral administration, for buccal administration, or for sublingual administration. [00292] In some embodiments, the pharmaceutical composition is formulated for intravenous, intramuscular, or subcutaneous administration. [00293] In some embodiments, the pharmaceutical composition is formulated for intrathecal or intracerebroventricular administration. [00294] In some embodiments, the pharmaceutical composition is formulated for topical administration. 7.8.3. Pharmacological compositions adapted for injection [00295] For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives can be included, as required. [00296] In various embodiments, the unit dosage form is a vial, ampule, bottle, or pre- filled syringe. In some embodiments, the unit dosage form contains 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 75 mg, or 100 mg of the pharmaceutical composition. In some embodiments, the unit dosage form contains 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg of the pharmaceutical composition. In some embodiments, the unit dosage form contains 250 mg of the pharmaceutical composition. [00297] In typical embodiments, the pharmaceutical composition in the unit dosage form is in liquid form. In various embodiments, the unit dosage form contains between 0.1 mL and 50 ml of the pharmaceutical composition. In some embodiments, the unit dosage form contains 1 ml, 2.5 ml, 5 ml, 7.5 ml, 10 ml, 25 ml, or 50 ml of pharmaceutical composition. [00298] In particular embodiments, the unit dosage form is a vial containing 1 ml of the pharmaceutical composition at a concentration of 0.01 mg/ml, 0.1 mg/ml, 0.5 mg/ml, or 1mg/ml. In some embodiments, the unit dosage form is a vial containing 2 ml of the pharmaceutical composition at a concentration of 0.01 mg/ml, 0.1 mg/ml, 0.5 mg/ml, or 1mg/ml. [00299] In some embodiments, the pharmaceutical composition in the unit dosage form is in solid form, such as a lyophilate, suitable for solubilization. [00300] Unit dosage form embodiments suitable for subcutaneous, intradermal, or intramuscular administration include preloaded syringes, auto-injectors, and autoinject pens, each containing a predetermined amount of the pharmaceutical composition described hereinabove. [00301] In various embodiments, the unit dosage form is a preloaded syringe, comprising a syringe and a predetermined amount of the pharmaceutical composition. In certain preloaded syringe embodiments, the syringe is adapted for subcutaneous administration. In certain embodiments, the syringe is suitable for self-administration. In particular embodiments, the preloaded syringe is a single use syringe. [00302] In various embodiments, the preloaded syringe contains about 0.1 mL to about 0.5 mL of the pharmaceutical composition. In certain embodiments, the syringe contains about 0.5 mL of the pharmaceutical composition. In specific embodiments, the syringe contains about 1.0 mL of the pharmaceutical composition. In particular embodiments, the syringe contains about 2.0 mL of the pharmaceutical composition. [00303] In certain embodiments, the unit dosage form is an autoinject pen. The autoinject pen comprises an autoinject pen containing a pharmaceutical composition as described herein. In some embodiments, the autoinject pen delivers a predetermined volume of pharmaceutical composition. In other embodiments, the autoinject pen is configured to deliver a volume of pharmaceutical composition set by the user. [00304] In various embodiments, the autoinject pen contains about 0.1 mL to about 5.0 mL of the pharmaceutical composition. In specific embodiments, the autoinject pen contains about 0.5 mL of the pharmaceutical composition. In particular embodiments, the autoinject pen contains about 1.0 mL of the pharmaceutical composition. In other embodiments, the autoinject pen contains about 5.0 mL of the pharmaceutical composition. 7.9. Unit dosage forms [00305] The pharmaceutical compositions may conveniently be presented in unit dosage form. [00306] The unit dosage form will typically be adapted to one or more specific routes of administration of the pharmaceutical composition. [00307] In various embodiments, the unit dosage form is adapted for administration by inhalation. In certain of these embodiments, the unit dosage form is adapted for administration by a vaporizer. In certain of these embodiments, the unit dosage form is adapted for administration by a nebulizer. In certain of these embodiments, the unit dosage form is adapted for administration by an aerosolizer. [00308] In various embodiments, the unit dosage form is adapted for oral administration, for buccal administration, or for sublingual administration. [00309] In some embodiments, the unit dosage form is adapted for intravenous, intramuscular, or subcutaneous administration. [00310] In some embodiments, the unit dosage form is adapted for intrathecal or intracerebroventricular administration. [00311] In some embodiments, the pharmaceutical composition is formulated for topical administration. [00312] The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. 7.10. Methods of use [00313] The ABPs described herein can be used in therapeutic methods. [00314] In vivo and/or in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the condition, and should be decided according to the judgment of the practitioner and each subject's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. [00315] An oligopeptide or polypeptide is within the scope of the present disclosure if it has an amino acid sequence that is at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to least one of the CDRs provided herein. The ABP of the present disclosure can comprise a CDR of a PD-L1 binding agent that cross-blocks the binding of at least one of antibodies A1-A25 to PD-L1, and/or is cross-blocked from binding to PD-L1 by at least one of antibodies A1-A25; and/or to a CDR of a PD-L1 binding agent wherein the binding agent can block the binding of PD-L1 to its ligands. The ABP of the present disclosure can comprise a CDR of a TGF-β binding agent that cross-blocks the binding of at least one of antibodies to TGF-β (e.g., fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11), and/or is cross-blocked from binding to TGF-β by at least one of antibodies to TGF-β (e.g., fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11); and/or to a CDR of a TGF-β binding agent wherein the binding agent can block the binding of TGF-β to its ligands. [00316] PD-L1 binding domains are within the scope of the present disclosure if they have amino acid sequences that are at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a variable region of at least one of antibodies A1-A25, and cross-block the binding of at least one of antibodies A1-A25 to PD-L1, and/or are cross- blocked from binding to PD-L1 by at least one of antibodies A1-A25; and/or can block the inhibitory effect of PD-L1 on its ligands. [00317] TGF-β binding domains are within the scope of the present disclosure if they have amino acid sequences that are at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a variable region of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11, and cross-block the binding of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11 to TGF-β, and/or are cross-blocked from binding to TGF-β by fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11; and/or can block the inhibitory effect of TGF-β on its ligands. [00318] ABPs according to the disclosure may have a binding affinity for human PD-L1 and/or TGF-β of less than or equal to 5 x 10^-7M, less than or equal to 1 x 10^-7M, less than or equal to 0.5 x 10^-7M, less than or equal to 1 x 10^-8M, less than or equal to 1 x 10^-9M, less than or equal to 1 x 10^-10M, less than or equal to 1 x 10^-11M, or less than or equal to 1 x 10^-12 M. [00319] The affinity of an ABP, as well as the extent to which an ABP inhibits binding, can be determined by one of ordinary skill in the art using conventional techniques, for example those described by Scatchard et al. (Ann. N.Y. Acad. Sci.51:660-672 (1949)) or by surface plasmon resonance (SPR; BIAcore, Biosensor, Piscataway, NJ). For surface plasmon resonance, target molecules are immobilized on a solid phase and exposed to ligands in a mobile phase running along a flow cell. If ligand binding to the immobilized target occurs, the local refractive index changes, leading to a change in SPR angle, which can be monitored in real time by detecting changes in the intensity of the reflected light. The rates of change of the SPR signal can be analyzed to yield apparent rate constants for the association and dissociation phases of the binding reaction. The ratio of these values gives the apparent equilibrium constant (affinity) (see, e.g., Wolff et al., Cancer Res.53:2560-65 (1993)). [00320] An ABP according to the present disclosure may belong to any immunoglobin class, for example IgG, IgE, IgM, IgD, or IgA. It may be obtained from or derived from an animal, for example, fowl (e.g., chicken) and mammals, which includes but is not limited to a mouse, rat, hamster, rabbit, or other rodent, cow, horse, sheep, goat, camel, human, or other primate. The antibody may be an internalizing antibody. Production of antibodies is disclosed generally in U.S. Patent Publication No.2004/0146888 A1. [00321] In the methods described above to generate ABPs according to the disclosure, including the manipulation of the specific A1-A25 CDRs or CDRs of fresolimumab or anti-TGF- β clone 1D11 or a humanized version of anti-TGF-β clone 1D11 into new frameworks and/or constant regions, appropriate assays are available to select the desired ABPs (i.e. assays for determining binding affinity to PD-L1 and/or TGF-β; cross-blocking assays; Biacore-based competition binding assay;” in vivo assays). 7.10.1. Methods of treating a disease responsive to a PD-L1 or TGF-β inhibitor or activator [00322] In another aspect, methods are presented for treating a subject having a disease responsive to a PD-L1 and/or a TGF-β inhibitor or activator. The disease can be cancer, autoimmune disease, or viral or bacterial infection. In some embodiments, the disease is AIDS, Alzheimer’s disease. fibrosis, or wound healing. In some embodiments, the disease is idiopathic pulmonary fibrosis(IPF), focal segmental glomerulosclerosis, Diffuse Systemic Sclerosis, Osteogenesis Imperfecta, Myelofibrosis, or Polycythemia Vera. [00323] The terms “treatment,” “treating,” and the like are used herein to generally mean obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic, in terms of completely or partially preventing a disease, condition, or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure for a disease or condition and/or adverse effect, such as a symptom, attributable to the disease or condition. “Treatment” as used herein covers any treatment of a disease or condition of a mammal, particularly a human, and includes: (a) preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it; (b) inhibiting the disease or condition (e.g., arresting its development); or (c) relieving the disease or condition (e.g., causing regression of the disease or condition, providing improvement in one or more symptoms). Improvements in any conditions can be readily assessed according to standard methods and techniques known in the art. The population of subjects treated by the method of the disease includes subjects suffering from the undesirable condition or disease, as well as subjects at risk for development of the condition or disease. [00324] The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of protein aggregation disease being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980. [00325] In some embodiments, the pharmaceutical composition is administered by inhalation, orally, by buccal administration, by sublingual administration, by injection or by topical application. [00326] In some embodiments, the pharmaceutical composition is administered in an amount sufficient to modulate survival of neurons or dopamine release. In some embodiments, the major cannabinoid is administered in an amount less than 1g, less than 500 mg, less than 100 mg, less than 10 mg per dose. [00327] In some embodiments, the pharmaceutical composition is administered once a day, 2-4 times a day, 2-4 times a week, once a week, or once every two weeks. [00328] A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated. For example, the pharmaceutical composition can be administered in combination with one or more drugs targeting a different check point receptor, such as PD-1 inhibitor (e.g., anti-PD-1 antibody), CTLA-4 inhibitor (e.g., anti-CTLA-4 antibody) or TIGIT inhibitor (e.g., anti-TIGIT antibody). 8. EXAMPLES [00329] Below are examples of specific embodiments for carrying out the present disclosure. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present disclosure in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for. [00330] The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3^rd Ed. (Plenum Press) Vols A and B(1992). Furthermore, methods of generating and selecting antibodies explained in Adler et al., A natively paired antibody library yields drug leads with higher sensitivity and specificity than a randomly paired antibody library, MAbs (2018), and Adler et al., Rare, high-affinity mouse anti- PD-L1 antibodies that function in checkpoint blockade, discovered using microfluidics and molecular genomics, MAbs (2017), which are incorporated by reference in its entirety herein, can be employed. 8.1. Example 1:Generation of anti-PD-L1 antigen binding protein Mouse Immunization and Sample Preparation: [00331] First, transgenic mice carrying inserted human immunoglobulin genes were immunized with soluble PD-L1 immunogen of SEQ ID NO: 7001 (i.e., His-tagged PD-L1 protein (R&D Systems)) using TiterMax as an adjuvant. One µg of immunogen was injected into each hock and 3 µg of immunogen was administered intraperitoneally, every third day for 15 days. Titer was assessed by enzyme-linked immunosorbent assay (ELISA) on a 1:2 dilution series of each animal’s serum, starting at a 1:200 dilution. A final intravenous boost of 2.5 µg/hock without adjuvant was given to each animal before harvest. Lymph nodes (popliteal, inguinal, axillary, and mesenteric) were surgically removed after sacrifice. Single cell suspensions for each animal were made by manual disruption followed by passage through a 70 µm filter. Next, the EasySep^TM Mouse Pan-B Cell Isolation Kit (Stemcell Technologies) negative selection kit was used to isolate B cells from each sample. The lymph node B cell populations were quantified by counting on a C-Chip hemocytometer (Incyto) and assessed for viability using Trypan blue. The cells were then diluted to 5,000–6,000 cells/mL in phosphate- buffered saline (PBS) with 12% OptiPrep^TM Density Gradient Medium (Sigma). This cell mixture was used for microfluidic encapsulation. Approximately one million B cells were run from each of the six animals through the emulsion droplet microfluidics platform. Generating paired heavy and light chain libraries: [00332] A DNA library encoding scFv from RNA of single cells, with native heavy-light Ig pairing intact, was generated using the emulsion droplet microfluidics platform or vortex emulsions. The method for generating the DNA library was divided into 1) poly(A) + mRNA capture, 2) multiplexed overlap extension reverse transcriptase polymerase chain reaction (OE- RT-PCR), and 3) nested PCR to remove artifacts and add adapters for deep sequencing or yeast display libraries. The scFv libraries were generated from approximately one million B cells from each animal that achieved a positive ELISA titer. [00333] For poly(A) + mRNA capture, a custom designed co-flow emulsion droplet microfluidic chip fabricated from glass (Dolomite) was used. The microfluidic chip has two input channels for fluorocarbon oil (Dolomite), one input channel for the cell suspension mix described