Multifunctional protein molecules comprising decorin and use thereof

Abstract

This invention relates to multifunctional protein molecules comprising a core proteoglycan and their uses. Specifically, this invention relates to multifunctional protein molecules comprising a core proteoglycan and a targeting peptide, such as an antibody, as well as methods for their production and uses.

Description

[Technical Field] This invention relates to multifunctional protein molecules comprising a core proteoglycan and their uses. Specifically, this invention relates to multifunctional protein molecules comprising a core proteoglycan and a targeting peptide, such as an antibody, as well as methods for their production and uses. [Previous Technology] VEGF Angiogenesis is the physiological process by which new blood vessels form from pre-existing blood vessels. This differs from angiogenesis, which involves the de novo formation of endothelial cells from mesodermal cell precursors. The first blood vessels in a developing embryo form through angiogenesis, and thereafter angiogenesis is responsible for most (if not all) of blood vessel growth during development and in disease. Angiogenesis is a normal and important process in growth and development, as well as wound healing and granulation tissue formation. However, it is also a fundamental step in the transformation 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 called vascular permeability factor (VPF), is a cell-produced signaling protein that stimulates angiogenesis and blood flow. It is part of the system that restores oxygen supply to tissues when blood circulation is insufficient. Serum VEGF concentrations are higher in bronchial asthma and diabetes. Normal functions of VEGF include the formation of new blood vessels during embryonic development, after injury, after exercise, and the formation of new blood vessels (collateral circulation) that bypass blocked blood vessels. When VEGF is overexpressed, it can lead to disease. Solid tumors cannot grow beyond a limited size without sufficient blood supply; cancers that express VEGF can grow and metastasize. Overexpression of VEGF can lead to vascular diseases of 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, specifically the platelet-derived growth factor family of cystine-containing growth factors. It is an important signaling protein involved in angiogenesis (de novo formation of the embryonic circulatory system) and angiogenesis (growth of blood vessels from a pre-existing vascular system). Checkpoint inhibitors. A crucial part of the immune system is its ability to distinguish between normal cells and cells it perceives as "foreign." This allows the immune system to attack foreign cells while preserving normal cells. For this purpose, it uses "checkpoints," molecules on certain immune cells that need to be activated (or deactivated) to initiate an immune response. Cancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system. Drugs targeting these checkpoints hold promise as a treatment for cancer. Checkpoint inhibitors attempt to overcome one of the main defenses of the immune system against cancer. Immune system T cells constantly patrol the body in response to signs of disease or infection. When they encounter another cell, they detect certain proteins on the cell's surface that act as markers of the cell's identity. If the proteins indicate that the cell is normal and healthy, the T cell leaves it. If the proteins indicate that the cell is infected or cancerous, the T cell attacks it. Once the T cell attacks, the immune system adds a series of additional molecules to prevent the attack from damaging normal tissues in the body. These molecules are called immune checkpoints. Checkpoint inhibitors block these normal proteins on cancer cells, or proteins on T cells that respond to these proteins. The result is the removal of a barrier that prevents T cells from recognizing these cells as cancer cells and causing the immune system to attack them. Three checkpoint inhibitors have received fast-track approval from the U.S. Food and Drug Administration for the treatment of cancer: 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 targeting VEGF or immune checkpoints are needed. [Summary of the Invention] This invention relates to multifunctional protein molecules comprising a core proteoglycan and their uses. Specifically, this invention relates to multifunctional protein molecules comprising a core proteoglycan and a targeting peptide, such as an antibody, as well as methods for their production and uses. Therefore, in some embodiments, the present invention provides a multifunctional protein molecule comprising at least one core proteoglycan molecule or a functional portion thereof linked to an antigen-binding protein. In some preferred embodiments, the antigen-binding protein is selected from the group consisting of VEGF-A antigen-binding proteins and checkpoint inhibitor antigen-binding proteins. 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, OX40, 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, and 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, avermab, durvalumab, nivolumab, and pembrolizumab. In some preferred embodiments, the core proteoglycan polypeptide is a core proteoglycan core protein. In some preferred embodiments, the core proteoglycan core protein contains a mutation at position 4 of the mature core proteoglycan core protein. In some preferred embodiments, the mutation is a serine-to-alanine mutation. In some preferred embodiments, the core proteoglycan core protein lacks substantial modification at position 4 of the mature core proteoglycan core protein by a glycosaminoglycan molecule. In some preferred embodiments, the fusion protein comprises two or more copies of the core proteoglycan polypeptide. In some preferred embodiments, at least one functional portion of the core proteoglycan molecule comprises one or more core proteoglycan domains that bind to signaling molecules selected from the group consisting of: transformed growth factor-β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor 2 (VEGFR2), hepatocyte growth factor receptor (HGFR), insulin-like growth factor 1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), myostatin, and C1q. In some preferred embodiments, the TGF-β binding domain comprises amino acids Asp45-Lys359 or Leu155-Val260 of full-length endogenous human core proteoglycan. In some preferred embodiments, the multifunctional protein molecule comprises two or more copies of at least one functional portion of the core proteoglycan molecule. In some preferred embodiments, the core proteoglycan molecule is operatively linked to the 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 core proteoglycan molecule is chemically linked to the antigen-binding portion. In some preferred embodiments, the present invention provides a nucleic acid or nucleic acid set encoding the aforementioned multifunctional protein molecule. In some preferred embodiments, the present invention provides one or more vectors comprising nucleic acids or nucleic acid sets. In some preferred embodiments, the present invention provides a host cell comprising the one or more vectors. In some preferred embodiments, the present invention provides a method for inhibiting target proteins and signaling molecules in cells, comprising: contacting cells with a multifunctional protein molecule as described above or a carrier as described above under conditions that inhibit the activity of at least one target protein and at least one signaling protein in the cells, wherein the target protein is 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, TIGIT, and 4-1BB. In some preferred embodiments, the cells are in vitro or in vivo cells. In some preferred embodiments, the cells are in a subject. In some preferred embodiments, contact results in inhibition of the activity of a group selected from the following components: 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. In some preferred embodiments, the cancer is selected from the group consisting of lung cancer, colorectal cancer, liver cancer, kidney cancer, cervical cancer, ovarian cancer, and glioblastoma. In some preferred embodiments, the signaling protein is selected from the group consisting of: transformed growth factor-β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor 2 (VEGFR2), hepatocyte growth factor receptor (HGFR), insulin-like growth factor 1 receptor (IGF-1R), various epidermal growth factor receptors (EGFR), myosin, and C1q. In some preferred embodiments, the signaling protein is transformed growth factor-β (TGF-β). In some preferred embodiments, the present invention provides a method for treating a condition characterized by angiogenesis or tumor growth, comprising: administering to the subject the multifunctional protein molecule or carrier described above under conditions 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, kidney cancer, cervical cancer, ovarian cancer, and glioblastoma.

