MULTIFUNCTIONAL PROTEIN MOLECULES COMPRISING DECORIN AND THEIR USE

Abstract

The present invention relates to multifunctional protein molecules comprising decorin and their uses. In particular, the present invention relates to multifunctional protein molecules comprising decorin and a targeting polypeptide such as an antibody, and methods for their production and uses.

Description

MULTIFUNCTIONAL PROTEIN MOLECULES COMPRISING DECORIN AND THEIR USE CROSS REFERENCE TO RELATED REQUESTS This application claims priority to United States Provisional Application No. 62 / 693,766, filed July 3, 2018, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION The present invention relates to multifunctional protein molecules comprising decorin and its uses. In particular, the present invention relates to multifunctional protein molecules comprising decorin and a targeting polypeptide such as an antibody and methods of their production and uses. BACKGROUND OF THE INVENTION VEGF Angiogenesis is the physiological process by which new blood vessels are formed from pre-existing vessels. This is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels of the developing embryo are formed through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and granulation tissue formation. However, it is also a critical step in the transition of tumors from a benign to a malignant state, leading to the use of angiogenesis inhibitors in cancer treatment. Vascular Endothelial Growth Factor (VEGF), originally known as Vascular Permeability Factor (VPF), is a signaling protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. The serum concentration of VEGF is high in bronchial asthma and diabetes mellitus. The normal function of VEGF is to create new blood vessels during embryonic development, new blood vessels after injury, muscle after exercise, and new vessels (collateral circulation) to bypass blocked vessels. When VEGF is overexpressed, it can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and metastasize. VEGF overexpression can cause vascular disease in the retina of the eye and other parts of the body. Drugs such as bevacizumab and ranibizumab can inhibit VEGF and control or slow these diseases. VEGF is a subfamily of growth factors, to be specific, the platelet-derived growth factor family of cystine knot growth factors. They are important signaling proteins involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). checkpoint inhibitors An important part of the immune system is its ability to distinguish between normal cells in the body and those it sees as “foreign”. This allows the immune system to attack foreign cells while leaving normal cells alone. To do this, it uses "checkpoints" - molecules on certain immune cells that need to be activated (or inactivated) to initiate an immune response. Cancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system. But drugs that target these checkpoints hold great promise as cancer treatments. Checkpoint inhibitors seek to overcome one of cancer's main defenses against an attack by the immune system. The T cells of the immune system constantly patrol the body for signs of disease or infection. When they find another cell, they probe for certain proteins on its surface, which serve as a badge of the cell's identity. If the proteins indicate that the cell is normal and healthy, the T cell leaves it alone. If the proteins suggest that the cell is infected or cancerous, the T cell will lead an attack against it. Once the T cells initiate an attack, the immune system builds up a series of additional molecules to prevent the attack from damaging normal tissues in the body. These molecules are known as immune checkpoints. Checkpoint inhibitors block these normal proteins in cancer cells, or the proteins in T cells that respond to them. The result is to remove the reapers that prevent T cells from recognizing the cells as cancerous and unleashing an immune system assault on them. Three checkpoint inhibitors have received rapid US Food and Drug Administration (FDA) approval for cancer, including ipilimumab (Yervoy®), pembrolizumab (Keytruda®), and nivolumab ( Opdivo®). These and other immune checkpoint therapies represent one of the most promising frontiers in cancer treatment today. Additional therapeutic agents that target VEGF or immune checkpoints are needed. BRIEF DESCRIPTION OF THE INVENTION The present invention relates to multifunctional protein molecules comprising decorin and its uses. In particular, the present invention relates to multifunctional protein molecules comprising decorin and a targeting polypeptide such as an antibody and methods of their production and uses. Accordingly, in some embodiments, the present invention provides multifunctional protein molecules comprising at least one decorin molecule or functional portion thereof linked to an antigen-binding protein. In some preferred embodiments, the antigen binding protein is selected from the group consisting of a VEGF-A antigen binding protein and a checkpoint inhibitor antigen binding protein. In some preferred embodiments, the checkpoint inhibitor antigen-binding protein binds to a checkpoint inhibitor protein selected from the group consisting of PD-1, PD-L1, CTLA-4, PD-L2, CD27 , CD28, CD40, CD47, CD115, CD122, CD137, 0X40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, NOX2, TIM-3, VISTA, SIGLEC-7, TIGIT and 4-1BB. In some particularly preferred embodiments, the checkpoint inhibitor antigen-binding protein binds to a checkpoint inhibitor protein selected from the group consisting of PD-1, PD-L1, CTLA-4, PD-L2. In some preferred embodiments, the antigen binding protein is an antibody. In some preferred embodiments, the antibody is a monoclonal antibody. In some preferred embodiments, the monoclonal antibody is selected from the group consisting of bevacizumab, ranibizumab, ipilimumab, atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab. In some preferred embodiments, the decorin polypeptide is a decorin core protein. In some preferred embodiments, the decorin core protein comprises a mutation at position 4 of the mature decorin core protein. In some preferred embodiments, the mutation is a serine to alanine mutation. In some preferred embodiments, the decorin core protein lacks substantial modification by glycosaminoglycan molecules at position 4 of the mature decorin core protein. In some preferred embodiments, the fusion protein comprises two or more copies of the decorin polypeptide. In some preferred embodiments, said at least one functional portion of a decorin molecule comprises a domain or domains of decorin that bind to a signaling molecule selected from the group consisting of Transforming Growth Factor-β (TGF-β). -β), Connective Tissue Growth Factor (CTGF), PlateletDerived Growth Factor (PDGF), Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) 2 ), Hepatocyte Growth Factor Receptor (HGFR), Insulin-like Growth Factor 1 Receptor (IGF-1R), Epidermal Growth Factor Receptor ( EGFRs, Epidemial Growth Factor Receptors), myostatin and C1q. In some preferred embodiments, the TGF-β binding domain comprises full-length endogenous human decorin Asp45-Lys359 amino acids or full-length endogenous human decorin Leu155-Val260 amino acids. In some preferred embodiments, the multifunctional protein molecule comprises two or more copies of said at least one functional portion of a decorin molecule. In some preferred embodiments, the decorin molecule is operably linked to an antibody heavy chain. In some preferred embodiments, the antigen binding protein is bispecific. In some preferred embodiments, the antigen binding protein is multispecific. In some preferred embodiments, the multifunctional protein molecule is a fusion protein. In some preferred embodiments, the decorin molecule is chemically linked to the antigen-binding protein. In some preferred embodiments, the present invention provides a nucleic acid or set of nucleic acids encoding a multifunctional protein molecule as described above. In some preferred embodiments, the present invention provides a vector or vectors comprising the nucleic acid or set of nucleic acids. In some preferred embodiments, the present invention provides a host cell comprising the vector(s). In some preferred embodiments, the present invention provides methods of inhibiting a target protein and signaling molecule in a cell, comprising: contacting the cell with a multifunctional protein molecule, nucleic acid molecule, or vector as described above under conditions such that at least one activity of the target protein and at least one activity of a signaling protein in the cell are inhibited, wherein the target protein is selected from the group consisting of, VEGF-1, PD-1, PD-L1 , CTLA-4, PD-L2, CD27, CD28, CD40, CD47, CD115, CD122, CD137, 0X40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, NOX2, TIM -3, VISTA, SIGLEC-7, TIGIT and 4-1 BB. In some preferred embodiments, the cell is in vitro or in vivo. In some preferred embodiments, the cell is in a subject. In some preferred embodiments, contacting results in the inhibition of an activity selected from the group consisting of angiogenesis, PD-1 activity, PD-L1 activity, CTLA-4 activity, PD-L2 activity, CD27 activity , CD28 activity, CD40 activity, CD47 activity, CD115 activity, CD122 activity, CD137 activity, 0X40 activity, GITR activity, ICOS activity, A2AR activity, B7-H3 activity, B7 activity -H4, BTLA activity, IDO activity, KIR activity, LAG3 activity, NOX2 activity, TIM-3 activity, VISTA activity, SIGLEC-7 activity, TIGIT activity, and 4-1 BB activity. In some preferred embodiments, the cancer is selected from the group consisting of lung cancer, colorectal cancer, liver cancer, breast cancer, kidney cancer, cervical cancer, ovarian cancer, and glioblastoma. In some preferred embodiments, the signaling protein is selected from the group consisting of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), receptor 2 of the vascular endothelial growth factor (VEGFR2), hepatocyte growth factor receptor (HGFR), insulin-like growth factor receptor 1 (IGF-1R), various epidermal growth factor receptors (EGFRs), myostatin, and C1q. In some preferred embodiments, the signal protein is transforming growth factor β (TGF-β). In some preferred embodiments, the present invention provides methods of treating a disorder characterized by angiogenesis or tumor growth, comprising: administering a multifunctional protein molecule, nucleic acid molecule, or vector as described above to a subject under conditions such that inhibit angiogenesis or tumor growth in the subject. In some preferred embodiments, the tumor is selected from the group consisting of lung cancer, colorectal cancer, liver cancer, breast cancer, kidney cancer, cervical cancer, ovarian cancer, and glioblastoma. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic diagram of a fusion protein of the present invention. Figure 2 is a map of an expression construct of the present invention. Figure 3 is a map of an expression construct of the present invention. Figure 4 is an SDS-PAGE gel of medium from the pooled CHO cell line expressing the bevacizumab fusion protein. Lane 10. Molecular weight standards. Row 11. Sample of unreduced medium. Row 12. Sample of reduced medium. Figure 5 is an SDS-PAGE gel of purified Avelumab-Galacorin fusion molecule. Row 1: Molecular weight markers. Lane 2: Purified unreduced Avelumab-Galacorin fusion. Lane 3: Reduced purified Avelumab-Galacorin fusion. Figure 6 is a SEC-HPLC chromatogram of purified Avelumab-Galacorin fusion molecule. The percentage of monomer was greater than 98%. Figure 7 is a graph of tumor growth in a C57BL / 6 mouse MC-38 human colorectal cancer model after a single IV dose of all four treatments. Definitions To facilitate understanding of the invention, a number of terms are defined below. As used herein, the term "decorin" refers to a protein molecule having a mature protein sequence that is at least 80% identical to SEQ ID NOs: 1, 2, or 6 or a portion thereof. As used herein, the term "decorin core protein" refers to a decorin protein molecule that has a mutation at amino acid 4 of mature decorin and is substantially devoid of modification with a glycosaminoglycan (GAG; i.e., not is gagilated) at amino acid 4. As used herein, the term "multifunctional protein molecule" refers to protein molecules that comprise two or more polypeptide sub-portions derived from at least two different sources. Multifunctional protein molecules can be recombinant fusion proteins encoded by a fusion gene or can be made by chemical addition (eg, by covalent modification) of one polypeptide to another polypeptide. For example, the fusion proteins of the present invention may preferably comprise one or more decorin molecules or functional portions thereof linked to an antigen-binding protein via a linker sequence or may be "chemical fusions" wherein one or more decorin molecules or functional portions thereof are covalently linked to an antigen-binding protein, eg, via a modified amino acid. As used herein, the term "host cell" refers to any eukaryotic cell (for example, mammalian cells, bird cells, amphibian cells, plant cells, fish cells, and insect cells), whether placed in vitro or in vivo. As used herein, the term "cell culture" refers to any culture of cells in vitro. Included within this term are continuous cell lines (eg, with an immortal phenotype), primary cell cultures, finite cell lines (eg, non-transformed cells), and any other crcQzn / Lznz / q / Yi cell population maintained in vitro, including oocytes and embryos. As used herein, the term "vector" refers to any genetic element, such as a plasmid, phage, transposon, cosmid, chromosome, virus, virion, etc., that is capable of replication when associated with the elements of appropriate control cells and that can transfer genetic sequences between cells. Thus, the term includes cloning and pressure vehicles, as well as viral vectors. As used herein, the terms "complementary" or "complementarity" are used in reference to polynucleotides (ie, a sequence of nucleotides) related by base pairing rules. For example, the sequence 5'-A-G-T-3'", is complementary to the sequence "3'-T-C-A-5'". Complementarity may be partial”, in which only some of the nucleic acid bases are related according to the base pairing rules. Or, there may be "complete" or total complementarity between the nucleic acids. The degree of complementarity between nucleic acid strands has significant effects on the efficiency and strength of hybridization between nucleic acid strands. This is of particular importance in amplification reactions, as well as detection methods that depend on binding between nucleic acids. The terms "homology" and "percent identity" when used in relation to nucleic acids refer to a degree of complementarity. There may be partial homology (ie partial identity) or full homology (ie full identity). A partially complementary sequence is one that at least partially inhibits a completely complementary sequence from hybridizing to a target nucleic acid sequence and is referred to using the functional term "substantially homologous." The inhibition of hybridization of the sequence completely complementary to the target sequence can be examined using a hybridization assay (Southern hybridization or Northern hybridization solution and the like) under low stringency conditions. A substantially homologous sequence or probe (i.e., an oligonucleotide that is capable of hybridizing to another oligonucleotide of interest) will compete to inhibit the binding (i.e., hybridization) of a fully homologous sequence to a target sequence under low stringency conditions. . This is not to say that low stringency conditions are such that nonspecific binding is permitted; low stringency conditions require that the binding of two sequences to each other be a specific (ie, selective) interaction. Lack of non-specific binding can be assayed by use of a second target that lacks even a partial degree of complementarity (eg, less than about 30% identity); in the absence of non-specific binding the probe does not hybridize to the second non-complementary target. The terms "in operable combination," "in operable order," and "operably linked" as used herein refer to the linkage of nucleic acid sequences in such a way as to produce a nucleic acid molecule capable of directing transcription. of a given gene and / or the synthesis of a desired protein molecule. The term also refers to the linkage of amino acid sequences in such a way that a functional protein is produced. As used herein, the term "signal sequence" refers to any DNA sequence that, when operably linked to a recombinant DNA sequence, encodes a signal peptide capable of causing secretion of the recombinant polypeptide. In general, signal peptides comprise a signal of about 15 to 30 hydrophobic amino acid residues (see, for example, Zwizinski et al., J. Biol. Chem. 255(16): 7973-77