above, and one input channel for oligo-dT beads (NEB) at 1.25 mg/ml in cell lysis buffer (20 mM Tris pH 7.5, 0.5 M NaCl, 1 mM ethylenediaminetetraacetic acid (EDTA), 0.5% Tween-20, and 20 mM dithiothreitol). The input channels were etched to 50 µm by 150 µm for most of the chip’s length, narrow to 55 µm at the droplet junction, and were coated with hydrophobic Pico-Glide (Dolomite). Three Mitos P-Pump pressure pumps (Dolomite) were used to pump the liquids through the chip. Droplet size depends on pressure, but typically droplets of ~45 mm diameter are optimally stable. Emulsions were collected into chilled 2 ml microcentrifuge tubes and incubated at 40 °C for 15 minutes for mRNA capture. The beads were extracted from the droplets using Pico-Break (Dolomite). In some embodiments, similar single cell partitioning emulsions were made using a vortex. [00334] For multiplex OE-RT-PCR, glass Telos droplet emulsion microfluidic chips were used (Dolomite). mRNA-bound beads were re-suspended into OE-RT-PCR mix and injected into the microfluidic chips with a mineral oil-based surfactant mix (available commercially from GigaGen) at pressures that generate 27 µm droplets. The OE-RT-PCR mix contains 2x one-step RT-PCR buffer, 2.0 mM MgSO4, SuperScript III reverse transcriptase, and Platinum Taq (Thermo Fisher Scientific), plus a mixture of primers directed against the IgK C region, the IgG C region, and all V regions (FIG.2). The overlap region was a DNA sequence that encodes a Gly-Ser rich scFv linker sequence. The DNA fragments were recovered from the droplets using a droplet breaking solution (available commercially from GigaGen) and then purified using QIAquick PCR Purification Kit (Qiagen). In some embodiments, similar OE-RT-PCR emulsions were made using a vortex. [00335] For nested PCR (FIG.2), the purified OE-RT-PCR product was first run on a 1.7% agarose gel for 80 minutes at 150 V. A band at 1200–1500 base pair (bp) corresponding to the linked product was excised and purified using NucleoSpin Gel and PCR Clean-up Kit (Macherey Nagel). PCR was then performed to add adapters for Illumina sequencing or yeast display; for sequencing, a randomer of seven nucleotides is added to increase base calling accuracy in subsequent next generation sequencing steps. Nested PCR was performed with 2x NEBNext High-Fidelity amplification mix (NEB) with either Illumina adapter containing primers or primers for cloning into the yeast expression vector. The nested PCR product was run on a 1.2% agarose gel for 50 minutes at 150V. A band at 800–1100 bp was excised and purified using NucleoSpin Gel and PCR Clean-up Kit (Macherey Nagel). [00336] In some embodiments, scFv libraries were not natively paired, for example, randomly paired by amplifying scFv directly from RNA isolated from B cells (FIG.1). 8.2. Example 2: Isolation of PD-L1 binders by yeast display Library Screening: [00337] Human IgG1-Fc (Thermo Fisher Scientific) and PD-L1 (R&D Systems) proteins were biotinylated using the EZ-Link Micro Sulfo-NHS-LC-Biotinylation kit (Thermo Fisher Scientific). The biotinylation reagent was resuspended to 9 mM and added to the protein at a 50- fold molar excess. The reaction was incubated on ice for 2 hours and then the biotinylation reagent was removed using Zeba desalting columns (Thermo Fisher Scientific). The final protein concentration was calculated with a Bradford assay. [00338] Next, the six DNA libraries were expressed as surface scFv in yeast. A yeast surface display vector (pYD) that contains a GAL1/10 promoter, an Aga2 cell wall tether, and a C-terminal c-Myc tag was built. The GAL1/10 promoter induces expression of the scFv protein in medium that contains galactose. The Aga2 cell wall tether was required to shuttle the scFv to the yeast cell surface and tether the scFv to the extracellular space. The c-Myc tag was used during the flow sort to stain for yeast cells that express in-frame scFv protein. Saccharomyces cerevisiae cells (ATCC) were electroporated (Bio-Rad Gene Pulser II; 0.54 kV, 25 uF, resistance set to infinity) with gel-purified nested PCR product and linearized pYD vector for homologous recombination in vivo. Transformed cells were expanded and induced with galactose to generate yeast scFv display libraries. [00339] Two million yeast cells from the expanded scFv libraries were stained with anti-c- Myc (Thermo Fisher Scientific A21281) and an AF488-conjugated secondary antibody (Thermo Fisher Scientific A11039). To select scFv-expressing cells that bind to PD-L1, biotinylated PD- L1 antigen was added to the yeast culture (7 nM final) during primary antibody incubation and then stained with PE-streptavidin (Thermo Fisher Scientific). Yeast cells were flow sorted on a BD Influx (Stanford Shared FACS Facility) for double- positive cells (AF488C/PEC), and recovered clones were then plated on SD-CAA plates with kanamycin, streptomycin, and penicillin (Teknova) for expansion. The expanded first round FACS clones were then subjected to a second round of FACS with the same antigen at the same molarity (7 nM final). Plasmid minipreps (Zymo Research) were prepared from yeast recovered from the final FACS sort. Tailed-end PCR was used to add Illumina adapters to the plasmid libraries for deep sequencing. [00340] In a typical FACS dot plot, the upper right quadrant contains yeast that stain for both antigen binding and scFv expression (identified by a C-terminal c-Myc tag). The lower left quadrant contains yeast that do not stain for either the antigen or scFv expression. The lower right quadrant contains yeast that express the scFv but do not bind the antigen. The frequency of binders in each repertoire was estimated by dividing the count of yeast that double stain for antigen and scFv expression by the count of yeast that express an scFv. Libraries generated from immunized mice yielded low percentages of scFv binders (ranging from 0.08%–1.28%) when sorted at 7 nM final antigen concentration. There was no clear association between serum titer and the frequency of binders in a repertoire. Following expansion of these sorted cells, a second round of FACS at 7 nM final antigen concentration was used to increase the specificity of the screen. The frequency of binders in the second FACS was always substantially higher than the first FACS, ranging from 8.39%–84.4%. Generally, lower frequency of binders in the first sort yielded lower frequency of binders in the second sort. Presumably, this is due to lower gating specificity for samples that have fewer bona fide binders in the original repertoire. Deep repertoire sequencing: [00341] PD-L1-binding clones were recovered as a library (“a library of PD-L1 binding clones”), and subjected to deep repertoire sequencing. Deep repertoire sequencing determines the sequences of all paired variable (V(D)J) regions of both heavy and light chain sequences. The library of PD-L1 binding clones were deposited under ATCC Accession No. PTA-125513 under the Budapest Treaty on November 20, 2018, under ATCC Account No.97361 (American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, VA 20110 USA). Each clone in the library contains an scFv comprising a paired variable (V(D)J) regions of both heavy and light chain sequences originating from a single cell. Deep repertoire sequencing determines the sequences of all paired variable (V(D)J) regions of both heavy and light chain sequences. Some of the heavy and light chain sequences obtained from sequencing the yeast scFv library are provided in SEQ ID NOS: 1-25 and SEQ ID NOS: 101-125. Additional sequences obtained from sequencing the yeast scFv library are provided in SEQ ID NOS 8000-8305. Specifically, their variable light chain (V_L) sequences include SEQ ID NOS: 8000-8152. Their heavy chain (V_H) sequences include SEQ ID NOS: 8153-8305. [00342] Deep antibody sequencing libraries were quantified using a quantitative PCR Illumina Library Quantification Kit (KAPA) and diluted to 17.5 pM. Libraries were sequenced on a MiSeq (Illumina) using a 500 cycle MiSeq Reagent Kit v2, according to the manufacturer’s instructions. To obtain high quality sequence reads with maintained heavy and light chain linkage, sequencing was performed in two separate runs. In the first run (“linked run”), the scFv libraries was directly sequenced to obtain forward read of 340 cycles for the light chain V-gene and CDR3, and reverse read of 162 cycles that cover the heavy chain CDR3 and part of the heavy chain V-gene. In the second run (“unlinked run”), the scFv library was first used as a template for PCR to separately amplify heavy and light chain V-genes. Then, forward reads of 340 cycles and reverse reads of 162 cycles for the heavy and light chain Ig were obtained separately. This produces forward and reverse reads that overlap at the CDR3 and part of the V- gene, which increases confidence in nucleotide calls. [00343] To remove base call errors, the expected number of errors (E) for a read were calculated from its Phred scores. By default, reads with E >1 were discarded, leaving reads for which the most probable number of base call errors is zero. As an additional quality filter, singleton nucleotide reads were discarded because sequences found two or more times have a high probability of being correct. Finally, high-quality, linked antibody sequences were generated by merging filtered sequences from the linked and unlinked runs. Briefly, a series of scripts that first merged forward and reverse reads from the unlinked run was written in Python. Any pairs of forward and reverse sequences that contained mismatches were discarded. Next, the nucleotide sequences from the linked run were used to query merged sequences in the unlinked run. The final output from the scripts is a series of full-length, high-quality variable (V(D)J) sequences, with native heavy and light chain Ig pairing. [00344] To identify reading frame and FR/CDR junctions, a database of well-curated immunoglobulin sequences was first processed to generate position-specific sequence matrices (PSSMs) for each FR/CDR junction. These PSSMs were used to identify FR/CDR junctions for each of the merged nucleotide sequences generated using the processes described above. This identified the protein reading frame for each of the nucleotide sequences. CDR sequences that have a low identify score to the PSSMs are indicated by an exclamation point. Python scripts were then used to translate the sequences. Reads were required to have a valid predicted CDR3 sequence, so, for example, reads with a frame-shift between the V and J segments were discarded. Next, UBLAST was run using the scFv nucleotide sequences as queries and V and J gene sequences from the IMGT database as the reference sequences. The UBLAST alignment with the lowest E-value was used to assign V and J gene families and compute %ID to germline. [00345] Each animal yielded 38–50 unique scFv sequences present at 0.1% frequency or greater after the second FACS selection, including a total of 25 unique scFv candidate binders (SEQ ID Nos: 1-25 for light chains; SEQ ID Nos: 101-125 for heavy chains). The light chain having a sequence of SEQ ID NO: [n] and the heavy chain having a sequence of SEQ ID NO: [100+n] are a cognate pair from a single cell, and forming a single scFv. For example, the light chain of SEQ ID NO:1 and the heavy chain of SEQ ID NO:101 are a cognate pair, the light chain of SEQ ID NO:24 and the heavy chain of SEQ ID NO:124 are a cognate pair, etc. [00346] A25 was derived from a mutagenesis screen of A1. [00347] In this method, the two rounds of FACS resulted in enrichment of the PD-L1- binding scFvs. In addition, many scFv were not detected in the sequencing data from the initial population of B cells from the immunized mice and most of the scFv present in the pre-sort mouse repertoires were eliminated following FACS. Therefore, this work suggests that most of the antibodies present in the repertoires of immunized mice are not strong binders to the immunogen and that this method can enrich for rare nM-affinity binders from the initial population of B cells from immunized mice. 8.3. Example 3: Biological characteristics of PD-L1 antigen binding proteins [00348] scFv sequences that were present at low frequency in pre-sort libraries and became high frequency in post-sort libraries were then synthesized as full-length mAbs in Chinese hamster ovary (CHO) cells. These mAbs comprise the 2–3 most abundant sequences in the second round of FACS for each animal. Target Binding Profiles: [00349] The binding specificity and affinity of each full-length antibody towards PD-L1 were determined using BLI and/or SPR. Anti-human PD-L1 affinities were measured using SPR (except for A25, which was performed using BLI). Anti-cyno PD-L1 and anti-mouse PD-L1 affinities were measured using BLI. [00350] For BLI, antibodies were loaded onto an Anti-Human IgG Fc (AHC) biosensor using the Octet Red96 system (ForteBio). Loaded biosensors were dipped into antigen dilutions beginning at 300 nM, with 6 serial dilutions at 1:3. Kinetic analysis was performed using a 1:1 binding model and global fitting. [00351] For SPR, a moderate density (»1,000 Response Units) of an antihuman IgG-Fc reagent (Southern Biotech 2047-01) was amine-coupled to a Xantec CMD-50M chip (50nm carboxymethyldextran medium density of functional groups) activated with 133 mM EDC (Sigma) and 33.3 mM S-NHS (ThermoFisher) in 100 mM MES pH 5.5. Then, goat anti-Human IgG Fc (Southern Biotech 2047-01) was coupled for 10 minutes at 25 mg/m L in 10 mM Sodim Acetate pH 4.5 (Carterra Inc.). The surface was then deactivated with 1 M ethanolamine pH 8.5 (Carterra Inc.). Running buffer used for the lawn immobilization was HBS-EPC (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% Tween 20, pH 7.4; Teknova). [00352] The sensor chip was then transferred to a continuous flow microspotter (CFM; Carterra Inc.) for array capturing. The mAb supernatants were diluted 50-fold (3–10 mg/mL final concentration) into HBS-EPC with 1 mg/mL BSA. The samples were each captured twice with 15-minute and 4-minute capture steps on the first and second prints, respectively, to create multiple densities, using a 65 mL/min flow rate. The running buffer in the CFM was also HBS- EPC. [00353] Next, the sensor chip was loaded onto an SPR reader (MX- 96 system; Ibis Technologies) for the kinetic analysis. PD-L1 was injected at five increasing concentrations in a four-fold dilution series with concentrations of 1.95, 7.8, 31.25, 125, and 500 nM in running buffer (HBS-EPC with 1.0 mg/mL BSA). PD-L1 injections were 5 minutes with a 15-minute dissociation at 8 mL/second in a non-regenerative kinetic series. An injection of the goat anti- Human IgG Fc capture antibody at 75 mg/mL was injected at the end of the series to verify the capture level of each mAb. Binding data was double referenced by subtracting an interspot surface and a blank injection and analyzed for ka (on-rate), kd (off-rate), and KD (affinity) using the Kinetic Interaction Tool software (Carterra Inc.). [00354] For cell surface binding studies, human PD-L1 expressing Flp-In CHO (Thermo Fisher Scientific) cells were generated and mixed at a 50:50 ratio with cells not expressing hPD- L1. One million cells were stained with 1 µg of the disclosed anti-PD-L1 recombinant antibodies in 200 µl of MACS Buffer (DPBS with 0.5% bovine serum albumin and 2 mM EDTA) for 30 minutes at 4 C. Cells were then co-stained with anti-human irrelevant target-APC and anti- human IgG Fc-PE antibodies for 30 minutes at 4C. An anti-human PD-L1 antibody (Atezolizumab, Genentech) was used as a control for these mixing experiments and cell viability was assessed with DAPI. Flow cytometry analysis was conducted on a BD Influx at the Stanford Shared FACS Facility and data was analyzed using FlowJo. [00355] We identified antibodies that specifically bind to PD-L1. Affinity to PD-L1 (K_D) of each antibody is provided in TABLE 6.