Implementation Method

[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 polypeptides secreted from cell types targeted for tissue-specific expression (e.g., secretory milk proteins expressed in and secreted from mammary gland secretory cells). However, secretory DNA sequences are not limited to such sequences. Secretory DNA sequences derived from proteins secreted from many cell types and organisms can also be used (e.g., secretion signals from t-PA, serum albumin, lactoferrin, and growth hormone, as well as secretion signals from microbial genes encoding secretory polypeptides, such as those from yeast, filamentous fungi, and bacteria). As used herein, the term "purified" refers to a molecule (nucleic acid sequence or amino acid sequence) that has been removed from its normal environment, isolated, or separated. Therefore, an "isolated nucleic acid sequence" is a purified nucleic acid sequence. A "substantially purified" molecule is at least 60% free of, preferably at least 75% free of, and more preferably at least 90% free of other components that would normally be associated with it. For the purposes of this document, a "receptor human framework" is a framework comprising an amino acid sequence derived from a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework of the human immunoglobulin framework or the human common framework as defined below. A receptor human framework "derived from" the human immunoglobulin framework or the human common framework may contain the same amino acid sequence as the human immunoglobulin framework or the human common framework, or may contain variations in the amino acid sequence. In some embodiments, the number of amino acid variations is 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, or 2 or fewer. In some embodiments, the sequence of the VL receptor human framework is identical to the VL human immunoglobulin framework sequence or the human common framework sequence. "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its conjugate (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the inherent binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its conjugate Y is generally expressed by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below. "Affinity-matured" antibody systems refer to antibodies that have one or more alterations in one or more hypervariable regions (HVRs) compared to the parent antibody, which does not have such alterations, and these alterations result in an improved affinity of the antibody for the antigen. The term "antibody" is used in the broadest sense in this document and covers a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired antigen-binding activity. "Antibody fragment" refers to a molecule other than a complete antibody that contains a portion of a complete antibody and binds to the antigen bound by the complete antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; bifunctional antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. "Antibody that binds to the same antigenic determinant" refers to an antibody that blocks the binding of the reference antibody to its antigen by 50% or more in a competitive assay, and conversely, the reference antibody that blocks the binding of the antibody to its antigen by 50% or more in a competitive assay. This document provides exemplary competitive assays. The term "chimeric" antibody system refers to an antibody in which one part of the heavy chain and / or light chain is derived from a specific source or species, while the remaining part of the heavy chain and / or light chain is derived from different sources or species. The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five main antibody classes: IgA, IgD, IgE, IgG, and IgM, and several of these classes can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The constant domains of the heavy chain corresponding to different classes of immunoglobulins are respectively called α, δ, ε, γ, and μ. "Effective function" refers to the biological activity attributable to the Fc region of an antibody, which varies with antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation. The "effective amount" of a drug (such as a pharmaceutical compound) means the amount that effectively achieves the desired therapeutic or preventive outcome at the necessary dosage and for the necessary duration. The term "antigen determinant" refers to the specific site on an antigen molecule where an antibody binds. The term "Fc region" as used herein is used to define a C-terminal region in an immunoglobulin heavy chain that contains at least a portion of a constant region. This term includes both native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the C-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the amino acid residues in the Fc region or constant region are numbered according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991. "Framework" or "FR" refers to the variable domain residues excluding the hypervariable region (HVR) residues. A variable domain FR typically consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the HVR and FR sequences generally appear in the VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4. The terms “full-length antibody,” “intact antibody,” and “all antibody” are used interchangeably in this document and refer to antibodies whose structure is substantially similar to that of natural antibodies or have a heavy chain containing an Fc region as defined herein. The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells in which exogenous nucleic acids have been introduced, including their progeny. Host cells include "transformed cells" and "transformed progeny," which include primary transformed cells and their progeny regardless of the number of generations. Progeny may not be identical to parental cells in terms of nucleic acid contents and may contain mutations. This article includes mutant progeny with the same function or biological activity as those screened or selected for the original transformed cells. "Human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody produced by humans or human cells, or an antibody derived from a non-human source using a human antibody lineage or other human antibody coding sequence. This definition of human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. "Human common framework" refers to the framework of the most frequently occurring amino acid residues selected from the human immunoglobulin VL or VH framework sequence. Generally, the human immunoglobulin VL or VH sequence is selected from a subset of variable domain sequences. Generally, this subset is as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1-3. In one embodiment, for VL, the subset is subgroup κ I as described in Kabat et al. (ibid.). In one embodiment, for VH, the subset is subgroup III as described in Kabat et al. (ibid.). "Humanized" antibody systems refer to chimeric antibodies comprising amino acid residues from non-human HVR and amino acid residues from human FR. In some embodiments, a humanized antibody will substantially comprise at least one and typically all of the two variable domains, wherein all or substantially all of the HVR (e.g., CDR) correspond to the non-human antibody, and all or substantially all of the FR correspond to the human antibody. Humanized antibodies may, where appropriate, comprise at least a portion of the antibody constant region derived from a human antibody. The "humanized form" of an antibody (e.g., a non-human antibody) refers to an antibody that has undergone humanization. As used herein, the term "hypervariant region" or "HVR" refers to regions within the antibody variable domain that exhibit sequence hypervariability and / or form structurally defined loops ("hypervariant loops"). Generally, a natural tetrachain antibody contains six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). HVRs typically contain amino acid residues from the hypervariant loop and / or from the "complementarity-determining region" (CDR), which has the highest sequence variability and / or participates in antigen recognition. Exemplary hypervariant loops are located 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) are present at amino acid residues 24-34 of L1, amino acid residues 50-56 of L2, amino acid residues 89-97 of L3, amino acid residues 31-35B of H1, amino acid residues 50-65 of H2, and amino acid residues 95-102 of H3. (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Besides CDR1 in VH, CDRs typically contain amino acid residues that form hypercyclic rings. CDRs also contain "specificity-determining residues" or "SDRs" that act as contact antigens. SDRs are contained within the region of the CDR known as the abbreviated CDR or a-CDR. Exemplary a-CDR) (a-CDR-L1, a-CDR-L2, a-CDR-L3, a-CDR-H1, a-CDR-H2, and a-CDR-H3) are present at amino acid residues 31-34 of L1, amino acid residues 50-55 of L2, amino acid residues 89-96 of L3, amino acid residues 31-35B of H1, amino acid residues 50-58 of H2, and amino acid residues 95-102 of H3. (See Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008).) Unless otherwise indicated, HVR residues and other residues (e.g., FR residues) in the variable domain are numbered in this document according to Kabat et al. (ibid.). "Individual" or "subject" refers to a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates, such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human. "Isolated antibody" is an antibody that has been separated from its components in its natural environment. In some embodiments, the antibody is purified to a purity greater than 95% or 99%, as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed-phase HPLC). For a review of methods used to analyze antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007). "Isolated nucleic acid" refers to nucleic acid molecules that have been separated from components of their natural environment. Isolated nucleic acids include nucleic acid molecules contained in cells, which are generally present in these cells, but which are located outside chromosomes or at chromosomal locations different from their natural chromosomal locations. As used herein, the term "monoclonal antibody" refers to an antibody derived from a substantially homogeneous population of antibodies, meaning that the individual antibodies constituting the population are consistent and / or bind to the same antigenic determinant, except for possible variant antibodies, such as those containing naturally occurring mutations or those arising