[1980] , Gray et al. ., Gene 39(2): 247-54

[1985] , and Martial et al., Science 205: 602-607

[1979] ). Such secretion signal sequences are preferably derived from genes encoding secreted polypeptides of the target cell type for tissue-specific expression (eg, milk proteins secreted for expression and secretion by mammary secretory cells). Secretory DNA sequences, however, are not limited to such sequences. Secretory DNA sequences of proteins secreted from many cell types and organisms can also be used (for example, the secretion signals for t-PA, serum albumin, lactoferrin, and growth hormone, and secretion signals from microbial genes that encode secreted polypeptides such as from yeast, filamentous fungi, and bacteria). As used herein, the term "purified" refers to molecules, whether nucleic or amino acid sequences, that are removed from their normal environment, isolated, or separated. An "isolated nucleic acid sequence" is therefore a purified nucleic acid sequence. "Substantially purified" molecules are at least 60% free, preferably at least 75% free, and more preferably at least 90% free of other components with which they are normally associated. An "acceptor human framework" for the purposes of this document is a framework comprising the amino acid sequence of a light chain (VL) variable domain framework or a heavy chain (VH) variable domain framework derived from a human immunoglobulin or a human consensus framework, as defined below. A human acceptor framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence therefrom, or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the human VL acceptor framework is identical in sequence to the human VL immunoglobulin framework sequence or human consensus framework sequence. "Affinity" refers to the strength of the total sum of non-covalent interactions between a single binding site on a molecule (eg, an antibody) and its binding partner (eg, an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (eg, antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific exemplary and illustrative modalities for measuring binding affinity are described below. An "affinity matured" antibody refers to an antibody with one or more alterations in one or more Hypervariable Regions (HVRs), compared to a base antibody that does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for the antigen. The term "antibody" is used herein in the broadest sense and encompasses different antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies), and antibody fragments as long as exhibit the desired antigen binding activity. An "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(abj2j diabodies; linear antibodies; single chain antibody molecules (eg, scFv); and multispecific antibodies formed from of antibody fragments. An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks the binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the antibody reference block the binding of the antibody to its antigen in a competition assay by 50% or more. An exemplary competition assay is provided herein. 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 particular source or species. or different species. The "class" of an antibody refers to the type of constant domain or constant region that its heavy chain possesses. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (¡sotypes), for example, IgGi, IgG2, IgGs, IgG^ IgAi, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. "Effector functions" refer to those biological activities attributable to the Fe region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1 q binding and Complement Dependent Cytotoxicity (CDC); Fe receptor binding; Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC); phagocytes; down-regulation of cell surface receptors (eg, B-cell receptor); and activation of B cells. An "effective amount" of an agent, eg, a pharmaceutical formulation, refers to an effective amount, in dosages and periods of time necessary, to achieve the desired therapeutic or prophylactic result. The term "epitope" refers to the particular site on an antigen molecule to which an antibody binds. The term "Fe region" herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a constant region portion. The term includes native sequence Fe regions and variant Fe regions. In one embodiment, an IgG heavy chain Fe region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, the C-terminal Lysin (Lys447) of the Fe region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fe region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al. , “Sequences of proteins of immunological interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Consequently, the HVR and FR sequences generally appear in the following sequence in VH (oVL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4. The terms "full length antibody", "intact antibody", and "whole antibody" are used interchangeably herein to refer to an antibody that is substantially similar in structure to a native antibody structure or that has heavy chains that contain a Fe region as defined in this document. The terms "host cell", "host cell line", and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells", which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. The progeny may not be completely identical in nucleic acid content to an original cell, but may contain mutations. Included herein are mutant progeny that have the same function or biological activity as screened for or selected for in the originally transformed cell. A"human antibody" is one having an amino acid sequence corresponding to that of an antibody produced by a human or human cell or derived from a non-human source utilizing human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody that comprises non-human antigen-binding residues. A "human consensus framework" is a framework representing the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection for human immunoglobulin VL or VH is from a subset of variable domain sequences. Generally, the subset of sequences is a subset as in Kabat et al., Sequences of proteins of immunological interest”, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is the kappa I subgroup as in Kabat et al., supra. In one embodiment, for OAB, the subgroup is subgroup III as in Kabat et al., supra. A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, and usually two, variable domains, in which all or substantially all of the HVRs (eg, CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody crcQzn / Lznz / q / Yi may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A"humanized" form of an antibody, eg, a non-human antibody, refers to an antibody that has undergone humanization. The term "hypervariable region" or "HVR", as used herein, refers to each of the regions of an antibody variable domain that are structurally defined loops hypervariable in sequence and / or shape ("hypervariable loops"). . Generally, native four-chain antibodies comprise six HVRs; three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3). HVRs generally comprise amino acid residues from hypervariable loops and / or "Complementarity Determining Regions" (CDRs), the latter being of higher sequence variability and / or involved in antigen recognition. Exemplary hypervariable loops occur at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 ( H3). (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987).). Exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3) occur at amino acid residues 24-34 of L1, 50-56 of L2, 89-97 from L3, 31-35B from H1, 50-65 from H2, and 95-102 from H3. (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, (1991).). With the exception of CDR1 in VH, the CDRs generally comprise the amino acid residues that form the hypervariable loops. CDRs also comprise "specificity determining residues", or SDRs", which are antigen-contacting residues. SDRs are contained within regions of CDRs called abbreviated CDRs or aCDRs. Exemplary a-CDRs (a-CDR-L1, a-CDR-L2, a-CDR-L3, a-CDR-H1, a-CDR-H2, and a-CDR-H3) occur at amino acid residues 31 -34 from L1, 50-55 from L2, 89-96 from L3, 31-35B from H1, 50-58 from H2, and 95-102 from H3. (See Almagro and Fransson, Front. Bíoscí. 13:1619-1633 (2008).). Unless otherwise indicated, HVR residues and other residues in the variable domain (eg, FR residues) are listed herein according to Kabat et al., supra. An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (for example, cows, sheep, cats, dogs, and horses), primates (for example, human and non-human primates such as monkeys), rabbits, and rodents (for example, , mice and rats). In certain embodiments, the subject individual is a human. An "isolated" antibody is one that has been separated from a component of its natural environment. In some embodiments, an antibody is greater than 95% purified with 99% purity as determined by, for example, electrophoresis (for example, SDS-PAGE, Isoelectric Focusing (IEF), capillary electrophoresis) or chromatography (by example, reverse phase or ion exchange HPLC). For a review of methods for evaluating antibody purity, see, for example, Flatman et al., J. Chromatogr. 8848:79-87 (2007). An "isolated nucleic acid" refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location. The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, that is, the individual antibodies comprising the population are identical and / or bind to the same epitope, except for possible variant antibodies, eg, containing naturally occurring mutations or arising during the production of a monoclonal antibody preparation, such variants generally being present in minor amounts. Unlike polyclonal antibody preparations, which generally include different antibodies directed against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on an antigen. Therefore, the "monoclonal" modifier indicates the character of the antibody that is being obtained from a substantially homogeneous population of antibodies, and should not be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention can be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage display methods, and methods using transgenic animals that contain all or part of the human immunoglobulin sites, such methods and other exemplary methods for making monoclonal antibodies being described herein. "Native antibodies" refer to naturally occurring immunoglobulin molecules with variable structures. For example, native IgG antibodies are approximately 150,000 dalton heterotetrameric glycoproteins, composed of two identical light chains and two identical heavy chains that are linked by disulfide bonds. From the N- to the C-terminus, each heavy chain has a variable region (VH), also referred to as a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N- to the C-terminus, each light chain has a variable region (VL), also referred to as a variable light domain or light chain variable domain, followed by a Constant Light (CL) domain. ). The light chain of an antibody can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain. "Percent (%) amino acid sequence identity" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with amino acid residues in the reference polypeptide sequence, after align sequences and introduce gaps, if necessary, to achieve maximum percent sequence identity, and without considering any conservative substitutions as part of sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a number of ways that are within the skill of the art such as using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR). Those of skill in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared. For the purposes of this document, however, the % amino acid sequence identity values ​​are generated using the ALIGN-2 sequence comparison computer program. The sequence comparison computer program ALIGN-2 was licensed by Genentech, Inc., and the source code has been filed with user documentation at the United States Copyright Office, Washington D.C. 20559, where it is registered under copyright registration number from United States TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or can be compiled from source code. The ALIGN-2 program must be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given A amino acid sequence to, with, or against a given B amino acid sequence (which may alternatively be expressed as a given amino acid sequence A having or comprising a certain % amino acid sequence identity a, with, or against a given amino acid sequence B) is calculated as follows: 100 times the X / Y fraction where X is the number of amino acid residues scored as identical matches by the ALIGN-2 sequence alignment program in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that when the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not be equal to the % identity of amino acid sequence of B with a. Unless specifically stated otherwise, all % amino acid sequence identity values ​​used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. The term "pharmaceutical formulation" refers to a preparation that is in such a form as to allow the biological activity of an active ingredient contained therein to be effective, and that does not contain additional components that are unacceptably toxic to a subject to whom it would be administered. the formulation. A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. As used herein, "treatment" (and grammatical variations thereof such as "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be carried out either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the occurrence or recurrence of disease, alleviation of symptoms, lessening of any direct or indirect pathological consequence of the disease, preventing metastasis, slowing the rate of disease progression, improving or palliation of the disease state, and remission or improvement of the prognosis. In some embodiments, the antibodies of the invention are used to retard the development of a disease or slow the progress of a disease. The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in the binding of antibody to antigen. The variable domains of the heavy chain and crcQzn / Lznz / q / Yi light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four framework regions (FRs) and three hypervariable regions (HVRs). preserved. (See, for example, Kindt et al. Kuby Immunology, 6th Ed., W.H. Freeman and Co., page 91 (2007).). A single VH or VL domain may be sufficient to confer antigen binding specificity. In addition, antibodies that bind to a particular antigen can be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991). The term "vector" as used herein refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors." DETAILED DESCRIPTION OF THE INVENTION The present invention relates to multifunctional molecules comprising a decorin molecule or functional portion thereof operably linked to an antigen binding protein such as an immunoglobulin molecule, truncated fragment of an antigen molecule, or a single chain antibody. . In particular, the present invention relates to fusion polypeptides comprising decorin and a VEGF or immune checkpoint targeting polypeptide (preferably a checkpoint inhibitor) and methods of their production and uses. Embodiments of the present invention provide fusion polypeptides comprising a decorin polypeptide fused to an antigen-binding protein of interest, nucleic acids encoding such polypeptides, and uses thereof. Exemplary compositions and methods are described herein. The decorin used in the fusion molecules can be wild-type decorin, decorin core protein, or functional portions of any of these proteins, such as the portion(s) that bind TGF-β, or other molecules. signaling agents such as connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (HGFR), hepatocyte growth factor receptor (HGFR), growth factor similar to insulin type 1 (IGF-1R), different epidermal growth factor receptors (EGFRs), myostatin, and C1 q. I. Decorin In preferred embodiments, the multifunctional protein molecules of the present invention comprise one or more decorin polypeptides or functional portions thereof. Decorin has been shown to suppress transforming growth factor-beta-induced expression of plasminogen activator inhibitor-1 (see, eg, Wahab et al., Biochem J. 2002 Mar 15;362(Pt 3):643 -649; incorporated herein by reference in its entirety). Transforming growth factor-beta (TGF-β) is a key mediator of Extracellular Matrix (ECM) accumulation in sclerotic kidney diseases such as diabetic nephropathy. While not limited to a particular mechanism, it is contemplated that the combination of decorin and a VEGF binding protein will enhance the efficacy over the VEGF binding protein itself, by inhibiting TGF-β activity. in combination with VEGF blockade. Native decorin is a glycoprotein with an attached glycosaminoglycan and an average molecular weight of 90140 kD. In some preferred embodiments, the decorin is decorin core protein, ie, a substantially non-gagylated decorin. In some embodiments, the decorin core protein comprises a mutation at amino acid 4 (ie, the 4th amino acid from the N-terminus) of the mature decorin core protein molecule. In some embodiments, the mutation is a serine to alanine mutation. In some embodiments, the decorin core protein is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:6 (mature decorin core protein) as long as the decorin core protein comprises a mutation in amino acid 4 (ie, the 4th amino acid from the N-terminus) of the mature decorin core protein molecule. Decorin is commonly expressed as a pre-pro-protein. The present invention provides multifunctional protein molecules comprising an antigen-binding protein in operable association with one or more decorin mature peptide sequences or functional portions thereof. In some embodiments, the decorin core protein portion of the fusion polypeptide is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:6 (mature decorin core protein) or a functional portion of the same. In some embodiments, the decorin core protein comprises a mutation at amino acid 4 (ie, the 4th amino acid from the N-terminus) of the mature decorin core protein molecule. The present invention further provides nucleic acid sequences encoding fusion proteins, as well as vectors comprising the nucleic acid sequences. In some embodiments, the decorin core protein portion of the fusion polypeptide is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:5 (mature decorin core protein) provided that the core protein decorin comprises a mutation at amino acid 4 (ie, the 4th amino acid from the N-terminus) of the mature decorin core protein molecule. In some embodiments, the decorin molecule used in the multifunctional protein molecules may comprise one or more functional portions of the decorin molecule. Decorin molecules have a number of functional portions or domains, for example, those described in Járvinen and Prince, BioMed Research Int'l, Vol. 2015, Article ID 654765 (incorporated by reference herein in its entirety.). In some preferred embodiments, the functional portion of decorin binds to or otherwise interacts with transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), Vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (HGFR), insulin-like growth factor receptor 1 (IGF-1R), various epidermal growth factor receptors (EGFRs) , myostatin or C1q. Preferred functional portions of decorin maintain functional activity (such as binding to one of the signal molecules just described) and are preferably at least 90%, 95%, 99%, or 100% identical to the corresponding native decorin sequence. Preferred decorin functional portions are shorter than the full length native decorin molecule, and for example, may be 10 to 300 amino acids in length or 10 to 120 amino acids in length. For example, the functional portion of the decorin molecule can be at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:64 (TGF-β decorin binding domain, ASP45- Full length endogenous human decorin LYS359), SEQ ID NO:65 (two copies of the TGF-β decorin binding domain, ASP45-LYS359, separated by linker), SEQ ID NO:66 (binding domain decorin TGF-β binding domain, LEU155-VAL260 full-length endogenous human decorin), SEQ ID NO:67 (two copies of TGF-β decorin binding domain, LEU155-VAL260, separated by linker). Exemplary decorin polypeptides and method for purifying decorin are described, for example, in WO 2006038107; incorporated herein by reference in its entirety. Exemplary nucleic acid and amino acid sequences of decorin are provided below in Figures 1 and 2. SEQ ID NO. Sequence SEQ ID NO:46 Decorin Core Protein DEAAGIGPEVPDDRDFEPSLGPVCPFRCQCHLRWQCSDLGLDKVPKDLPPDT TLLDLQNNKITEIKDGDFKNLKNLHALILVNNKISKVSPGAFTPLVKLERLYLSKN QLKELPEKMPKTLQELRAHENEITKVRKVTFNGLNQMIVIELGTNPLKSSKGIENG AFIALPQGMLSPSKYL HLDGNKISRVDAASLKGLNNLAKL GLSFNSISAVDNGSLANTPHLRELHLDNNKLTRVPGGLAEHKYIQWYLHNNNI SWGSSDFCPPGHNTKKASYSGVSLFSNPVQYWEIQPSTFRCVYVRSAIQLGN YK SEQ ID NO:47 Decorin Propeptide GPFQQRGLFDFMLE SEQ ID NO:48GCAGATTACGGTTACTA Decorin Propeptide TTATGCTAGAA SEQ ID NO:49 Decorin core protein GATGAGGCTGCAGGGATAGGCCCAGAAGTTCCTGATGACCGCGACTTCGA GCCCTCCCTAGGCCCAGTGTGCCCCTTCCGCTGTCAATGCCATCTTCGAGT GGTCCAGTGTTCTGATTTGGGTCTGGACAAAGTGCCAAAGGATCTTCCCCC TGACACAACTCTGCTAGACCTGCAAAACAACAAAATAACCGAAATCAAAGAT GGAGACTTTAAGAACCTGAAGAACCTTCACGCATTGATTCTTGTCAACAATA AAATTAGCAAAGTTAGTCCTGGAGCATTTACACCTTTGGTGAAGTTGGAACG ACTTTAATCAGCTGTCCAAGG CCCAAA ACTCTTCAGGAGCTGCGTGCCCATGAGAATGAGATCACCAAAGTGCGAAAA GTTACTTTCAATGGACTGAACCAGATGATTGTCATAGAACTGGGCACCAATC CGCTGAAGAGCTCAGGAATTGAAAATGGGGCTTTCCAGGGAATGAAGAAG CTCTCCTACATCCGCATTGCTGATACCAATATCACCAGCATTCCTCAAGGTCTACTCGATTCATGATACCT CAGAGT TGATGCAGCTAGCCTGAAAGGACTGAATAATTTGGCTAAGTTGGGATTGAG TTTCAACAGCATCTCTGCTGTTGACAATGGCTCTCTGGCCAACACGCCTCAT CTGAGGGAGCTTCACTTGGACAACAACAAGCTTACCAGAGTACCTGGTGGG CTGGCAGAGCATAAGTACATCCAGGTTGTCTACCTTCATAACAGATAATTGTCACTGTCATGTC CACCTGGACACAACACCAAAAAAGG CTTCTTATTCGGGTGTGAGTCI I I ICAGCAACCCGGTCCAGTACTGGGAGA TACAGCCATCCACCTTCAGATGTGTCTACGTGCGCTCTGCCATTCAACTCG GAAACTATAAGTGA SEQ ID NO. Sequence 5 SEQ ID NO:64 Decorin TGF-β binding domain ASP45-LYS359 GDFKÑLKNLIMLm^ DTNjTSIPQGLPPSLTE.^ SLANTF1±RE|JdLD!WKLTRyPGGLAEHKY|M SEQ ID NO:65 TGF-β binding domain to decorin ASP45-LYS359, two copies separated by linker DFEPSLGPyCPFRCQC.HLRWQCSDLGLDKyPKDLPPDTTLLDLQNNK|TE|KD ELRAHEMaT.K-VBKyT.ENG DTNITSIPQGLPPSLTELHLDGNKISRVDAASLKGLNNLAKLGLSFNSISAVDNG .slañtTFQYPSYWLSFWYPSYWMSY RSAULGNYKSGGGGSDFEPS. LPGVCPFRCQCHI^yyQCSDLGLDKVPKDLPPDTTLLDLQIWKITElKDGDFKN LANIJHAIXyNNKI^^ PQGLPPSLTELHLDGNKISRyDAASLKGLNNLAKLGLSFNSISAyDNGSLANTP HLRELHLDNNKLTRVPGGLAEHKYIQWYLHNNNISWGSSDFCPPGHNTKKA SEQ ID NO:66 TGdomain a1 delacin LE5binding TGdomain 5-VAL260 LRAHENHffiyRKyTFTOAIQMMI^^ TN.ITSJP^ 20 1 SEQ ID NO:67 TGF-β binding domain a la dennrin I Π Η^Α / ΔΙ 9ΚΠ Binding agents LRAHE.N.a.TKyRK^ Tnitsi.p.qgl^ GSLRAHENEITKVRKVTFNGLNQMIVIELGTNPLKSSGIENGAFQGMKKLSYIRI Preferred embodiments of the present invention provide multifunctional protein molecules comprising one or more decorin molecules or functional portion(s) thereof that are operably linked to a binding agent of Interest. Preferred binding agents of interest include, but are not limited to, antigen binding proteins including immunoglobulins and fragments or derivatives thereof such as single chain antibodies that bind to molecules such as VEGF (vascular endothelial growth factor ) and checkpoint inhibitor proteins such as CTLA-4 (cytotoxic T lymphocyte antigen 4), PD-1 (programmed cell death protein 1), PD-L1 (programmed death ligand 1), PD-L2 ( programmed death ligand 2), CD27, CD28, CD40, CD47, CD115, CD122, CD137, 0X40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, NOX2, TIM-3 , 30 VISTA, SIGLEC-7, TIGITY 4-1BB. Binding agents (eg, antigen-binding proteins) generally interact with or specifically bind to a target. For example, the binding agents disclosed herein generally interact specifically with regions of, for example, VEGF, CTLA-4, PD-1, or PD-I, which are collectively referred to herein as target proteins. "Binding specifically" to a target protein means that the amount of binding to the target protein is greater than the amount of binding to non-target protein targets (eg, there may be background non-specific binding). Generally, the specific binding of binding agents to a protein, for example, can be achieved by binding to a specific sequence of amino acids within a protein target. These sequences can be referred to as epitopes. Molecules containing the epitopes can be used to stimulate binding agents such as antibodies and can be referred to as immunogens. Binding agents can also recognize specific two-dimensional and / or three-dimensional structures as part of the epitope. The antigen-binding protein can be monospecific, bispecific, or multispecific. The specific interaction or binding of a binding agent with its target is believed to be a type of equilibrium reaction. In one example, specific binding can be quantified. Quantitation can use a dissociation constant, it is known in the art that Kd is a type of equilibrium constant that describes the propensity, in this case, for an antibody to separate from the antigen or epitope to which it has bound. Therefore, Kd describes the affinity that an antibody has for an epitope. The lower the Kd, the higher the affinity of a binding agent for its target. In certain embodiments, the binding agent is a monoclonal antibody. The antibody (eg, monoclonal antibody) can also be any suitable isotype or subclass of isotypes. The binding agent may well be a derivative of an antibody such as, for example, a Fab single chain antibody, F(ab')2, Fab', Fv, single chain, monospecific antibody, bispecific antibody, trispecific antibody, antibody multivalent, chimeric antibody, humanized antibody, human antibody, shark antibody, nanobody (eg antibody comprising a single monomeric variable domain), camelid antibody (eg family Camelidae) microbody, intrabody (eg antibody intracellular), or defucosylated antibody and / or derivative thereof. Binding agent mimetics and / or antibodies are also contemplated within the present invention. The binding agent may also comprise a detectable tag and / or effector moiety bound thereto. When the binding agent is an antigen-binding protein such as an immunoglobulin or derivative thereof, it can be identified by reference to the nucleotide and / or amino acid sequence corresponding to its variable and / or complementarity determining regions ( CDRs). For example, an exemplary binding agent that is, is derived from, or relates to the monoclonal antibodies described herein may comprise a heavy and / or light chain each comprising one or more constant and / or variable regions. . Variable regions generally comprise one or more CDRs that largely determine the binding specificity of the antibody. These monoclonal antibodies can be identified by analysis of the nucleotide sequences encoding the variable regions. Monoclonal antibodies can also be identified by analysis of the amino acid sequences of (eg, encoded by nucleotide sequences) the variable regions. Amino acids in the multifunctional protein molecules of the present invention may also be substituted for any other amino acids as desired by one of skill in the art. For example, one of skill in the art can make conservative substitutions by replacing particular amino acids with others as is known in the art. Any of the amino acid sequences of the antigen-binding proteins described herein may also be combined with any other variable region and / or CDR in crcozn / L^nz / q / Yi in any order and / or combination to form binding agents. hybrid and / or fusion joining and / or inserting into other heavy and / or light chain variable regions using standard techniques. These can be used in conjunction with any constant region. CDRs (complementarity determining regions) are amino acid sequences of antibodies that are responsible, at least in part, for the binding of an antibody to a specific target. It is understood by those of skill in the art that CDRs can be identified using any of a number of techniques and / or schemes. The CDRs of the binding agents shown herein can be identified using any of these techniques. For example, one of skill in the art can identify CDRs using the Kabat numbering scheme, the Chothia numbering scheme, the Enhanced Chothia numbering scheme, and / or any of the available CDR definition schemes (for example, AbM, contact definition, and I or as described by MacCullum, et al., J Mol. Biol, 262(5):732-745, 1996. A summary of different schemes, based in part on, for example, Kabat et al., "Sequences of Proteins of Immunological Interest," 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD, NIH Publication No. 91-3242 (1991), and Al-Lazikani et al. , "Standard conformations for the canonical structures of immunoglobulins", J.Mol.Biol.273:927-948, 1997. These systems for identifying CDRs are merely exemplary and others may be suitable. , as would be understood by one of skill in the art The CDRs so identified can be used to identify suitable binding agents. For example, equivalents of one or more monoclonal antibodies described herein. Such CDRs may also be combined with one another in any order and / or combination to form chimeric and / or fusion linkers and / or inserted into the other heavy and / or light chain variable regions using standard techniques. In some embodiments, the CDR sequences of antigen-binding proteins described herein bind to the constant regions of any antibody molecule from the same or different species (eg, human, goat, rat, sheep, chicken) of from which the variable region amino acid sequence was derived. Deamidation of asparagine residues to aspartic acid or isoaspartic acid is a common post-conversion modification of proteins. Deamidation can occur more frequently when asparagine is part of an asparagine-glycine dipeptide (Asp-Gly or N-G; the "NG" sequence). Deamidation can have detrimental effects on proteins. In one example, deamidation can potentially cause a change in the three-dimensional structure of a protein. In another example, for an antibody, deamidation in a region that affects antigen binding (eg, variable regions and / or CDRs) can potentially cause lower, or loss of, antibody binding to antigen. Consequently, in some embodiments, amino acid residues potentially susceptible to post-conversion deamidation are replaced with those less or not susceptible. In one example, asparagine and / or glycine is substituted to modify the NG sequence, eg, any amino acid that will delete the NG sequence. Antibody constant regions are derived from any of, for example, human (for example, IgG (IgG1, IgG2, IgG3, IgG4), IgM, IgA (IgA1 and IgA2), IgD, and IgE), canine (for example, IgG (IgGA, IgGB, IgGC, IgGD) IgA, crcQzn / Lznz / q / Yi IgD, IgE, and IgM), chicken (for example, IgA, IgD, IgE, IgG, IgM, IgY), goat (for example, IgG), mouse (for example, IgA, IgG, IgD, IgE, IgM), pig (eg IgA, IgG, IgD, IgE, IgM), rat (eg IgA, IgG, IgD, IgE, IgM), feline (eg IgA, IgD, IgE, IgG, IgM) and / or a fragment and / or derivative thereof (eg, as chimeric antibodies). In one example, the binding agents are antibodies that have modified glycosylation patterns. IgG molecules, for example, generally contain N-linked oligosaccharides. Some IgG molecules contain a double-stranded complex oligosaccharide attached to the heavy chain of the antibody. In human IgG, the oligosaccharide is generally linked to an asparagine residue at position 297 (N297) of the heavy chain (in the constant Fe region of the antibody heavy chain). Generally, a fucose binds to the GLcNAC residue on the oligosaccharide that is closest to N297. The absence of fucose may enhance the ability of antibodies to mediate antibody-dependent cellular cytotoxicity (ADCC). It is contemplated that removal of the fucose enhances the ability of the antibody to interact with Fe receptors. Antibodies of this type are referred to as "defucosylated." Defucosylated antibodies can be produced using techniques described herein that may be known in the art. In some embodiments, a nucleic acid sequence encoding an antibody can be expressed in a cell line that has modified glycosylation capabilities (eg, deleted, modified, or decreased fucosyl transferase) and fails to add typical fucose moieties. . A variety of these cell lines are known. In some embodiments, the antibodies disclosed herein bind VEGF, but contain defucosylated oligosaccharides. Binding agents (eg, antibodies) can include other modifications that can result in decreased interaction with Fe receptors. For example, alternative or additional amino acid substitutions can be made to the antibody molecules described herein. As described above, in some embodiments, the binding agents may be antibodies or immunoglobulins. The term "antibody" or "antibodies" can refer to whole or fragmented antibodies in unpurified or partially purified form (eg, hybridoma supernatant, ascites, polyclonal antisera) or in purified form. A "purified" antibody can be one that is separated from at least about 50% of the proteins with which it was initially encountered (eg, as part of a hybridoma supernatant or ascites preparation). A purified antibody can be one that is separated from at least about 60%, 75%, 90%, or 95% of the proteins with which it was initially encountered. Suitable derivatives can also be fragments (for example Fab, F(abj2) or single chain antibodies, such as Fv, for example). The antibodies can be of any suitable origin or form, including, for example, murine (for example, produced by murine hybridoma cells) or expressed as chimeric antibodies, and the like. Methods for preparing and using different types of antibodies are well known to those skilled in the art and would be suitable for practicing the present invention (see, for example, Harlow, et al. Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988 Harlow, et al., Using Antibodies: A Laboratory Manual, Portable Protocol No. 1, 1998; Kohler and Millstein, Nature, 256:495, 1975; Jones et al., Nature, 321:522-525, crcQzn / Lznz / q / Yi 1986; Riechmann et al., Nature, 332:323-329, 1988; Lend it, Curr. Op. Struct. Biol., 2:593-596, 1992; Verhoeyen et al., Science, 239:1534-1536, 1988; Hoogenboomet al., J Mol. Biol., 227:381, 1991; Marksetal., J Mol. Biol., 222:581, 1991; Colé et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77, 1985; Boerner et al., J Immunol., 147(1):8695, 1991; Marks et al., BioiTechnology 10, 779-783, 1992; Lonberg et al., Nature 368:856-859, 1994; Morrison, Nature 368:812-13, 1994; Fishwild et al., Nature Biotechnology 14, 845-51, 1996; Neuberger, Nature Biotechnology 14, 826, 1996; Lonberg and Huszar, Intern. Rev. Immunol. 13:65-93, 1995; as well as United States Patent Nos. 4,816,567, 5,545,807, 5,545,806, 5,569,825, 5,625,126, 5,633,425, and 5,661,016). In some preferred embodiments, the antigen-binding protein binds to a checkpoint inhibitor selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, CD27, CD28, CD40, CD47, CD115, CD122, CD137, OX40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, NOX2, TIM-3, VISTA, SIGLEC-7, TIGIT and 41BB. In some embodiments, the antigen-binding protein inhibits the activity of a checkpoint inhibitor selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, CD27, CD28, CD40, CD47, CD115, CD122, CD137, 0X40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, NOX2, TIM-3, VISTA, SIGLEC-7, TIGIT and 41BB. In some embodiments, the antibody is a commercially available human or humanized monoclonal antibody that is directed to VEGF (for example, Bevacizumab (Avastin), Ranibizumab (Lucentis), or Pegaptanib (Macugen)) or a checkpoint system molecule. CTLA-4 (for example, Ipilimumab (Yervoy)), PDL1 (for example, Atezolizumab (Tecentriq), Avelumab (Bavencio), or Durvalumab (Imfinzi)), or PD-1 (for example, Nivolumab (Opdivo) or Pembrolizumab ( Keytruda)). Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A). VEGF-A is a growth factor protein that stimulates angiogenesis in a variety of diseases, especially cancer. Bevacizumab was the first angiogenesis inhibitor available in the United States of America. Ipilimumab (Yervoy) is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system and is classified as a checkpoint inhibitor drug. T lymphocytes can recognize and kill cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows lymphocytes to continue killing cancer cells. Cancer cells produce antigens, which can be used by the immune system to identify them. These antigens are recognized by dendritic cells that present the antigens to cytotoxic T lymphocytes (CTLs) in the lymph nodes. CTLs recognize cancer cells through these antigens and destroy them. However, together with the antigens, the dendritic cells present an inhibitory signal. That signal binds to a receptor, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) receptor, on the CTL and turns off the cytotoxic reaction. This allows cancer cells to survive. Ipilimumab binds to CTLA-4, blocking the inhibitory signal, allowing the CTLs to kill cancer cells. Atezolizumab (Tecentriq) is a fully humanized, engineered IgG1 crcQzn / Lznz / q / Yi isotype monoclonal antibody against the PD-L1 protein. Avelumab (Bavencio) is a fully human monoclonal antibody that binds to PDL1. Durvalumab (Imfinzi) is a fully human monoclonal antibody that binds to PD-L1. Together, these molecules can be referred to as PD-L1 inhibitors and are classified as immune checkpoint inhibitors. PD-L1 can be highly expressed in certain tumors, leading to reduced activation of immune cells (cytotoxic T cells in particular) that might otherwise recognize and attack cancer. PD-L1 checkpoint inhibitors block the interaction of PD-L1 with Programmed Cell Death Protein 1 (PD-1) and CD80 receptors (B7-1Rs). Inhibition of PD-L1 removes the immune inhibitory effect and thus generates an antitumor response. Nivolumab (Opdivo) is a human monoclonal antibody that binds to PD-1. Pembrolizumab (Keytruda) is a humanized antibody that binds to PD-1. Together, these molecules can be referred to as PD-1 inhibitors and are classified as immune checkpoint inhibitors. These molecules work by blocking a negative regulator of T cell activation, thus allowing the immune system to attack the tumor. This is an example of an immune checkpoint blockade. PD-1 is a protein on the surface of activated T cells. As discussed above, if PD-L1 or PDL2 binds to PD-1, the T cell becomes inactive. Many cancer cells make PD-L1, which stops T cells from attacking tumors. Nivolumab blocks the binding of PD-L1 to PD-1, allowing the T cell to work. It will be understood by those of skill in the art that the CDRs or variable regions of the referenced antibodies can be isolated (eg, by cloning) and inserted into other antigen-binding protein structures or derivatives (eg, a Fab, an F(abj2, a single chain Fab' antibody, a single chain Fv antibody, bispecific antibody, trispecific antibody, multivalent antibody, humanized antibody, nanobody, camelid antibody, microbody, or intrabody) as desired.Thus, the The present invention encompasses antigen-binding proteins that are derived from the reference antibodies and that are identified by reference to the CDRs of variable regions of the reference antibodies, For example, in some preferred embodiments, the antigen-binding proteins of The present invention comprises the heavy and light chain variable regions of Bevacizumab, Ranibizumab, Pegaptanib, Ipilimumab, Atezolizumab, Avelumab, Durvalumab, Nivolumab or Pembrolizumab. In other preferred embodiments, the antigen-binding proteins comprise one, two, or all three of CDR1, CDR2, and CDR3 of the heavy and light chain variable regions of Bevacizumab, Ranibizumab, Pegaptanib, Ipilimumab, Atezolizumab, Avelumab, Durvalumab, Nivolumab, or Pembrolizumab. III. multifunctional polypeptides Embodiments of the present invention provide multifunctional polypeptides and / or polynucleotides encoding a fusion polypeptide comprising a decorin polypeptide operably linked to a binding agent. Also provided in some embodiments are compositions comprising these binding agents, polypeptides, peptides, polynucleotides, expression vectors, and / or host cells. In certain embodiments, the compositions comprise a pharmaceutically acceptable carrier. In some preferred embodiments, the binding agent on the multifunctional protein molecule is an antibody as described above. Provided in Figure 1 is a diagram of a decorin-antibody fusion of the present invention that targets VEGF. The experienced artisan will recognize that other antigen-binding proteins described herein can be substituted for the VEGF antibody described in Figure 1. Referring to Figure 1, the fusion protein comprises the heavy and light chains of an antibody that binds VEGF (eg, Bevacizumab). A decorin molecule is operably linked to the C-terminus of each heavy chain via a peptide linker. The present invention is not limited to the use of any particular peptide linker, or to the linkage of the decorin molecule to any particular amino acid of the antigen-binding protein. In some preferred embodiments, the decorin molecule is linked via the C-terminus of either one or two of the antibody heavy chains, via the C-terminus of either one or two of the antibody light chains, by via the N-terminus of either one or two of the antibody heavy chains, via the N-terminus of either one or two of the antibody light chains, or via an amino acid in the constant region of any of one or two of the antibody heavy chains that is chemically modified to allow binding of polypeptides such as the decorin molecule. Accordingly, the fusion proteins of the present invention may comprise one or preferably two decorin molecules or functional portions thereof and may comprise more than two decorin molecules or functional portions thereof. A number of nucleic acid constructs encoding multifunctional protein molecules of the present invention are provided in the Examples. The following table provides a summary of the sequences. SEQ ID NO:1 Bevacizumab-Decorin Fusion Heavy Chain Genetic Sequence with Signal Sequence (SS) SEQ ID NO:2 Bevacizumab-Decorin Fusion Heavy Chain Protein Sequence with SS SEQ ID NO:3 Bevacizumab light chain genetic sequence with SS SEQ ID NO:4 Bevacizumab light chain protein sequence with SS SEQ ID NO:5 Signal sequence for heavy and light chains SEQ ID NO:6 Linker sequence between decorin and heavy chain SEQ ID NO:7 Decorin SEQ ID NO:8 Bevacizumab heavy chain protein sequence SEQ ID NO:9 Bevacizumab light chain protein sequence SEQ ID NO:10 Ipilimumab-Galacorin fusion heavy chain genetic sequence with SS SEQ ID NO: 11 Ipilimumab-Galacorin fusion heavy chain protein sequence with SS SEQ ID NO: 12 Ipilimumab light chain genetic sequence with SS SEQ ID NO: 13 Ipilimumab light chain protein sequence with SS SEQ ID NO: 14 Sequence Ipilimumab heavy chain protein sequence SEQID NO:15 Ipilimumab light chain protein sequence SEQID NO:16 Atezolizumab-Galacorin fusion heavy chain genetic sequence with SS SEQ ID NO:17 Atezolizumab-Galacorin fusion heavy chain protein sequence with SS SEQ ID NO:18 Atezolizumab light chain genetic sequence with SS SEQ ID NO:19 Atezolizumab light chain protein sequence with SS SEQ ID NO:20 Sequence Atezolizumab heavy chain protein sequence SEQ ID NO:21 Atezolizumab light chain protein sequence SEQ ID NO:22 Avelumab-Galacorin fusion heavy chain genetic sequence with SS SEQ ID NO:23 Heavy chain protein sequence of Avelumab-Galacorin fusion with SS SEQ ID NO:24 Avelumab light chain genetic sequence with SS SEQ ID NO:25 Avelumab light chain protein sequence with SS SEQ ID NO:26 Avelumab heavy chain protein sequence SEQ ID NO:27 Avelumab light chain protein sequence SEQ ID NO:28 Durvalumab-Galacorin fusion heavy chain genetic sequence with SS SEQ ID NO:29 Durvalumab-Galacorin fusion heavy chain protein sequence with SS SEQ ID NO:30 Durvalumab light chain genetic sequence with SS SEQ ID NO:31 Durvalumab light chain protein sequence with SS SEQ ID NO:32 Durvalumab heavy chain protein sequence SEQ ID NO:33 Durvalumab light chain protein sequence SEQ ID NO:34 Nivolumab-Galacorin fusion heavy chain genetic sequence with SS SEQ ID NO:35 Nivolumab-Galacorin fusion heavy chain protein sequence with SS SEQ ID NO: 36 Nivolumab light chain genetic sequence with SS SEQ ID NO:37 Nivolumab light chain protein sequence with SS SEQ ID NO:38 Nivolumab heavy chain protein sequence SEQ ID NO:39 Nivolumab light chain protein sequence Nivolumab SEQ ID NO:40 Genetic sequence of Pembrolizumab-Galacorin fusion heavy chain with SS SEQ ID NO:41 Protein sequence of Pembrolizumab-Galacorin fusion heavy chain with SS SEQ ID NO:42 Genetic sequence of light chain of Pembrolizumab with SS SEQ ID NO:43 Pembrolizumab light chain protein sequence with SS SEQ ID NO:44 Pembrolizumab heavy chain protein sequence SEQ ID NO:45 Pembrolizumab light chain protein sequence SEQ ID NO: 50 Genetic sequence of Avelumab-Galacorin fusion heavy chain SEQ ID NO:51 Protein sequence of Avelumab-Galacorin fusion heavy chain SEQ ID NO:52 Genetic sequence of Avelumab light chain SEQ ID NO:53 Protein sequence Avelumab Light Chain SEQ ID NO:54 Avelumab-Galacorin2x Fusion Heavy Chain Genetic Sequence SEQ ID NO:55 Avelumab-Galacorin2x Fusion Heavy Chain Protein Sequence SEQ ID NO:56 Heavy Chain Genetic Sequence Avelumab-Galacorin / Decorin TGF-Beta binding domain fusion (full-length endogenous human Decorin Asp45-Lys359) crcozn / L^nz / q / Yi SEQ ID NO:57 TGF-Beta binding domain fusion heavy chain protein sequence of Avelumab-Galacorin / Decorin (full-length endogenous human Decorin Asp45-Lys359) SEQ ID NO:58 Heavy chain genetic sequence Avelumab-Galacorin / Decorin 2x fusion TGF-Beta binding domains (full length endogenous human Decorin Asp45-Lys359) sequence SEQ ID NO:59 Heavy chain protein sequence 2x fusion TGF-Beta binding domains Avelumab-Galacorin / Decorin Beta (Full-length endogenous human Decorin Asp45-Lys359) SEQ ID NO:60 Genetic sequence of TGF-binding domain fusion heavy chain Avelumab-Galacorin / Decorin Beta (Leu155-Val260 of full length endogenous human Decorin) SEQ ID NO:61 Avelumab-Galacorin / Decorin TGF-Beta binding domain fusion heavy chain protein sequence (Leu155-Val260 of full length endogenous human Decorin) SEQ ID Fusion Heavy Chain Genetic Sequence 2x TGF-Beta Binding Domain of Avelumab-Galacorin / Decorin (Full Length Endogenous Human Decorin Leu155-Val260) SEQ ID NO:63 Fusion Heavy Chain Protein Sequence 2x Avelumab-Galacorin / Decorin TGF-Beta binding domain (Leu155-Val260 full-length endogenous human Decorin) Thus, in some preferred embodiments, the fusion proteins of the present invention comprise the heavy and light chain variable regions of Bevacizumab, Ranibizumab, Pegaptanib, Ipilimumab, Atezolizumab, Avelumab, Durvalumab, Nivolumab, or Pembrolizumab operably linked to a molecule of decorin, preferably a decorin core protein. In other preferred embodiments, the fusion proteins comprise one, two, or all three of CDR1, CDR2, and CDR3 of the Bevacizumab, Ranibizumab, Pegaptanib, Ipilimumab, Atezolizumab, Avelumab, Durvalumab, Nivolumab, or Pembrolizumab heavy and light chain variable regions linked operably to a decorin molecule, preferably a decorin core protein. In some preferred embodiments, the decorin molecule (or molecules if more than one copy is used) is decorin core protein having at least 80%, 90%, 95%, 99%, or 100% identity to SEQ ID NO:7. In other preferred embodiments, the decorin molecule (or molecules if more than one copy is used) is a decorin TGF-β binding domain having at least 80%, 90%, 95%, 99%, or 100 % identity to SEQ ID NO:64 or 66. In some preferred embodiments, decorin core protein inhibits TGF-β activity. In some preferred embodiments, the decorin core protein comprises one or more mutations that cause the decorin core protein to be non-gagylated. In some preferred embodiments, the decorin core protein comprises a mutation at amino acid 4 (ie, the 4th amino acid from the N-terminus) of the mature decorin core protein molecule. In some preferred embodiments, the decorin core protein molecule is linked to the heavy or light chain of a target antibody via a linker sequence. The present invention is not limited to any particular linker sequence. In some preferred embodiments, the linker sequence is link ID SEQ NO: 6. In some particularly preferred embodiments, the linker sequence is attached to the N-terminus of the antibody heavy chain and position between the heavy chain and the decorin core protein. Consequently, in some preferred embodiments, heavy chain fusion can be represented by the following formula: Heavy chain protein - linker - decorin core protein In other preferred embodiments, the fusions can be represented by means of the following formulas: C-terminal heavy chain protein - linker - decorin C-terminal light chain protein - linker - decorin Decorin - linker - N-terminal heavy chain protein Decorin - linker - N-terminal light chain protein Decorin-linker-constant region where the decorin can be wild-type decorin, decorin core protein, or a functional portion thereof as described in detail above and where the linkage is via amide bonds in a protein fusion as known in the art or chemically modified amino acid in the N-terminal, C-terminal or constant region of the antigen-binding protein. For example, aldehyde-labeled immunoglobulin (Ig) polypeptides can be converted by a formylglycine-generating enzyme to produce a 2-formylglycine-modified Ig polypeptide (FGIy). A FGIy-modified Ig polypeptide can be covalently linked site-specifically with a moiety of interest to provide an Ig conjugate. See, for example, US Patent No. 10,183,998, incorporated by reference herein in its entirety. In some preferred embodiments, a secretion signal sequence precedes the heavy chain protein sequence to allow secretion from host cells during protein production. Likewise, in some preferred embodiments, a secretion signal sequence precedes the light chain protein sequence to allow secretion from host cells during protein production. In some preferred embodiments, where the targeting molecule is Bevacizumab, the heavy chain sequence is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:8 and the light chain sequence is at least 90%, 95%, 99% or 100% identical to SEQ ID NO:9. In some preferred embodiments, the targeting molecule binds to or inhibits VEGF-A. In some preferred embodiments, where the targeting molecule is Ipilimumab, the heavy chain sequence is at least 90%, 95%, 99% or 100% identical to SEQ ID NO:14 and the light chain sequence is at least 90%, 95%, 99% or 100% identical to SEQ ID NO:15. In some preferred embodiments, the targeting molecule binds to or inhibits CTLA-4. In some preferred embodiments, where the targeting molecule is Atezolizumab, the heavy chain sequence is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:20 and the light chain sequence is at least 90%, 95%, 99% or 100% identical to SEQ ID NO:21. In some preferred embodiments, the targeting molecule binds to or inhibits PD-L1. In some preferred embodiments, where the targeting molecule is Avelumab, the heavy chain sequence is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:26 and the light chain sequence is at least 90%, 95%, 99% or 100% identical to SEQ ID NO:27. In some preferred embodiments, the targeting molecule binds to or inhibits PD-L1. In some preferred embodiments, where the targeting molecule is Durvalumab, the heavy chain sequence is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:32 and the light chain sequence is at least 90%, 95%, 99% or 100% identical to SEQ ID NO:33. In some preferred embodiments, the targeting molecule binds to or inhibits PD-L1. In some preferred embodiments, where the targeting molecule is Nivolumab, the heavy chain sequence is at least 90%, 95%, 99% or 100% identical to SEQ ID NO:38 and the light chain sequence is at least 90%, 95%, 99% or 100% identical to SEQ ID NO:39. In some preferred embodiments, the targeting molecule binds to or inhibits PD-1. In some preferred embodiments, where the targeting molecule is Pembrolizumab, the heavy chain sequence is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:44 and the light chain sequence is at least 90%, 95%, 99% or 100% identical to SEQ ID NO:45. In some preferred embodiments, the targeting molecule binds to or inhibits PD-1. In certain embodiments, fusion protein preparations are provided. Such preparations may comprise, for example, unpurified or purified fusion proteins. Generally, such preparations include a buffer such as phosphate- or tris-buffered saline (PBS or TBS, respectively). The preparations can also be formulated to contain excipients, such as stabilizers, for example. In some preferred embodiments, the present invention further provides nucleic acid expression constructs encoding the fusion proteins of the present invention. Accordingly, in some embodiments, the expression constructs encode the fusion protein sequences described above and are operably associated with additional nucleic acid sequences required for expression in the selected expression system. In one example, the fusion protein-encoding nucleotide sequences are constructed in a vector system, and then expressed in host cells. In one example, the host cells are cultured cells. In one example, the vector system is used in cultured mammalian cells under conditions where the fusion proteins are expressed. The fusion polynucleotides of the present invention can be used to produce fusion polypeptides by recombinant techniques. Thus, for example, the polynucleotide can be included in any of a variety of expression vectors to express a polypeptide. In some embodiments of the present invention, vectors include, but are not limited to, retroviral vectors, chromosomal, non-chromosomal, and synthetic DNA sequences (eg, SV40 derivatives, bacterial plasmids, phage DNA; baculovirus, yeast plasmids). , vectors derived from combinations of plasmids and phage DNA, and viral DNA such as vaccinia, adenovirus, fowlpox virus, and pseudorabies). It is contemplated that any vector may be used as long as it is replicable and viable in the host. In some preferred embodiments, the vectors are retroviral vectors as described in US Patent Nos. 6,852,510 and 7,332,333 in US Patent Publication Nos. 200402335173 and 20030224415, all of which are incorporated herein by reference in its entirety. In some especially preferred embodiments, the vectors are pseudotyped retroviral vectors. In particular, some embodiments of the present invention provide recombinant constructs comprising one or more of the sequences as broadly described above. In some embodiments of the present invention, the constructs comprise a vector, such as a plasmid or viral vector, into which a sequence of the invention has been inserted, in a forward or reverse orientation. In still other embodiments, the heterologous framework sequence is assembled in appropriate phase with the conversion initiation and termination sequences. In preferred embodiments of the present invention, the appropriate DNA sequence is inserted into the vector using any of a variety of procedures. In general, the DNA sequence is inserted into an appropriate restriction endonuclease site(s) by procedures known in the art. Large numbers of suitable vectors are known to those of skill in the art, and are commercially available. Such vectors include, but are not limited to, the following vectors: 1) Bacterial pQE70, pQE60, pQE-9 (Qiagen), pBS, pD10, Phagescript, ps¡X174, pbluescript SK, pBSKS, pNH8A, pNH16a, pNH18A, pNH46A (Stratagene); ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia); 2) Eukaryote - pWLNEO, pSV2CAT, pOG44, PXT1, pSG (Stratagene) pSVK3, pBPV, pMSG, pSVL (Pharmacia); and 3) Baculovirus - pPbac and pMbac (Stratagene). Any other plasmid or vector can be used as long as it is replicable and viable in the host. In some preferred embodiments of the present invention, the mammalian expression vectors comprise an origin of replication, a suitable promoter and enhancer, and also any necessary ribosome binding sites, polyadenylation sites, splice donor and acceptor, termination sequences conversion, and 5' flanking unconverted sequences. In other embodiments, DNA sequences derived from SV40 splicing, and polyadenylation sites can be used to provide the required unconverted genetic elements. In certain embodiments of the present invention, the DNA sequence in the expression vector is operably linked to an appropriate expression control sequence(s) (promoter) to direct mRNA synthesis. Promoters useful in the present invention include, but are not limited to, the LTR or SV40 promoter, the E. coli lac or trp, lambda phage Pl and Pr, T3 and T7 promoters, and immediate early cytomegalovirus (CMV). , Herpes Simplex Virus (HSV) thymidine kinase, and mouse metallothionein-1 promoters and other promoters known to control gene expression in prokaryotic or eukaryotic cells or their viruses. In other embodiments of the present invention, recombinant expression vectors include origins of replication and selectable markers that allow transformation of the host cell (for example, resistance to dihydrofolate reductase or neomycin for eukaryotic cell culture, or resistance to tetracycline or ampicillin). in E. coli). In some embodiments of the present invention, transcription of the DNA encoding the polypeptides of the present invention by higher eukaryotes is increased by inserting an enhancer sequence into the vector. Enhancers are oís-acting elements of DNA, usually 10 to 300 bp that act on a promoter to increase its transcription. Enhancers useful in the present invention include, but are not limited to, the SV40 enhancer on the late side of the 100 to 270 bp origin of replication, a cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the origin replication, and adenovirus enhancers. In other embodiments, the expression vector also contains a ribosome binding site for conversion initiation and a transcription terminator. In still other embodiments of the present invention, the vector may also include appropriate sequences to amplify expression. In a further embodiment, the present invention provides host cells containing the constructs described above. In some embodiments of the present invention, the host cell is a higher eukaryotic cell (eg, a mammalian or insect cell). In other embodiments of the present invention, the host cell is a lower eukaryotic cell (eg, a yeast cell). In still other embodiments of the present invention, the host cell may be a prokaryotic cell (eg, a bacterial cell). Specific examples of host cells include, but are not limited to, Escherichia coli, Salmonella typhimurium, Bacillus subtilis, and different species within the genera Pseudomonas, Streptomyces, and Staphylococcus, as well as Saccharomycees cerivisiae, Schizosaccharomycees pombe, Drosophila S2 cells, Spodoptera Sf9, Chinese Hamster Ovary (CHO) cells, monkey kidney fibroblast lines COS-7, (Gluzman, Cell 23:175