[00356] The affinity of each antibody against PD-L1, as determined using SPR (Carterra), the on rate, off rate, and K_D are shown in TABLE 7. A25 was derived from a mutagenesis screen of A1, and its affinity was determined using BLI (ForteBio).

In vitro cellular assays: [00357] For analysis of the antibodies’ ability to block the PD-1/PD-L1 interaction, the PD-1/PD-L1 Blockade Bioassay (Promega) was used according to the manufacturer’s instructions. On the day prior to the assay, PD-L1 aAPC/CHO-K1 cells were thawed into 90% Ham’s F-12/10% fetal bovine serum (FBS) and plated into the inner 60 wells of two 96-well plates. The cells were incubated overnight at 37 °C, 5% CO₂. On the day of assay, antibodies were diluted in 99% RPMI/1% FBS. The antibody dilutions were added to the wells containing the PD-L1 aAPC/CHO-K1 cells, followed by addition of PD-1 effector cells (thawed into 99% RPMI/1% FBS). The cell/antibody mixtures were incubated at 37 °C, 5% CO₂ for 6 hours, after which Bio- Glo Reagent was added and luminescence was read using a Spectramax i3x plate reader (Molecular Devices). Fold-induction was plotted by calculating the ratio of [signal with antibody]/[signal with no antibody], and the plots were used to calculate the IC50 using SoftMax Pro (Molecular Devices). In-house produced pembrolizumab was used as a positive control, and an antibody binding to an irrelevant antigen was used as a negative control. [00358] Binding of PD-1 to PD-L1 leads to inhibition of T cell signaling. Antibodies that bind PD-L1 and antagonize PD-1/PD-L1 interactions can therefore remove this inhibition, allowing T cells to be activated. PD-1/PD-L1 checkpoint blockade was tested through an in vitro cellular Nuclear Factor of Activated T cells (NFAT) luciferase reporter assay. In this assay, antibodies whose anti-PD-L1 epitopes fall inside the PD-L1 binding domain antagonize PD- 1/PD-L1 interactions, resulting in an increase of the NFAT-luciferase reporter. The full-length mAb candidates that can bind PD-L1 expressed in CHO cells were assayed. To generate an IC50 value for each mAb, measurements were made across several concentrations. It was found that some full-length mAbs are functional in checkpoint blockade in a dose dependent manner as summarized in TABLE 6. The results from the PD-L1 blocking assay are also shown in FIG.3. [00359] The ability of each antibody to block the interaction of PD-L1 and CD80 was evaluated with ELISA. Plates were coated with rhPD-L1-Fc and then blocked with 1x PBS with 2% w/v BSA. After blocking a dilution series of the indicated antibody was added to the plate. Then, to determine how much CD80 was still able to bind plate bound PD-L1, after the plates were washed, rhCD80-His was added to the plate. Unbound CD80-His was washed away and mouse anti-His-HRP was added. TMB was used to determine how much CD80-His bound to the plate bound PD-L1 in the presence of each antibody. The EC50 for blocking CD80 is shown in TABLE 8.