during the production of the monoclonal antibody formulation, which are generally present in small quantities. In contrast to multiclonal antibody formulations, which typically comprise different antibodies targeting different determinants (antigenic determinants), each monoclonal antibody system in a monoclonal antibody formulation targets a single determinant on the antigen. Therefore, the modifier "monoclonal" indicates that the antibody is characterized by being derived from a substantially homogeneous population of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies intended for use according to the invention can be produced by a variety of techniques, including but not limited to fusion tumor methods, recombinant DNA methods, phage presentation methods, and methods using transgenic animals containing all or part of the human immunoglobulin locus, as described herein and other exemplary methods for producing monoclonal antibodies. "Natural antibodies" refer to naturally occurring immunoglobulin molecules with varying structures. For example, natural IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 Daltons, composed of two identical light chains and two identical heavy chains linked by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH) (also called a variable heavy domain or heavy chain variable domain), followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL) (also called a variable light domain or light chain variable domain), followed by a constant light (CL) domain. The light chains of antibodies can be assigned to one of two types (called κ (kappa) and λ (lambda)) based on the amino acid sequence of their constant domains. The "amino acid sequence identity percentage (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to those in the reference polypeptide sequence after alignment of the reference polypeptide sequence with the candidate sequence, with gaps introduced where necessary to achieve the maximum sequence identity percentage, and without considering conserved substitutions as part of sequence identity. Alignment to determine the amino acid sequence identity percentage can be performed in various ways within the skill of the art, such as using publicly available computer software like BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR). Those skilled in the art can determine the appropriate parameters for sequence alignment, including any algorithm required to achieve maximum alignment across the full length of the sequences being compared. However, for the purposes of this document, the sequence alignment computer program ALIGN-2 is used to generate the amino acid sequence identity % value. The ALIGN-2 sequence comparison computer program was created by Genentech Corporation, and its source code is archived in the user documentation of the US Copyright Office, Washington DC, 20559, under US Copyright Registry No. TXU510087. The ALIGN-2 program is publicly available from Genentech Corporation, South San Francisco, California, or can be compiled from the source code. The ALIGN-2 program should be compiled for use with UNIX operating systems, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and remain unchanged. In the case where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A relative to, and / or with respect to, a given amino acid sequence B (which can also be expressed as a given amino acid sequence A having or containing a certain % amino acid sequence identity relative to, and / or with respect to, a given amino acid sequence B) is calculated as follows: 100 × score X / Y, where X is the number of amino acid residues that are scored as a consistent match by the ALIGN-2 sequence alignment program in the A vs. B alignment, and Y is the total number of amino acid residues in B. It should be understood that if 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 relative to B will not be equal to the % amino acid sequence identity of B relative to A. Unless otherwise specifically stated, all amino acid sequence identity % values ​​used herein were obtained using the ALIGN-2 computer program as described in the preceding paragraph. The term "medicinal compound" refers to a formulation which is in a form that allows the biological activity of the active ingredient contained therein to be effective and does not contain any additional components that would have unacceptable toxicity to the individual to whom the compound will be administered. "Pharmaceutical-acceptable carriers" refer to components in a pharmaceutical formulation that are non-toxic to the subjects, excluding the active ingredient. Pharmaceutical-acceptable carriers include, but are not limited to, buffer solutions, excipients, stabilizers, or preservatives. As used herein, "treatment" (and its grammatical variations such as "treat" or "treating") refers to a clinical intervention aimed at altering the natural course of disease in the treated individual, and may be for the purpose of prevention or in the clinicopathological course of the disease. Desired therapeutic effects include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological outcome of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and mitigating or improving prognosis. In some embodiments, the antibodies of the present invention are used to delay the onset of disease or slow its progression. The term "variable region" or "variable domain" refers to a domain in the heavy or light chain of an antibody that participates in the binding of the antibody to the antigen. The heavy chain variable domain and light chain variable domain (VH and VL, respectively) of natural antibodies generally have similar structures, with each domain containing four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007).) A single VH or VL domain is sufficient to confer antigen-binding specificity. Furthermore, antibodies binding to a specific antigen can be isolated using the VH or VL domains of the antibody binding to that antigen to screen libraries 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). As used herein, the term "vector" refers to a nucleic acid molecule capable of proliferating another attached nucleic acid. This term includes vectors that exhibit autonomously replicating nucleic acid structures as well as vectors incorporated into the genome of the host cell to which they are introduced. Some vectors can instruct the expression of the nucleic acid to which they are operatively linked. Such vectors are referred to herein as "expression vectors." This invention relates to multifunctional molecules comprising a core proteoglycan molecule or a functional portion thereof operatively linked to an antigen-binding protein, such as an immunoglobulin molecule, a truncated fragment of an antigen molecule, or a single-chain antibody. Specifically, this invention relates to fusion peptides comprising a core proteoglycan and VEGF or an immune checkpoint-targeting peptide (preferably a checkpoint inhibitor), methods for their preparation, and uses thereof. Embodiments of this invention provide fusion peptides comprising a core proteoglycan peptide fused to an antigen-binding protein of interest, nucleic acids encoding such peptides, and uses thereof. Exemplary compositions and methods are described herein. The core proteoglycan utilized in the functional molecule may be wild-type core proteoglycan, core proteoglycan core protein, or a functional portion of any of these proteins (such as the portion that binds TGF-β), or other signaling molecules such as connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor 2 (VEGFR2), hepatocyte growth factor receptor (HGFR), insulin-like growth factor 1 receptor (IGF-1R), various epidermal growth factor receptors (EGFR), myosin, and C1q. I. Core Proteoglycan In a preferred embodiment, the multifunctional protein molecule of the present invention comprises one or more core proteoglycan polypeptides or functional portions thereof. The performance of core proteoglycans in inhibiting transforming growth factor-β-induced plasminogen activator inhibitor-1 has been shown (see, for example, Wahab et al., Biochem J. 2002 Mar 15; 362(Pt 3): 643-649; which is incorporated herein by reference in its entirety). Transforming growth factor-β (TGF-β) is a key mediator of extracellular matrix (ECM) accumulation in sclerosing nephropathy such as diabetic nephropathy. While not limited to a specific mechanism, it is anticipated that the combination of core proteoglycans and VEGF-binding proteins will improve efficacy beyond that of VEGF-binding proteins alone by inhibiting TGF-β activity and blocking VEGF binding. Natural core proteoglycans are glycoproteins with linked glycosaminoglycans and an average molecular weight of 90-140 kD. In some preferred embodiments, the core proteoglycan is a core proteoglycan core protein, i.e., a substantially non-glycosaminoglycanized core proteoglycan. In some embodiments, the core proteoglycan core protein contains a mutation at amino acid 4 (i.e., the fourth amino acid at the N-terminus) of the mature core proteoglycan core protein molecule. In some embodiments, the mutation is a serine to alanine mutation. In some embodiments, the core proteoglycan core protein is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:6 (mature core proteoglycan core protein), provided that the core proteoglycan core protein contains a mutation at amino acid 4 (i.e., the fourth amino acid at the N-terminus) of the mature core proteoglycan core protein molecule. Core proteoglycans typically function as pre-proproteins. This invention provides a multifunctional protein molecule comprising an antigen-binding protein operatively associated with one or more mature core proteoglycan peptide sequences or functional portions thereof. In some embodiments, the core proteoglycan core protein portion of the fusion polypeptide is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:6 (mature core proteoglycan core protein) or its functional portion thereof. In some embodiments, the core proteoglycan core protein contains a mutation at amino acid 4 (i.e., the fourth amino acid at the N-terminus) of the mature core proteoglycan core protein molecule. The present invention further provides a nucleic acid sequence encoding a fusion protein, and a vector containing the nucleic acid sequence. In some embodiments, the core proteoglycan core protein portion of the fusion polypeptide is at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:5 (mature core proteoglycan core protein), provided that the