[1981] ), C127, 3T3, 293, 293T, lines HeLa and BHK cell phones. The constructs in host cells can be used in a conventional manner to produce the gene product encoded by the recombinant sequence. In some embodiments, introduction of the construct into the host cell can be accomplished by retroviral transduction, calcium phosphate transfection, DEAE-Dextran-mediated transfection, or electroporation (see, for example, Davis et al.

[1986] Basic Methods in Molecular Biology). Alternatively, in some embodiments of the present invention, the polypeptides of the invention may be produced synthetically by conventional peptide synthesizers. The proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free conversion systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by Sambrook, et al. (1989) Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y. In some embodiments of the present invention, after transformation of a suitable host strain and growth of the host strain to an appropriate cell density in medium, the protein is secreted and the cells are cultured for an additional period. In other embodiments of the present invention, cells are generally harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification. In still other embodiments of the present invention, microbial cells employed in protein expression may be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or the use of cell lysing agents. Additional embodiments provide kits that include fusion proteins and optionally other crcQzn / Lznz / q / Yi components useful, necessary, or sufficient to utilize the fusion proteins (eg, therapeutic, research, and screening applications). The kit fusion proteins can be provided in any suitable form, including frozen, lyophilized, or in a pharmaceutically acceptable buffer such as TBS or PBS. The fusion proteins described herein and or derivatives thereof can also be incorporated into compositions for use in vitro or in vivo. The antibody, fusion protein, or derivatives thereof can also be fixedly bound to functional effector moieties such as cytotoxic drugs or toxins, or active fragments thereof such as diphtheria A chain, exotoxin A chain, ricin chain. A, abrin A chain, curcin, crotin, fenomycin, enomycin, among others. The functional portions may also include radiochemicals. In one embodiment, the effector moieties can be tightly bound to the binding agents. In one example, the detectable labels are fixedly attached to the binding agents via chemical bonds. In one example, the chemical bonds are covalent chemical bonds. In one example, the effector moieties are conjugated to the binding agents. The fusion proteins described herein can be prepared as an injectable preparation, such as in suspension in a non-toxic parenterally acceptable diluent or solvent. Suitable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution, TBS, and PBS, among others. The formulation may contain excipients, such as stabilizers, for example. In certain applications, the antibodies are suitable for use in vitro. In other applications, the antibodies are suitable for use in vivo. Preparations suitable for use in any case are well known in the art and will vary depending on the particular application. Fusion proteins can be combined with one or more pharmaceutically acceptable carriers prior to administration to a host. A pharmaceutically acceptable carrier is a material that is not biologically or otherwise undesirable, eg, the material can be administered to a subject, without causing any undesirable biological effects or interacting in a detrimental manner with any of the other components of the composition. pharmaceutical in which it is contained. The carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be known to one of skill in the art. Suitable pharmaceutical carriers and their formulations are described in, for example, Remington s: The Science and Practice of Pharmacy, 2nd Edition, David B. Troy, ed., Lippicott Williams & Wilkins (2005). Generally, an appropriate amount of a pharmaceutically acceptable salt is used in the formulation to produce the isotonic formulation. Examples of pharmaceutically acceptable carriers include, but are not limited to, sterile water, saline, buffered solutions such as Ringer's solution, and dextrose. The pH of the solution is generally about 5 to 8 or about 7 to 7.5. Other carriers include sustained release preparations such as semi-permeable matrices of solid hydrophobic polymers containing polypeptides or fragments thereof. The matrices can be in the form of shaped articles, for example, films, liposomes, or microparticles. It will be apparent to those of skill in the art that certain carriers may be more preferable depending on, for example, the route of administration and concentration of the composition being administered. Carriers are those suitable for administration of polypeptides and / or fragments thereof to humans or other subjects. Pharmaceutical compositions can also include carriers, thickeners, diluents, buffers, preservatives, surface active agents, adjuvants, immunostimulants, in addition to the fusion protein. The pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, and anesthetics. IV. Applications The embodiments of the present disclosure provide compositions and methods for research, screening, and therapeutic applications. For example, embodiments of the present invention provide methods for treating a variety of diseases using the multifunctional protein molecules described herein. In some embodiments, the compositions and methods of the present invention are used to treat diseased cells, tissues, organs, or pathological conditions and / or disease states in an animal (for example, a mammalian patient including, but not limited to , humans and veterinary animals). In this sense, various diseases and pathologies are susceptible to treatment or prophylaxis using the present methods and compositions. An exemplary, non-limiting list of these diseases and conditions includes, but is not limited to, pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, cancer brain, primary brain carcinoma, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head and neck carcinoma, breast carcinoma, ovarian carcinoma, carcinoma of the lung, small cell lung carcinoma, Wilms tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostate carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, carcinoma of the adrenal cortex, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, lymphocytic leukemia chronic, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin lymphoma, soft tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia and retinoblastoma, and the like, and macular degeneration. Some embodiments of the present invention provide methods for administering an effective amount of a fusion polypeptide of the invention and at least one additional therapeutic agent (including, but not limited to, chemotherapeutic antineoplastics, apoptosis-modulating agents, antimicrobials, antivirals, antifungals, etc.). , and anti-inflammatory agents) and / or therapeutic technique (for example, surgical intervention, and / or radiotherapies). In a particular embodiment, the additional therapeutic agent(s) is / are me / an anti-cancer agent. A number of suitable anticancer agents are contemplated for use in the methods of the present invention. In fact, the present invention contemplates, but is not limited to, the administration of numerous anti-cancer agents such as: agents that induce apoptosis; polynucleotides (eg, antisense, ribozymes, siRNA); polypeptides (eg, enzymes and antibodies); biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (eg, antibodies conjugated to anticancer drugs, toxins, defensins), toxins; radionuclides; biological response modifiers (eg interferons (eg IFN-α) interleukins (eg IL-2)); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (eg, all-trans-retinoic acid); gene therapy reagents (eg, antisense therapy reagents and nucleotides); tumor vaccines; angiogenesis inhibitors; proteasome inhibitors; NF-KB modulators; anti-CDK compounds; HDAC inhibitors; and the like. Numerous other examples of chemotherapeutic compounds and cancer therapies suitable for co-administration with the disclosed compounds are known to those of skill in the art. In certain embodiments, anticancer agents comprise agents that induce or stimulate apoptosis. Agents that induce apoptosis include, but are not limited to, radiation (eg, X-rays, gamma rays, UV rays); Tumor Necrosis Factor (TNF)-related factors (eg, TNF-family receptor proteins, TNF-family ligands, TRAIL, antibodies to TRAIL-R1 or TRAIL-R2); kinase inhibitors (for example, epidermal growth factor receptor (EGFR) kinase inhibitor, vascular endothelial growth factor (VGFR) kinase inhibitor, fibroblast growth factor receptor (FGFR) kinase inhibitor Receptor), Platelet-Derived Growth Factor Receptor (PDGFR) kinase inhibitor, and BcrAbl kinase inhibitors (such as GLEEVEC)); antisense molecules; antibodies (eg, HERCEPTIN, RITUXAN, ZEVALIN, and AVASTIN); anti-estrogens (eg, raloxifene and tamoxifen); anti-androgens (eg flutamide, bicalutamide, finasteride, aminoglutetamide, ketoconazole and corticosteroids); cyclooxygenase 2 (COX-2) inhibitors (eg, celecoxib, meloxicam, NS-398, and non-steroidal anti-inflammatory drugs (NSAIDs)); anti-inflammatory drugs (eg, butazolidin, DECADRON, DELTASONE, dexamethasone, dexamethasone intensol, DEXONE, HEXADROL, hydroxychloroquine, METICORTEN, ORADEXON, ORASONE, oxyphenbutazone, PEDIAPRED, phenylbutazone, PLAQUENIL, prednisolone, prednisone, PRELONE, and TANDEARIL); and cancer chemotherapy drugs (for example, irinotecan (CAMPTOSAR), CPT-11, fludarabine (FLUDARA), dacarbazine (DTIC), dexamethasone, mitoxantrone, MYLOTARG, VP-16, cisplatin, carboplatin, oxaliplatin, 5-FU, doxorubicin , gemcitabine, bortezomib, gefitinib, bevacizumab, TAXOTERE, or TAXOL); cell signaling molecules; ceramides and cytokines; staurosporine, and the like. In still other embodiments, the compositions and methods of the present invention provide a compound of the invention and at least one antihyperproliferative or antineoplastic agent selected from alkylating agents, antimetabolites, and natural products (for example, and herbs and other compounds derived from plants and / or animals). Alkylating agents suitable for use in the present compositions and methods include, but are not limited to: 1) nitrogen mustards (eg, mechlorethamine, cyclophosphamide, ifosfamide, melphalan (L-sarcolysine); and chlorambucil); 2) ethyleneimines and methylmelamines (for example, hexamethylmelamine and thiotepa); 3) alkyl sulfonates (eg, busulfan); 4) nitrosoureas (eg, carmustine (BCNU); lomustine (CCNU); semustine (methyl-CCNU); and streptozocin (streptozotocin)); and 5) triazenes (eg, dacarbazine (DTIC; dimethyltriazenoimidazolecarboxamide). In some embodiments, suitable antimetabolites for use in the present compositions and methods include, but are not limited to: 1) folleo acid analogs (eg, methotrexate (ametopterin)); 2) pyrimidine analogs (eg, fluorouracil (5-fluorouracil; 5-FU), floxuridine (fluorodeoxyuridine; FudR), and cytarabine (cytosine arabinoside)); and 3) purine analogs (eg, mercaptopurine (6-mercaptopurine; 6-MP), thioguanine (6-thioguanine; TG), and pentostatin (2,-deoxycoformycin)). In yet other embodiments, chemotherapeutic agents suitable for use in the compositions and methods of the present invention include, but are not limited to: 1) vinca alkaloids (eg, vinblastine (VLB), vincristine); 2) epipodophyllotoxins (eg etoposide and teniposide); 3) antibiotics (eg, dactinomycin (actinomycin D), daunorubicin (daunomycin; rubidomycin), doxorubicin, bleomycin, plicamycin (mitramycin), and mitomycin (mitomycin C)); 4) enzymes (eg, L-asparaginase); 5) biological response modifiers (eg, interferon-alpha); 6) platinum coordination complexes (eg, cisplatin (cis-DDP) and carboplatin); 7) anthracenediones (eg mitoxantrone); 8) substituted ureas (eg hydroxyurea); 9) methylhydrazine derivatives (eg, procarbazine (N-methylhydrazine; MIH)); 10) adrenal cortical suppressants (eg, mitotane (ο,ρ'-DDD) and aminoglutethimide); 11) adrenocorticosteroids (eg, prednisone); 12) progestins (eg, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate); 13) estrogens (for example, diethylstilbestrol and ethinylestradiol); 14) antiestrogens (for example, tamoxifen); 15) androgens (for example, testosterone propionate and fluoxymesterone); 16) antiandrogens (eg, flutamide): and 17) gonadotropin-releasing hormone analogues (eg, leuprolide). Any oncolytic agent that is routinely used in a cancer therapy context finds use in the compositions and methods of the present invention. For example, the United States Food and Drug Administration (FDA) maintains a formulary of oncolytic agents approved for use in the United States of America. International agencies homologous to the U.S.F.D.A. they maintain similar forms. The following Table provides a list of exemplary anti-neoplastic agents approved for use in the United States of America. Those of skill in the art will appreciate that the "product labels" required on all approved chemotherapeutic products in the United States of America describe approved indications, dosing information, toxicity data, and the like, for the exemplary agents. Aldesleukin (des-alanyl-1, serine-125 human interleukin-2) Proleukin Chiron Corp., Emeryville, CA Alemtuzumab (IgG1 κ anti-CD52 antibody) Campath Millennium and ILEXPartners, LP, Cambridge, MA Alitretinoin (9-cis-retinoic acid ) Panretin Ligand Pharmaceuticals, Inc., San Diego CA Allopurinol (1,5-dihydro-4 H -pyrazolo[3,4-d]p¡r¡m¡n4-one monosodium salt) Zyloprim GlaxoSmithKIine, Research Triangle Park, NC Altretamine (N,N,N',N',N,N,-hexamethyl-1,3,5-triaz¡ne-2,4,6-triamine) Hexalen US Bioscience, WestConshohocken, PA Amifostine (ethanethiol , 2-[(3-aminopropyl)amino]-, dihydrogen phosphate (ester)) Ethyol US Bioscience Anastrozole (1,3-benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1 H-1, 2,4triazol-1-ylmethyl)) Arimidex AstraZeneca Pharmaceuticals, LP, Wilmington, DE Arsenic trioxide Trisenox Cell Therapeutic, Inc., Seattle, WA Asparaginase (L-asparagine amidohydrolase, type EC-2) Elspar Merck & Co., Inc ., Whitehouse Station, NJ BCG L¡ve (Freeze-dried preparation of an attenuated strain of Mycobacterium bovis (Badilas Calmette-Gukín [BCG], Montreal substrain) TICE BCG Organon Teknika, Corp., Durham, NC bexarotene capsules (4-Acid [1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2naphthalenyl)ethenyl]benzoic) Targretin Ligand Pharmaceuticals bexarotene gel Targretin Ligand Pharmaceuticals Bleomycin (cytotoxic glycopeptide antibiotics produced by Streptomyces vertidllus ', bleomycin A2 and bleomycin B2) Blenoxane Bristol-Myers Squibb Co., NY, NY Capecitabine (5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine) Xeloda Roche Carboplatin (platinum, diamine [1,1-cyclobutanedicarboxylate(2-)-0, O']-,(SP- 4-2)) Paraplatinum Bristol-Myers Squibb Carmustine (1,3-bis(2-chloroethyl )-1-nitrosourea) BCNU, BICNU Bristol-Myers Squibb Carmustine with Polifeprosan Implant 20 Gliadel Wafer Guilford Pharmaceuticals, Inc., Baltimore, MD Celecoxib (as 4-[5-(4-methylphenyl)-3-(trifluoromethyl) -lH-pyrazol-1-yl]benzenesulfonamide) Celebrex Searle Pharmaceuticals, England crcQzn / Lznz / q / Yi Chlorambucil (4-[bis(2chloroethyl)amino]benzenebutanoic acid) Leukeran GlaxoSmithKIine Cisplatin (PtCI2H6N2) Platinol Bristol-Myers Squibb Cladribine (2-chloro-2'-deoxy-b-D-adenosine) Leustatin, 2CdA R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ Cyclophosphamide (2-[bis(2-chloroethyl)am¡no]tetrahydro-2H-13,2-oxazaphosphorine 2-oxide monohydrate) Cytoxan, Neosar Bristol-Myers Squibb Cytarabine (1-b-D- Arabinofuranosylcytosine, C9H13N3O5) Cytosar-U Pharmacia & Upjohn Company liposomal cytarabine DepoCyt Skye Pharmaceuticals, Inc., San Diego, CA Dacarbazine (5-(3,3-dimethyl-l-triazene)-imidazole-4 -carboxamide (DTIC)) DTIC-Dome BayerAG, Leverkusen, Germany Dactinomycin, Actinomycin D (actinomycin produced by Streptomyces parvullus, C62Hs6Nl2016) Cosmegen Merck Darbepoetin alfa (recombinant peptide) Aranesp Amgen, Inc., Thousand Oaks, CA Liposomal daunorubicin ( (8S-c¡s)-8-acet¡l-10-[(3-amino-2,3,6-tridesox¡- á-L-l¡xo-hexop¡ranos¡l)ox¡] hydrochloride -7,8,9,1O-tetrahydro-6,8,11-trihydroxy-1-methoxy¡-5,12-naphthazenedione) DanuoXome Nexstar Pharmaceuticals, Inc., Boulder, CO Daunorubicin HCI, daunomycin ((1S) hydrochloride ,3 S )-3-acetyl-1,2,3,4,6,11-hexahydro3,5,12-trihydroxy-10-methoxy¡-6,11 -dioxo-1-naphthacenyl 3-amino- 2,3 ,6-trideoxy-(alpha)-L-lixo-hexopyranoside) Cerubidin Wyeth Ayerst, Madison, NJ Denileukin diftitox (recombinant peptide) Ontak Seragen, Inc., Hopkinton, MA Dexrazoxane ((S)-4,4'-(1 -methyl-1,2-ethanediyl)b¡s-2,6-p¡peraz¡nad¡one) Zinecard Pharmacia & Upjohn Company Docetaxel ((2R,3S)-N-carboxy-3-phenyl ester Isoserine, N-tert-butyl, 13-ester with 5b-20-epoxy-12a,4,7b,10b,13a-hexahydroxytax-11en-9-one 4-acetate 2-benzoate, trihydrate) Taxotere Aventis Pharmaceuticals, Inc. , Bridgewater, NJ Doxorubicin HCI ((8S,10S)-10-[(3-am¡no-2,3,6-tr¡deox¡-a-L¡xohexopyranosyl)oxy] -8-glycol¡l-7 hydrochloride ,8,9,1 O-tetrahydro-6,8,11trih¡drox¡-1-methoxy-5,12-naphthazenedione hydrochloride) Adriamycin, Rubex Pharmacia & Upjohn Company crcQzn / Lznz / q / Yi doxorubicin Adriamycin Intravenous Injection PFS Pharmacia & Upjohn Company liposomal doxorubicin Doxil Sequus Pharmaceuticals, Inc., Menlo park, CA dromostanolone propionate (17b-hydroxy¡-2a-methyl-5a-androstan-3-one propionate) Dromostanolone Eli Lilly & Company, Indianapolis, IN dromostanolone propionate Injection Masteron Syntex, Corp., Palo Alto, CA Elliott's Solution B Elliott's Solution B Orphan Medical, Inc Epirubicin ((8S-cis)-10-[(3-amino- 2,3,6-tridesoxy¡-a-Larabino-hexop¡ranos¡l)ox¡]-7,8,9,10-tetrahydro-6,8,11trihydroxy-8-(hydroxyacetyl)-l-methoxy-5 ,12-naphthazenedione) Ellence Pharmacia & Upjohn Company Epoetin alfa (recombinant peptide) Epogen Amgen, Inc Estramustine (estra-1,3,5(10)-triene-3,17-diol(17(beta))-, 3- [bis(2chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate, or estradiol 3-[bis(2chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate) Emcyt Pharmacia & Upjohn Company Phosphate Etoposide (4'-Demethylepipodophyllotoxin 9-[4,6-O-(R)-etlliden-(beta)-Dglucopyranoside], 4'-(dihydrogen phosphate)) Etopofos Bristol-Myers Squibb Etoposide, VP-16 (4 '-Demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-(beta)-Dglucopyranoside]) Vepesid Bristol-Myers Squibb Exemestane (6-methyleneandrosta-1,4-diene-3,17-dione) Aromasin Pharmacia & Upjohn Company Filgrastim (r-metHuG-CSF) Neupogen Amgen, Inc floxuridine (intra-arterial) (2'-deoxy-5-fluorouridine) FUDR Roche Fludarabine (fluorinated nucleotide analog of the antiviral agent vidarabine, 9-b-D-arabinofuranosyladenine ( ara-A)) Fludara Berlex Laboratories, Inc., Cedar Knolls, NJ Fluorouracil, 5-FU (5-fluoro-2,4(1H,3H)-pyrimidinedione) Adrucil ICN Pharmaceuticals, Inc., Humacao, Puerto Rico Fulvestrant (7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra1,3,5-(10)-triene-3,17-beta-d iol) Faslodex IPR Pharmaceuticals , Guayama, Puerto Rico crcozn / L^nz / q / Yi Gemcitabine (2'-deox¡-2',2'-difluorocy¡t¡d¡ne monohydrochloride (b-isomer)) Gemzar Eli Lilly Gemtuzumab ozogamicin (hP67.6 anti-CD33) Mylotarg Wyeth Ayerst Goserelin acetate Zoladex implant AstraZeneca Pharmaceuticals Hydroxyurea Hydrea Bristol-Myers Squibb Ibritumomab Tiuxetan (immunoconjugate resulting from a covalent thiourea link between the monoclonal antibody Ibritumomab and the chelator-linker tiuxetan [N-[2-bis(carbox¡methyl)am¡no]- 3(p-Isothiocyanatophenyl)- propyl]-[N-[2-b¡s(carboxymethyl)am¡no]-2-(methyl)-ethyl]glycine) Zevalin Biogen IDEC, Inc., Cambridge MA Idarubicin ( 5,12-Naftazenodlone, 9-acetyl-7-[(3-amino-2,3,6-trideoxy(alpha)-L-lixo-hexopyranos¡l)ox¡]-7,8,9,10-tetrahydro -6,9,11 trihydroxyhydrochloride, (7S-cis)) Idamycin Pharmacia & Upjohn Company Ifosfamide (3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3 ,2-oxazaphosphorine 2-oxide) IFEX Bristol-Myers Squibb Imatinib Mesylate (4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl ]amino]-phenyl]benzamide methanesulfonate) Gleevec Novartis AG, Basel, Switzerland Interferon alpha-2a (recombinant peptide) Roferon-A Hoffmann-La