[00360] In vitro cell killing assays are used to test antibodies for efficacy against tumor cells. Fresh tumor samples are first obtained from donors. Single cell suspensions are generated from the tumors using a commercial kit (Miltenyi), and then isolate PD-L1-positive cells are isolated using FACS. Next, using a commercial kit (BioVision), populations of target cells are labeled with carboxyfluorosuccinimide ester (CFSE) and 7-aminoactinomycin D (7-AAD). CFSE labels live cells and 7-AAD labels apoptotic and necrotic cells. A dilution series of anti- PD-L1 antibodies and NK cells are then mixed with the PD-L1-expressing tumor cells. Cell killing, or ADCC, is then quantified using FACS. [00361] Similar assays are performed with tumor cell lines instead of primary tumor cells. Cell killing is also measured directly using label-free measurement devices such as the xCELLigence Sytem from Acea Biosciences. Epitope binning: [00362] Epitope binning was performed using high-throughput Array SPR in a modified classical sandwich approach. A sensor chip was functionalized using the Carterra CFM and methods similar to the SPR affinity studies, except a CMD-200M chip type is used (200nm carboxymethyl dextran, Xantec) and mAbs were coupled at 50 mg/mL to create a surface with higher binding capacity (~3,000 reactive units immobilized). The mAb supernatants were diluted at 1:1 or 1:10 in running buffer, depending on the concentration of the mAb in the supernatant. [00363] The sensor chip was placed in the MX-96 instrument, and the captured mAbs (“ligands”) were crosslinked to the surface using the bivalent amine reactive linker bis(sulfosuccinimidyl) suberate (BS3, ThermoFisher), which was injected for 10 minutes at 0.87 mM in water. Excess activated BS3 was neutralized with 1 M ethanolamine pH 8.5. For each binning cycle, a 7-minute injection of 250 mg/mL human IgG (Jackson ImmunoResearch 009- 000-003) was used to block reference surfaces and any remaining capacity of the target spots. [00364] Next, 250 nM PD-L1 protein were injected onto the sensor chip, followed by injections of the diluted mAb supernatants (“analytes”) or buffer blanks as negative controls. Thus, the analyte mAb only bound to the antigen if it was not competitive with the ligand mAb. At the end of each cycle, a one minute regeneration injection was performed using a solution of 4 parts Pierce IgG Elution Buffer (ThermoFisher #21004), one part 5 M NaCl (0.83 M final), and 1.25 parts 0.85% H3PO4 (0.17% final). [00365] A network community plot algorithm in an SPR epitope data analysis software package (Carterra Inc.) was then used to determine epitope bins. Note that the clustering algorithm groups mAbs for which only analyte data are available separately from the mAbs for which both ligand and analyte data are available. This phenomenon is an artifact of the incomplete competitive matrix. mAbs with both ligand and analyte data had more mAb-mAb measurements, resulting in more mAb-mAb connections, which led to a closer relationship in the community plot. [00366] The epitope binning revealed that most of the antibodies were in the same bin as atezolizumab (FIG.4). 8.4. Example 4: In vitro functional characterization of commercially available anti-PD-L1 plus anti-TGF-β bispecifics [00367] The in vitro binding and functional testing of several model anti-PD-L1 x anti- TGF-β bispecific or bifunctional molecules and their associated monoclonal antibody (mAb) controls were studied. The particular assays presented here include ELISA to assess binding to each antigen, ELISA to assess simultaneous binding to both antigens, ELISA to test blocking of the PD-L1/CD80 interaction, binding to PD-L1 expressed on the surface of mammalian cells by flow cytometry, cell-based functional assays to assess blockade of PD-1/PD-L1 signaling, and cell-based functional assays to confirm sequestration of soluble TGF-β to block cellular TGF-β signaling. [00368] It has been shown that anti-PD-L1 can synergize with anti-TGF-β to limit tumor progression in murine efficacy models. Additionally, the bifunctional molecule M7824, which is the anti-PD-L1 avelumab plus a TGF-β trap (which is the extracellular domain of human TGF-β RII), has been shown to have anti-tumor activity in early clinical trials. [00369] The variable regions of avelumab (FDA-approved anti-PD-L1 with intact Fc receptor binding), atezolizumab (FDA-approved anti-PD-L1 lacking Fc receptor binding), and fresolimumab (an aTGF-β mAb in clinical trials) were cloned into antibody expression vectors containing their respective antibody constant regions. For atezolizumab, the N297A mutation present in the commercial product was included. The proteins were expressed from transiently- transfected CHO cells and purified using protein A chromatography. [00370] The sequences (SEQ ID NO: 9255 for the light chain and SEQ ID NO: 9256 for the heavy chain) of the clinical bifunctional molecule M7824 was obtained from patent WO2018205985A1 describing the molecule, and it was cloned into a general mammalian expression vector and expressed and purified as above. Additionally, a version of M7824 with a N297A mutation was also produced (where N297A prevents binding to Fc receptors, eliminating Fc effector functions including antibody-dependent cell-mediated cytotoxicity). The bispecific molecules (Avel x Freso – SEQ ID NO: 9257 for the light chain and SEQ ID NO: 9258 for the heavy chain) were designed by replacing the TGF β RII domain with the fresolimumab heavy and light chain variable sequence (SEQ ID NO: 9261 for the heavy chain; SEQ ID NO: 9262 for the light chain) as an scFv, and where indicated the avelumab anti-PD-L1 antibody variable domains were replaced with atezolizumab sequence (SEQ ID NO: 9266 for the light chain and SEQ ID NO: 9267 for the heavy chain). [00371] The bispecifics were designed in two different formats (2:2 format or 2:1 format) as illustrated in FIG.8. The 2:2 format includes two binding domains specific to TGF-β whereas the 2:1 format includes only one binding domain specific to TGF-β. Each binding domain illustrated in FIG.8 includes one scFv light chain variable region and one scFv heavy chain variable region. For example, Atezo x Freso comprises a light chain of SEQ ID NO: 9264 and a heavy chain of SEQ ID NO: 9265. The 2:1 format further included a knob/hole Fc mutation which helps enhance heterodimerization. The bispecifics listed in the below table were expressed and tested.

ELISA for testing binding to human PD-L1 [00372] An ELISA was used to test the constructs for binding to human PD-L1. All anti- PD-L1 monoclonals and bispecific antibodies bound human PD-L1 with high affinity. The M7824 bifunctionals (which are based on avelumab) and Avelumab x Fresolimumab bispecific showed reduced binding in this assay relative to monoclonal avelumab, which was previously seen in the preclinical work for M7824 (Lan et al., 2018). Fresolimumab, which binds TGF-β and provides this functional moiety in the bispecific molecules, shows no off-target binding. ELISA for testing binding to human TGF-β [00373] An ELISA was used to test the constructs for binding to human TGF-β. The monoclonal fresolimumab and the bispecifics containing the fresolimumab scFv all bind strongly to human TGF-β isoforms 1, 2, and 3 as expected. M7824 and the N297A derivative show reduced binding to human TGF-β isoform 2 when surface-adsorbed, as seen previously (Lan et al., 2018). ELISA for testing binding to mouse TGF- β [00374] An ELISA was used to test the constructs for binding to mouse TGF-β. The monoclonal fresolimumab, and the bispecifics containing the fresolimumab scFv all bind to mouse TGF-β isoforms 1 and 2. M7824 and the N297A derivative show some binding to mouse TGF-β isoform 1, though no binding to isoform 2 was observed (consistent with the weaker binding of these molecules to human TGF-β 2). [00375] A summary of the results is presented in the Table below.