core proteoglycan core protein contains a mutation at amino acid 4 (i.e., the fourth amino acid at the N-terminus) of the mature core proteoglycan core protein molecule. In some embodiments, the core proteoglycan molecule utilized in a multifunctional polypeptide molecule may comprise one or more functional moieties of the core proteoglycan molecule. The core proteoglycan molecule has numerous functional moieties or domains, such as those described in Järvinen and Prince, BioMed Research Int'l, Vol. 2015, Article ID 654765 (which is incorporated herein by reference in its entirety). In some preferred embodiments, the core proteoglycan functional moieties bind to or interact with transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor 2 (VEGFR2), hepatocyte growth factor receptor (HGFR), insulin-like growth factor 1 receptor (IGF-1R), various epidermal growth factor receptors (EGFR), myosin, or C1q, or otherwise. Preferably, the core proteoglycan functional moieties retain functional activity (such as binding to one of the signaling molecules just described) and preferably are at least 90%, 95%, 99%, or 100% identical to the corresponding native core proteoglycan sequence. The preferred core proteoglycan functional portion is shorter than the full-length natural core proteoglycan molecule and can be, for example, 10 to 300 amino acids long or 10 to 120 amino acids long. For example, the functional portion of the core proteoglycan molecule can be at least 90%, 95%, 99%, or 100% identical to SEQ ID NO:64 (core proteoglycan TGF-β binding domain, full-length endogenous human core proteoglycan ASP45-LYS359), SEQ ID NO:65 (two copies of core proteoglycan TGF-β binding domain, ASP45-LYS359, separated by a linker), SEQ ID NO:66 (core proteoglycan TGF-β binding domain, full-length endogenous human core proteoglycan LEU155-VAL260), and SEQ ID NO:67 (two copies of core proteoglycan TGF-β binding domain, LEU155-VAL260, separated by a linker). Exemplary core proteoglycan polypeptides and methods for purifying core proteoglycans are described, for example, in WO 2006038107; which is incorporated herein by reference in its entirety. The exemplary core proteoglycan nucleic acid and amino acid sequences are provided below and in Figures 1 and 2. II. Binding Agents A preferred embodiment of the present invention provides a multifunctional protein molecule comprising one or more core proteoglycan molecules or functional portions thereof operatively linked to a binder of interest. The preferred binder of interest includes, but is 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 (planned cell death protein 1), PD-L1 (planned death ligand 1), PD-L2 (planned death ligand 2), 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. Binders (e.g., antigen-binding proteins) typically interact with or bind specifically to a target surface. For example, the binders disclosed herein typically interact specifically with regions such as VEGF, CTLA-4, PD-1, or PD-1, collectively referred to herein as target proteins. "Specifically" binding to a target protein means that the amount bound to the target protein is greater than the amount bound to non-target proteins (e.g., background non-specific binding may exist). Typically, for example, the specific binding of a binder to a protein can be achieved by binding to a specific amino acid sequence within the protein target. These sequences may be called antigenic determinants. Molecules containing antigenic determinants can be used to stimulate binders such as antibodies and may be called immunogens. Binders may also recognize specific 2-dimensional and / or 3-dimensional structures that are part of an antigenic determinant. Antigen-binding proteins can be monospecific, bispecific, or multispecific. The specific interaction or binding of a binder to its target is considered an equilibrium reaction. In one instance, specific binding can be quantified. Quantification can be achieved using a dissociation constant, or, in this technique, Kd, ​​which is known as an equilibrium constant describing the tendency of the antibody to dissociate from the antigen or antigenic determinant it binds to under these conditions. Therefore, Kd describes the antibody's affinity for the antigenic determinant. The lower the Kd, the higher the affinity of the binder for its target. In some embodiments, the conjugate is a monoclonal antibody. The antibody (e.g., a monoclonal antibody) may also be any suitable isotype or isotype subclass. The conjugate may also be an antibody derivative, such as Fab, F(ab')2, Fab' single-chain antibody, Fv, single-chain, monospecific antibody, bispecific antibody, trispecific antibody, multivalent antibody, chimeric antibody, humanized antibody, human antibody, shark antibody, nanoantibody (e.g., an antibody containing a single monomeric variable domain), camel antibody (e.g., from the Camelidae family) microsomes, intracellular antibody (e.g., an intracellular antibody), or de-trehalosylated antibody and / or its derivatives. Analogs of the conjugate and / or antibody are also contemplated within the scope of this invention. The conjugate may also include a detectable label and / or effector moiety linked thereto. When the binder is an antigen-binding protein such as an immunoglobulin or a derivative thereof, it can be identified by referring to the nucleotide and / or amino acid sequences corresponding to its variable region and / or complementarity-determining region (“CDR”). For example, exemplary binders derived from or associated with the monoclonal antibodies described herein may comprise heavy and / or light chains, each containing one or more constant and / or variable regions. The variable region typically contains one or more CDRs, which largely determine the binding specificity of the antibody. Such monoclonal antibodies can be identified by analyzing the nucleotide sequence encoding the variable region. Monoclonal antibodies can also be identified by analyzing the amino acid sequence of the variable region (e.g., encoded by the nucleotide sequence). The amino acids in the multifunctional protein molecules of this invention can also be replaced by any other amino acid as desired by those skilled in the art. For example, those skilled in the art can perform conserved substitutions by replacing specific amino acids with other amino acids, as is known in the art. Any amino acid sequence of the antigen-binding protein described herein can also be combined with any other variable region and / or CDR in any order and / or combination using standard techniques to form hybridization and / or fusion binders and / or insert other heavy chain and / or light chain variable regions. These can be used in conjunction with any constant region. The CDR (Complementarity Determinant Region) is an amino acid sequence derived from an antibody that is at least partially responsible for the binding of the antibody to a specific target. Those skilled in the art will understand that several techniques and / or schemes can be used to identify the CDR. The CDR of the binder shown herein can be identified using any of these techniques. For example, those generally skilled in the art can use the Kabat numbering scheme, the Chothia numbering scheme, the enhanced Chothia numbering scheme, and / or any available CDR definition scheme (e.g., AbM, contact definition, and I, or as described by MacCullum et al., J Mol. Biol, 262(5):732-745, 1996) to identify the CDR. The overview of the various protocols is partly based on, for example, Kabat et al., "Sequences of Proteins of Immunological Interest," 5th edition, 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. As will be understood by those skilled in the art, these systems for identifying CDRs are merely exemplary, and other systems may be suitable. CDRs thus identified can be used to identify suitable binders, such as equivalents of one or more monoclonal antibodies described herein. Such CDRs can also be combined with each other in any order and / or combination using standard techniques to form hybridization and / or fusion binders and / or insert other heavy and / or light chain variable regions. In some embodiments, the CDR sequence of an antigen-binding protein described herein is linked to the constant region of any antibody molecule from the same or different species (e.g., human, goat, rat, sheep, chicken) from which the variable region amino acid sequence originates. Deaminering aspartic acid residues to aspartic acid or isoaspartic acid is a common post-translational modification of proteins. Deaminering occurs more frequently when aspartic acid is part of an aspartic acid-glycine dipeptide (Asp-Gly or NG; "NG" sequence). Deaminering can have adverse effects on proteins. In one instance, deaminering may potentially cause changes in the three-dimensional structure of the protein. In another instance, for antibodies, deaminering in regions affecting antigen binding (e.g., variable regions and / or CDRs) may potentially lead to reduced or lost antibody binding to the antigen. Therefore, in some embodiments, amino acid residues that may be susceptible to post-translational deacetylation are substituted with less affected or unaffected amino acid residues. In one example, aspartic acid and / or glycine are substituted to modify the NG sequence, for example, by eliminating any amino acid from the NG sequence. The constant region of an antibody is derived from any of the following: for example, human (e.g., IgG (IgG1, IgG2, IgG3, IgG4), IgM, IgA (IgA1 and IgA2), IgD and IgE), dog (e.g., IgG (IgGA, IgGB, IgGC, IgGD), IgA, IgD, IgE and IgM), chicken (e.g., IgA, IgD, IgE, IgG, IgM, IgY), goat (e.g., IgG), mouse (e.g., IgA, IgG, IgD, IgE, IgM), pig (e.g., IgA, IgG, IgD, IgE, IgM), rat (e.g., IgA, IgG, IgD, IgE, IgM), cat (e.g., IgA, IgD, IgE, IgG, IgM) and / or fragments and / or derivatives thereof (e.g., as chimeric antibodies). In one instance, the binder is an antibody with a modified glycosylation pattern. For example, IgG molecules typically contain an N-linked oligosaccharide. Some IgG molecules contain a biantennary complex oligosaccharide linked to the antibody heavy chain. In human IgG, the oligosaccharide is typically linked to an aspartic acid residue at position 297 (N297) of the heavy chain (in the constant Fc region of the antibody heavy chain). Typically, trehalose is linked to a GLcNAC residue in the oligosaccharide closest to N297. The absence of trehalose enhances the antibody-mediated antibody-dependent