Roche, Inc., Nutley, NJ Interferon alpha-2b (recombinant peptide) Intron A (Betaseron lyophilized) Schering AG, Berlin, Germany Irinotecan HCI ((4S)-4,11-dimethyl-4-h¡drox¡-9-[(4piperi-dinopiperidino)carbonyloxy]-1H-pyran[3] hydrochloride trihydrate ',4': 6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)dione) Camptosar Pharmacia & Upjohn Company Letrozole (4,4'-(1H-1,2,4- Triazol-1-ylmethylene) dibenzonitrile) Femara Novartis Leucovorin (L-glutamic acid, N[4[[(2amino-5-formyl1,4,5,6,7,8 hexahydro4oxo6-pteridinyl)methyl]am¡ no]benzoyl], calcium salt (1:1)) Wellcovorin, Leucovorin Immunex, Corp., Seattle, WA Levamisole HCI ((-)-(S)-2,3,5,6-tetrahydro-6- fen¡l¡midazo[2,1-b]tlazol CiiHi2N2S-HCI) Ergamisol Janssen Research Foundation, Titusville, NJ crcozn / L^nz / q / Yi Lomustine (1 -(2-chloro-ethyl)-3-c¡clohex¡l-1-n¡trosourea) CeeNU Bristol-Myers Squibb Mechlorethamine, Nitrogen Mustard (2-chloro-N-(2-chloroethyl)- Hydrochloride N-methylethanamin) Mustargen Merck Megestrol acetate 17a(acetyloxy¡)-6-methylpregna-4,6-diene-3,20-dione Megace Bristol-Myers Squibb Melphalan, L-PAM (4-[b¡ s(2-chloroethyl)am¡no]-L-phen¡lalan¡na) Alkeran GlaxoSmithKIine Mercaptopurine, 6-MP (1,7-dihydro-6 H-purine-6-thione monohydrate) Purinethol GlaxoSmithKIine Mesna (2- sodium mercaptoethanesulfonate) Mesnex Asta Medica Methotrexate (N-[4-[[(2,4-diamino-6- pter¡d¡n¡l)methyl]methyllam¡no]benzo¡l]-L Acid -glutamic acid) Methotrexate Lederle Laboratories Methoxalene (9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one) Uvadex Therakos, Inc., Way Exton, Pa Mitomycin C Mutamycin Bristol-Myers Squibb Mitomycin C Mitozytrex SuperGen, Inc., Dublin, CA Mitotane (1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane) Ly sodren Bristol-Myers Squibb Mitoxantrone (1,4 Dihydrochloride -dihidrox¡-5,8-b¡s[[2- [(2- hidroxiet¡l)am¡no]ethyl]am¡no]-9,10-anthracened¡one) Novantrone Immunex Corporation Nandrolone phenpropionate Durabolin-50 Organon, Inc., West Orange, NJ Nofetumomab Verluma Boehringer Ingelheim Pharma KG, Germany Oprelvekin (IL-11) Neumega Genetics Institute, Inc., Alexandria, VA Oxaliplatin (cis-[(1R,2R)-1,2 -cyclohexanediamine-N,N'] [oxalato(2-)-O,O'] platinum) Eloxatin Sanofi Synthelabo, Inc., NY, NY Paclitaxel (5β, 20-Epoxy-1,2a, 4, 7β, 10β, 13a-hexahydroxytax-11 -en-9one 4,10-diacetate 2-benzoate 13-ester with (2R, 3S)- Nbenzoyl-3-phenylisoserine) TAXOL Bristol-Myers Squibb Pamidronate (Phosphonic acid (3- amino-1 -hydroxypropylidene) bis-, disodium salt, pentahydrate, (APD)) Aredia Novartis crcQzn / Lznz / q / Yi Pegademase ((Monomethoxy polyethylene glycol succinimidyl) 11-17 -adenosine deaminase) Adagen (Bovine Pegademase) Enzon Pharmaceuticals, Inc., Bridgewater, NJ Pegaspargase (Monomethoxy polyethylene glycol succinimidyl L-asparaginase) Oncaspar Enzon Pegfilgrastim (covalent conjugate of recombinant methionyl G-CSF human ) and monomethoxy polyethylene glycol) Neulasta Amgen, Inc Pentostatin Nipent Parke-Davis Pharmaceutical Co., Rockville, MD Pipobroman Vercyte Abbott Laboratories, Abbott Park, IL Plicamycin, Mithramycin (Antibiotic produced by Streptomyces plicatus) Mithracin Pfizer, Inc., NY, NY Porfimer sodium Photofrin QLT Phototherapeutics, Inc., Vancouver, Canada Procarbazine (N-isopropyl-p-(2-methylhydraz¡no)-ptoluamide monohydrochloride) Matulane SigmaTau Pharmaceuticals, Inc., Gaithersburg, MD Quinacrine (6-chloro-9 -( 1-methyl-4-diethyl-amine)butylamino-2-methoxyacridine) Atabrine Abbott Labs Rasburicase (recombinant peptide) Elitek Sanofi-Synthelabo, Inc., Rituximab (anti-CD20 recombinant antibody) Rituxan Genentech, Inc., South San Francisco , CA Sargramostim (recombinant peptide) Prokine Immunex Corp Streptozocin (2-deoxy-2-[[(methylnitrosoam¡no)carbon¡l]am¡no]-a(and b)-D glucopyranosay 220 mg anhydrous citric acid) Zanosar Streptozocin Pharmacia & Upjohn Company Talc (Mg3Si4Oio (OH)2) Sclerosol Bryan, Corp., Woburn, MA Tamoxifen ((Z)2-[4-(1,2-diphenyl-l-butenyl)phenoxy]-N,N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxylate (1:1)) Nolvadex AstraZeneca Pharmaceuticals Temozolomide (3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as -tetrazine-8carboxamide) Temodar Schering crcQzn / Lznz / q / Yi teniposide, VM-26 (4'-demethylep¡podof¡lotox¡na 9-[4,6-0-(R)-2-tenylidene-(beta)D-glucopyranoside]) Vumon Bristol-Myers Squibb Testolactone (acid 13 -h i droxy -3-oxo-13,17-secoandrosta-1,4-dien-17-oico [dgr ]-lactone) Teslac Bristol-Myers Squibb Thioguanine, 6-TG (2-am¡no-1,7- dihydro-6 H -purine-6-thione) Thioguanine GlaxoSmithKIine Thiotepa (Aziridine, Ι,Τ,Γ-phosphinothioilidinetris-, or Tris(1-aziridinyl)phosphine sulfide) Thioplex Immunex Corporation Topotecan HCI ((S)-10 Monohydrochloride -[(dimethylamino)methyl]-4-ethyl-4,9dihydroxy-1H-pyrano[3', 4': 6,7]indolizino[1,2-b]quinoline-3,14-(4H, 12H)-dione) Hicamtina GlaxoSmithKIine Toremifene (2-(p-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]-phenoxy¡)-N,Ndimethylethylamine citrate (1:1) ) Fareston Roberts Pharmaceutical Corp., Eatontown, NJ Tositumomab, I 131 Tositumomab (recombinant murine immunotherapeutic monoclonal lambda anti-CD20 lgG2a antibody (1131 is a radioimmunotherapeutic antibody)) Bexxar Corixa Corp., Seattle, WA Trastuzumab (anti-HER2 IgGi kappa antibody recombinant monoclonal) Herceptin Genentech, Inc Tretinoin, ATRA (all-trans retinoic acid) Vesanoid Roche Mustard Uracil Mustard Capsules Uracil Roberts Labs Valrubicin, N-trifluoroacetyladriamycin-14-valerate ((2S-c¡ s)-2-[1,2 ,3,4,6,11 -hexah i dro-2,5,12-trih id roxy -7 methox¡-6,11-dioxo-[[4 2,3,6-trideox¡-3- [(trifluoroacetyl )am¡no-a-L- / / xo-hexopyranos¡l]ox¡l]-2-naphthacen¡l]-2-oxoeth¡l pentanoate) Valstar Anthra -> Medeva Vinblastine, Leurocristine (C46H56N4Ol0'H2SO4) Velban Eli Lilly Vincristine (θ46Η56Ν4θΐ0 Η2δθ4) Oncovin Eli Lilly Vinorelbine (3',4'-d¡dehydro-4'-deox¡-C'-norv¡ncaleucoblast¡na [R-(R*,R*)2,3-d ¡ hid roxibutanod i oate (1:2)(salt)]) Navelbine GlaxoSmithKIine Zoledronate, Zoledronic acid ((1 -H¡drox¡-2-¡m¡dazol-1 -yl-phosphonoethyl) phosphonic acid monohydrate) Zometa Novartis crcozn / L^nz / q / Yi Anti-cancer agents further include compounds that have been identified as having anti-cancer activity. Examples include, but are not limited to, 3-AP, 12-O-tetradecanoylphorbol-13-acetate, 17AAG, 852A, ABI-007, ABR-217620, ABT-751, ADI-PEG 20, AE-941, AG- 013736, AGRO100, alanosine, AMG 706, G250 antibody, antineoplastons, AP23573, apaziquone, APC8015, atiprimod, ATN-161, atrasenten, azacitidine, BB-10901, BCX-1777, bevacizumab, BG00001, bicalutamide, BMS 2475, bortezomib -1, buserelin, calcitriol, CCI-779, CDB2914, cefixime, cetuximab, CG0070, cilengitide, clofarabine, combretastatin A4 phosphate, CP-675,206, CP-724,714, CpG 7909, curcumin, decitabine, DENSPM, doxercalciferol, E7070, E7389, ecteinascidin 743, efaproxiral, eflornithine, EKB569, enzastaurin, erlotinib, exisulin, fenretinide, flavopiridol, fludarabine, flutamide, fotemustine, FR901228, G17DT, galiximab, gefitinib, genistein, glufosfamide, GTI-2040, histrelin, HSPharington, HSPharington, HSPharington -96, hu14.18-interleukin-2 fusion protein, HuMax-CD4, iloprost, imiquimod, infliximab, interleukin-12, IPI-504, irofulven, ixabepilone, lapatinib, lenalidomide, lestaurtinib, leuprolide, LMB-9 immunotoxin, lonafarnib, luniliximab, mafosfamide, MB07133, MDX-010, MLN2704, monoclonal antibody 3F8, monoclonal antibody J591, motexafine, MS-275, MVAMUC1-IL2, nilutamide, nitrocamptothecin, nolatrexed dihydrochloride, nolvadex, NS-9, 06-benzylguanine, oblimersen sodium, ONYX-015, oregovomab, OSI-774, panitumumab, paraplatin, PD-0325901, pemetrexed, PHY906, pioglitazone, pirfenidone, pixantrone, PS-341, PSC 833, PXD101, pyrazoloacridine, R115777, RAD001, ranpyrnase analog rebecamycin, rhuAngiostatin protein, rhuMab 2C4, rosiglitazone, rubitecan, S-1, S-8184, satraplatin, SB-, 15992, SGN-0010, SGN-40, sorafenib, SR31747A, ST1571, SU011248, suberoylanilide hydroxamic acid, suramin, talabostat , talampanel, tariquidar, temsirolimus, TGFa-PE38 immunotoxin, thalidomide, thymalfasin, tipifarnib, tirapazamine, TLK286, trabectedin, trimetrexate glucuronate, TroVax, UCN-1, valproic acid, vinflunine, VNP40101M, volociximab, vorinostat, VX-680, ZD1839 , ZD6474, zileuton and zosuchidar trihydrochloride. For a more detailed description of anti-cancer and other therapeutic agents, those of skill in the art refer to any number of instructional manuals including, but not limited to, Physician's Desk Reference and Goodman and Gilman's "Pharmaceutical Basis of Therapeutics". 10th Edition, Eds. Hardman et al., 2002. In some embodiments of the present invention, a fusion protein of the invention and one or more therapeutic agents or anti-cancer agents are administered to an animal under one or more of the following conditions: at different periodicities, at different durations, at different concentrations, by different routes of administration, etc. Fusion proteins within the scope of this invention include all fusion proteins described herein, wherein the fusion proteins of the present invention are contained in an amount that is effective to achieve their intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Generally, the compounds can be administered to mammals, eg, humans, orally at a dose of 0.0025 to 50 mg / kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of body weight of the mammal being treated for disorders that respond to the induction of apoptosis. In one embodiment, about 0.01 to 0.01 mg / kg is administered orally to treat, alleviate, or prevent such disorders. For intramuscular injection, the dose is generally approximately half the oral dose. For example, a suitable intramuscular dose would be approximately 0.0025 to 25 mg / kg, or approximately 0.01 to 5 mg / kg. The unit oral dose may comprise about 0.01 to 1000 mg, eg, about 0.1 to 100 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets or capsules, each containing about 0.1 to 10 mg, conveniently about 0.25 to 50 mg of the compound or its solvates. In a topical formulation, the compound may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier. In one embodiment, the compound is present at a concentration of about 0.07-1.0 mg / ml, eg, about 0.1-0.5 mg / ml, and in one embodiment, about 0.4 mg / ml. The pharmaceutical compositions of the invention can be administered to any patient who can experience the beneficial effects of the compounds of the invention. Primarily among such patients are mammals, eg humans, the invention is not intended to be so limited. Other patients include veterinary animals (cows, sheep, pigs, horses, dogs, cats, and the like. The compounds and pharmaceutical compositions thereof can be administered by any means that achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, or topical routes. Alternatively, or at the same time, administration may be by the oral route. The dosage administered will depend on the age, health, and weight of the recipient, type of concurrent treatment, if any, frequency of treatment, and the nature of the desired effect. The pharmaceutical preparations of the present invention are manufactured in a manner which is per se known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Therefore, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules, then adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium phosphate or hydrogen phosphate, as well as binders such as paste. starch, using, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone. If desired, disintegrating agents may be added, such as the aforementioned starches and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Auxiliaries are mainly flow regulating and lubricating agents, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate and / or polyethylene glycol. The dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate are used. Dyestuffs or pigments may be added to tablet or dragee coatings, for example, in order to characterize combinations of active compound doses. Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules may contain the active compounds in the form of granules that can be mixed with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds in one embodiment are dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. Additionally, stabilizers can be added. Possible pharmaceutical preparations that can be used rectally include, for example, suppositories, which comprise a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. Additionally, it is also possible to use rectal gelatin capsules consisting of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons. Formulations suitable for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. Additionally, suspensions of the active compounds can be administered as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, eg sesame oil, or synthetic fatty acid esters, eg ethyl oleate or triglycerides or polyethylene glycol-400. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension include, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. Optionally, the suspension can also contain stabilizers. The topical compositions of this invention are formulated in one embodiment as oils, creams, lotions, ointments, and the like by choosing appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight (greater than C12) alcohol. Carriers can be those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants as well as color or fragrance imparting agents may also be included, if desired. Additionally, transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in the US Patents United States Nos. 3,989,816 and 4,444,762; each incorporated herein by reference in its entirety. Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one that includes about 30% almond oil and about 70% white soft paraffin by weight. Lotions may conveniently be prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol. One of skill in the art will readily recognize that the foregoing merely represents a detailed description of certain preferred embodiments of the present invention. Various modifications and alterations to the compositions and methods described above can be readily accomplished using available skill in the art and are within the scope of the invention. EXPERIMENTAL Example 1 expression constructs This example describes the design of expression constructs that are inserted into expression vectors for recombinant production of fusion proteins. Anti-VEGF Bevacizumab-Galacorin fusion heavy chain genetic sequence (SEQ ID NO:1): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTaTTCCATGCCACCCAGGCCGAGGTGCAGCTGGT GGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATACACCTTTAC CAACTATGGCATGAACTGGGTCCGCCAGGCTCCAGGgGAAGTGGCTGGTAGCT ACTTACACT GGTGAGCCAACATATGCAGCTGACTTCAAGCGCCGGTTTACCTTCTCTTTGGACACCTCCAAGTCCACGGCCTATCT GCAAATGAACAGCCTGCGGGCCGAGGACACGGCCGTATATTACTGTGCGAAATACCCCCACTACTACGGTAGTAGC CACTGGTACTTTGACGTGTGGGGCCAGGGAACCCTGGTCACCCGTCCCTCGTCGTCCCGTCG CTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGT CCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGACAGGCCATCACCG GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCC CACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCCTTTCCCCCCAAAACCCAAGGACACCTCAT GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTCAGGACGATGTCGATGTCGG CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC CTCCCAGCCCCCATCGAGAAAACCATTCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCC CATCCCGGAAGACGATGATGCCGACCTG TCAAAGGCTTCTATCCCAGCGACATCGC CGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTC CTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGAQqfqfqqfqG ccGATGAG GCTGCAGGGATAGGCCCAGAAGITCCLGAJGACCGCGACTTCGAGCCCTCCCTAGGCCCA^ TGTCAATGCCATCnCGAGTGGTCCAGTGIICJWTTGGGTCTGGACAAAGTGCCAAAGGAIGTTCCCCCTGACAC AACTCTGCTAGACCTGCAAAACAACAAATM^^ ATTGATTCTIGTCAACAATAAAAITAGCAAAGITAGTCCIGGAGCATTTACACCTTTGGTGAAGTTGGAACGACJTTAT GIGICCAAGAATCAGCIGAAGGAATIGCCAGAAAAAAIGCCCAAAACTCTICAGGAGCTGCGTGCCCATGAGAATGA GATCACCAAAGTGCGAAAAGTTACTTTCAATGGACTGAACCAGATGATTGTCATAGAACTGGGACAGAGATCCGATO^AGATCCGATO\ GGCTJICCAGGGAAI^^ ACCAGCATTCCTCAAGGTCTTCCTCCTTCCCTTACGGAATTACATCTTGATGGCAACAAAATCAGCAGAGTTGATGCA GCTAGCCTGAAAGGACTGAATAAITTGGCTAAGTTGGGATTGAGTTICAACAGCATCTCTGCTGTTGACAATGGCTCI CTGGCCAACACGCCTCAJCTGA^GGAGCTTCACTTGGACAACAACAAGCTTAGACAGAGTAGCTAGCAGTAG TCCAGGTTGTCTACCTTCAIMCAACAATATC^ GACACAACACCAAAAAAGGCTTCTIAIICGGGTGTGAGJCTTTTCAGCAACCCGGTCCAGTACTGGGAGATACAGCCA TCCACCTTCAGATGTGTCTACGTGCGCIGIGCCATTCAACJCGGAAACTAIAAGTGA The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. The linker coding sequence is shown in italics. The Galacorin coding sequence is underlined with a wavy line. Bevacizumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:2): MMSFVSLLLVGILFHATQAEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINT YTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVF PLAPSSKSTSGGTAALGCLVLVQWSSGALVQWNSSGALV LYSLSSWTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSLNKALPAPIEKTISKAKGQPREPQVYTLPPVSREEMTCLVK PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGKSGGGGSP.EAAG.IGPEyPD.m KNLKNLHALILVNNKISKVSPGAFTPLVKLERLYLSKNQLKELPEKMPKTLQELRAHENEITKVRKVTFNGLNQMIVIELGTN PLKSSGIENGADAFQGMNILPTSK ISRVDAASLKGLNNLAKLGLSFNSISAVDNGSLAN YVRSAIQLGNYK The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. The linker sequence is shown in italics. The Galacorin sequence is underlined with a wavy line. Bevacizumab light chain genetic sequence (SEQ ID NO:3): crcQzn / Lznz / q / Yi ataATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTGTTCCATGCCACCCAGGCCGACATCCAGATGACC CAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTGCAAGTCAGGACATTAGCAA TTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTGATCTAACCTG ACTCAGG GGTCCCATCTAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATT TTGCAACTTATTACTGCCAACAGTATAGTACCGTGCCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGA ACTGTGGCTGCACCATCTGTCTTCATCTTCTCCGCCATCTGATGATCCGGCTGCAGT CTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCA GACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGTCCGTCACAAAGGTTAGCT The signal peptide coding sequence is shown in bold. The light chain coding sequence is underlined with a straight line. Bevacizumab light chain protein sequence (SEQ ID NO:4): MMSFVSLLLVGILFHATQADIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVUYFTSSLHS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLN NFYPREAKVQWKVDNALVQSGNSKTYDSKELT HKVYACEVTHQGLSSPVTKSFNRGEC The signal peptide sequence is shown in bold. The light chain sequence is underlined with a straight line. Component amino acid sequences: Signal sequence for heavy and light chains (SEQ ID NO:5): MMSFVSLLLVGILFHATQA Sequence of linker between decorin and heavy chain (SEQ ID NO:6): SGGGGS Decorin (SEQ ID NO:7): DEAAGIGPEVPDDRDFEPSLGPVCPFRCQCHLRWQCSDLGLDKVPKDLPPDTTLLDLQNNKITEIKDGDFKNLK NLHALILVNNKISKVSPGAFTPLVKLERLYLSKNQLKELPEKMPKTLQELRAHENEITKVRKVTFNGLNQMIVIELGTNPLKS SGIENGAFQGMKKLSYIRIADTNITSIPQGLPPSLTELLAHSLDA NSISAVDNGSLANTPHL RELHLDNNKLTRVPGGLAEHKYIQWYLHNNNISWGSSDFCPPGHNTKKASYSGVSLFSNPVQYWEIQPSTFRCVYVRS AIQLGNYK Bevacizumab heavy chain protein sequence (SEQ ID NO:8): EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSL DTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHSSGTVLPSLQWSSGCLPA ICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Bevacizumab light chain protein sequence (SEQ ID NO:9): DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTI SSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC crcQzn / Lznz / q / Yi anti-CTLA4 Genetic sequence of Ipilimumab-Galacorin fusion heavy chain (SEQ ID NO:10): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCcagqtgcagctgqtggaqtc cggcggcggcgtcgtgcagcccggccggtccctgcqgctgtcctgcgccgcctccggcttcaccttctcctcctacaccatgcactgggtgcggcaggccccccgcaaggt gcctcctgaggt ggcaacaacaagtactacgccgactccgtgaagggccggttcaccatctcccgcgacaactccaagaacaccctgtac ctgcagatgaactccctgcgggccgaggacaccgccatctactactgcgcccggaccggctggctgggccccttcgactactggggccagggcaccctggtgaccgtgt cctccGCCTCCACGAGTCCAGCCCCAGCACTCAG CTCTGGGGGCACAGCGGCC CTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCA GCTTGGGCACCCAGACCTACATCTCAGCAACGCCAGACGTCAG ggGTTGAGCC CAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCT TCCCCCCAAAACCCAAGGACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCA CGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGAGGACGGTCGATAGATGATG GA GGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATTCCAAAGCCAAAGGGCAGCCC