ELISA for testing concurrent binding to human PD-L1 and TGF-β isoform 1 [00376] The ability of bi-specific constructs to bind both TGF-β1 and PD-L1 was assessed by enzyme-linked immunosorbent assay (ELISA). A concurrent binding ELISA (FIG.9) was developed to examine if the test article simultaneously binds to both TGF-β1 protein and mouse PD-L1 protein. Mouse PD-L1 protein was used to demonstrate utility in a mouse model. Binding to human PD-L1 is demonstrated elsewhere. [00377] A plate was coated overnight at 4°C with human TGF-β1 (Peprotech #100-21), washed, blocked with 5% dry milk in PBST for 1 hour at room temperature, and washed. Test articles were diluted from 50 nM into blocking buffer in 5-fold steps and were added to the plate and incubated shaking for 1 hour at room temperature. The plate is washed and mouse PD-L1- His (R&D systems #9048-B7-100) was diluted into blocking buffer at 0.5 ug/mL and added to the plate, incubated shaking for 1 hour at room temperature. The plate is washed and secondary anti-His HRP antibody (Biolegend #652504) is diluted to 0.25 ug/ml in blocking buffer and added to the plate, incubated shaking for 1 hour at room temperature. The plate is washed and TMB solution (Thermo #34028) is added to the plate, after 2 minutes, 1N HCl is added to stop the reaction. The plate is read on a Spectramax plate reader and 450 nm absorbance values are recorded. [00378] The concurrent binding ELISA results provided in FIG.10 demonstrate the ability of bi-specific constructs to bind both TGF-β1 and mPD-L1, and a lack of signal from Atezolizumab or Fresolimumab monoclonal antibodies demonstrates specificity of the assay. [00379] The monospecific antibodies avelumab and fresolimumab did not show any signal in this experiment, while all bispecifics and bifunctionals showed a very similar dose- response when co-bound to TGF-β isoforms 1 and human PD-L1. ELISA for testing blocking the PD-L1/CD80 interaction [00380] An ELISA to test blocking of the PD-L1/CD80 interaction was performed. [00381] ELISA plates were coated with PD-L1, then the indicated monoclonal or bispecific antibodies were added. The clinical anti-PD-L1 monoclonal antibody atezolimumab (atezo) was used as a positive control, and the anti-TGF-β monoclonal antibody fresolimumab (freso), which does not bind PD-L1, was used as a negative control. Bispecific molecules consist of atezo linked to the scFv form of the anti-TGF-β antibodies freso or 1D11. The scFvs are fused to either one (2:1) or both (2:2) IgG heavy chains of atezo. After incubation to allow antibody binding, CD80 with a 6x Histidine tag was then added. Bound CD80 was detected with an HRP- linked anti-His antibody. Antibodies that block the interaction between PD-L1 and CD80 lead to decreased signal at higher concentrations. [00382] As provided in FIG.11, fresolimumab was not able to block binding of CD80 to human PD-L1; however, atezolizumab and all bispecific and bifunctional molecules showed a similar inhibition of binding. FACS for testing binding of ABPs to PD-L1 on the mammalian cell membrane [00383] PD-L1 cell line staining was performed and analyzed by FACS. An equal mixture of CHO cells stably expressing either PD-L1 or the irrelevant antigen CTLA-4 were incubated with the indicated monoclonal or bispecific antibodies. The clinical anti-PD-L1 monoclonal antibody atezolimumab (atezo) was used as a positive control, and the anti-TGF-β monoclonal antibody fresolimumab (freso), which does not bind PD-L1, was used as a negative control. Bispecific molecules consist of atezo linked to the scFv form of the anti-TGF-β antibodies freso or 1D11. The scFvs are fused to either one (2:1) or both (2:2) IgG heavy chains of atezo. After incubation to allow antibody binding to the surface antigen, bound antibody (Binding+) was detected with a PE-conjugated anti-human IgG1 secondary antibody. Off-target cells (CTLA-4+) were detected by staining with an APC-conjugated anti-CTLA-4 secondary antibody. [00384] The results are provided in FIG.12. The bispecifics, bifunctionals, and monospecific anti-PD-L1 all showed strong binding to the PD-L1 expressing cell lines, with no staining of the negative control CTLA-4-expressing cell line. As expected, fresolimumab showed no binding to either cell line. PD-1/PD-L1 signaling blockade [00385] PD-1/PD-L1 signaling blockade was assayed. A PD-1/PD-L1 blockade assay (Promega) was used to test the ability of bi-specific antibody constructs to block the PD-1 and PD-L1 signaling pathway. The blockade assay (Promega J1250) was performed according to manufacturer specifications, and luminescence was read with a SepctraMax i3x plate reader. A full detailed protocol can be found in paragraph [00311] of WO 2020/140090 A9. [00386] As provided in FIG.14, the bispecifics, bifunctionals, and monospecific anti-PD- L1 all showed a strong dose-dependent inhibition of PD-1/PD-L1 signaling, as evidenced by a large increase in luminescence at high antibody concentrations. All example bi-specific constructs showed blocking ability comparable to a positive control monoclonal antibody ‘Atezo’. As expected, fresolimumab had no impact on PD-1/PD-L1 signaling. TGF-β signaling blockade [00387] Soluble TGF-β sequestration was assayed. TGF-β-receptor-expressing cells containing an SBE (SMAD binding element) reporter were plated and incubated overnight. The next day, cells were incubated with the indicated antibody. The clinical anti-PD-L1 monoclonal antibody atezolimumab (atezo) was used as a negative control, and the anti-TGF-β monoclonal antibody fresolimumab (freso) and anti-TGF-β clone 1D11 were also tested. Bispecific molecules consist of atezo linked to the scFv form of the anti-TGF-β antibodies freso or 1D11. The scFvs are fused to either one (2:1) or both (2:2) IgG heavy chains of atezo. After a 4 hour incubation, recombinant murine TGF-β1, TGF-β2, or human TGF-β3 were added at a final concentration of 20ng/mL. After a 16 hour incubation, one-step luciferase reagent was added to each well with relative luminescence units (RLU) measured on a plate reader. High RLU values are the result of TGF-β signaling through the receptor, while low values suggest soluble TGF-β is sequestered by the antibody and thus unable to bind the receptor. [00388] As provided in FIG.13, atezolizumab showed no sequestration of soluble human TGF-β isoform 1, 2 or 3, resulting in full luciferase signal. Fresolimumab showed a moderate dose-response curve, as opposed to the bispecific and bifunctional molecules, which showed a very sharp profile. As expected, based on prior binding tests, the bifunctional molecules M7824 and M7824 (N297A) were not able to sequester human TGF-β2 as well as the bispecific molecules. [00389] The results demonstrate that the anti-PD-L1 x anti-TGF-β bispecific molecules are stable and have expected in vitro function. 8.5. Example 5: In vivo testing of atezolizumab (anti-PD-L1 ABP) with or without anti-TGF-β antibody in hPD-L1 knock-in mice bearing MC38 tumors [00390] An in vivo efficacy study was performed testing atezolizumab (anti-PD-L1) with or without anti-TGF-β ABP in hPD-L1 knock-in (KI) mice bearing MC38 tumors expressing hPD-L1. The anti-TGF-β ABP used was an anti-mouse TGF-β monoclonal antibody clone 1D11 from BioCell (Clone 1D11.16.8, BioCell catalog # BE0057). Another anti-PD-L1 ABP (i.e., aPD-L1.3 (PN-1439, also described as clone 1 or A1 herein)) was also tested. [00391] Mice used were hPD-L1 knock-in (KI) mice in the C57BL/6 background, and naïve Wild-type C57BL/6 for naïve control animals for re-challenge. The study design is provided in the Table below.

[00392] Tumors were collected from the mice and processed for formalin-fixed paraffin- embedded (FFPE). Percent body weight change was determined. End point immunohistochemistry (IHC) analysis was performed to look for the level of immune cell infiltration (CD3-stained cells) upon treatment with the following groups: Group 1 (PBS): PBS control, BIW x3 weeks dosing; Group 4 (aPD-L1): Atezolizumab (2 mg/kg), BIW x3 weeks dosing Group 11 (aPD-L1 + aTGF-β): Atezolizumab (2 mg/kg) + aTGF-β (1D11; 10 mg/kg), BIW x3 weeks dosing [00393] Both doses and dosing regimens of atezolizumab led to similar tumor growth inhibition. BIW (two times a week) x3 weeks dosing, but not day 0, 3, and 6, combination treatment with atezolizumab in combination with anti-TGF-β ABP improved tumor control compared to atezolizumab alone and led to complete responses in 50% (3/6) of animals. Furthermore, tumor re-challenge of the complete response (CR) animals showed that all CRs induced by atezolizumab or atezolizumab + aTGF-β led to productive memory responses leading to durable responses. End-point tumor immunohistochemistry revealed that combination therapy with atezolizumab together with anti-TGF-β enhanced immune cell infiltration into the tumor over atezolizumab alone. aPD-L1.3 was not found to be efficacious in this model. 8.6. Example 6: In vivo testing of multiple anti-PD-L1 mAbs in combination with anti-TGF-β in hPD-L1 knock-in mice bearing MC38 tumors [00394] The anti-tumor activity of multiple PD-L1 mAbs described herein were evaluated in hPD-L1 knock-in mice bearing MC38 tumors expressing hPD-L1. The anti-PD-L1 antibodies (and commercially available aPD-L1 atezolizumab as a control) were cloned onto a mouse IgG2a backbone (SEQ ID NO: 9263) to limit the development of anti-drug antibodies (ADAs), and LALA-PG mutations were introduced to eliminate Fc effector function. This way anti-PD- L1 induced checkpoint activity could be tested in the absence of antibody mediated depletion of PD-L1⁺ cells. Also investigated was the ability of each of the anti-PD-L1 mAbs to synergize with anti-TGF-β clone 1D11 in limiting tumor growth of MC38 tumors expressing anti-PD-L1 in hPD-L1 KI mice. Also investigated was whether or not atezolizumab and/or anti-TGF-β needs to be administered past day 6 in order for atezolizumab + anti-TGF-β to induce a synergistic anti- tumor response. [00395] In addition to atezolizumab, the following anti-PD-L1 antibodies were assayed: aPD-L1.5 (also referred to as clone 5 or A5 herein); aPD-L1.30 (also referred to as clone 7 or A7 herein); and aPD-L1.3.6 (also referred to as clone 25 or A25 herein). The mice used were hPD- L1 KI (knock in) in the C57BL/6. The study design is provided in the Table below.