cytotoxicity (ADCC). Removing trehalose is intended to enhance the antibody's ability to interact with the Fc receptor. This type of antibody is referred to as "de-trehalylated". De-trehalylated antibodies can be produced using techniques described herein and known in the art. In some embodiments, the nucleic acid sequence encoding the antibody can be expressed in cell lines whose glycosylation capacity has been altered (e.g., lacking, altering, or having a smaller amount of trehalosyltransferase) and in which a typical trehalose moiety cannot be added. Several such cell lines are known. In some embodiments, the antibodies disclosed herein bind to VEGF but contain trehalosylated oligosaccharides. The binding agent (e.g., the antibody) may include other modifications that can lead to reduced interaction with the Fc receptor. For example, the antibody molecule described herein may be substituted or have additional amino acids replaced. As described above, in some embodiments, the conjugate may be an antibody or an immunoglobulin. The term "antibody" may refer to a whole antibody or fragmented antibody in unpurified or partially purified form (e.g., fusion tumor supernatant, ascites, multiclonal antiserum) or purified form. A "purified" antibody may be an antibody that is separated from at least about 50% of the protein it originally coexists with (e.g., as part of a fusion tumor supernatant or ascites preparation). A purified antibody may be an antibody that is separated from at least about 60%, 75%, 90%, or 95% of the protein it originally coexists with. Suitable derivatives may also be fragments (e.g., Fab, F(ab')2, or single-chain antibodies, such as Fv). Antibodies may be from any suitable source or form, including, for example, mouse (e.g., produced from mouse fusion tumor cells), or appear as chimeric antibodies and similar antibodies. Methods for preparing and utilizing various types of antibodies are well known to those skilled in the art and are applicable to the practice of this 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 Milstein, Nature, 256:495, 1975; Jones et al., Nature, 321:522-525, 1986; Riechmann et al., Nature, 332:323-329, 1988; Presta, Curr. Op. Struct. Biol., 2:593-596, 1992; Verhoeyen et al., Science, 239:1534-1536, 1988; Hoogenboom et al., J Mol. Biol., 227:381). 1991; Marks et al., J Mol. Biol., 222:581, 1991; Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77, 1985; Boerner et al., J Immunol., 147(1):86-95, 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; and U.S. 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 checkpoint inhibitors 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 4-1BB. In some embodiments, antigen-binding proteins inhibit the activity of checkpoint inhibitors 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 4-1BB. In some embodiments, the antibody is a commercially available human or humanized monoclonal antibody that targets VEGF (e.g., bevacizumab, ranibizumab, or pilgatanib) or immune system checkpoint molecules such as CTLA-4 (e.g., ipilimumab, Yervoy), PD-L1 (e.g., atezolizumab, avermab, or durvalumab, Imfinzi) or PD-1 (e.g., 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 various diseases, particularly cancer. Bevacizumab was the first angiogenesis inhibitor available for use in the United States. Ipilimumab (Yervoy) is a monoclonal antibody that activates the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. T lymphocytes recognize and destroy cancer cells. However, inhibitory mechanisms interrupt this destruction. Ipilimumab shuts down this inhibitory mechanism, allowing lymphocytes to continue destroying cancer cells. Cancer cells produce antigens that the immune system can use to recognize them. These antigens are recognized by dendritic cells, which present them to cytotoxic T lymphocytes (CTLs) in the lymph nodes. CTLs use these antigens to recognize and destroy cancer cells. However, along with the antigens, dendritic cells present an inhibitory signal. This signal binds to the receptor cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CTLs and shuts down the cytotoxic response. This allows cancer cells to survive. Ipilimumab binds to CTLA-4, blocking the inhibitory signal and allowing CTLs to destroy cancer cells. Atezolizumab (Tecentriq) is a fully humanized, engineered monoclonal antibody targeting the IgG1 isoform of the protein PD-L1. Bavencio is a fully human monoclonal antibody that binds to PD-L1. Imfinzi is a fully human monoclonal antibody that binds to PD-L1. These molecules are collectively 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 (especially cytotoxic T cells) that may otherwise recognize and attack cancer. PD-L1 checkpoint inhibitors block the interaction between PD-L1 and planned cell death protein 1 (PD-1) and the CD80 receptor (B7-1R). Inhibition of PD-L1 eliminates the effects of immunosuppressive agents and thus generates an anti-tumor response. Nivolumab (Opdivo) is a human monoclonal antibody that binds to PD-1. Pembrolizumab (Keytruda) is a humanized antibody that binds to PD-1. These molecules together are known as PD-1 inhibitors and are classified as immune checkpoint inhibitors. These molecules work by blocking negative regulators of T cell activation, thus enabling the immune system to attack tumors. This is an example of immune checkpoint blockade. PD-1 is a protein on the surface of activating T cells. As discussed above, if PD-L1 or PD-L2 binds to PD-1, T cells become inactive. Many cancer cells produce PD-L1, which inhibits T cells from attacking tumors. Nivolumab blocks the binding of PD-L1 to PD-1, allowing T cells to function. Those skilled in the art will understand that the CDR or variable region of the mentioned antibody can be isolated (e.g., by selection) and grafted as needed to other frameworks or antigen-binding protein derivatives (e.g., Fab, F(ab')2, Fab' single-chain antibodies, Fv single-chain antibodies, bispecific antibodies, trispecific antibodies, multivalent antibodies, humanized antibodies, nanoantibodies, camel antibodies, microbodies, or intracellular antibodies). Therefore, this invention covers antigen-binding proteins derived from reference antibodies and recognized by the CDR of the variable region of the reference antibody. For example, in some preferred embodiments, the antigen-binding protein of this invention comprises heavy and light chain variable regions derived from bevacizumab, ranibizumab, pilgartanib, ipilimumab, atezolizumab, avermectin, durvalumab, nivolumab, or pembrolizumab. In other preferred embodiments, the antigen-binding protein comprises one, two, or all three of the CDR1, CDR2, and CDR3 of the heavy and light chain variable regions of bevacizumab, ranibizumab, pilgartanib, ipilimumab, atezolizumab, avermectin, duvalib, nivolumab, or pembrolizumab. III. Multifunctional Peptide Embodiments of the present invention provide multifunctional polypeptides and / or polynucleotides encoding multifunctional polypeptides, wherein the fusion polypeptide comprises a core proteoglycan polypeptide operatively linked to a binder. In some embodiments, compositions comprising such binders, polypeptides, peptides, polynucleotides, expression vectors, and / or host cells are also provided. In some embodiments, the compositions comprise pharmaceutically acceptable carriers. In some preferred embodiments, the binding agent in the multifunctional protein molecule is an antibody as described above. Figure 1 provides a diagram of the core proteoglycan-antibody fusion of the present invention targeting VEGF. Those skilled in the art will recognize that other antigen-binding moieties described herein may replace the VEGF antibody described in Figure 1. Referring to Figure 1, the fusion protein comprises heavy and light chains of an antibody (e.g., bevacizumab) that binds to VEGF. The core proteoglycan molecule is operatively 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 linking of the core proteoglycan molecule to any particular amino acid of the antigen-binding protein. In some preferred embodiments, the core proteoglycan molecule is linked via the C-terminus of one or two antibody heavy chains, via the C-terminus of one or two antibody light chains, via the N-terminus of one or two antibody heavy chains, via the N-terminus of one or two antibody light chains, or via a chemically modified amino acid in a constant region of one or two antibody heavy chains to allow the linking of polypeptides such as the core proteoglycan molecule. Therefore, the fusion protein of the present invention may contain one or more core proteoglycan molecules or their functional portions, and may contain more than two core proteoglycan molecules or their functional portions. Numerous nucleic acid constructs encoding the multifunctional protein molecules of this invention are provided in the examples. The following diagram provides an overview of the sequences. Therefore, in some preferred embodiments, the fusion protein of the present invention comprises heavy and light chain variable regions from bevacizumab, ranibizumab, pilgatanib, ipilimumab, atezolizumab, avermectin, durvalumab, nivolumab, or pembrolizumab, which are operatively linked to a core proteoglycan molecule, preferably a core proteoglycan core protein. In other preferred embodiments, the fusion protein comprises one, two, or all three of CDR1, CDR2, and CDR3 from the heavy and light chain variable regions of bevacizumab, ranibizumab, pilgatanib, ipilimumab, atezolizumab, avermectin, durvalumab, nivolumab, or pembrolizumab, which are operatively linked to a core proteoglycan molecule, preferably a core proteoglycan core protein. In some preferred embodiments, the core proteoglycan molecule (or multiple molecules, when using more than one copy) is a core proteoglycan core protein that has at least 80%, 90%, 95%, 99%, or 100% identity with SEQ ID NO:7. In other preferred embodiments, the core proteoglycan molecule (or multiple molecules, when using more than one copy) is a core proteoglycan TGF-β binding domain that has at least 80%, 90%, 95%, 99%, or 100% identity with SEQ ID NO:64 or 66. In some preferred embodiments, the core proteoglycan core protein inhibits TGF-β activity. In some preferred embodiments, the core proteoglycan core protein contains one or more mutations that result in the core proteoglycan core protein being non-glycosaminoglycanized. In some preferred embodiments, the core proteoglycan core protein contains a mutation at amino acid 4 (i.e., the fourth amino