CGAGAACCACAGGTGTACACCCTGCCTCCATCCCGcgatGAGCTGACCAACACTGACCCTGTCAGCAG CCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCAC GCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACCGCAGAAGAGCCTCTCCGCT gafccGATGAGGCIGCAGSSAIAGGCCCAGAAGTICCTGATGACCGGGACTTCGAGCCCI CCCTAGGCCCAGTGIGCGCCTICCGCIGTCAATGCCATCTTCGAGIGGTCCAGTGTTCTGATTTGGGTCTGGACAAA GTGCCAAAGGATCTTCCCCCTGACACAACTCTGCTAGACCTGCAAAACAACAAAATAACCGAAATCAAAGATGGAGA CCTTTGGTGAAGTTGGAACGACTTTATCTGTCCAAGAATCAGCTGAAGGAAJTGCCAGAAAAAATGCCCAAAACTCTT CAGGAGCTOCGTGCCCATGAGAALGAGATCACCAAAGTGCGAAAAGnAQITTCAATGGACTGAACCAGATGALTGT CATAGAACTGGGCACCAATCCGCTGAAGAGCTCAGGAATTGAAAATGGGATCGACTTCAGACTCAGG GATACCAAWCACCAGCATTCCTCAAGGTCTTCCTCCTTCCCTTACGGAATTACATC GGCAACAAAATCAGCAGAGTTGATGCAGCTAGCCTGAAAGGACTGAATAATTTGGCTAAGTTGGGATTGAGTTTCAA CAGCATCTCTGCTGTTGACAATGGCTCTCTGGCCAACACGCCTCATCTGAGGGAGCTTCACTTGGACAACAACAAGC TTACCAGAGTACCTGGTGGGCTGGCAGAGCATAAGTACATCCAGGTTGTCTACCTTCATAACAACAATATCTCTGTA GTTGGATCAAGTGACTTCTGCCCACCTGG.ACACACACCAAAAAAG.GCTTCGATTCGATTGCATTCGATTCG TCCAGTACTGGGAGATACAGCCATCCACCTTCAGATGTGTCTACGTGCGCTCTGCCATTCAAC~CGGAAACT ATAAGTGA The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. The linker coding sequence is shown in italics. The Galacorin coding sequence is underlined with a wavy line. Ipilimumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO: 11): MMSFVSLLLVGILFHATQAQVQLVESGGGWQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYD GNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPALGCLVKDYFPEPVL YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKADISKAKGQPREPQVYTLPPSRDELTVKNQVENQVSA KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSG GGGSDEAAGlGFEyPDDRDFEPSLGPyCPFRCQCHmWQCSDLGLDKyPIW UJAULyNNKISKySPGAFTPÜ / KLERLYLS^^ ELHLDNNKLTRVPGGLAEHKYIQWYLHNNNISWGSSDFCPPGHNTKKASYSGVSLFSNPVQYWEIQPSTFRCVYVRSAI QLGNYK The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. The linker sequence is shown in italics. The Galacorin sequence is underlined with a wavy line. Ipilimumab light chain genetic sequence (SEQ ID NO:12): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCgagatcgtqctgacccagtc ccccqqcaccctqtccctqtccccccqqcqaqcqqqcccacctqtcctqccqqqcctcccaqtccqtqqgctcctcctacctqqcctqqtaccaqcaqaaqcccqqccqcctaqcccqqcctacctaqqcct qccttctcccqcqccaccqqcatccccqaccqqttctccqqctccqqctccqqcaccqacttcaccctqaccatctcccgqctqqqaq cccqaqqqacttcqccqtgtactactqccaqcaqtacqqctcctccccctqqaccttcqqccaqqgcaccaaqqtqqaqatcaaqcqaACTGTGTGCTGCTGCACGTCCATGCATGTCGATGTCG CTTAAGTCCGGAACTGCTAGCGTTGTGTGCCTGCTGAATAACTT CTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACA GAGCAGGACAGCAAGGACAGCACCTACGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACAC AAAGTCTACGCCCGATCGACGACGTC AGCTTCAACAGGGGAGAGTGTT AG The signal peptide coding sequence is shown in bold. The light chain coding sequence is underlined with a straight line. Ipilimumab light chain protein sequence (SEQ ID NO:13): MMSFVSLLLVGILFHATQAEIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSR ATGIPDRFSGSGSGTDFLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCL LNNFYPREAKVQWKVDNALQSGNSQESVTEDSKVTE YACEVTHQGLSSPVTKSFNRGEC The signal peptide sequence is shown in bold. The light chain sequence is underlined with a straight line. Component amino acid sequences: Signal sequence for heavy and light chains (SEQ ID NO:5): Sequence of linker between decorin and heavy chain (SEQ ID NO:6): Name (SEQ ID NO:7): Ipilimumab heavy chain protein sequence (SEQ ID NO:14): QVQLVESGGGWQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVGHTLFPAYLSSGVGHTVLSSTYLNSG VNHKPSNTKVDKRVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEKVESNGLTYPSDIAVEWESNG KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Ipilimumab light chain protein sequence (SEQ ID NO:15): EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLT ISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSPLSSTLTKVADYEKVCENG CE Anti-PD-L1 Genetic sequence of Atezolizumab-Galacorin fusion heavy chain (SEQ ID NO:16): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAGGTACAACTCGT GGAATCCGGCGGGGGACTCGTCCAACCGGGTGGTAGTCTCAGGTTGAGCTGCGCTGCGAGCGGTTTCACTTTCTC AGACTCATGGGATTCATTGGGTGCGCCAAGCACCTGGAAAAGGGTTGGAATGGTCGTCGTCGTCGTC ACTACGCTGATTCAGTAAAGGGGCGGTTCACAATTTCAGCCGATACTTCCAAAAATACGGCTTACCT GCAAATGAACTCTTTGAGGGCGGAGGATACGGCGGTCTACTACTGTGCACGCAGGCACTGGCCTGGAGGGTTCGA TTATTGGGGTCAAGGCACTTTGGTAACCGTATCCTCCGCTTCTACCAAAGGCCCATCAGCTCCTCCACTGTCGTCGTCG GCCGCACTTGGATGTCTCGTCAAAGACTACTTTCCTGAGCCGGTAACTGTG TCATGGAACTCCGGCGCCCTCACTAGCGGCGTCCATACATTTCCAGCGGTTCTCCAGTCAAGTGGCCTCTACAGCC TGTCCAGTGTAGTTACTGTCCCGTCTTCTAGTCTGGGAACGCAAACATATATTTGCAATGTGAATCATAAGCCTAGGA ACACAAATTAAGATAAG CAAAACGCATACCTGTCCGCCTTGTCCGGCCCCCGA ACTCTTGGGCGGCCCATCAGTCTTTCTCTTCCCGCCCAAACCTAAGGACACGTTGATGATAAGTCGCACGCCCGAG GTTACATGCGTCGTAGTCGATGTCAGCCACGAGGATCCGGAGGTAAAGTTTAACTGGTATGTAGACGGAGTTGAAGT ACACAACGCCAAAACTAAACCGAGAGAGGAGCAGTACGCATCAACCTATCGCGTAGTATCTGTATTCACGATAGTCAACTG CAAGTGCAAAGTTTCTAATAAAGCCCTCCCTGCACCAATCGAAAAGACT ATTTCAAAGCCAAAGGACAACCAAGAGAACCACAAGTTTATACAKGCCACCTAGTCGCGAGGAGATGACTAAAAA CCAAGTGTCCCTTACTTGTCTCGTAAAGGGTTTCTATCCAAGCGACATAGCAGTTGAGTGGGAAAGTAATGGCCAGC CGGAAAACCAACTTCACCAGATGACTTCCGATG TTTGTATAGTAAACTCACAGTTG ATAAGAGTCGATGGCAGCAGGGGAATGTTTTTTCTTGCTCTGTGATGCACGAGGCGCTCCACAACCACTATACGCAA AAGTCCCTCAGCCTGAGCCCCGGGAAATCCGGGGG7GGCGGATCCGATGAGGCTGCAGGGATAGGCCCAGAAGTT CCTGATGACCGCGACTTCGAGCCGATCCCTAGGCCGATCCG CTTCGAGIGGTGG AGTGTTCTGATTTGGGTCTGGACAAAGTGCCW^GATCITCCCCCTGACAOAACTCTGCTAGACCTGCAAAACAAC AAAATAACCGAAATCAAAGATGGAGACTTTAAGAACCTGAAGMCCTTCACGCATTGATTCTTGTCAACAATAAAATTA GCAAAGTWICCTGGAGCanTACACCIITGCTGAAWOCTGATCGACTAGTCAGATGATGA AAAAATGCCCAAAACTCTTCAGGAGCTGCGTGCCCATGAGAATGAGATCACCAAAGLGCGAAAAGTTACT TTCAATGGACTGAACCAGATGATTGTCABGMCTGGGCACCAATCCGCTGAAGAGCTCAGGAATTGAAAATGGGGC TTTCCAGGGAATGAAGAAGCICICCTACATCCGCATIGCIGATACCAATATCACCAGCATTCCICAAGCACCCITCCGACIGAT IFCACCITCGACIGAT I AGCAGAGI^^ GGGTAAGnGGGAnGAGTITCAACAGCATCTCTGCTGTTGACAATGGCTCTCTGGCCAACACGCCTCATCTG AGCTTCACTTGGACAACAACMGCTTACCAGAGTACCTOGTGGGCTGGCAGAGCATAAGTACATCCAGGTTGTCTAC CTTCAITWJAACAMAJCTCTGTAGTTOGATCA^^ TCGGGTGTGAGTCTTTTCGGAACTCGGAATCGAT CCACCTTCj^GATOTGTCTACGTGC GCTCTGCCATTCAACTCGGAAACTATAAGTGA The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. The linker coding sequence is shown in italics. The Galacorin coding sequence is underlined with a wavy line. Atezolizumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO: 17): MMSFVSLLLVGILFHATQAEVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPY GGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPS SKSTSGGTAFPLAPSGCLVKDYGEPVTSVSLVQWNSLVSY SSWTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQWESKVESYTKNQWESVSA TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSG GGGSDEAAGLGPB / PDDRDFEPSl^PVCPFRCQCHmWCíCSDLGLDm Ο1ΑυυΖΝΝΚΙ8Κν8Ρ0ΑΕΙΡΙΛ / ΚίΕβίΥ|ΚίΕβίΥ| ELHLDNNKLTRVPGGLAEHKYIQWYLHNNNISWGSSDFCPPGHNTKKASYSGVSLFSNPVQYWEIQPSTFRCVYVRSAI QLGNYK The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. The linker sequence is shown in italics. The Galacorin sequence is underlined with a wavy line. Atezolizumab light chain genetic sequence (SEQ ID NO: 18): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGACATTCAGATGAC ACAATCACCTAGCAGTCTGAGTGCGAGCGTAGGTGATCGCGTAACGATTACCTGCAGGGCCTCTCAAGACGTGTCA ACGGCAGTGGCGTGGTACCAGCAGAAGCCTGGTAAAGCTCCTAAGCTCTCCTCATCTATTAGTAGTAG AAGATTTTCCGGAAGCGGATCAGGTACAGATTTTACTTTGACTATCAGTAGTTTGCAGCCAGAGG ATTTCGCTACATATTACTGTCAACAATATCTCTATCACCCTGCCACTTTTGGACAAGGGACTAAAGTCGAAATAAAAC GAACAGTGGCCGCACCAAGCGTTTTTATCTTTCCCCCATCCGACGAGCAGTTGAAGAGCGGCACCGCGTCCGTGTAGTGACTGTTAGCTCAGC TGCAATGGAAAGTTGATAATGCGCTTCAATCCGGAAACT CACAAGAATCAGTAACAGAACAAGACTCTAAAGACAGTACATATTCTCTTAGTAGCACACTCACTCTTTCAAAGGCTG ACTATGAGAAACATAAAGTGTACGCTTGTGAAGTGACACATCAAGGTCTTAGCTCCCCAGTAACTAAGAGCTTTAATA GGGGCGAGTGCTGA The signal peptide coding sequence is shown in bold. The light chain coding sequence is underlined with a straight line. Atezolizumab light chain protein sequence (SEQ ID NO: 19): MMSFVSLLLVGILFHATQADIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLN NFYPREAKVQWKVDNALQSGNSKDSTTYSKVDSK KVYACEVTHQGLSSPVTKSFNRGEC The signal peptide sequence is shown in bold. The light chain sequence is underlined with a straight line. Component amino acid sequences: Signal sequence for heavy and light chains (SEQ ID NO:5): Sequence of linker between decorin and heavy chain (SEQ ID NO:6): Decorin (SEQ ID NO:7): Atezolizumab heavy chain protein sequence (SEQ ID NO:20): EVQLVESGGGLVQPGGSLRLSCAASGFFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISAD TSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVGHTVLPSSTYLSSGVGHTLFPAVL VNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGP NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Atezolizumab light chain protein sequence (SEQ ID NO:21): DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTI SSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Anti-PD-L1 Genetic sequence of Avelumab-Galacorin fusion heavy chain (SEQ ID NO:22): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAGGTACAGCTTTT GGAGTCAGGCGGGGGGCTCGTCCAACCTGGGGGGTCACTCCGGTTGTCATGTGCTGCCAGTGGCTTCACATTTCC ATCTTACATTATGATGTGGGTTCGACAGGCCCCTGGGAAGTGGCTGCTGCTGCTGCTG GGAATTACCTTCTATGCCGACACGGTAAAGGGTCGCTTCACTATAAGTCGAGATAACAGCAAAAATACGCTGTATCT CCAGATGAACTCTCTCAGGGCTGAGGACACAGCTGTATATTACTGCGCGCGGATTAAGTTGGGGACCGTCACAACA GTGGATTACTGGGGTCAAGGCACTCTGGTAACCGTATCCTCAGCATCCACCAAGGGCCCCAACTGTGTATTTCCGTAGTATTCCGTAAG CGGCACAGCCGCTCTCGGTTGCCTGGTTAAGGACTACTTCCCAGAACCTGT CACTGTCAGTTGGAACTCAGGCGCATTGACATCTGGTGTCCATACATTCCCCGCAGTCCTGCAAAGCTCTGGACTTT ACAGTCTTAGTAGCGTAGTGACAGTCCCATCTTCAAGTCTTGGGACCCAAACTTATAATTTGCAACGTAAATCATAAACGTAAGTACCAACATTAAGAAC AACGCATACATGCCCACCATGTCCCGCT CCGGAACTCCTGGGCGGCCCGTCCGTTTTTCTCTTTCCCCCAAAGCCCAAGGATACGCTTATGATCAGCAGAACAC CGGAAGTTACTTGTGTAGTCGTTGACGTGTCTCACGAAGATCCCGAAGTCAAATTTAATTGGTATGTGGATGGCGTC GAAGTGCACAACGCAAAAACCAAACCCATAGAGAGTAACGTAACGTAACGTAACGTAACGTAGTCAGATGTCGTAGTCAACGTCACGTAGTCAAATTGATGTCGTAGTCA TACGG TCCTCCACCAGGACTGGTTGAATGGCAAGGAGTACAAGTGCAAAGTGAGCAATAAAGCGTTGCCAGCCCCGATCGAAAAAACCATCAGCAAGGCCAAGGGACAGCCTAGAGAGCCGCAGGTTTACACCTTGCCGCCATCAAGGGATGAACTG ACTAAAACCAGGTATCCCTGACCTGCCTGGTTAAGGGTTTTTAGGACCAGTGAATTAG CCAGAGAACAACTACAAAACGAACACCTCCCGTTCTGGATTCCGATGGCAGCTTTTTCTTGTATTCTAAAC TCACCGTGGATAAATCCCGATGGCAGCAAGGCAACGTCTTTCTCCTGCAGCGTGATGCATGAAGCCTTGCACAACCA CTATACCCAAAAGAGTCTCAGCCTGTCACCcGGGAAArcCGGGGGÍGGCGGArcGACGATGAGGATAGCTG GCGACTICGAGCCCTCCGIAGGCCCAGTGTGCCCCTTCCGCTGTCAATGCCATCTI CGAGTGGTCCAGTGTTCTGATTTGGGTCTGGACAAAGTGCCAAAGGATCTTCCCCCTGACACAACTCTGCTAGACCT CAATAAAAnAGCAAAGTTAGICCTGGAGCATTIACACCTTTGGTGAAGTTGGAACGACTTTATGTGICCAAGAATCA GCTG^GGAATTCCCAGAAAAAATGCQCAAAACTCTICAGGAGCTGC^^ CGAAAAGILACIJTCAATGGACTGAACCAGATGAIIGT^^ TGAAAAIGGGGCTITCCAGGGAATGAAGAAGCTCICCTACATCCGCATTGCTGATACCAATATCACCAGCAITCCIC AAGGTCTTCCTCCTTCCCTTACGGAATTACATCTTGATGGCAACAAAATCAGCAGAGTTGATGCAGCTAGCCTGAAA GGACTGAATAATTTGGCTAAGTTGGGATTGAGTTTCAACAGCATCTCTGCTGTTGACAATGGCTCTCTGGCCAACAC GCCTCATCTGAGGGAGCTTCACTTGGACAACAACAAGCTTACCAGAGTACCTGGTGGGCTGGCAGAGCATAAGTAC ATCCAGGnOTCXACKyrxCATAACAACAMATCTOIGTAGXIGGAXCMGIG^ AAAAAGGCTTCTIAITCGGGIOTGAGTCTTTTCAGCAACCCGGTCCAGTACTGGGAGAMCAGCCATCCACCTTCAG ATG.TGT.CIACGTGCGCTCXGCCAXTCAACTCGG-AAA.C.TAXAAGTGA The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. The linker coding sequence is shown in italics. The Galacorin coding sequence is underlined with a wavy line. Avelumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:23): MMSFVSLLLVGILFHATQAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPS GGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAFPALGCLVKDYGEPVTSLVQWNSLVSY SSWTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTVKVEGVESLTYTPSLT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSGG GGSDEAAGKSREVPDDTyDFEPSySPyC^^ HALILVNNKISKVSPGAFTPLVKLERLY.LSKNQLKELPEKMPKTLQELRAHEMEITKVRKVTFNGLNQMIVIELGTNPLKSSGI ENGAFQGMKKLSYIRIADINIXSIPQGLPPSn.ELHLDGNKISRVDAASLKGLNNLAKLGXSFNSISA^^ HLDNNKLTRVPGGLAEHKYIQWYLHNNNISWGSSDFCPPGHNTKKASYSGVSLFSNPVQYWEIQPSTFRCVYVRSAIQ LGNYK The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. The linker sequence is shown in italics. The Galacorin sequence is underlined with a wavy line. Avelumab light chain genetic sequence (SEQ ID NO:24): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCCAGTCTGCACTTAC ACAACCGGCGTCCGTTTCCGGATCTCCAGGACAGAGCATTACTATCAGTTGCACGGGAACCTCCTCAGACGTAGGGGGTATAATTATGTGTCTTGGTATCAACAGCATCCCGGGAAAGCCCCCAAATGATGATGATCAGGATGATCAG TAATCGATTTAGCGGGTCTAAATCTGGTAACACAGCATCCCTCACTATTAGTGGACTGCAAG CAGAAGATGAGGCAGACTATTATTGCAGTAGCTATACGTCTAGTTCCACCCGCGTTTTTGGCACTGGGACGAAAGTC ACCGTTCTCGGACAACCAAAAGCAAACCCCACCGTGACTCTGTTTCCGCCTAGCAGCGAAGAATTGCAGGCCAATACGTAA GGCCACTACGGCGCCTACCT CTGTGACAGTCGCGTGGAAAGCCGACGGCAGCCC TGTTAAAGCTGGAGTCGAGACCACGAAGCCGTCCAAGCAGAGTAACAATAAGTATGCTGCATCCAGTTATTCTCTCTC TCACTCCGGAACAGTGGAAGTCCCATCGGTCCTATAGTTGCCAAGTGACCCATGAGGGTTCCACCGTAGAGAAAAC GGTAGCACCTACCGAATGTAGTTGA The signal peptide coding sequence is shown in bold. The light chain coding sequence is underlined with a straight line. Avelumab light chain protein sequence (SEQ ID NO:25): MMSFVSLLLVGILFHATQAQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSN RPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKAT LVACLISDFYPGAVTVAWKADGSPSPVKAGTTSVELTKYLT WKSHRSYSCQVTHEGSTVEKTVAPTE CS The signal peptide sequence is shown in bold. The light chain sequence is underlined with a straight line. Component amino acid sequences: Signal sequence for heavy and light chains (SEQ ID NO:5): Sequence of linker between decorin and heavy chain (SEQ ID NO:6): Decorin (SEQ ID NO:7): Avelumab heavy chain protein sequence (SEQ ID NO:26): EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDN SKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVGHLFPAVLQNSTTYLVSSLV NHKPSNTKVDKKVEPKSCDKTHTTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSQLDENNYWESPTNGFLTSK DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Avelumab light chain protein sequence (SEQ ID NO:27): QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTA SLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKA DGSPVKAGVETTKPSKQSLNTKYAASSYTV APTECS Anti-PD-L1 Durvalumab-Galacorin fusion heavy chain genetic sequence (SEQ ID NO:28): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAGGTCCAGCTTGT TGAAAGCGGTGGTGGCCTCGTGCAGCCTGGTGGCAGTTTGCGGTTGTCTTGCGCAGCTAGTGGTTTTACCTTTCTCC AGATACTGGATGTCATGGGTCCGACAGGCCCCTGGCAAGGGATAGATTAGG GACGGTT CTGAAAAGTACTATGTAGACTCCGTCAAAGGAAGATTTACTATTAGTCGAGACAACGCCAAGAATAGCCTCTACCTTC AGATGAATTCTTTTGCGAGCGGAGGACACAGCCGTATATTACTGCGCACGAGAAGGGGGGTGGTTCGGTGAACTGGC TTTTGACTACTGGGGGCAAGGTACGCTTGTCACGGTGAGCACTCTGCCTCGTCGTA CTCCATCTAGTAAGTCAACTTCTGGAGGTACTGCGGCATTGGGATGCCTTGTTAAGGATTATTTCCCGAACCTGTAA CTGTGAGCTGGAATTCAGGTGCCCTCACCTCTGGTGTACATACCTTTCCAGCAGTTTTGCAATCTTCCGGTTTGTACT CTCTTAGTTCAGTTGTAACTGTCCCCTCTTCCTCTCTTGGTACCCAAACATACATTTGTAATGTCAATCACAAACCAAG CAATACCAAGGTAGACAAGCGGGTGGAACCCAAATCTTGTGACAAAACTCATACCTGCCCACCATGTCCCGCCCCG GAGTTTGAAGGAGGTCCAAGTGTATTTCTTTTCCCGCCTAAGCCTAAGGATACCCTCATGACCAGATAGTCGTGTG GTAGACGTGAGTCACGAAGATCCCGAAGTTAAATTTAATTGGTATGTGGACGGGGTGGAA GTCCATAACGCGAAGACAAAGCCACGCGAAGAGCAGTACAATTCCACGTACAGGGTGGTTAGCGTGCTTACCGTCC TGCATCAAGATTGGCTGAACGGGAAAGAATACAAATGCAAAGTATCCAACAAGGCGTTGCCTAACCGAGTATCGAACACTGA ACCCCAGGTCTATACACTGCCGCCCAGCAGAGAAGAGATGACGA AAAATCAAGTATCCCTTACGTGTCTCGTCAAAGGCTTCTACCCTTCCGATATTGCTGTAGAGTGGGAATCTAACGGG CAGCCGGAAAATAACTACAAGACTACTCCGCCAGTACTTGATTCAGACGGCTCCTTCTTCCTTTATTCAAAACTCACC GTAGATAAAAGTAGGTGATGCAACGTAGTAGTAGATGATGTAGTAGTAG CGTTGCATAACCATTATACA CAGAAATCACTCAGCCTGTCCCCCGGGAAATCCGGGGreGCGGArcCGATGAGGCTGCAGGGATAGGCCCAGAA GTICCTGATGACCGCGACTTCGAGCCCTCGCTAGGCCCAGTGTGCCCCITCCGCTGICAAIGCCAICTTCGAGTGG TCCAGTGTTCJjGAITTGGHIGLGGACAAAGJMSGAT^t^ AACAAAAJAACCGAAATCAAAGATGGAGACTTTAAGAACCTGAAGAACCrrcACGCATTGATTCTTGTCAACAATAAA ATTAGCAAAGIIAGTCCTGGAGGAITTACACCTTTGGTGAAGTIGGAACGACITTATCTGTCCAAGAATCAGCTGAAG GAATTGCCAG.AAAAAATGCCCAAAACTCTTCAGGAGCTOCGTGCCCATGAGAAIGAGACTGAACCAAAGTGTG GATGATTGTCATAGAACTGGGCACCMrCCGCTGAAGAGCTCAGGAATTGAAAATGGGGCTTTCCAGGGAATGAAGAAGCTCTCCTACATCCGCArroCTGATACCAATATCACCAGCATTCCTCAAGGTCTT cctccttcccttacggaattacatcttgatggcaacaaaatcagcagagttgatgcagctagcctgaaaggactGATTCGAA TAATJTGATTG CTCTGCTGJIGACAATGGCTCTCTGGCCAACACGCCTCATCI GAGGGAGCnCACTTGGACAACA^GAAGCTTACCAGAGTACCTGGTGGGCTGGCAGAGCATAAGTACATCCAGGTT GTCTACCTIGATAACAACAATATCTCTGTAGTTOGATCAAGTGACrrCTGCCCACCTGGACACAACCAAAAAAGGCT TCGATGACGTCGTCGCTGCTGCT TGGGAGATACAGCCATCCACCTTCAGATGTGTCTA CGTGCGCTCTGCCATTCAACTCGGAAACTATAAGTGA The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. The linker coding sequence is shown in italics. The Galacorin coding sequence is underlined with a wavy line. Durvalumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:29): MMSFVSLLLVGILFHATQAEVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQ DGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVSGDYFPEPALGCLVSGHTSFALG LYSLSSWTVPSSSLGTQTYICNVNHKPSN TKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPGVSREEMTVKNK ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG KSGGGGSDE.AA.G!GEEyPDDRDFE.PcrcQzn / Lznz / q / Yi LKNLHALILVNNKISKVSPGAFTPLVKLERLYLSKNQLKELPEKMPKTLQELRAHENEITKVRKVTFNGLNQMIVIELGTNPL KSSGIENGAFQGMKKLSYIR ADTNITSIPQGLPPSLTELHLDGNK SRVDAASLKGLNNLAKLGLSFNSISAVDNGSLANTP RSAIQLGNYK The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. The linker sequence is shown in italics. The Galaconna sequence is underlined with a wavy line. Durvalumab light chain genetic sequence (SEQ ID NO:30): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAGATAGTTTTGAC TCAAAGCCCTGGAACGCTCTCTTTGTCTCCCGGCGAGCGGGCGACCTTTCCTGTAGGGCTAGCCAGAGGGTATCT TCCTCTTACCTGGCATGGTACCAGCAAAAGCCCGGACAAGCCCCCCGACTTCTGAATCCATGACGCTCG GATTTCAGGGAGTGGCTCTGGTACCGATTTTACGCTTACGATTTCCAGGCTGGAGCC CGAGGATTTCGCAGTGTATTACTGTCAACAATACGGCAGCTTGCCCTGGACCTTTGGACAAGGAACCAAGGTAGAGA TCAAAAGGACCGTTGCCGCCCCGTCACGTGTTCATCTTCCCTCCGAGCGATGAGCAACTTAAAAGTGGAACTGTACAAGTCCGTTGATCTG CCAAGGTACAGTGGAAAGTGGATAATGCCCTCCAATCTG GCAATAGCCAAGAGTCTGTCACAGAGCAGGACAGCAAGGACTCAACTTATTCACTTAGCTCCACCCCTGACGCTGAGT AAAGCAGACTACGAGAAGCATAAGGTGTATGCTTGTGAGGTTACACACCAAGGCTTGTCTTCTCCTGTCACGAAGTC TTTCAATAGCTGGCGAATG The signal peptide coding sequence is shown in bold. The light chain coding sequence is underlined with a straight line. Durvalumab light chain protein sequence (SEQ ID NO:31): MMSFVSLLLVGILFHATQAEIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSR ATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCL LNNFYPREAKVQWKVDNALQSGNSQVTYYSTACELT VTHQGLSSPVTKSFNRGEC The signal peptide sequence is shown in bold. The light chain sequence is underlined with a straight line. Component amino acid sequences: Signal sequence for heavy and light chains (SEQ ID NO:5): Sequence of linker between decorin and heavy chain (SEQ ID NO:6): Decorin (SEQ ID NO:7): Durvalumab heavy chain protein sequence (SEQ ID NO:32): EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHSSGTVLPSTLPSTY ICNVNHKPSNTKVDKRVEPKSCDKTHTC PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSV LTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSVFFLYWKLTVMFHALCSNNQ YTQKSLSLSPGK Durvalumab light chain protein sequence (SEQ ID NO:33): EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLT ISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHSFKTSGNGESVECV Anti-PD-1 Nivolumab-Galacorin fusion heavy chain genetic sequence (SEQ ID NO:34): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCCAAGTCCAGCTCGT GGAATCAGGAGGGGGTGTAGTCCAACCAGGGCGGAGCCTCCGACTTGATTGTAAAGCATCAGGAATTACATTTTCT AATAGCGGAATGCATTGGGTCCGACAAGCGCCAGGCAAGGGACTGGAATGGGTCGCGGTGATATGGTATGATGGA TCAAAACGCTATTATGCGGACTCTGTGAAGGGTCGATTCACTATTAGCAGAGATACTACGATCATC ACTTAGGGCAGAGGACACAGCGGTGTACTATTGCGCGACGAACGACGATTATTGGGGCCAAGGGA CATTGGTAACGGTGAGTTCTGCTAGTACTAAAGGGCCTTCCGTCTTCCCACTCGCCCCTTGTTCTAGAAGTACTAGT GAGTCAACAGCTGCTTTGGGTTGCTTGGTTAAAGACTTCTCGTCCTGAACCCGTGACTGTGTCTTGGAATTTGATAATG CATTCCCAGCAGTATTGCAGAGCTCTGGCTTGTATTCTCTCTCCTCAGTGGTGACAGT ACCTTCCTCCTCTCCTTGGCACAAAAACTTACACATGTAATGTAGACCATAAACCATCAAACACGAAAGTTGACAAGAG AGTAGAAAGCAAGTATGGGCTCCCATGTCCCCCGTGCCCGGCGCCCGAGTTCCTGGGTGGTCCGTCAGTCGCTTCAGATAGATTCAG AGTCGGACGCCGGAGGTCACATGTGTAGTAGTTGATGTCTTCCA GGAGGATCCTGAGGTGCAGTTTAACTGGTACGTCGATGGTGTTGAGGTACACAACGCCAAAACTAAGCCGAGGGAA GAGCAGTTCAATTCAACATATCGGGTCGTGTCCGTATTGACAGTTCTGCACCAAGATTGGTTGAACGGAAAAGAGTA TAAGTTTCAGGACTCAG AAAAACCATTTCCAAAAGCGAAAGGCCAACCTCGGG AACCTCAGGTATATACCTTGCCACCCAGCCAAGAAGAAATGACTAAAAACCAGGTTAGTTTGACATGTTTGGTTAAAG GCTTTTACCCGTCCGACATTGCCGTCGAGTGGGAAAGCAATGGGCAGCCTGAAAATAACTACAAGACAACCCCACC AGTATTGGATTCCGACGGTTCCTTCTGTCGTACGTAG GCAAGAGGGGAATG TCTTTTCCTGTAGTGTCATGCACGAAGCACTTCACAACCATTACACCCAAAAATCATTGTCCCTGTCACTGGGGAAAÍ CCGGGGGTGGCGGA7~0CGATGAGGCTGCAGGGATAGGCCCAGAAGT~CCTGATGACCGCGACTTCGAGCCCTCCCC CCAAAGGATCITCCCCCIGACACAACTCTGCTAGACCIGCAAAACAACAAAATAACCGAAAICAAAGATGGAGACIII AAGAACCTGAAAGAACCTTCACGCATTGATTCrrGTCAACAATAAAAITAGCAAAGIIAGTCCTGGAGCATTTACACCT TTGGTGAAGTTGGAACGACTTTATCTGTCCAAGAATCAGCTGAAGGAATTGCCAGAAAAAATGCCCAACAGACTGATACGTC ACCAAAGTGCGAAAAGTTACTTTCAATGGACIGAAGGAGATGATIGICAT AGAACTGGGCACCAATCCGCTGAAGAGCTCAGGAATTGAAAATGGGGCTTTCCAGGGAATGAAGAAGCTCTCCTAC ATCCGCATTGCTGATACCAATATCACCAGCATTCCTCAAGGTCTTCCTCCTTCCCTTACGGAATTACATCTTGATGGC AACAAAATCAGCAGAGTTGATGGAGCTAGCCTGAAAGGACTGAATAAT~TGGCTAAGTTGGGATTGAGTTTCAACAG CATCTCTGCTGnGACAATGGCTCTCTGGCCAAGACGCTCATCIOAGGGAGCTAACACTTGCTGTAG GCTGGCAGAGCATAAGTACATCCAGGLTGTCTACCTTCATAACAACMIATCTCTGTAGTT GGAICAAGTGACTTCTGCCCACCIGGACACAACACCAAAAAAGGCTTCTTATICGGGTGIGAGICTTTTCAGCAACCC GGTCCAGTACTGGGAGATACAGCCATCCACCTTCAGATGTCTCTACGTGCGCTCTGCCA^^ AGTGA The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. The linker coding sequence is shown in italics. The Galacorin coding sequence is underlined with a wavy line. Nivolumab-Galacorin fusion heavy chain protein sequence (SEO ID NO:35): MMSFVSLLLVGILFHATQAQVQLVESGGGWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWY DGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTS ESTAALGCLVKDYFPEPVTVSWNSGALTSLTSGVHTTVLFSSGVHTFLSSG KTYTCNVDHKPSNTKVDKRVE SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS TYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYWESKPSQEEMTKNQVSLTCLVKY FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKSGGGGSDEAA GIGPEyPDDRD-F.