[00396] The results are shown in FIGs.5A-5F and show that atezolizumab on a mouse IgG2a-LALA-PG Fc backbone (with L234A, L235A, and P329G mutations) was able to induce TGI (tumor growth inhibition) similarly to commercial atezolizumab. aPD-L1.5 and aPD-L1.30 on a mouse IgG2a-LALA-PG backbone induced TGI to a similar level as atezolizumab, while aPD-L1.3.6 was less effective. Combination therapy of anti-TGF-β plus atezolizumab, atezolizumab-mIgG2a-LALA-PG, or aPD-L1.5-mIgG2a-LALA-PG had enhanced TGI over monotherapy alone. These anti-PD-L1 ABPs were able to synergize with anti-TGF-β to limit tumor progression. [00397] Combination therapy of anti-TGF- β plus aPD-L1.30-mIgG2a-LALA-PG or PD- L1.3.6-mIgG2a-LALA-PG did not enhance TGI compared to monotherapy alone. [00398] Continued dosing of anti-TGF- β beyond day 6 was required for synergy from atezolizumab + anti-TGF- β. The enhancement in TGI when atezolizumab was dosed on days 0, 3, and 6 with anti-TGF- β dosed BIW x3 weeks over both mAbs dosed BIW x3 weeks could be due to anti-PD-L1 being administered earlier (3 doses in the first week versus 2 doses). 8.7. Example 7: In vitro functional characterization of anti-PD-L1-LALA-PG mAbs [00399] A number of in vitro functional validations were performed on a number of PD- L1 monoclonal antibodies (mAbs) with LALA-PG mutations introduced into the Fc backbone to eliminate Fc effector function. One of the major mechanisms of action of PD-L1 antibodies is the blockade of PD-L1 binding to PD-1. However, PD-L1 antibodies with intact Fc effector function can also mediate depletion of PD-L1+ cells. Some companies have elected to develop anti-PD- L1 molecules with intact effector function as this can lead to depletion of PD-L1+ tumor cells. As immune cells, including dendritic cells and activated T cells, can also express PD-L1. The anti-PD-L1 antibodies with effector function can unintentionally limit long-lasting anti-tumor immune responses. In these experiments, Fc mutations were identified that maintain the blocking activity of anti-PD-L1 antibodies but lack Fc effector functions.

[00400] Anti-PD-L1 antibodies can induce ADA-induced hypersensitivity in mice. Switching anti-PD-L1 antibodies to a mouse Fc backbone can limit the development of ADA, thus allowing anti-PD-L1s to be administered longer in murine models. [00401] The PD-L1 Fc mutations were introduced into multiple antibodies on two backbones, and the ability of each mAb to bind PD-L1 expressed on the surface of mammalian cells and to block PD-1/PD-L1 signaling using a cell-based assay was assessed. The two backbones were as follows: [00402] Mouse IgG2a: to limit the development of anti-drug antibodies (ADA) for in vivo mouse studies [00403] Human IgG1: the starting backbone that could be used for a final therapeutic molecule. [00404] In addition to atezolizumab, the following anti-PD-L1 were used: aPD-L1.1 (also described as clone 2 or A2 herein); aPD-L1.5 (also described as clone 5 or A5 herein); aPD- L1.15 (also described as clone 3 or A3 herein); aPD-L1.3.6 (also described as clone 25 or A25 herein). [00405] Results. Each anti-PD-L1 mAb was assessed for its ability to bind full-length PD- L1 expressed on the surface of mammalian cells. All the mAbs tested bound CHO cells expressing PD-L1, and no off-target binding to the parental cells was detected (data not shown). [00406] The PD-1/PD-L1 Blockade Bioassay kit (Promega) was used to assess the mAbs ability to affect cellular PD-1/PD-L1 signaling. When PD-L1 is bound to PD-1 on the surface of the other cells, there is no expression of luciferase, and mAb binding to PD-L1 disrupts the interaction with PD-1, leading to luciferase expression. The PD-1 blocking assay results are shown in the Table below.

105

[00407] Anti-PD-L1s on a mouse IgG2a-LALA-PG Fc backbone retained binding to cell surface expressed PD-L1 and potent blocking of the PD-1/PD-L1 interaction by a cell-based assay. Most anti-PD-L1s on the wild-type human IgG1, human IgG1-LALA-PG, and mouse IgG2a-LALA-PG backbone had very similar abilities to block the PD-1/PD-L1 interaction. These data supported the testing of the anti-tumor activity of these mAbs in vivo as described herein. 8.8. Example 8: In vivo testing of the combination of anti-PD-L1 and anti-TGF-β in a mouse model bearing EMT6 tumors [00408] An in vivo anti-tumor efficacy study was performed testing atezolizumab (aPD- L1) ± aTGF-β (clone 1D11) in mice bearing EMT6 tumors orthotopically implanted in the mammary fat pad (MFP). [00409] Animals were injected orthotopically in the 4th right mammary fat pad of BALB/C mice with 250,000 EMT6 cells suspended in 0.1 mL 1x PBS. When tumors reached an average tumor volume of 176.56 mm³ with a range of 15 – 400 mm³, animals were matched by tumor volume into blinded groups used for dosing, and dosing was initiated on Day 0. Mice were observed for 28 days post initiation of dosing, with individual animals being removed from the study as their tumor volumes measured >2000 mm³. [00410] The study design is provided in the Table below.

* Control and atezo: The first dose was 10 mg/kg via IV, followed by 5 mg/kg via IP for 8 doses. ** aTGF-β (clone 1D11, BioXcell): The first dose was 10 mg/kg via IV, followed by 10 mg/kg via IP for 8 doses. *** Atezo and aTGF-β (clone 1D11) were combined into a single dosing cocktail for administration. For the first dose 10 mg/kg atezo and 10 mg/kg aTGF-β (clone 1D11) were combined and administered IV. For subsequent doses 5 mg/kg atezo and 10 mg/kg aTGF-β (clone 1D11) were combined and administered IP. [00411] The results are shown in FIG.6A and FIG.6B and demonstrated that Atezolizumab + aTGF-β (clone 1D11) limited tumor progression more effectively compared to control. 8.9. Example 9: In vivo testing of the combination of anti-PD-L1 and anti-TGF-β in CT26 tumor model mice [00412] An in vivo efficacy study was performed testing interperitoneally (i.p.) administered anti-PD-L1 (atezolizumab) with anti-TGF-β in order to evaluate the anti-tumor activity of anti-PD-L1 ± anti-TGF-β in the CT26 syngeneic tumor model. [00413] Mice (55 BALB/c) were injected subcutaneously with 0.1 mL containing 5x10⁵ CT26 cells suspended in 1x PBS into the left flank. Mice were randomized into 4 groups based on day 9 measurements. The tumor volume mean (TVM) was 41.64 mm³ with a range of 27.68- 64.28 mm³. Dosing of anti-CTLA-4 began on day 9. Dosing of anti-PD-L1 (clone 10F.9G2), Atezo and anti-TGF-β combination therapy, and PBS began on day 11 when the mean tumor volume was 70.63 mm³ with a range of 28.83-162.5mm³. Tumor volumes were measured three times weekly and a final tumor volume was measured on the day study reached endpoint. Individuals animals were removed from the study as their tumor volumes measured >2000 mm³. Last day of dosing for BIWx3 weeks treatment groups was day 29. Measurements and observations continued until day 33. [00414] As shown herein, an anti-PD-L1 (atezolizumab) + anti-TGF-β treatment enhances immune infiltration and leads to tumor growth inhibition. This was repeated here in another tumor model. An antibody to mouse PD-L1 (clone 10F.9G2; BioCell Catalog # BE0101) was used as positive control since others have shown tumor growth inhibition with this clone in the CT26 tumor model. [00415] The study design is provided in the Table below.

[00416] The results are provided in FIG.7A and FIG.7B and show that intraperitoneal administration of atezolizumab and anti-TGF-β in combination is more effective than PBS alone in controlling the growth of CT26 tumors (p = 0.026, Wilcoxon rank-sum test). Two animals in the combination treatment group were complete responders (where the tumor measurements regressed to 0 mm³). 8.10. Example 10: Generation of anti-TGF-β antigen binding protein [00417] The 1D11 antibody sequence (SEQ ID NO: 9259 for the light chain and SEQ ID NO: 9260 for the heavy chain) was humanized using CDR grafting plus back mutation without sacrificing binding affinity of the original antibody. The structure of the original antibody was modelled by a computer-aided homology modelling program. Humanized antibodies were designed using CDR grafting. Briefly, the CDRs of the original antibody were grafted into the human acceptors to obtain humanized light chains and humanized heavy chains for each parental antibody.4 heavy chains (VH1 (SEQ ID NO: 9268), VH2 (SEQ ID NO: 9269), VH3 (SEQ ID NO: 9270), and VH4 (SEQ ID NO: 9271)) and 4 light chains (VL1 (SEQ ID NO: 9272), VL2 (SEQ ID NO: 9273), VL3 (SEQ ID NO: 9274), and VL4 (SEQ ID NO: 9275)) were paired with each other as provided in the below table for affinity measurement.