acid at the N-terminus) of the mature core proteoglycan core protein molecule. In some preferred embodiments, the core proteoglycan core protein molecule is linked to the heavy or light chain of the target antibody via a linker sequence. This invention is not limited to any particular linker sequence. In some preferred embodiments, the linker sequence is SEQ ID NO:6. In some particularly preferred embodiments, the linker sequence is linked to the N-terminus of the antibody heavy chain and is located between the heavy chain and the core proteoglycan core protein. Therefore, in some preferred embodiments, the heavy chain fusion can be represented by the following formula: Heavy chain protein - Linker - Core proteoglycan core protein In other preferred embodiments, the fusion may be represented by the following formula: C-terminal heavy chain protein-linker-core proteoglycan; C-terminal light chain protein-linker-core proteoglycan; core proteoglycan-linker-N-terminal heavy chain protein; core proteoglycan-linker-N-terminal light chain protein; constant region-linker-core proteoglycan. The core proteoglycan may be, as detailed above, a wild-type core proteoglycan, a core proteoglycan core protein, or a functional portion thereof, and the linkage is via an amino acid, as is known in the art in fusion proteins, or via a chemically modified amino acid at the N-terminus, C-terminus, or constant region of an antigen-binding protein. For example, an aldehyde-labeled immunoglobulin (Ig) polypeptide may be converted by a methoxyglycine synthase to produce a 2-methoxyglycine (FGly)-modified Ig polypeptide. The FGly-modified Ig polypeptide can then covalently and site-specifically bind to the moiety of interest to obtain an Ig conjugate. See, for example, U.S. Patent No. 10,183,998, which is incorporated herein by reference in its entirety. In some preferred embodiments, the secretion signal sequence precedes the heavy chain protein sequence to allow secretion from the host cell during protein production. Similarly, in some preferred embodiments, the secretion signal sequence precedes the light chain protein sequence to allow secretion from the host cell during protein production. In some preferred embodiments, when 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, when 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, when the target 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 target molecule binds to or inhibits PD-L1. In some preferred embodiments, when the targeting molecule is avermab, 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, when the targeting molecule is duvastatin, 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, when the target 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 target molecule binds to or inhibits PD-1. In some preferred embodiments, when the target 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 target molecule binds to or inhibits PD-1. In some embodiments, formulations of the fusion protein are provided. Such formulations may contain, for example, unpurified or purified fusion proteins. Typically, such formulations include buffers, such as phosphate or Tris-buffered saline (PBS or TBS, respectively). The formulation may also be formulated to contain excipients, such as stabilizers. In some preferred embodiments, the present invention also provides a nucleic acid performance construct encoding the fusion protein of the present invention. Thus, in some embodiments, the performance construct encodes the aforementioned fusion protein sequence and is operatively associated with other nucleic acid sequences desired for performance in a selected performance system. In one instance, the nucleotide sequence encoding the fusion protein is constructed into a vector system and then expressed in a host cell. In another instance, the host cell is a cultured cell. In yet another instance, the vector system is used in mammalian cultured cells to express the fusion protein. The fusion polynucleotides of this invention can be used to generate fusion peptides via recombination technology. Therefore, for example, the polynucleotides can be contained in any of a variety of expression vectors for expressing peptides. In some embodiments of this invention, the vectors include, but are not limited to, retroviral vectors, chromosomal, non-chromosomal, and synthetic DNA sequences (e.g., derivatives of SV40, bacterial plasmids, bacteriophage DNA; vectors of combinations of baculovirus, yeast plasmids, plasmid-derived and bacteriophage DNA, and viral DNA, such as vaccinia virus, adenovirus, fowlpox virus, and pseudorabies virus). It is contemplated that any vector can be used, as long as it is replicable and viable in the host. In some preferred embodiments, the vector is a retroviral vector, as described in U.S. Patent Nos. 6,852,510 and 7,332,333 and U.S. Patent Publications Nos. 200402335173 and 20030224415, all of which are incorporated herein by reference in their entirety. In some particularly preferred embodiments, the vector is a pseudotyped retroviral vector. Specifically, some embodiments of the present invention provide recombinant constructs comprising one or more sequences as summarized above. In some embodiments of the present invention, the construct comprises a vector, such as a plasmid or viral vector, wherein the sequences of the present invention have been inserted in either a forward or reverse orientation. In other embodiments, the heterologous structural sequence is assembled together with translation initiation and termination sequences at appropriate stages. In a preferred embodiment of the present invention, a suitable DNA sequence is inserted into a vector using any of a variety of procedures. Generally, the DNA sequence is inserted into a suitable restriction endonuclease site using techniques known in this art. A large number of suitable vectors are known to those skilled in the art and are commercially available. Such vectors include, but are not limited to, the following: 1) Bacteria—pQE70, pQE60, pQE-9 (Qiagen), pBS, pD10, phagescript, psiX174, pbluescript SK, pBSKS, pNH8A, pNH16a, pNH18A, pNH46A (Stratagene); ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia); 2) Eukaryotes—pWLNEO, pSV2CAT, pOG44, PXT1, pSG (Stratagene), pSVK3, pBPV, pMSG, pSVL (Pharmacia); and 3) Baculoviruses—pPbac and pMbac (Stratagene). Any other plastid or vector can be used, as long as it can replicate and survive in the host. In some preferred embodiments of the invention, the mammalian expression vector includes an origin of replication, a suitable promoter and enhancer, and any necessary ribosome binding sites, polyadenylation sites, splice donor and acceptor sites, transcription termination sequences, and 5' flanking non-transcriptional sequences. In other embodiments, DNA sequences derived from SV40 splicing and polyadenylation sites can be used to provide the desired non-transcriptional genetic elements. In some embodiments of the invention, the DNA sequence in the expression vector is operatively linked to a suitable expression control sequence (promoter) to direct mRNA synthesis. Promoters that can be used in this invention include, but are not limited to, the LTR or SV40 promoter; E. coli lac or trp; bacteriophage λPL and PR, T3 and T7 promoters; and cytomegalovirus (CMV) immediate early, herpes simplex virus (HSV) thymidine kinase and mouse metallothionein-I promoters; and other promoters known to control gene expression in prokaryotic or eukaryotic cells or their viruses. In other embodiments of the invention, the recombinant expression vector includes an origin of replication and selectable markers that allow host cell transformation (e.g., dihydrofolate reductase or neomycin resistance in eukaryotic cell cultures, or tetracycline or ampicillin resistance in E. coli). In some embodiments of the present invention, transcription of DNA encoding the polypeptide of the present invention from higher eukaryotes is increased by inserting enhancer sequences into a vector. Enhancers are cis-acting elements of DNA, typically about 10 to 300 bp, that act on promoters to increase their transcription. Enhancers that can be used in the present invention include, but are not limited to, the SV40 enhancer 100 to 270 bp after the origin of replication, the cytomegalovirus early promoter enhancer, the polyoma enhancer posterior to the origin of replication, and the adenovirus enhancer. In other embodiments, the expression vector also contains a ribosome binding site for translation initiation and a transcription terminator. In other embodiments of the invention, the vector may also include a suitable sequence for amplifying expression. In a further embodiment, the present invention provides a host cell containing the above-described structure. In some embodiments of the present invention, the host cell is a higher eukaryotic cell (e.g., a mammalian or insect cell). In other embodiments of the present invention, the host cell is a lower eukaryotic cell (e.g., a yeast cell). In other embodiments of the present invention, the host cell may be a prokaryotic cell (e.g., a bacterial cell). Specific examples of host cells include, but are not limited to, Escherichia coli, Salmonella typhimurium, Bacillus subtilis, and various species of Pseudomonas, Streptomyces and Staphylococcus, as well as Saccharomycees cerivisiae, Schizosaccharomycees pombe, Drosophila S2 cells, Spodoptera Sf9 cells, Chinese hamster ovary (CHO) cells, and the COS-7 line (Gluzman, Cell 23:175

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