-EP.SLGPVCPFRGQCHLRWQGSDL.GLDKyP.KDLPPDTTLL.DLQNNKnEJKD-G-DFKO KISKySPGAFTPLyKLERLYLSKtOJ<B£EKM^^GMJKlJILTIMPIRICOD^^GMKIlfjYIRICOD LTRVPGaAEHJlYIQyyWÍMlWGSSDFC^PGHNTKKASY^ The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. The linker sequence is shown in italics. The Galacorin sequence is underlined with a wavy line. Nivolumab light chain genetic sequence (SEO ID NO:36): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAAATCGTATTGAC TCAGTCCCCTGCTACACTTTCACTGAGTCCGGGTGAGCGGGCGACTTTGTCATGTCGGGCATCACAGAGTGTAAGT AGTTATCTGGCCTGGTATCAACAGAAACCGGGACAGGCTCCTCGCCTGCACTGATTTATGACCGATCGG CGAGGTTCTCAGGGTCTGGATCAGGTACTGACTTTTACCCTTACGATCTCTTCTCTCGAACCTGAG GATTTCGCTGTCTATTACTGCCAGCAGTCTTTCTAACTGGCCGAGAACATTTGGTCAAGGGACAAAAGTCGAGATTAA GCGAACTGTCGCAGCGCCATCTGTCTTTATCTTCCCTCCAAGCGAACGAACAGCTTAAGAGTGGCACCGGACCAGTCTGATTAGGATTAACTG CAGTGGAAGGTGGATAACGCTCTGCAGTCTGGGAA CTCTCAGGAAAGTGTAACAGAACAAGACTCCAAAGACTCAACCTACTCTCTTAGTTCCACGTTGACCCTCTCCAAAGC GGACTATGAGAAGCATAAGGTCTACGCTTGCGAGGTAACACACCAGGGGCTGAGTAGTCCGGTTACGAAGAGCTTC AACAGAGGGGAATGCTGA The signal peptide coding sequence is shown in bold. The light chain coding sequence is underlined with a straight line. Nivolumab light chain protein sequence (SEQ ID NO:37): MMSFVSLLLVGILFHATQAEIVLTQSPATLSSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRAT GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLN NFYPREAKVQLSKVDNALQSGNSKQESVTESTQDSLTDSKY ACEVTHQGLSSPVTKSFNRGEC The signal peptide sequence is shown in bold. The light chain sequence is underlined with a straight line. Component amino acid sequences: Signal sequence for heavy and light chains (SEQ ID NO:5): Sequence of linker between decorin and heavy chain (SEQ ID NO:6): Decorin (SEQ ID NO:7): Nivolumab heavy chain protein sequence (SEQ ID NO:38): QVQLVESGGGWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISR DNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYVSLSSTKTVPSD RVESKYGPPCPPCPAPEFLGG PSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNG KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQLDPENNYKFTTYFSSRVSDVSDGV VMHEALHNHYTQKSLSLSLGK Nivolumab light chain protein sequence (SEQ ID NO:39): EIVLTQSPATLSSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTIS SLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEVKHKSFGVECTSVECTS Anti-PD-1 Pembrolizumab-Galacorin fusion heavy chain genetic sequence (SEQ ID NO:40): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCCAGGTGCAATTGGT CCAAAGTGGGGTCGAGGTCAAGAAGCCAGGAGCTTCTGTAAAAGTTTCATGTAAGGCATCTGGGTATACCTTCACGA ACTACTATATGTATTGGGTGCGTCCAAGCGCCAGGGCAGGGCCTCGGAATCGGATCAAGG GGCACCAACTTTAACGAAAAGTTTAAAAAACCGGGTCACCTTGACAACGGACAGTAGCACGACTACCGCTTATATG GAGCTGAAGAGTTTGCAGTTTGATGATACTGCGGTTTATTATTGTGCACGCAGAGATTATAGGTTCGACATGGGCTT CGACTACTGGGGTCAAGGTACTACGGTAACTGTATCATCTGCTAGTACAATTAGGCCCCCTTCCG ACGTCCGAAAAGCACCGCTGCACTTGGGTGCCTTGTAAAAGACTATTTTCCAGAGCCAGTTAC CGTGTCTTGGAATAGTGGCGCACTTACGTCCGGGGTGCACACTTTTCCGGCTGTCTTGCAATCCTCTGGACTCTATT crcQzn / Lznz / q / Yi CCTTGAGTAGCGTCGTAACAGTACCAAGTAGTAGTCTCGGCACCAAAACGTATACGTGCAATGTTGATCATAAGCCT AGCAACACGAAAGTTGACAAAAGAGTTGAGAGTAAATATGGACCCCCCTGTCCGCCATGCCCGGCCCCTGAATTCC TTGGGGGCCCGTCTGTATTTCTTTTCCGCCCAAGCCGAAGGATACACTGATGATAGAGCAGACGTAG CGTAAGCCAGGAAGATCCTGAGGTGCAATTTAATTGGTATGTGGACGGGGTCGAGGTTCATA ATGCAAAAACAAAACCCCGAGAGGAGCAATTTAATTCAACGTACAGAGTCGTTAGCGTACTTACAGTGCTGCACCAG GATTGGCTCAACGGCCGAAGGAGTATAAGTGCAAGGTGTCTAATAAAGGTTTGCCCTCCAGTATAGAAAAAACGTATAGAAAACAGACT CAAGTATATACCCTCCCACCCTCCCAAAGAAGATGACAAAGAACCAA GTGAGTCTCACATGCCTCGTCAAGGGTTTCTACCCAAGCGATATAGCCGTAGAGTGGGAATCAAATGGTCAGCCGG AGAATAACTACAAACTACTCCGCCAGTCTTGGATAGCGACGGGTCTTTTTTCCTGTACTCTAGGCTGACGGTGGAC AAGTCAAGATGATGCAGTTAGATGACTG GAGGCTTCCACAATCATTATACACAAAAA AGTTTGTCTCTGTCATTGGGGAAATCCGGGGGTGGCGGArCCGATGAGGCTGCAGGGATAGGCCCAGAAGTTCCT GAI.GAC.C.GCGACTTCGAGCCCT.CCCTAGGC.CCAGTGT.GC.CCCXTCGGCTGTCAATGC.CAIQXTC GXXCXGAXXXGGGXCXGGACAAAGXGCCAAAGGAXCIXCCCCCXGACACAACXCIGCXAGACCXGCAAAACAACAAA AIAACCaAAAXCAAAGAXGGAGACTXXAAGAACCXGAAGAACCXXCAGGCAIXGAXXCXXGXCAACAAXAAAAXXAGC AAAGXXAGXCCXGGAGCAXXXGAXACCGAXAGCXX XGICCAAGAAXCAGCXGAAGGAAXXGCCAGAAAAAAXGCCCAAAACXCXXCAGGAGCXGCGXGCCCAIGAGAAXGAG^ CAAXGGACXGAACCAGAXGAXIOXCAXAGAACXGGGCACCAAIOCGCXGAAGA^ XCCAGGGAAXGAAGAAGCXCXCCXACAXCCGCAXXGCXGAXACCAAXAICACCAGCAIXCCXCAAGGXCIXCCXCCXX CCCXXACGGAAXXACAICXXGAXGGCAACAAAXCAGCAGAGXIGAXGCAGCXAGCCXGAAAGGACXGAAXAAIXXGCXAAGXXGGGAXXGAGXICAXACAGC CXCXGGCCAACACGCCXCAXCXGAGGGA GCXXCACXXGGACAACAACAAGCXXACCAGAGXACCXGGXGGGCXGGCAGAGCAIAAGXACAXCCAGGXXG.XCXACC XICAXAACAACAAXAXCXCXGXAGXXGGAXCAAGJGACXXCXGCCCACCXGGACACAACACCAAAAXAAGXCXGC cagcaacccggxccagxaclgggagaxacagccaiccaccxxcagaxgxgxciacgxgcg CXCXGCCAIXCAACXCGGAAACXAXAAGIGA The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. The linker coding sequence is shown in italics. The Galacoinna coding sequence is underlined with a wavy line. Pembrolizumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:41): MMSFVSLLLVGILFHAXQAQVQLVQSGVEVKKPGASVKVSCKASGYXFXNYYMYWVRQAPGQGLEWMGGINP SNGGXNFNEKFKNRVXLXXDSSXXXAYMELKSLQFDDXAVYYCARDYRFDMGFDYWGQGXXVXVSSASXKGPSVFPLA PCSRSXVESKVALS GVHXFPAVLQSSGLYSLSSWXVPSSSLGXKXYXCNVDHKPSNX KVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDXLMISRXPEVXCVWDVSQEDPEVQFNWYVDGVEVHNAKXKP REEQFNSXYRWSVLXVLHQDWLNGKEYKCKVSNKGLPSSIEQXLNSX VSLXCLVKG FYPSDIAVEWESNGQPENNYKXXPPVLDSDGSFFLYSRLXVDKSRWQEGNVFSCSVMHEALHNHYXQKSLSLSLGKSGG GGSDEMGIG-PEyP-DDRDEE^ HALILVNNKISKVSPGAFTPLVKLERLYLSKNQLKELPEKMPKTLQELRAHENEITKVRKVTFNGLNQMIVIELGTNPLKSSGI ENGAFQGMKKLSY RIADTN TSIPQG-PPSLTELHLDGNKISRVDAASLKGLNNLAKLGLSFNSISAVDNGSLANTPHLREL HLWJKLTWGGLAEHOQWYLHWJWLSK LG. The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. The linker sequence is shown in italics. The Galacorin sequence is underlined with a wavy line. Pembrolizumab light chain genetic sequence (SEQ ID NO:42): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAAATTGTTCTTACG CAGAGTCCAGCAACTTTGTCACTCTCTCCCGGCGAACGAGCGACATTGTCCTGTCGCGCGAGTAAGGGTGTCTCAA CATCTGGATACTCATATCTGCATTGGTACCAGCAAAAACCGGGACAAGCGCCGCGATTGCCGATCTAGTCTATCGATTATG TGCCTGCGAGGTTCTCCGGTAGTGGATCAGGCACCGATTTCACTTTGACCATCAGCAGCCT CGAACCAGAAGATTTTGCCGTCTACTACTGCCAACATAGCAGGGATTTGCCACTGACATTCGGCGGGGGTACGAAA GTTGAGATTAAACGGACTGTAGCGGCACCTTCTGTCTTCATCTTCCCACCAAGCGATGAGCAGCTTAAAGACTTCGTAGTACACT TTTATTCCGCGAGAAGCCAAGGTCCAATGGAAGGTGGATAACGCTTTGC AATCCGGTAACTCACAGGAGTCAGTAACAGAGCAAGATAGTAAAGATAGCACGTATTCACTTAGCAGTACCCTTACT CTTAGCAAGGCTGATTATGAAAAACATAAGGTATATGCGTGCGAGGTAACGCACCAAGGACTTAGCTCCCCAGTGAC GAAGGCTGATTGAACGTGCTGGTAACGT The signal peptide coding sequence is shown in bold. The light chain coding sequence is underlined with a straight line. Pembrolizumab light chain protein sequence (SEQ ID NO:43): MMSFVSLLLVGILFHATQAEIVLTQSPATLSSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLAS YLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESDSKADTTYSK VYACEVTHQGLSSPVTKSFNRG EC. The signal peptide sequence is shown in bold. The light chain sequence is underlined with a straight line. Component amino acid sequences: Signal sequence for heavy and light chains (SEQ ID NO:5): Sequence of linker between decorin and heavy chain (SEQ ID NO:6): Decorin (SEQ ID NO:7): Pembrolizumab heavy chain protein sequence (SEQ ID NO:44): QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTT DSSTTTAYMELKSLQFDDTAVYYCARDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKD crcQzn / Lznz / q / Yi YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLH QDWLNGKEYKCKTLVSNKGLPSSIEGMTEPPSQEE KNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK Pembrolizumab light chain protein sequence (SEQ ID NO:45): EIVLTQSPATLSSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTD FTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSPEVSTLTHLSKVAPS SFNRGEC Anti-PD-L1 Genetic sequence of Avelumab-Galacorin fusion heavy chain (SEQ ID NO:50): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAGGTACAGCTTTT GGAGTCAGGCGGGGGGCTCGTCCAACCTGGGGGGTCACTCCGGTTGTCATGTGCTGCCAGTGGCTTCACATTTCC ATCTTACATTATGATGTGGGTTCGACAGGCCCCTGGGAAGTGGCTGCTGCTGCTGCTG GGAATTACCTTCTATGCCGACACGGTAAAGGGTCGCTTCACTATAAGTCGAGATAACAGCAAAAATACGCTGTATCT CCAGATGAACTCTCTCAGGGCTGAGGACACAGCTGTATATTACTGCGCGCGGATTAAGTTGGGGACCGTCACAACA GTGGATTACTGGGGTCAAGGCACTCTGGTAACCGTATCCTCAGCATCCACCAAGGGCCCCAACTGTGTATTTCCGTAGTATTCCGTAAG CGGCACAGCCGCTCTCGGTTGCCTGGTTAAGGACTACTTCCCAGAACCTGT CACTGTCAGTTGGAACTCAGGCGCATTGACATCTGGTGTCCATACATTCCCCGCAGTCCTGCAAAGCTCTGGACTTT ACAGTCTTAGTAGCGTAGTGACAGTCCCATCTTCAAGTCTTGGGACCCAAACTTATAATTTGCAACGTAAATCATAAACGTAAGTACCAACATTAAGAAC AACGCATACATGCCCACCATGTCCCGCT CCGGAACTCCTGGGCGGCCCGTCCGTTTTTCTCTTTCCCCCAAAGCCCAAGGATACGCTTATGATCAGCAGAACAC CGGAAGTTACTTGTGTAGTCGTTGACGTGTCTCACGAAGATCCCGAAGTCAAATTTAATTGGTATGTGGATGGCGTC GAAGTGCACAACGCAAAAACCAAACCCATAGAGAGTAACGTAACGTAACGTAACGTAACGTAGTCAGATGTCGTAGTCAACGTCACGTAGTCAAATTGATGTCGTAGTCA TACGG TCCTCCACCAGGACTGGTTGAATGGCAAGGAGTACAAGTGCAAAGTGAGCAATAAAGCGTTGCCAGCCCCGATCGAAAAAACCATCAGCAAGGCCAAGGGACAGCCTAGAGAGCCGCAGGTTTACACCTTGCCGCCATCAAGGGATGAACTG ACTAAAACCAGGTATCCCTGACCTGCCTGGTTAAGGGTTTTTAGGACCAGTGAATTAG CCAGAGAACAACTACAAAACGACACCCTCCCGTTCTGGATTCCGATGGCAGCTTTTTCTTGTATTCTAAAC TCACCGTGGATAAATCCCGATGGCAGCAAGGCAACGTCTTTCTCCTGCAGCGTGATGCATGAAGCCTTGCACAACCA CTATACCCAAAAGAGTCTCAGCCTGTCACCcGGGAAATCCGGGGAAATCCGGGGGGCTGGGGCAGGATTCGGATCC gacitcgagccctccciaggcccagtgtgccccticcgctgtcaatgccatcti CGAGTGGTCCAGTGTTCTGATTTGGGTCTGGACAAAGTGCCAAAGGATCTTCCCCCTGACACAACTCTGCTAGACCT GCAAAACAACAAAATAACCGAAATCAAAGATGGAGACTITAAGAACCTGA^GAACCTTCACGCATTGATT^ CAATAAAATIAGCAGATTTAGCAAGATGTIAGTAGICAG GAACGACIITATCIGTCCAAGAAICA GCTGAAGGAATTGCCAGAAAAAATGCCCAAAACTCTTCAGGAGCTGCGTGCCCATGAGAATGAGATCACCAAAGTG CGAAAAGTTACTTTCAATGGACTGAACCAGATGATTGTCATAGAACTGGGCACCAATCCGCTGAAGAGCTCAGGAAT TGAAMTGGG3CTTTCCAGGGMTGMGAAGCTCTCCTACATCCG0ATTGCTGATACCMTATCAC3AGCATTCCTC AAGGTCTTCCTCCTTCCCnACGGAMTTACATCLTGATGGCAACAAATCAGCAGAGTTGATGCAGCTAGCATGCATG^GATGCATG GAGnTCAACAGCATCTCTGCTGTTGACAATGGCTMCTGGCCAACAC GCCTCATCTGAGGGAGCnCACTTGGACAACAACMGCTTACCAGAGTACCTGGTGGGCTGGCAGAGCATAAGTAC ATCCAGGTTGXCTACCTTCATMCMG.MTATCTCTGTAGTIGGATGAAGTGACTTCTGCCCAGCIGGACACMGA.eeWMAGTCGTTIGCGTCGGMTG CGGTCCAGTACTGGGAGATACAGCCATCCACCTTCAG ATGIGTCTACGIGGGGTCTGCCAnGMGTCGGMAGTATMGTGA The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. The linker coding sequence is shown in italics. The Galacorin coding sequence is underlined with a wavy line. Avelumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:51): MMSFVSLLLVGILFHATQAEVQLLESGGGLVQPGGSLRLSCMSGFTFSSYIMMWVRQAPGKGLEWVSSIYPS GGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTMLGCLVKDYGEPVTSVSLVQWNSLVSY SSWTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTVKVEGVESLTYTPSLT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSGG GGSDEMGIGPEyPDDHDEPSLGPyGPFRCQCHLRWQGSDLGLDKyPKDLPPDTT^ HAULWWSKysPGAFTPLmXRnESKNQLKELraMPO^ ENGAFGíG|yOLSWOMTSLPQGL£JPSIJWWXWDGN£JWWYGN£ELTH tWO / y^SDrcPPGHHTKKMXSGySLFS^ LGNYK. The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. The linker sequence is shown in italics. The Galacorin sequence is underlined with a wavy line. Avelumab light chain genetic sequence (SEQ ID NO:52): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCCAGTCTGCACTTAC ACMCCGGCGTCCGTTTCCGGATCTCCAGGACAGAGCATTACTATCAGTTGCACGGGMCCTCCTCAGACGTAGGG GGGTATMTTATGTGTCTTGGTATCMCAGCATCCCGGGAMGCCCCCAMCTGATGATCTACGATGTCCGATMGTAGATGATMGT CGGGTCTAMTCTGGTMCACAGCATCCCTCACTATTAGTGGACTGCMG CAGMGATGAGGCAGACTATTATTGCAGTAGCTATACGTCTAGTTCCACCCGCGTTTTTTGGCACTGGGACGAMGTC ACCGTTCTCGGACMCCAAMGCAMCCCCACCGTGACTCTGTTTCCGCCTAGCAGCGMGMTTGCAGGCCMTM GGCGACACTCGTATGACTCTTATCCGTCCGTCGG GAMGCCGACGGCAGCCC TGTTAMGCTGGAGTCGAGACCACGMGCCGTCCMGCAGAGTMCMTMGTATGCTGCATCCAGTTATTCTCTCTC TCACTCCGGAACAGTGGAAGTCCCATCGGTCCTATAGTTGCCAAGTGACCCATGAGGGTTCCACCGTAGAGAAAAC GGTAGCACCTACCGAATGTAGTTGA The signal peptide coding sequence is shown in bold. The light chain coding sequence is underlined with a straight line. Avelumab light chain protein sequence (SEQ ID NO:53): MMSFVSLLLVGILFHATQAQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSN RPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKAT LVACLISDFYPGAVTVAWKADGSPSPVKAGTTSVELTKYLT WKSHRSYSCQVTHEGSTVEKTVAPTE is. The signal peptide sequence is shown in bold. The light chain sequence is underlined with a straight line. Anti-PD-L1 In some embodiments, the constructs comprise two or more copies of Galacorin or other decorin molecule linked to each C heavy chain gene or a portion of the Galacorin molecule (eg, TGF-Beta binding portion) linked to the gene. heavy chain as a single entity or as two or more copies. There are multiple TGF-Beta binding domains in the Galacorin / Decorin molecule. These domains are configured in any suitable configuration. In some embodiments, each of the options described above binds to a b¡- or multispecific antibody directed at 2 or more targets. Exemplary sequences are shown below. Avelumab-Galacorin 2x Fusion Heavy Chain Genetic Sequence (SEQ ID NO:54): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAGGTACAGCTTTT GGAGTCAGGCGGGGGGCTCGTCCAACCTGGGGGGTCACTCCGGTTGTCATGTGCTGCCAGTGGCTTCACATTTCC ATCTTACATTATGATGTGGGTTCGACAGGCCCCTGGGAAGGGGCTGGAGTGGGTTTCCTCCATCTACCCCTCCGGGGGGAATTACCTTTCTATGCCGACACGGTAAAGGGTCGCTTCACTATAAGTCAATACTAAG GAACTCTCTCAGGGCTGAGGACACAGCTGTATATTACTGCGCGCGGATTAAGTTGGGGACCGTCACAACA GTGGATTACTGGGGTCAAGGCACTCTGGTAACCGTATCCTCAGCATCCACCAAGGGCCCAAGTGTATTCCCGCTGG CCCTTCAAGTAAATCCACGTCTGGCGGCACAGCCGCTCTCGGTTGCCTGGTTAAGCACTACTTCGTCC TTGACATCTGGTGTCCATACATTCCCCGCAGTCCTGCAAAGCTCTGGACTTT ACAGTCTTAGTAGCGTAGTGACAGTCCCATCTTCAAGTCTTGGGACCCAAACTTATATTTGCAACGTAAATCATAAAC CCTCCAACACTAAAGTAGACAAAAAAGTAGAGCCGAAATCTTGCGACAAAACGCATACATGCCCACCATGTCCCGCT CCGGAGACTCCCTTCCGGTCTTCAAG ATACGCTTATGATCAGCAGAACAC CGGAAGTTACTTGTGTAGTCGTTGACGTGTCTCACGAAGATCCCGAAGTCAAATTTAATTGGTATGTGGATGGCGTC GAAGTGCACAACGCAAAAACCAAACCCAGAGAGGAACAGTATAACAGCACGTATCGAGTGGTCTCCGTACTTACGG TCTCCACCAGGACTGGTTGAATGGCAAGCAGTACAGTAGGAT TCGA AAAAACCATCAGCAAGGCCAAGGGACAGCCTAGAGAGCCGCAGGTTTACACCTTGCCGCCATCAAGGGATGAACTG ACTAAAAACCAGGTATCCCTGACCTGCCTGGTTAAGGGTTTTTACCCCAGTGATATAGCGGTTGAATGGGAGTCTAA CGGGCAGCCAGAGAACAACTACAAAACGAACCTCCCGTTCTGGATTCCGATGGCAGCTTTTCTTGTATTCTAAAC TCACCGTGGATAAATCCCGATGGCAGCAAGGCAACGTCTTTCTCCTGCATCGATGCCATGCATCCA AGAGTCTCAGCCTGTCACCcGGGAAArCCGGGGGrGGCGGArCCGATGAGGCTGCAGGGATAGG CCCAGAAGTTCCTGATGACCGCGACT.TCGAGCCCTCCCTAGGCCCAGTGTGCCCCTTC.CGCTGTCAATGCCATTCTT CGAGTGGTCCAGTGITCTGAnTGGGTCTGGACAAAGTGCCAGACTAGGATCTTCAACTACACT G ATAACCGAAAATCAAAGATGGAGACTTTAAGAACCTGAAGAACCTTCACGCATTGATTCTTGTCAA CAATAAAATTAGCAAAGTTAGTCCTGGAGCATTTACACCTTTGGTGMGTTGGAACGACTTTATCTGTCCAAGAATCA GCTGAAGGMTTGCCAGAAAAAATGCCCAAAACTCTTCAGGAGCTGCGTGCCCATGAGAATGAGATCACCAAAG.GACTCATTCGAATGATAG ACTGGGCACCAATCCGCTGAAGAGCTCAGGAAT TGAAAATGGGGCTTTCCAGGGAAIOAAGAAGCTCTCCTAGATCCGCATTGCTGAW AAGGTCTICCTCCTTCCCITACGGAATIACAICITGATGGCAACAAAATCAGCAGAGnGATGCAGCTAGCCIGAAA GGACTGAATAATTTGGCTAAGTTGGGATIGAGnTCAACAGCAICTCTGCTGTTGACAAIGGCTCTCTGGCCAACAC GCCTOALCTGAGGGAGCnCACTTGGACAACAACAAGCTTACCAGAGTACCTGGTGAGGCATAGTAGC. ATCCAGGIIGTCTACCTTCATAACAACAATATCTCIMAGTTGGATCAAGTGACTTCTGCCCACCTGGACACAACACC aaaaaggcttcttaitcgggtgigagicitttc ATGTGTCTACGTGCGCTCTGCCATTCAACTCGGAAACTATAAGÍCCGGGGGrGGCGGAÍCCGATGAGGCTGCAGGG ATAGGCCCAGAAGITCCTGATGACCGCGACTTCGAGCCCTCCCTAGGCCCAGTGTGCCCCTTCCGCTGTCAATGCC ATCTTCGAGTGGTCCAGTGTTCTGATTTGGGTCTGGAACAGATCTTGCCACTG ACCTGCAAAACAACAAMTMCCGAAATCAAAGATGGAGACTTJAAGAACCTGAAGAACCTTCACGCATTGAIICrr GTCAACAATAAAAnAGCMAGrrAGJCCTGGAGCMTTACACCniGGTGAAGTTGGAACGACTITATCTGTCCAAG AATCAGCTGAAGWJTGCCAGAAAAATGCCCAAAACTCTTCAGGAGCTGCGTGCCCATGACAGAATGAGTTACACTGACT GAACCAGATGATTGTCATAGAACTGGGCACCAATCCGCTGAAGAGCTCAG GMnGAAAAIGGGGCTTTCCAGGG.AATGAAGAAG.CTCTCCTACATCCGCATTGCTGATACCAATATCACCAGCATT CCTCAAGGICTTCCTCCTTCCCTTACGGAATTACATTCTTGATGGCAACAAAATCAGCAGAGTTGATGCAGCIAGCCT gaaaggactgaataggattattgg gctgttgacaatggctctctggcca ACACGCCTCATCTGAGGGAGCTTCACTTGGACAACAACAAGCTTACCAGAGTACCTGGTGGGCTGGCAGAGCATAA GTACATCCAGGTIGICIACCTTCATAACAACAATATCTCTGIAGTIGGATCAAGTGACITCTGCCCACCTGGACACAA CACCAAAAAGGCTTCTTATTCGGGTGTGAGTCTCTTCGATGACTCGATCGATG CCACCT The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. Linker coding sequences are shown in italics. Galacorin coding sequences are underlined with a wavy line. Avelumab-Galacoñna 2x fusion heavy chain protein sequence (SEQ ID NO:55): MMSFVSLLLVGILFHATQAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPS crcQzn / Lznz / q / Yi GGITFYAPTVKGRFTISRPNSKNTLYLQMNSLRAEPTAVYYCARIKLGTVTTVPYWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCPKRTCPPTKVD KKVEPKRTCPPTFLAPP VWPVSHEPPEVKFNWYVPGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHSPGYTQKSLGGPPPELVGSLEVGSLG SLGPyCPFRGQCHLRWQCSDLGLDKyPKDLPPDTTLLDLQNNKITEIKDGDFKNLKNL HAULyN.NKI-SKV^ .EN.GAEQG-MK-KLSYm HmNNKLJRVPGGlAeOQyyYIJH!^^ ΡΟΝΥΚδΟσΟΟδΡΕΜΌΙΟΡΤΜΌΡΕΌΗΞΡδΚΒΙ^ Tm.KS.gG!EN.