[00418] Plasmids containing the designed antibodies were transfected and expressed in 25 mL of EXPI293F cell culture. Recombinant IgGs secreted into the medium were purified using protein A affinity chromatography and buffer-exchanged into PBS using a PD-10 desalting column. Antibody concentration after measured by OD280 and purified yield was based on the volume and concentration. [00419] The affinity of purified antibody binding TGF-β1 was measured by Surface Plasmon Resonance (SPR) using a BiacoreT200 instrument (GE Healthcare). Human TGF-β1 was immobilized on the sensor chip. Antibody was used as analyte. Data was analyzed by BiacoreT200 evaluation software to obtain dissociation (kd) and association (ka) constants. Equilibrium dissociation constants (KD) were calculated from the ratio of kd over ka. Blocking data is from a TGF-β activity assay (BPS BioSciences) with examples shown in FIG.15. [00420] A blockade assay (BPS Biosciences) was used to test the ability of humanized 1D11 antibodies to block the TGF-β1 / TGF-βR signaling pathway. For the blockade assay (BPS Bioscience # 60653), TGF-β/SMAD SBE reporter HEK293 cells were thawed and plated into a 96-well microplate overnight. On day 2, antibodies were serially diluted 1/3 starting from a concentration of 50 ug/ml and added to the plate containing reporter cells. Four hours after addition of the antibody, TGF-β1 protein (Peprotech #100-21) was added at 40 ng/ml and the plate containing cells was incubated overnight. On day 3, ONE-Step luciferase assay reagent (BPS bioscience #60690-1) was added, incubated and mixed for 15 minutes, and luminescence was read on a Spectramax i3x plate reader (Molecular Devices). Full TGF-βR blocking data is shown in FIG.15. [00421] Twelve out of the sixteen humanized 1D11 sequences show promise as candidate anti-TGF-β antibodies. These twelve antibodies express well in a mammalian expression system, bind the target protein with high affinity, and block the signaling activity of TGF-β1 with TGF- βR. 8.11. Example 11: In vivo testing of anti-PD-L1 plus anti-TGF-β bispecifics in mice bearing CT26 tumors [00422] The in vivo stability of anti-PD-L1 x anti-TGF-β bispecific antibodies were tested in BALB/c mice bearing subcutaneous CT26. The study was performed with five BALB/C mice per treatment arm. On day 0, tumor-bearing mice were administered commercial atezolizumab (2mg/kg), atezolizumab x fresolimumab 2:2 (3mg/kg), atezolizumab x fresolimumab 2:1 (3mg/kg), atezolizumab x 1D112:2 (3mg/kg), or vehicle solution (PBS) by intraperitoneal injection. Mice were then bled 24 hours post dosing on Day 1 and bled again 72 hours post dosing on Day 3. Serum titers from each time point were measured using both anti-human IgG (to determine total human Fc in circulation) and PD-L1/TGF-β-1 co-binding (to determine the amount of bi-functional bi-specific antibody in circulation) ELISAs. Anti-human IgG ELISA [00423] ELISA plates were coated with Goat Anti-Human IgG, Mouse adsorbed antibody (SouthernBiotech 2044-01) at 2 ug/mL and incubated overnight at 4°C. The plates were then blocked with Ultrablock (Bio-rad BUF033B) for 1 hour on a plate shaker at room temperature. A titration series of mice serum samples were added to the plate with a starting 1/100 dilution. In addition, bsmAb standards, starting at 10 ug/mL were also added. BsmAb standards were spiked in with mouse sera to match that of the final sera concentration in the serum samples. After addition of samples and controls the plates were incubated on a plate shaker 1 hour at room temperature to allow antibody binding. Excess, unbound antibodies were removed by washing with PBST. After washing, a secondary antibody, Goat Anti-Human IgG, Mouse adsorbed Biotin conjugated antibody (SouthernBiotech 2044-08), was then added to the plates at 0.2 μg/mL. After incubation on a plate shaker for 1 hour at room temperature, the plates were washed to remove the unbound secondary antibody. Bound secondary antibodies were then detected with Streptavidin conjugated to HRP (Pierce 21330). After incubation on a plate shaker for 1 hour at room temperature and washing, the plates were developed with TMB substrate. After sufficient signal was achieved, development was stopped by the addition of 1 N hydrochloric acid. Absorbance at 450 nm was read using a Spectramax i3x plate reader (Molecular Devices). The concentration of human IgG antibodies in sera was then calculated by interpolating the absorbance value of the serum samples onto the corresponding standard curves. Graphs depict mean +/- SD. The results are summarized in the below table and FIG.16.

numbers were not included in the final average calculations. **% retention, D1 to D3: (D3 concentration (nM) ÷ D1 concentration (nM))*100 PD-L1 and TGF-β1 Co-binding ELISA [00424] ELISA plates were coated with human TGF-β1 (Peprotech 100-21-10) at 1 ug/mL and incubated overnight at 4°C. The plates were then blocked with Ultrablock (Bio-rad BUF033B) for 1 hour on a plate shaker at room temperature. A titration series of murine serum samples were added to the plate with a starting 1/5 dilution. In addition, bsMab standards starting at 100 ug/mL were also added. BsmAb standards were spiked in with mouse sera to match that of the final sera concentration in the serum samples. To allow antibody binding, the plates were incubated on a plate shaker 1 hour at room temperature. Then, excess, unbound antibodies were removed by washing with PBST. After washing, a His-conjugated human PD-L1 (R&D Systems 9049-B7-100) was added to the plates at 0.5 μg/mL. After incubation on a plate shaker for 1 hour at room temperature, the plates were washed to remove the unbound human PD-L1. Bound PD- L1 were then detected with Mouse HRP-conjugated Anti-His antibody (BioLegend 652504). After incubation on a plate shaker for 1 hour at room temperature and washing, the plates were developed with TMB substrate. After sufficient signal was achieved, development was stopped by the addition of 1 N hydrochloric acid. Absorbance at 450 nm was read using a Spectramax i3x plate reader (Molecular Devices). The concentration of bispecific antibody in sera was then calculated by interpolating the absorbance value of the serum samples onto the corresponding standard curves. Note for the Atezolizumab x 1D112:2 treatment arm only sera for a single mouse was tested in the PD-L1/TGF-β1 co-binding ELISA and as that sera appeared not to have any signal reflecting co-binding to PD-L1 and TGF-β1 this bi-specific was assumed to have little stability in vivo and the additional murine sera samples from this arm were not run in the PD- L1/TGF-β 1 co-binding ELISA. Graphs depict mean +/- SD. [00425] The results are summarized in the below table and FIG.17. The data suggest that Atezolizumab x Fresolimumab bi-specifics are stable in vivo and retain the ability to concurrently bind to PD-L1 and TGF-β. On the other hand, the Atezo x 1D112:2 bi-specific has a reduced half-life in vivo and is less stable in vivo.

In vivo anti-tumor efficacy [00426] Balb/c mice bearing CT26 tumors were randomized into groups and then were treated with the indicated monoclonal (Atezolizumab, Fresolimumab, Atezolizumab and Fresolimumab, or Atezolizumab and 1D11) or bi-specific (Atezo x Freso 2:2) antibodies or PBS control i.p. Atezo (atezolizumab) was given at 2 mg/kg, Freso (fresolimumab) was given at 2 or 10 mg/kg as indicated, and 1D11 was given at 10 mg/ml. Graphs show mean tumor volume +/- SEM from day of randomization and initiation of dosing through day 42. mAb + mAb (Atezo + Freso or Atezo + 1D11) indicates that both monoclonal antibodies were dosed in combination. Atezo x Freso indicates that the Atezo x Freso 2:2 bi-specific was dosed at 3 mg/kg. Following randomization monoclonal antibodies and PBS were dosed biweekly for 3 weeks. As bi-specific antibodies often have a shorter half-life than monoclonal antibodies the bi-specific antibody was dosed every other day for 10 doses. Tumor volume shown is mean tumor volume +/- SEM in each group with 6-12 mice per a group.1 mouse in the Freso 10 mg/kg group was excluded after randomization due to an inflamed abdomen. Data from any mice found dead was not carried forward (1 mouse from the Atezo + 10 mg/kg Freso group and 1 mouse from the 10 mg/kg Freso group). Data from any mice euthanized due to tumor burden was carried forward until no mice remained in that group. The mean tumor volume of tumors randomized onto study was 41.3 mm³ at the time of randomization with a range of 24.3 to 64.8 mm³. Both graphs show the same data for PBS, Freso 2mg/kg, and Atezo groups, shown twice for simplicity of viewing the data. The results are provided in FIG.18A-18B. [00427] In the second set of experiments (FIG.18C-D) Balb/c mice bearing CT26 tumors were randomized into groups and then were treated with the indicated monoclonal (Atezolizumab, Fresolimumab, 1D11, or Atezolizumab plus 1D11) or bi-specific antibodies (Atezo x Freso 2:2 or Atezo x 1D112:2) or PBS control i.p. The monoclonal antibodies Atezo (atezolizumab), Freso (fresolimumab), and 1D11 were given at 2 mg/kg. Atezo + 1D11 indicates that the mice received the monoclonal antibodies atezo (2 mg/kg) plus anti-TGF β clone 1D11 (10mg/kg). Graphs show mean tumor volume or body weights (+/- SEM) starting the day of randomization and initiation of dosing. Atezo x Freso and Atezo x 1D11 indicate that the bi-specific was dosed at 3 mg/kg. Following randomization monoclonal antibodies and PBS were dosed biweekly for 5 doses. As bi-specific antibodies often have a shorter half life than monoclonal antibodies the bi-specific antibody was dosed every other day for 8 doses. Tumor volume shown in Fig.18C is mean tumor volume +/- SEM in each group with 10-20 mice per a group. The mean tumor volume from mice randomized onto the study was 30.3 mm³ at the time of randomization with a range of 19.4 to 44.6 mm³. [00428] Data provided in FIGs.18A-18D suggest that Atezo x Freso bi-specific antibody is more efficacious in limiting tumor progression than either monoclonal alone, data suggests that more TGF-β blocking may enhance the anti-tumor effect of atezo + anti-TGF-β suggesting a bi-specific with more anti-TGF-β scFvs may be more effective. 9. INCORPORATION BY REFERENCE [00429] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes. 10. EQUIVALENTS [00430] While various specific embodiments have been illustrated and described, the above specification is not restrictive. It will be appreciated that various changes can be made without departing from the spirit and scope of the present disclosure(s). Many variations will become apparent to those skilled in the art upon review of this specification.

Table 9 provides sequences and sequence identifiers for the antibody light chains, antibody heavy chains CDRs and human PD-L1

Table 10 provides the sequence identifiers for the light chain, heavy chain, and CDRs of the indicated clones

Table 11: Other sequences

Table 12: Amino acid sequences of antibodies described herein

4 heavy chain and 4 light chain variable region sequences for anti-TGF-β antigen binding protein

TGF-β clone 1D11 CDRs

fresolimumab

Claims

WHAT IS CLAIMED IS: 1. An isolated bispecific antigen binding protein (ABP) comprising a first antigen binding domain that specifically binds a human programmed death-ligand 1 (PD-L1) and a second antigen binding domain that binds a human transforming growth factor-β (TGF-β), wherein the first antigen binding domain comprises a first CDR1-L, a first CDR2-L, a first CDR3-L, a first CDR1-H, a first CDR2-H and a first CDR3-H and the second antigen binding domain comprises a second CDR1-L, a second CDR2-L, a second CDR3-L, a second CDR1-H, a second CDR2-H and a second CDR3-H, wherein the six CDRs of the first antigen binding domain consist of the sequences of the six CDRs of A2, A5, A3, or A7.