[1986] Basic Methods in Molecular Biology). Alternatively, in some embodiments of the invention, the polypeptides of the invention can be synthesized using a conventional peptide synthesizer. Proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems can also be used to produce such proteins using RNA derived from the DNA constructs of this invention. Selection and expression vectors suitable for prokaryotic and eukaryotic hosts are described in Sambrook et al. (1989), Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, NY. In some embodiments of the invention, after a suitable host strain has been transformed and the host strain has grown to an appropriate cell density in the culture medium, the protein is secreted and the cells are cultured for a period of time. In other embodiments of the invention, cells are typically harvested by centrifugation, the cells are disrupted by physical or chemical means, and the resulting crude extract is retained for further purification. In other embodiments of the invention, the microbial cells used for protein expression can be destroyed by any convenient method, including freeze-thaw cycles, sonication, mechanical disruption, or the use of cell lysis agents. Other embodiments provide kits that include the fusion protein and other components that, as appropriate, are useful, necessary, or sufficient for the use of the fusion protein (e.g., for therapeutic, research, and screening applications). The fusion protein in the kit may be provided in any suitable form, including frozen, lyophilized, or in pharmaceutically acceptable buffers such as TBS or PBS. The fusion proteins and / or their derivatives described herein may also be incorporated into compositions intended for use in vitro or in vivo. Antibodies, fusion proteins, or their derivatives may also be immobilized to functional effector moieties such as cytotoxic drugs or toxins, or their active fragments such as diphtheria A chain, exotoxin A chain, ricin A chain, abrin A chain, curcin, croton toxin, phenolmycin, neomycin, etc. The functional portion may also include a radioactive chemical substance. In one embodiment, the effect portion may be permanently attached to a binder. In one example, a detectable marker is permanently attached to a binder by chemical bonds. In one example, the chemical bonds are covalent bonds. In one example, the effect portion is conjugated to a binder. The fusion proteins described herein can be formulated into injectable formulations, for example, as suspensions in non-toxic, parenteral diluents or solvents. Suitable carriers and solvents include water, Ringer's solution and isotonic sodium chloride solution, TBS, and PBS. Formulations may contain excipients, such as stabilizers. In some applications, antibodies are suitable for in vitro use. In other applications, antibodies are suitable for in vivo use. Formulations suitable for use in either case are well known in the art and will vary depending on the specific 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 biologically or otherwise desirable, for example, that can be administered to a subject without causing any unwanted biological effects or interacting in a harmful manner with any other component of the pharmaceutical composition in which it is contained. As is well known to those skilled in the art, the carrier is of course selected to minimize any degradation of the active ingredient and any adverse side effects in the subject. Suitable pharmaceutical carriers and their formulations are described, for example, in Remington's: The Science and Practice of Pharmacy, 2nd ed., edited by David B. Troy, Lippicott Williams & Wilkins (2005). Typically, an appropriate amount of pharmaceutically acceptable salt is used in the formulation to make the formulation isotonic. Examples of pharmaceutically acceptable carriers include, but are not limited to, sterile water, saline, buffer solutions such as Ringer's solution and dextran. The pH of the solution is typically from about 5 to about 8 or from about 7 to about 7.5. Other carriers include sustained-release formulations, such as semi-permeable matrices of solid hydrophobic polymers containing peptides or fragments thereof. The matrix may be in the form of a molded article, such as a film, liposome, or microparticle. Certain carriers may be preferred, depending on factors such as the route of administration and the concentration of the constituents administered. The carrier is suitable for administering peptides and / or fragments thereof to humans or other subjects. In addition to fusion proteins, pharmaceutical compositions may also include carriers, thickeners, diluents, buffers, preservatives, surfactants, adjuvants, and immunostimulants. Pharmaceutical compositions may also contain one or more active ingredients, such as antimicrobial agents, anti-inflammatory agents, and anesthetics. IV. Uses Embodiments of the present invention 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 symptoms and / or disease states in animals (e.g., mammalian patients, including but not limited to humans and veterinary animals). In this regard, a wide variety of diseases and lesions are suitable for treatment or prevention using the methods and compositions of the present invention. A non-limiting exemplary list of such diseases and symptoms includes, but is not limited to, pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain cancer, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head and neck cancer, breast cancer, ovarian cancer, lung cancer, small cell lung cancer, nephroblastoma, cervical cancer, testicular cancer, bladder cancer, pancreatic cancer, gastric cancer, colon cancer, prostate cancer, urogenital cancer, thyroid cancer, esophageal cancer, myeloma, multiple myeloma, adrenal cancer, renal cell carcinoma, endometrial cancer, and other related diseases. Adenocortical carcinoma, malignant pancreatic insulinoma, malignant carcinoid, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, piloblastic leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, spontaneous thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteosarcoma, primary macroglobulinemia, retinoblastoma and similar diseases, and macular degeneration. Some embodiments of the present invention provide methods for administering an effective amount of the fusion polypeptide of the present invention and at least one additional therapeutic agent (including but not limited to chemotherapeutic anticancer drugs, apoptosis regulators, antimicrobial agents, antiviral agents, antifungal agents, and anti-inflammatory agents) and / or therapeutic techniques (e.g., surgical intervention and / or radiotherapy). In one specific embodiment, one or more additional therapeutic agents are anticancer agents. Many suitable anticancer agents are anticipated to be used in the methods of this invention. In fact, this invention covers, but is not limited to, administration of many anticancer agents, such as: agents inducing apoptosis; polynucleotides (e.g., antisense, ribozymes, siRNA); polypeptides (e.g., enzymes and antibodies); biomimics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (e.g., antibodies conjugated to anticancer drugs, toxins, defensins), toxins; radionuclides; biological response modifiers (e.g., interferons (e.g., IFN-α) and interleukins (e.g., IL-2)); adoptive immunotherapy agents; hematopoietic growth factors; agents inducing tumor cell differentiation (e.g., all-trans retinoids); gene therapy agents (e.g., antisense therapeutic agents and nucleotides); tumor vaccines; angiogenesis inhibitors; proteasome inhibitors; NF-κB modulators; antiCDK compounds; HDAC inhibitors; and analogues thereof. Many other examples of chemotherapy compounds and anticancer therapies suitable for co-administration with the disclosed compounds are known to those skilled in the art. In some embodiments, the anticancer agent comprises an agent that induces or stimulates apoptosis. Agents that induce apoptosis include, but are not limited to, radiation (e.g., X-rays, gamma rays, UV); tumor necrosis factor (TNF)-related factors (e.g., TNF family receptor proteins, TNF family ligands, TRAIL, TRAIL-R1, or TRAIL-R2 antibodies); kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitors, angiogenesis factor receptor (VGFR) kinase inhibitors, fibroblast growth factor receptor (FGFR) kinase inhibitors, platelet-derived growth factor receptor (PDGFR) kinase inhibitors, and Bcr-Abl kinase inhibitors (e.g., GLEEVEC)); antisense molecules; antibodies (e.g., HERCEPTIN, RITUXAN, ZEVALIN, and AVASTIN); anti-estrogens (e.g., raloxifene and tamoxifen); anti-androgens (e.g., flutamide, bicalutamide, finasteride, glucosamine, ketoconazole, and corticosteroids); and cyclooxygenase 2. (COX-2) inhibitors (e.g., celecoxib, meloxicam, NS-398, and nonsteroidal anti-inflammatory drugs (NSAIDs)); anti-inflammatory agents (e.g., phenbuzoline, DECADRON, DELTASONE, dexamethasone, dexamethasone oral concentrate, DEXONE, HEXADROL, hydroxychloroquine, METICORTEN, ORADEXON, ORASONE, phenylbutazone, PEDIAPRED, phenylbutazone, PLAQUENIL, prednisolone, prednisone, PRELO NE and TANDEARIL); and cancer chemotherapy drugs (such as 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; astrococci and similar agents. In other embodiments, the compositions and methods of the present invention provide the compounds of the present invention and at least one antiproliferative or antitumor agent selected from alkylating agents, antimetabolites, and natural products (e.g., herbal and other plant and / or animal-derived compounds). Alkylating agents suitable for the compositions and methods of the present invention include, but are not limited to: 1) nitrogen mustard (e.g., methyl di(chloroethyl)amine, cyclophosphamide, epoxetine, melphalan (L-sarcomain); and nitrogen mustard phenylbutyric acid); 2) ethyleneimine and methyl melamine (e.g., hexamethyl melamine and thiotepa); 3) alkyl sulfonates (e.g., busulfan); 4) nitrosoureas (e.g., carmustine (BCNU); lomustine (CCNU); semustine (methyl-CCNU); and streptozotocin (streptozomycin)); and 5) triazine (e.g., dacarbazine (DTIC; dimethyltriazine imidazomethylamine). In some embodiments, antimetabolites suitable for the compositions and methods of the present invention include, but are not limited to: 1) folic acid analogs (e.g., methotrexate / amethopterin); 2) pyrimidine analogs (e.g., fluorouracil (5-fluorouracil; 5-FU), fluorouridine (fluorodeoxyuridine; FudR), and cytarabine (cytosine arabinoside)); and 3) purine analogs (e.g., mercaptopurine (6-mercaptopurine; 6-MP), thioguanine (6-thioguanine; TG), and pentostatin (2'-deoxymyostatin)). In further embodiments, the chemotherapeutic agents suitable for the compositions and methods of the present invention include, but are not limited to: 1) vinca alkaloids (e.g., vincristine (VLB); 2) epipodophyllotoxin (e.g., etoposide and teniposide); 3) antibiotics (e.g., actinomycin (actinomycin D), daunorubicin (daunorubicin; erythromycin), erythromycin, bleomycin, promycin (photomycin), and mitomycin (mitomycin C)); 4) enzymes (e.g., L-aspartate aminotransferase); 5) biological response modifiers (e.g., interferon-α); 6) platinum coordination complexes (e.g., cisplatin (cis-DDP) and carboplatin); 7) anthraquinones (e.g., mitoxantrone); 8) Substituted ureas (e.g., hydroxyurea); 9) Methylhydrazine derivatives (e.g., procarbazine (N-methylhydrazine; MIH)); 10) Adrenocortical inhibitors (e.g., mitotane (o,p'-DDD) and aminopentadiene); 11) Adrenocortical hormones (e.g., prednisone); 12) Progestins (e.g., hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate); 13) Estrogens (e.g., diethylstilbestrol and ethinylestradiol); 14) Antiestrogens (e.g., tamoxifen); 15) Androgens (e.g., testosterone propionate and flumethasone); 16) Antiandrogens (e.g., flutamide); and 17) Gonadotropin-releasing hormone analogs (e.g., leuprorelin). Any oncolytic agent conventionally used in cancer treatment can be used in the compositions and methods of this invention. For example, the U.S. Food and Drug Administration maintains a set of formulations of oncolytic agents approved for use in the United States. The international counterparts of the USFDA maintain similar sets of formulations. The table below provides a list of exemplary antitumor agents approved for use in the United States. Those skilled in the art will understand that the required "product label" for all U.S.