^ CVYVRSAIQLGNYK. The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. Linker sequences are shown in italics. Galacorin sequences are underlined with a wavy line. Genetic sequence of AvelumabGalacorin / Pecorin TGF-Beta binding domains fusion heavy chain (full length endogenous human Pecorin Asp45-Lys359) (SEQ IP NO:56): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAGGTACAGCTTTT GGAGTCAGGCGGGGGGCTCGTCCAACCTGGGGGGTCACTCCGGTTGTCATGTGCTGCCAGTGGCTTCACATTTCC ATCTTACATTATGATGTGGGTTCGACAGGCCCCTGGGAAGTGGCTGCTGCTGCTGCTG GGAATTACCTTCTATGCCGACACGGTAAAGGGTCGCTTCACTATAAGTCGAGATAACAGCAAAAATACGCTGTATCT CCAGATGAACTCTCTCAGGGCTGAGGACACAGCTGTATATTACTGCGCGCGGATTAAGTTGGGGACCGTCACAACA GTGGATTACTGGGGTCAAGGCACTCTGGTAACCGTATCCTCAGCATCCACCAAGGGCCCCAACTGTGTATTTCCGTAGTATTCCGTAAG CGGCACAGCCGCTCTCGGTTGCCTGGTTAAGGACTACTTCCCAGAACCTGT CACTGTCAGTTGGAACTCAGGCGCATTGACATCTGGTGTCCATACATTCCCCGCAGTCCTGCAAAGCTCTGGACTTT ACAGTCTTAGTAGCGTAGTGACAGTCCCATCTTCAAGTCTTGGGACCCAAACTTATAATTTGCAACGTAAATCATAAACGTAAGTACCAACATTAAGAAC AACGCATACATGCCCACCATGTCCCGCT CCGGAACTCCTGGGCGGCCCGTCCGTTTTTCTCTTTCCCCCAAAGCCCAAGGATACGCTTATGATCAGCAGAACAC CGGAAGTTACTTGTGTAGTCGTTGACGTGTCTCACGAAGATCCCGAAGTCAAATTTAATTGGTATGTGGATGGCGTC GAAGTGCACAACGCAAAAACCAAACCCATAGAGAGTAACGTAACGTAACGTAACGTAACGTAGTCAGATGTCGTAGTCAACGTCACGTAGTCAAATTGATGTCGTAGTCA TACGG TCCTCCACCAGGACTGGTTGAATGGCAAGGAGTACAAGTGCAAAGTGAGCAATAAAGCGTTGCCAGCCCCGATCGAAAAAACCATCAGCAAGGCCAAGGGACAGCCTAGAGAGCCGCAGGTTTACACCTTGCCGCCATCAAGGGATGAACTG ACTAAAACCAGGTATCCCTGACCTGCCTGGTTAAGGGTTTTTAGGACCAGTGAATTAG CGGGCAGCCAGAGAACAACTACAAAACGACACCTCCCGTTCTGGATTCCGATGGCAGCTTTTTTCTTGTATTCTAAAC TCACCGTGGATAAATCCCGATGGCAGCAAGGCAACGTCTTCTCCTGCAGCGTGATGCATGAAGCCTTGCACAACCA CTATACCCAAAAGAGTCTCAGCCTGTCACCcGGGAAATCCGGGGGTGGACGGATCCGCCCTGTCCCG CCTTCCGCTGTCAATGCCATCTTCGAGTGGTCCAGTGTTCTGATTTGGGTCTGGACAAAGTGCCAAA GGATCTTCCC.CCTGACACAACTCTGCTAGACCTGCAAAACAA.CAAAATAACCGAAATCAAAGATGGAGACTTTAAGAA CCTGAAGAACCTTCACGCATTGATTCTTGTCAACAATAAAAITAGCAAAGTTAGTCCTGGACTGCATTATAGCACTAGCACTAG TCAGCTGAAGGAATTGCCAGAAAAAATGCCCAAAACTCTTCAGGAGC TGCGTGCCCATGAGAATGAGATCACCAAAGTGCGAAAAGTTACTITCAATGGACTGAACCAGATGA^ CTGGGCACCAATOCGCTGAAGAGCTCAGGAATTGAAAATGGGGCTTTCCAGGGAATGAAGAAGCTCTCCTACATCC GCATIGCTGATACCAATATCACCAG.CATTCCTCAAGGTCITCCTCCTTCCCTTACGGAATTACATCTTG^ AAATCAGCAGAGTTGAI^AGCTAGCCTGAAAGGACTOAATAATnGGCWGTTGGGMTCGAGIITCAGATGGCTGAGIITCAGATn GCCAACACGCCTCATCIGAGGGAGCTTCACTTGGACAAGAACAAGCTTACCAG. AGTACCTGGTGGGCTGGCAGAGCAIAAGTACATCCAGGTTGTCTACCTTCATAACAACAATATCTCTGTAGTTGGAT CAAGIGACTTCTGCCCACCTGGAOCAACACCAAAAAAGGCTTCTTATTCGGGTGTGAGTCTnTCAGCAACCCGGTC CAGTACTGGGAGATACAGCCATCCACCHCAGATGTGTCTACGIGCGCICTGCCATIGATAGTCAG The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. The linker coding sequence is shown in italics. The Galacorin / Decorin coding sequence (Asp45-Lys 359) is underlined with a wavy line. AvelumabGalacorin / Decorin (Full-length endogenous human Decorin Asp45-Lys359) fusion protein sequence of TGF-Beta binding domains fusion (SEQ ID NO:57): MMSFVSLLLVGILFHATQAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPS GGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAFPALGCLVKDYGEPVTSLVQWNSLVSY SSWTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTVKVEGVESLTYTPSLT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSGG GGSDFEPSLGPyCPFRCQCHLRyyQCSDlHfíKyPIWPDTIUDLQN^^ AFTPLVKLERLYLSKNQLKELPEKMPKTLQELRAHENEITKVRKVTFNGLNQMMELGTNPLKSSGIENGAFQGMKLSYI AEHKILQWLHNNNIS^ The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. The linker sequence is shown in italics. The Galacorin / Decorin (Asp45-Lys 359) sequence is underlined with a wavy line. Genetic sequence of 2x fusion heavy chain of Avelumab crcQzn / Lznz / q / Yi TGF-Beta binding domains Galacorin / Decorin (full length endogenous human Decorin Asp45-Lys359) (SEQ ID NO:58): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAGGTACAGCTTTT GGAGTCAGGCGGGGGGCTCGTCCAACCTGGGGGGTCACTCCGGTTGTCATGTGCTGCCAGTGGCTTCACATTTCC ATCTTACATTATGATGTGGGTTCGACAGGCCCCTGGGAAGTGGCTGCTGCTGCTGCTG GGAATTACCTTCTATGCCGACACGGTAAAGGGTCGCTTCACTATAAGTCGAGATAACAGCAAAAATACGCTGTATCT CCAGATGAACTCTCTCAGGGCTGAGGACACAGCTGTATATTACTGCGCGCGGATTAAGTTGGGGACCGTCACAACA GTGGATTACTGGGGTCAAGGCACTCTGGTAACCGTATCCTCAGCATCCACCAAGGGCCCCAACTGTGTATTTCCGTAGTATTCCGTAAG CGGCACAGCCGCTCTCGGTTGCCTGGTTAAGGACTACTTCCCAGAACCTGT CACTGTCAGTTGGAACTCAGGCGCATTGACATCTGGTGTCCATACATTCCCCGCAGTCCTGCAAAGCTCTGGACTTT ACAGTCTTAGTAGCGTAGTGACAGTCCCATCTTCAAGTCTTGGGACCCAAACTTATAATTTGCAACGTAAATCATAAACGTAAGTACCAACATTAAGAAC AACGCATACATGCCCACCATGTCCCGCT CCGGAACTCCTGGGCGGCCCGTCCGTTTTTCTCTTTCCCCCAAAGCCCAAGGATACGCTTATGATCAGCAGAACAC CGGAAGTTACTTGTGTAGTCGTTGACGTGTCTCACGAAGATCCCGAAGTCAAATTTAATTGGTATGTGGATGGCGTC GAAGTGCACAACGCAAAAACCAAACCCATAGAGAGTAACGTAACGTAACGTAACGTAACGTAGTCAGATGTCGTAGTCAACGTCACGTAGTCAAATTGATGTCGTAGTCA TACGG TCCTCCACCAGGACTGGTTGAATGGCAAGGAGTACAAGTGCAAAGTGAGCAATAAAGCGTTGCCAGCCCCGATCGAAAAAACCATCAGCAAGGCCAAGGGACAGCCTAGAGAGCCGCAGGTTTACACCTTGCCGCCATCAAGGGATGAACTG ACTAAAACCAGGTATCCCTGACCTGCCTGGTTAAGGGTTTTTAGGACCAGTGAATTAG CCAGAGAACAACTACAAAACGAACACCTCCCGTTCTGGATTCCGATGGCAGCTTTTTTCTTGTATTCTAAAC TCACCGTGGATAAATCCCGATGGCAGCAAGGCAACGTCTTTCTCCTGCAGCGTGATGCATGAAGCCTTGCACAACCA CTATACCCAAAAGAGTCTCAGCCTGTCACCcGGGAAArCCGGGGreGCGGArCCGA.C.C.TTC-C.TTC-C. IAGGC CCAGTGTGCCCCTTCCGCTGTCAATGCCATCnC^GTGGTCCAGTOTTCTG^ GGATCTTCCCCCTGACACAACTCTGCTAGACCIG^AAAACAACAAAAATAACCGAAATCAAAGATGGAGACTTTAAGAA CCTOAAGAACCTTCACGCATTGAJTCTTGTCAACAATAAAAIIAGCmGTTAGTCCTGGAGCATTTACACGAG.AAGTGATACGATG. GAAGGAATTGCCAGAAAAAATGCCCAAAACTCTICAGGAGC TGCGTGCCCATGAGAAIGAGATCACCAAAGTGCGAAAAGTTACTTTCAATGGACTGAACCAGATGATTGTCATAGM CTGGGCACCAATCCGCTGAAGAGCTCAGGAATTGAAAATGGGGCTnCCAGGGAATGAAGAAGCTCTCCTACATCC GCAnGCTCGATICACCAAIATCACCAGGCAnCCTACCAGC CATCTIGATGGCAACA AAATCAGCAGAGTTGATGCAGCTAGCCTGAAAGGACTGAATAATITGGCTAAGTTGGGATTGAGTTICAACAGCATC TCTGCTGTTGACAATGGCTCTCTGGCCAACACGCCTCATCTGAGGGAGCTTCACTTGGACAACAACAAGCTTACCAG CAAGTGACnCIGCCCACCTGGACACAACACCAAAAAG-GCTTCIIATTCGGGTGTGAGTCIITTCAGCAACCCGGIC CAGTACTGGGAGAIACAGC£ATCCACCTJOAGATGTGTCTACGTGCGCTCTGCCATTCAA.CTCGGAAACTATAAGTC CGGGGGTGGCGGATCCGACTTCGAGCCCTCCCTAGGCCCAGTGCACTGCCLCTTACGTCCGG CAGTGITCTGAITTGGGTCTGGACAAAGTGCCAAAGGAICITCCCCIGACACAACICIGCTAGACCIGCAAA ACAACAAAATAACCGAAATCAAAGATGGAGACTTTAAGAACCTGAAGAACCTTCACGCATTGATTCTTGTCAACAATA AAATTAGCAAAGTTAGTCCTGGAGCATTTACACCTTTGGTGAAGTTGGAACGACTTTATCTGTCCAAGAATCAGCTGA AGGAATTGCCAGAAAAAATGCCCAAAACTCTTCAGGAGCTGCGTGCCCATGAGAATGAGATCACCAAAGTGCGAAAA GTTACTnCAATG.GACTGAACCAGATGALTGI^TAGAACTGGGCACCAATCCGCTGAAGAGGACTGACTGATGAATG GAAGAAGCTCTCCTACATCCGCAITGCTGA]ACCAATATCACCAGCATTCCTCAAGGTC TTCCTCCr^CTTACGGAATIACAimGATGGCAACAAAATCAGCAGAGTTGATGCAGCTAGCCTGAAAGGACTG AATAATTTGGCJAAGTTGGGALTGAGTTTCAACAGCATCTCTGCTGTTGACAATGGCTCTCTGGCCAACACGCCTCATGACTTCAGACTGG CCTGGTGGGCTGGCAGAGCATAAG.TACATCCAGG TTGTCTACCTTCATAACAACAATATCTCTGTAGTTGGATCAAGTGACTTCTGCCCACCTGGACACAACACCAAAAAGG CTTCTTAHCGGGIGIGAGTCTTTTCAGCAACCCGGTCCAGTACTGGGAGATACAGCCATCCACCITGAGATGTGTC TACGTGACGCTCTGATATCAGT The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. Linker coding sequences are shown in italics. Galacorin / Decorin (Asp45-Lys 359) coding sequences are underlined with a wavy line. AvelumabGalacorin / Decorin (Full-length endogenous human Decorin Asp45-Lys359) 2x fusion heavy chain protein sequence of binding domains of TGF-Beta (SEQ ID NO:59): MMSFVSLLLVGILFHATQAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPS GGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAFPALGCLVKDYGEPVTSLVQWNSLVSY SSWTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTVKVEGVESLTYTPSLT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSGG GGSD.F.EBSLGEVCPFRCQC.HLRWQCSDLGLDKyPKDLPPDT.TLDLQN.NKI-TEIKDGDF.K.N.LKNLHA.U^ AFTPLVKLERLYLSKNQLKELPEKMPKTLQELRAHENENGLKVVRHENENGLKIT FQGMKKLSYI RIADmTSIPaGLFPSLTEIJHmGNKISRyDM AEHJWIQWYLHNNNISWGSSDFC^ PSLGPVCPFRCQCHLRWQCSDLGLDKVPKDLPPDTTLLDLQNNKITEIKDGDFKNLKNLHALILVNNKISKVSPGAFTPLV KLERLYLSKNQLKELPEKMPKTLQELRAHENEITKNPLKVRGISS QGMKKLSYIRIADTNI QyVYLHN.N.NISWG.S.SDFCPPG^^^^ The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. Linker sequences are shown in italics. Galacorin / Decorin (Asp45-Lys 359) sequences are underlined with a wavy line. Avelumab TGF-Beta binding domain fusion heavy chain genetic sequence Galacorin / Decorin (Full-length endogenous human Decorin Leu155-Val260) (SEQ ID NC:60): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAGGTACAGCTTTT GGAGTCAGGCGGGGGGCTCGTCCAACCTGGGGGGTCACTCCGGTTGTCATGTGCTGCCAGTGGCTTCACATTTCC ATCTTACATTATGATGTGGGTTCGACAGGCCCCTGGGAAGGGGCTGGAGTGGGTTTCCTCCATCTACCCCTCCGGGGGGAATTACCTTTCTATGCCGACACGGTAAAGGGTCGCTTCACTATAAGTCAATACTAAG GAACTCTCTCAGGGCTGAGGACACAGCTGTATATTACTGCGCGCGGATTAAGTTGGGGACCGTCACAACA GTGGATTACTGGGGTCAAGGCACTCTGGTAACCGTATCCTCAGCATCCACCAAGGGCCCAAGTGTATTCCCGCTGG CCCTTCAAGTAAATCCACGTCTGGCGGCACAGCCGCTCTCGGTTGCCTGGTTAAGCACTACTTCGTCC TTGACATCTGGTGTCCATACATTCCCCGCAGTCCTGCAAAGCTCTGGACTTT ACAGTCTTAGTAGCGTAGTGACAGTCCCATCTTCAAGTCTTGGGACCCAAACTTATATTTGCAACGTAAATCATAAAC CCTCCAACACTAAAGTAGACAAAAAAGTAGAGCCGAAATCTTGCGACAAAACGCATACATGCCCACCATGTCCCGCT CCGGAGACTCCCTTCCGGTCTTCAAG ATACGCTTATGATCAGCAGAACAC CGGAAGTTACTTGTGTAGTCGTTGACGTGTCTCACGAAGATCCCGAAGTCAAATTTAATTGGTATGTGGATGGCGTC GAAGTGCACAACGCAAAAACCAAACCCAGAGAGGAACAGTATAACAGCACGTATCGAGTGGTCTCCGTACTTACGG TCTCCACCAGGACTGGTTGAATGGCAAGCAGTACAGTAGGAT TCGA AAAAAACCATCAGCAAGGCCAAGGGACAGCCTAGAGAGCCGCAGGTTTACACCTTGCCGCCATCAAGGGATGAACTG ACTAAAACCAGGTATCCCTGACCTGCCTGGTTAAGGGTTTTTACCCCAGTGATATAGCGGTTGAATGGGAGTCTAA CGGGCAGCCAGAGAACAACTACAAAACGAACCTCCCCGTTCTGGATTCGATTCTTGTCTAACG ATAAAATCCCGATGGCAGCAAGGCAACGTCTTCTCCTGCAGCGTGATGCATGAAGCCTTGCACAACCA CTATACCCAAAAGAGTCTCAGCCTGTCACCcGGGAAArCCGGGGGrGGCGGArCCC.IGCGIGCCCAIGAGAAIGAG ATCACCAAAGTGCGAAAAGTMCKTCAATCGACIGAAQGAGATOAT]OTCATAGAAC^ GAGGTCAGGAATTGAAAATGGG^TTTCCAG^AATGAAGAAGCTCTCCTACATCCGGALTGCTGAIA^^ CCAGCMTCCTCAAGGTCTTCCTCCITCCCTIACGGAATTACATTCTTGATGGCAACAAAATCAGCAGAGTTGATGCAG CTAGCCTGAAAGGACTGAATAATTTGGCTAAGTTGGGATTGAGTTTCAA.CAGCATCTCTGCTGTTTGA The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. The linker coding sequence is shown in italics. The Galacorin / Decorin (Leu155-Val260) coding sequence is underlined with a wavy line. AvelumabGalacorina / Decoñna TGF-Beta binding domain fusion heavy chain protein sequence (Leu155-Val260 of full-length endogenous human Decorin) (SEQ ID NO:61): MMSFVSLLLVGILFHATQAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPS GGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAFPALGCLVKDYGEPVTSLVQWNSLVSY SSWTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTVKVEGVESLTYTPSLT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSGG GGSLRAHENEITKVRKVTFNGLNQMIVIELGTNPLKSSGIENGAFQGMKKLSYIRIADTNITSIPQGLPPSLTELHLDGNKISR VDAASLKGLNNLAKLGLSFNSISAV. The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. The linker sequence is shown in italics. The Galacorin / Decorin (Leu155Val260) sequence is underlined with a wavy line. Genetic sequence of Avelumab Galacorin / Decorin (full length endogenous human Decorin Leu155-Val260) TGF-Beta binding domain 2x fusion heavy chain (SEQ ID NO:62): ATGATGTCCTTTGTCTCTCTGCTCCTGGTTGGCATCCTATTCCATGCCACCCAGGCCGAGGTACAGCTTTT GGAGTCAGGCGGGGGGCTCGTCCAACCTGGGGGGTCACTCCGGTTGTCATGTGCTGCCAGTGGCTTCACATTTCC ATCTTACATTATGATGTGGGTTCGACAGGCCCCTGGGAAGGGGCTGGAGTGGGTTTCCTCCATCTACCCCTCCGGGGGGAATTACCTTTCTATGCCGACACGGTAAAGGGTCGCTTCACTATAAGTCAATACTAAG GAACTCTCTCAGGGCTGAGGACACAGCTGTATATTACTGCGCGCGGATTAAGTTGGGGACCGTCACAACA GTGGATTACTGGGGTCAAGGCACTCTGGTAACCGTATCCTCAGCATCCACCAAGGGCCCAAGTGTATTCCCGCTGG CCCTTCAAGTAAATCCACGTCTGGCGGCACAGCCGCTCTCGGTTGCCTGGTTAAGCACTACTTCGTCC TTGACATCTGGTGTCCATACATTCCCCGCAGTCCTGCAAAGCTCTGGACTTT ACAGTCTTAGTAGCGTAGTGACAGTCCCATCTTCAAGTCTTGGGACCCAAACTTATATTTGCAACGTAAATCATAAAC CCTCCAACACTAAAGTAGACAAAAAAGTAGAGCCGAAATCTTGCGACAAAACGCATACATGCCCACCATGTCCCGCT CCGGAGACTCCCTTCCGGTCTTCAAG ATACGCTTATGATCAGCAGAACAC CGGAAGTTACTTGTGTAGTCGTTGACGTGTCTCACGAAGATCCCGAAGTCAAATTTAATTGGTATGTGGATGGCGTC GAAGTGCACAACGCAAAAACCAAACCCAGAGAGGAACAGTATAACAGCACGTATCGAGTGGTCTCCGTACTTACGG TCTCCACCAGGACTGGTTGAATGGCAAGCAGTACAGTAGGAT TCGA AAAAAACCATCAGCAAGGCCAAGGGACAGCCTAGAGAGCCGCAGGTTTACACCTTGCCGCCATCAAGGGATGAACTG ACTAAAACCAGGTATCCCTGACCTGCCTGGTTAAGGGTTTTTACCCCAGTGATATAGCGGTTGAATGGGAGTCTAA CGGGCAGCCAGAGAACAACTACAAAACGAACCTCCCCGTTCTGGATTCGATTCTTGTCTAACG ATAAATCCCGATGGCAGCAAGGCAACGTCTTCTCCTGCAGCGTGATGCATGAAGCCTTGCACAACCA CTATACCCAAAAGAGTCTCAGCCTGTCACCcGGGAAATCCGGGGGTGGCGGATCCCTGCGTGCCCATGAGAATGAG ATCACCAAAGTGCGAAAAGTIACTTTCAATGGACTGAACCAGATGATTGTC^ GAGCTCAGGAATTGAAAATGGGGCTTTCCAGGGAATGAAGAAGCTCTCCTACATCCGCATTGCTGATACCAATATCA CCAGCATTCCTCAAGGTCTTCCTCCTTCCCTTACGGAATTACATCTTGATGGCAACAAAATCAGCAGAGTTGATGCAG ciagcclgaaaggacigaalaaiiiggctaagitgggaiigagiitcaacaggaiiciciggcigigitccGATCGATCTGG GAATGAGATCACCAAAGTGCGAAAAGTTACTTTCAATGGACTGAACCAGATGATTGI catagaacigqgcaccaatccgctgaac^cjqaggaattgaaaatggggcttttccagggaatgaagaagctctcc TACATCCGCATTGCTGATACCAATATCACCAGCATTCCTCAAGGTCTTCCTCCTTCCCTTACGGAATTACATCTTGATGGCAGAACAAATTGACTGATCAGAGAACATCTGAT ATTTGGCTAAGTTGGGATTGAGTTICAA CAGCATCTCTGCTGTTTGA crcQzn / Lznz / q / Yi The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is underlined with a straight line. Linker coding sequences are shown in italics. Galacorin / Decorin (Leu155-Val260) coding sequences are underlined with a wavy line. Avelumab Galacoñna / Decoñna TGF-Beta binding domain 2x fusion heavy chain protein sequence (Leu155-Val260 full-length endogenous human Decorin) (SEQ ID NO:63): MMSFVSLLLVGILFHATQAEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPS GGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAFPALGCLVKDYGEPVTSLVQWNSLVSY SSWTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTVKVEGVESLTYTPSLT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSGG GGSLRAHENEITKVRKVTFNGLNQMIVIELGTNPLKSSGIENGAFQGMKKLSYJRIADTNITSIPQGLPPSLTELHLDGNKISR yDAASLKONWUKUII^SlWSGGGGSLBAIOHim RIADINITS.IPQ^ The signal peptide sequence is shown in bold. The heavy chain sequence is underlined with a straight line. Linker sequences are shown in italics. Galacorin / Decorin (Leu 155-Val260) sequences are underlined with a wavy line. Example 2 This example describes the production of expression cell lines for the production of the fusion proteins described in Example 1. Retrovector production: The expression constructs described above were introduced into a HEK 293 cell line that constitutively produces MLV. gag, pro, and pol proteins. An envelope containing the expression plasmid was also co-transfected with either the bevacizumab light chain gene construct (see Figure 2 for vector map) or bevacizumabGalacorin heavy chain fusion (see Figure 3 for vector map). vector). The two joint transactions resulted in the production of a high titer replication-incompetent retrovector for either heavy or light chain galacorin, which was concentrated by ultracentrifugation and used for cell transduction (see, for example, Bleck, G.T. 2005. An alternative method for the rapid generation of stable, highly expressing mammalian cell lines (A Technical Review) Bioprocessing J. Sept / Oct pp 1-7 Bleck, G.T., 2010 GPEx® A Flexible Method for the Rapid Generation of Stable, High Expressing, Antibody Producing Mammalian Cell Lines Chapter 4 In: Current Trends in Monoclonal Antibody Development and Manufacturing, Biotechnology: Pharmaceutical Aspects, Edited by: S.J. Shire et al ©2010 American Association of Pharmaceutical Scientists, DO110.1007 / 978 -0-387-76643-0_4.). crcQzn / Lznz / q / Yi Summary. Characteristics of pCS-Bi-wayLC-WPRE(new ori), GDD2107.0003 Component Description Function / Notes 5' hCMV-MoMuSV LTR (R-U5) bp 142-766 promoter hCMV bp 767-911 MoMuSV R-U5 A fusion of the human CMV promoter to the R-U5 regions of the Murine Sarcoma Virus Moloney 5' LTR The human cytomegalovirus IE promoter has strong constitutive activity in most mammalian cells. It is used to create high titers of retrovector particles when transfected into packaging cells. The hCMV promoter is lost after the cell packaging step. Packaging region extended bp 981 - 1790 MoMuLV / SV packaging region of the LTR through an ATG site in the MLV Gag gene The packaging region allows for the creation of retrovector particles by allowing RNA to associate with gene products from MoMuLV Gag / Pol Promoter of sCMV bp 1822-2424 The immediate early promoter of simian CMV Alternative strong constitutive promoter to drive expression of the product gene. Biway light chain gene bp 2510-3211 Biway light chain CDS Biway light chain CDS cloned directly from Bio Basic pUC57 plasmid. WPRE bp 3230-3830 A fragment of the Pol gene of the woodchuck hepatitis B virus Region that is believed to help export unspliced ​​RNA and enhance protein expression. 3' LTR bp 3870-4463 The 3' LTR of MoMuLV Functions as a Poly A signal for RNA. It allows reverse transcription and insertion of retrovector DNA into mammalian cells from retrovector particles. E. coli origin of replication plasmid backbone and O-lactamase gene for ampicillin resistance bp 5765 < 6625 bp 1 -148 E. coli basic plasmid sequences Allows selection of bacteria containing plasmids in E. coli. coli and DNA replication in E. coli. These regions are lost after transfecting plasmids into packaging cells and creating retrovector particles. Summary. Characteristics of pFCS-BiwayGalacorina-WPRE-SIN (new origin), GDD2134.0001 Component Description Function / Notes 5' hCMV-MoMuSV LTR (R-U5) bp 149-865 promoter hCMV bp 866 - 1041 MoMuSV R-U5 A fusion of the full-length human CMV promoter to the R-U5 regions of CMV Moloney murine sarcoma 5' LTR The human cytomegalovirus IE promoter has strong constitutive activity in most mammalian cells. It is used to create high titers of retrovector particles when transfected into packaging cells. The hCMV promoter is lost after the cell packaging step. Extended packaging region bp lili - 1920 MoMuLV / SV packaging region of the LTR through an ATG site in the MLV Gag gene The packaging region allows for the creation of retrovector particles by allowing RNA to associate with gene products from MoMuLV Gag / Pol Promoter of sCMV bp 1952 - 2624 The immediate early promoter of simian CMV Alternative strong constitutive promoter to drive expression of the product gene. Biway HCGalacorin gene fusion bp 2650 - 5073 Biway HCGalacorin CDS complete Biway HC-linkerGalacorin CDS assembled by PCR and cloned by WPRE restriction digest bp 5089 - 5689 A fragment of the Hepatitis B virus Pol gene Woodchuck Region that is believed to help export unspliced ​​RNA and enhance protein expression. SIN 3' LTR bp 5730-6153 The 3' LTR of MoMuLV functions as a Poly A signal for RNA. It allows reverse transcription and insertion of retrovector DNA into mammalian cells from retrovector particles. On deletion proviral DNA in the U3 region doubles to 5' LTR thereby inactivating promoter activity of 5' LTR. Plasmid backbone - E. coli origin of replication and the Ξ-lactamase gene for ampicillin resistance bp 7472 - 8332 bp 1 -148 E. coli basic plasmid sequences Allows selection of bacteria containing plasmids in E . coli and DNA replication in E. coli. These regions are lost after transfecting plasmids into packaging cells and creating retrovector particles. Retrovector transduction of GCHO cells: The combined bevacizumab-galacorin fusion antibody cell line was produced by multiple cycles of cell transduction of the parental GPEx® Chinese Hamster Ovary (GCHO) cell line. ), with two light chain transductions followed by two heavy chain-galacorin transductions performed once a week for a period of 4 weeks. These translations were performed to generate a pooled cell line from each of the two gene products. Bevacizumab-Galacorin fusion fed-batch production from the pooled population of cells: Following transduction, the Bevacizumab-Galacorin fusion pooled cell line was expanded for productivity in a fed-batch study in duplicate shake flasks. 250 mL. 300,000 viable cells per mL were seeded in each shake flask in a 60 mL working volume of PF CHO LS medium (HyClone) and incubated in a humidified (70-80%) shake incubator at 130 rpm with CO2. at 5% and a temperature of 37°C. Cultures were fed four times during the production run using two different feeding supplements. Cultures were terminated when viabilities were <70%. Confirmation of fusion antibody production was determined by SDS-PAGE gel analysis (Figure 4) and by ELISA to quantify the amount of product produced. Cultures produce 360 ​​mg / L of the fusion antibody product. The product behaved as expected on SDS-PAGE showing a single predominant band under non-reduced conditions and two bands (galacorin-heavy chain fusion and light chain) under reduced conditions. The ~80 kDa size of the fusion heavy chain matches the expected size of that product and the light chain is the normal '25 kDa size. Example 3 This example describes the expression of an Avelumab-Galacorin fusion. The SEQ ID NO:50 gene construct was transiently transfected into ExpiCHO cells and fusion molecule production was carried out on the 250 mL scale. The fusion titration on the harvest day was 377 mg / L. The fusion was purified via a MabSelectSuRe protein A column. The resulting purified protein was buffer exchanged in 20 mM NaCitrate, pH 5.5, 50 mM NaCI using tangential flow filtration. The resulting material was examined using SDS-PAGE and SEC-HPLC gels. The product showed an expected size profile on the SDS-PAGE gel (Figure 5) and showed very low aggregation levels on SEC-HPLC (Figure 6). Material produced in prior production was used for evaluation in a mouse tumor model study. The study used C57BL / 6 mice and MC-38 human colorectal cancer cells. MC-38 cells were injected subcutaneously into forty C57BL / 6 mice. Tumors were allowed to grow to approximately 100 mm3 and then 10 mice were assigned to each of 4 different treatments. Each group received single-dose IV treatment and tumor size was measured over the following days. Treatment groups were Vehicle, Galacorin / Decorin 4 mg / kg, Avelumab / Anti-PD-L1 17 mg / kg, or Avelumab / Anti PD-L1-Decorin / Galacorin fusion 25 mg / kg. Tumor growth was inhibited by both Avelumab / Anti-PD-L1 and Avelumab / Anti PD-L1-Decorin / Galacorin fusion treatments compared to Vehicle and Decorin / Galacorin alone (Figure 7). . Additionally, Avelumab / Anti PD-L1-Decorin / Galacorin fusion treatment also inhibited growth more effectively than Avelumab / Anti-PD-L1 alone. All applications and patents mentioned in the above specification are incorporated herein by reference. Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it is to be understood that the invention as claimed should not be unduly limited to such specific embodiments. In fact, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the field of this invention are intended to be within the scope of the following claims.