2. The bispecific ABP of claim 1, wherein the six CDRs of the second antigen binding domain consist of the sequences of the six CDRs of fresolimumab or anti-TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11.

3. The bispecific ABP of claim 1 or claim 2, comprising two first antigen binding domains and two second antigen binding domains.

4. The bispecific ABP of claim 1 or claim 2 or claim 3, wherein the first antigen binding domain is a Fab format and the second antigen binding domain is an scFv format or the first antigen binding domain is an scFv format and the second antigen binding domain is a Fab format.

5. The bispecific ABP of any of the above claims, comprising a Fc region, optionally comprising a human IgG1, a human IgG2, or a human IgG4, and/or optionally the Fc region with a modified effector function, optionally comprising a LALAPG, a N297A, a DANA, a LALA, or a N297Q mutation.

6. The bispecific ABP of any one of claims 1-5, wherein the first antigen binding domain comprises the first CDR1-L having a sequence selected from SEQ ID NO: 1002, 1003, 1005, and 1007, a first CDR2-L having a sequence selected from SEQ ID NO: 2002, 2003, 2005, and 2007, a first CDR3-L having a sequence selected from SEQ ID NO: 3002, 3003, 3005, and 3007, a first CDR1-H having a sequence selected from SEQ ID NO: 4002, 4003, 4005, and 4007, a first CDR2-H having a sequence selected from SEQ ID NO: 5002, 5003, 5005, and 5007 and a first CDR3-H having a sequence selected from SEQ ID NO: 6002, 6003, 6005, and 6007.

7. The bispecific ABP of any one of claims 1-5, wherein the first antigen binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1002, a first CDR2-L having the sequence of SEQ ID NO: 2002, a first CDR3-L having the sequence of SEQ ID NO: 3002, a first CDR1-H having the sequence of SEQ ID NO: 4002, a first CDR2-H having the sequence of SEQ ID NO: 5002 and a first CDR3-H having the sequence of SEQ ID NO: 6002.

8. The bispecific ABP of any one of claims 1-5, wherein the first antigen binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1005, a first CDR2-L having the sequence of SEQ ID NO: 2005, a first CDR3-L having the sequence of SEQ ID NO: 3005, a first CDR1-H having the sequence of SEQ ID NO: 4005, a first CDR2-H having the sequence of SEQ ID NO: 5005 and a first CDR3-H having the sequence of SEQ ID NO: 6005.

9. The bispecific ABP of any one of claims 1-5, wherein the first antigen binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1003, a first CDR2-L having the sequence of SEQ ID NO: 2003, a first CDR3-L having the sequence of SEQ ID NO: 3003, a first CDR1-H having the sequence of SEQ ID NO: 4003, a first CDR2-H having the sequence of SEQ ID NO: 5003 and a first CDR3-H having the sequence of SEQ ID NO: 6003.

10. The bispecific ABP of any one of claims 1-5, wherein the first antigen binding domain comprises the first CDR1-L having the sequence of SEQ ID NO: 1007, a first CDR2-L having the sequence of SEQ ID NO: 2007, a first CDR3-L having the sequence of SEQ ID NO: 3007, a first CDR1-H having the sequence of SEQ ID NO: 4007, a first CDR2-H having the sequence of SEQ ID NO: 5007 and a first CDR3-H having the sequence of SEQ ID NO: 6007.

11. The bispecific ABP of any one of claims 1-10, wherein the second antigen binding domain comprises a second CDR1-L having the sequence of SEQ ID NO: 9276, a second CDR2-L having the sequence of SEQ ID NO: 9277, a second CDR3-L having the sequence of SEQ ID NO: 9278, a second CDR1-H having the sequence of SEQ ID NO: 9279, a second CDR2-H having the sequence of SEQ ID NO: 9280 and a second CDR3-H having the sequence of SEQ ID NO: 9281.

12. The bispecific ABP of any one of claims 1-10, wherein the second antigen binding domain comprises a second CDR1-L having the sequence of SEQ ID NO: 9282, a second CDR2-L having the sequence of SEQ ID NO: 9283, a second CDR3-L having the sequence of SEQ ID NO: 9284, a second CDR1-H having the sequence of SEQ ID NO: 9285, a second CDR2-H having the sequence of SEQ ID NO: 9286 and a second CDR3-H having the sequence of SEQ ID NO: 9287.

13. An isolated bispecific antigen binding protein (ABP) comprising a light chain having the sequence of SEQ ID NO: 9264 and a heavy chain having the sequence of SEQ ID NO: 9265.

14. An isolated bispecific antigen binding protein (ABP) comprising a light chain having the sequence of SEQ ID NO: 9257 and a heavy chain having the sequence of SEQ ID NO: 9258.

15. An isolated bispecific antigen binding protein (ABP) comprising a first antigen binding domain that specifically binds a human programmed death-ligand 1 (PD-L1) and a second antigen binding domain that binds a human transforming growth factor-β (TGF-β), wherein the first antigen binding domain comprises a first CDR1-L having a sequence selected from SEQ ID NO: 8306-8458, a first CDR2-L having a sequence selected from SEQ ID NO: 8459-8611, a first CDR3-L having a sequence selected from SEQ ID NO: 8612-8764, a first CDR1-H having a sequence selected from SEQ ID NO: 8765-8917, a first CDR2-H having a sequence selected from SEQ ID NO: 8918-9070 and a first CDR3-H having a sequence selected from SEQ ID NO: 9071-9223, and the second antigen binding domain comprises a second CDR1-L having a sequence selected from SEQ ID NO: 9276 and 9282, a second CDR2-L having a sequence selected from SEQ ID NO: 9277 and 9283, a second CDR3-L having a sequence selected from SEQ ID NO: 9278 and 9284, a second CDR1-H having a sequence selected from SEQ ID NO: 9279 and 9285, a second CDR2-H having a sequence selected from SEQ ID NO: 9280 and 9286 and a second CDR3-H having a sequence selected from SEQ ID NO: 9281 and 9287.

16. A pharmaceutical composition comprising the bispecific ABP of any of the above claims and an excipient.

17. A method of treating a disease comprising the step of administering to a subject in need thereof an effective amount of the bispecific ABP of any of claims 1-5 or the pharmaceutical composition of claim 5.

18. The method of claim 17, wherein the disease is selected from the group consisting of cancer, AIDS, Alzheimer’s disease. fibrosis, wound healing, a viral infection, and a bacterial infection.

19. The method of claim 17 or claim 18, further comprising the step of administering one or more additional therapeutic agents to the subject.

20. The method of claim 19, wherein the additional therapeutic agent is selected from CTLA-4 inhibitor, PD-1 inhibitor, TIGIT inhibitor, a chemotherapy agent, an immune- stimulatory agent, radiation, a cytokine, a polynucleotide encoding a cytokine and a combination thereof.

21. An isolated polynucleotide or set of isolated polynucleotides encoding the bispecific ABP of any one of claims 1-15.

22. A vector or set of vectors comprising the isolated polynucleotide or set of isolated polynucleotides of claim 21.

23. A host cell comprising the isolated polynucleotide of claim 21 or the vector of claim 22.

24. A method of producing an isolated bispecific antigen binding protein (ABP) that specifically binds human PD-L1 and TGF-β, comprising expressing the bispecific ABP in the host cell of claim 23, and isolating the bispecific ABP.

25. A combination of a first isolated antigen binding protein (ABP) that specifically binds a human programmed death-ligand 1 (PD-L1) and a second ABP that binds a human transforming growth factor-β (TGF-β), wherein the six CDRs of the first ABP consist of the sequences of the six CDRs of A2, A5, A3, or A7.

26. The combination of claim 25, wherein the six CDRs of the second ABP consist of the sequences of the six CDRs of fresolimumab or anti- TGF-β clone 1D11 or a humanized version of anti-TGF-β clone 1D11.

27. A method of treating a disease comprising the step of administering to a subject in need thereof an effective amount of the combination of claim 25 or claim 26.

28. The method of claim 27, wherein the first and second ABPs are not administered concurrently.

29. An isolated antigen binding protein (ABP) comprising a heavy chain variable region having a sequence selected from SEQ ID NOs: 9268-9271 and a light chain variable region having a sequence selected from SEQ ID NO: 9272-9275.

30. The ABP of claim 29, comprising a heavy chain variable region having a sequence of SEQ ID NO: 9268 and a light chain variable region having a sequence of SEQ ID NO: 9272.

31. The ABP of claim 29, comprising a heavy chain variable region having a sequence of SEQ ID NO: 9269 and a light chain variable region having a sequence of SEQ ID NO: 9273.

32. The ABP of claim 29, comprising a heavy chain variable region having a sequence of SEQ ID NO: 9270 and a light chain variable region having a sequence of SEQ ID NO: 9274.

33. The ABP of claim 29, comprising a heavy chain variable region having a sequence of SEQ ID NO: 9271 and a light chain variable region having a sequence of SEQ ID NO: 9275.

34. A pharmaceutical composition comprising the ABP of any one of claims 29-33.

35. A method of treating a disease comprising the step of administering to a subject in need thereof an effective amount of the ABP of any of claims 29-33 or the pharmaceutical composition of claim 34.

36. An isolated polynucleotide or set of isolated polynucleotides encoding the ABP of any one of claims 29-33.

37. A vector or set of vectors comprising the isolated polynucleotide or set of isolated polynucleotides of claim 36.

38. A host cell comprising the isolated polynucleotide of claim 36 or the vector of claim 37.