Claims

1. A multifunctional protein molecule comprising at least one decorin molecule or functional portion thereof linked to an antigen-binding protein.

2. The multifunctional protein molecule according to claim 1, wherein the antigen-binding protein is selected from the group consisting of a VEGF-A antigen-binding protein and a checkpoint inhibitor antigen-binding protein.

3. The multifunctional protein molecule according to claim 2, wherein the checkpoint inhibitor antigen-binding protein binds to a checkpoint inhibitor protein selected from the group consisting of PD-1, PD-L1, CTLA-4, PD-L2, CD27, CD28, CD40, CD47, CD115, CD122, CD137, OX40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, NOX2, TIM-3, VISTA, SIGLEC-7, TIG1T, and 4-1BB.

4. The multifunctional protein molecule according to claim 2, wherein the checkpoint inhibitor antigen-binding protein binds to a checkpoint inhibitor protein selected from the group consisting of PD-1, PD-L1, CTLA-4, PD-L2.

5. The multifunctional protein molecule according to any of claims 1 to 4, wherein the antigen-binding protein is an antibody.

6. The multifunctional protein molecule according to claim 5, wherein the antibody is a monoclonal antibody.

7. The multifunctional protein molecule according to claim 6, wherein the monoclonal antibody is selected from the group consisting of bevacizumab, ranibizumab, ipilimumab, atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.

8. The multifunctional protein molecule according to any of claims 1 to 7, wherein the decorin molecule is a decorin core protein.

9. The multifunctional protein molecule according to claim 8, wherein the decorin core protein comprises a mutation at position 4 of the mature decorin core protein.

10. The multifunctional protein molecule according to claim 9, wherein the mutation is a serine to alanine mutation.

11. The multifunctional protein molecule according to claim 8, wherein the decorin core protein lacks substantial modification by glycosaminoglycan molecules at position 4 of the mature decorin core protein.

12. The multifunctional protein molecule according to any of claims 1 to 11, wherein the fusion protein comprises two or more copies of the decorin polypeptide.

13. The multifunctional protein molecule according to any of claims 1 to 12, wherein the functional portion of a decorin molecule comprises a decorin domain or domains that bind to a signaling molecule selected from the group consisting of transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (HGFR), insulin-like growth factor receptor 1 (IGF-1R), epidermal growth factor receptors (EGFRs), myostatin, and C1q.

14. The multifunctional protein molecule according to claim 13, wherein the TGF-β binding domain comprises full-length endogenous human decorin amino acids Asp45-Lys359 or full-length endogenous human decorin amino acids Leu155-Val260.

15. The multifunctional protein molecule according to any of claims 13 or 14, wherein the multifunctional protein molecule comprises two or more copies of the functional portion of a decorin molecule.

16. The multifunctional protein molecule according to any of claims 2 to 15, wherein the decorin molecule is operably linked to an antibody heavy chain.

17. The multifunctional protein molecule according to any of claims 1 to 16, wherein the antigen-binding protein is bispecific.

18. The multifunctional protein molecule according to any of claims 1 to 16, wherein the antigen-binding protein is multispecific.

19. The multifunctional protein molecule according to any of claims 1 to 18, wherein the multifunctional protein molecule is a fusion protein.

20. The multifunctional protein molecule according to any of claims 1 to 18, wherein the decorin molecule or functional portion thereof is chemically linked to the antigen-binding protein.

21. A nucleic acid or set of nucleic acids encoding a multifunctional protein molecule according to any of claims 1 to 20.

22. A vector or vectors comprising the nucleic acid or set of nucleic acids according to claim 21.

23. A host cell comprising the vector or vectors according to claim 22.

24. Multifunctional protein molecule, nucleic acid molecule or vector according to any of claims 1 to 22 for use in inhibiting a target protein and a signaling molecule in a cell.

25. The use according to claim 24, wherein the target protein is selected from the group consisting of VEGF-1, PD-1, PD-L1, CTLA-4, PD-L2, CD27, CD28, CD40, CD47, CD115, CD122, CD137, OX40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, NOX2, TIM-3, VISTA, SIGLEC-7, TIGIT and 4-1BB.

26. Use in accordance with any of claims 24 to 25, wherein the cell is in vitro or in vivo.

27. Use in accordance with any of claims 24 or 25, wherein the cell is in a subject.

28. Use according to any of claims 24 to 27, wherein the contact results in the inhibition of a selected activity from the group consisting of angiogenesis, PD-1 activity, PD-L1 activity, CTLA-4 activity, PD-L2 activity, CD27 activity, CD28 activity, CD40 activity, CD47 activity, CD115 activity, CD122 activity, CD137 activity, OX40 activity, GITR activity, ICOS activity, A2AR activity, B7-H3 activity, B7-H4 activity, BTLA activity, IDO activity, KIR activity, LAG3 activity, NOX2 activity, TIM-3 activity, VISTA activity, SIGLEC-7 activity, TIGIT activity, and 4-1BB activity.

29. Use according to any of claims 24 to 28, wherein the cells are a cancer cell selected from the group consisting of lung cancer, colorectal cancer, liver cancer, breast cancer, kidney cancer, cervical cancer, ovarian cancer, and glioblastoma.

30. Use according to any of claims 24 to 29, wherein the signaling protein is selected from the group consisting of transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (HGFR), insulin-like growth factor receptor type 1 (IGF-1R), different epidermal growth factor receptors (EGFRs), myostatin, and O1q.

31. Use according to any of claims 24 to 30, wherein the signaling protein is transforming growth factor β (TGF-β).

32. Multifunctional protein molecule, nucleic acid molecule or vector according to any of claims 1 to 22 for use in treating a disorder characterized by angiogenesis or tumor growth.

33. Use according to claim 32, wherein the tumor is selected from the group consisting of lung cancer, colorectal cancer, liver cancer, breast cancer, kidney cancer, cervical cancer, ovarian cancer, and glioblastoma.