-approved chemotherapeutic agents describes the approved indications, dosage information, toxicity data, and similar information of the exemplary agent. Anticancer agents further include compounds identified as having anticancer 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, AMG706, antibody G250, antineoplastons, AP23573, apaziquone, APC8015, atipremod, ATN-161, atrasenten, azacitidine, BB-10901, BCX-1777, bevacizumab, BG00001, bicalutamide, and BMS. 247550, Bortezomib, Lichenstatin-1, Buserelin, Calcitriol, CCI-779, CDB-2914, Cefixime, Cetuximab, CG0070, Cilengidate, Clofarabine, Cobustatin A4 Phosphate, CP-675,206, CP-724,714, CpG7909, Curcumin, Decitabine, DENSPM, Doxercalciferol, E7070, E7389, Seaweed Extract 743, Efaproxiral, Eflornithine, EKB-569, Enzastaurin, Erlotinib, Exisulind, Fenretinide, Flavopiridol, Fludarabine, Flutamide, Formustin, FR901228, G17DT, Galiximab, Gefitinib, Genistein, Glufosfamide, GTI-2040, Histrelin, HKI-272, Homoharringtonine, HSPPC-96, Hu 14.18-Interleukin-2 fusion protein, HuMax-CD4, iloprost, imiquimod, infliximab, interleukin-12, IPI-504, irofulven, ixabepilone, lapatinib, lenalidomide, lestaurtinib, leuprorelin, LMB-9 Immunotoxins, lonafarnib, luniximab, mafosfamide, MB07133, MDX-010, MLN2704, monoclonal antibody 3F8, monoclonal antibody J591, motexafin, MS-275, MVA-MUC1-IL2, nilutamide, nitrocamptothecin, nolatrexed dihydrochloride dihydrochloride, nolvadex, NS-9, O6-benzylguanine, oblimersen sodium, ONYX-015, oregovomab, OSI-774, panitumumab, carboplatin, PD-0325901, pemetrexed, PHY906, pioglitazone, pirfenidone, pixantrone, PS-341, PSC833, PXD101, Pyrazoloacridine, R115777, RAD001, ranpirnase, rebeccamycin analogue, rhuAngiostatin protein, rhuMab 2C4, rosiglitazone, rubitecan, S-1, S-8184, saplatin, SB-, 15992, SGN-0010, SGN-40, sorafenib, SR31747A, ST1571, SU011248, suberoylanilide hydroxamic acid Suramin, talabostat, talampanel, tariquidar, temsirolimus, TGFa-PE38 immunotoxin, thalidomide, thymalfasin, tipifanib, tirapazamine, TLK286, trabectedin, trimetrexate glucuronate, TroVax, UCN-1, valproic acid, vinflunine, VNP40101M, volociximab, vorinostat, VX-680, ZD1839, ZD6474, zileuton, and zosuquidar trihydrochloride. For a more detailed description of anticancer agents and other therapeutic agents, those familiar with this technique may refer to many guidebooks, including but not limited to Physician's Desk Reference and Goodman and Gilman's "Pharmaceutical Basis of Therapeutics," 10th edition, Hardman et al., 2002. In some embodiments of the present invention, the fusion protein of the present invention and one or more therapeutic agents or anticancer agents are administered to animals under one or more of the following conditions: at different cycles, 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 content of the fusion protein of this invention effectively achieves its intended purpose. Although individual needs vary, determining the optimal range of effective amounts of each component is within the skill of this art. Typically, the compound can be orally administered to mammals, such as humans, at a dose of 0.0025 to 50 mg per kilogram of body weight of a mammal with a condition responsive to apoptosis induction, or an equivalent amount of its pharmaceutically acceptable salt. In one embodiment, an oral administration of about 0.01 to about 25 mg / kg is used to treat, improve, or prevent such conditions. For intramuscular injection, the dose is typically about half the oral dose. For example, a suitable intramuscular dose is about 0.0025 to about 25 mg / kg, or about 0.01 to about 5 mg / kg. A single oral dose may contain about 0.01 to about 1000 mg, for example about 0.1 to about 100 mg of the compound. The single dose may be administered once or more daily in the form of one or more tablets or capsules, each containing about 0.1 to about 10 mg, conveniently about 0.25 to 50 mg of the compound or a solvation thereof. In the local formulation, the compound may be present at a concentration of about 0.01 to 100 mg per gram of the load. In one embodiment, the compound is present at a concentration of about 0.07-1.0 mg / ml, for example, about 0.1-0.5 mg / ml, and in one embodiment, about 0.4 mg / ml. The pharmaceutical compositions of this invention can be administered to any patient who may experience the beneficial effects of the compounds of this invention. The most prominent of such patients are mammals, such as humans, but this invention is not intended to limit them thereto. Other patients include veterinary animals (cattle, sheep, pigs, horses, dogs, cats, and similar animals). Compounds and their pharmaceutical components may be administered by any means necessary to achieve their intended purpose. For example, they may be administered via parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, percutaneous, buccal, intrathecal, intracranial, intranasal, or local routes. Alternatively or concurrently, they may be administered orally. The dosage administered will depend on the recipient's age, health condition, weight, the type of concurrent treatments that may exist, the frequency of treatment, and the nature of the desired effect. The pharmaceutical formulations of the present invention can be manufactured in a manner known per se, such as by means of conventional mixing, granulation, preparation of sugar-coated pills, dissolution, or freeze-drying methods. Therefore, oral pharmaceutical formulations can be obtained by combining an active compound with a solid excipient, grinding the resulting mixture as appropriate, and, if necessary or required, adding suitable adjuvants before processing the granular mixture to obtain a tablet or sugar-coated pill core. Suitable excipients are particularly fillers, such as sugars (e.g., lactose or sucrose), mannitol or sorbitol, cellulose preparations and / or calcium phosphates (e.g., tricalcium phosphate or calcium hydrogen phosphate), and binders, such as starch pastes, using, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. Disintegrants, such as the aforementioned starches and carboxymethyl starch, croscarmellose, agar or alginate or their salts, such as sodium alginate, may be added if necessary. Additives are particularly flow conditioners and lubricants, such as silica, talc, stearic acid or its salts (e.g., magnesium stearate or calcium stearate), and / or polyethylene glycol. The core of the sugar-coated pill has a suitable coating that, if necessary, resists gastric juices. For this purpose, concentrated sugar solutions may be used, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, varnish solutions, and suitable organic solvents or solvent mixtures, as appropriate. To prepare coatings resistant to gastric juices, solutions of suitable cellulose preparations (such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate) are used. Dyes or pigments may be added to the coatings of lozenges or sugar-coated pills, for example, to identify or characterize combinations of active compound dosages. Other pharmaceutical preparations suitable for oral administration include push-in capsules made of gelatin, and soft-sealable capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Push-in capsules may contain an active compound in particulate form, which may be mixed with fillers (such as lactose), binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and stabilizers as appropriate. In soft capsules, the active compound, in one embodiment, is dissolved or suspended in a suitable liquid, such as fatty oil or liquid paraffin. Stabilizers may also be added. Possible pharmaceutical preparations that can be administered rectally include, for example, suppositories, which consist of a combination of one or more active compounds and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons. Alternatively, gelatin rectal capsules, which consist of a combination of active compounds and a base, may also be used. Possible base materials include, for example, liquid triglycerides, polyethylene glycol, or paraffin hydrocarbons. Suitable formulations for parenteral administration include aqueous solutions and alkaline solutions of the active compound in water-soluble forms (e.g., water-soluble salts). Additionally, suspensions of the active compound in suitable oily injectable suspensions can be administered. Suitable lipophilic solvents or mediators include fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate, triglycerides, or polyethylene glycol-400). Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and / or dextran. Stabilizers may also be included, depending on the circumstances. In one embodiment, the topical components of the present invention are formulated into oils, creams, lotions, ointments, and the like by selecting a suitable carrier. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (greater than C12). The carrier may be a carrier in which the active ingredient is soluble. If desired, emulsifiers, stabilizers, moisturizers, antioxidants, and coloring or fragrance agents may also be included. In addition, transdermal penetration enhancers may be used in such topical formulations. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762, each of which is incorporated herein by reference in its entirety. Ointments can be formulated by mixing a solution of an active ingredient, such as almond oil, with warm soft paraffin and then cooling the mixture. A typical example of such an ointment is one containing approximately 30% almond oil and approximately 70% white soft paraffin by weight. Lotions can be conveniently prepared by dissolving the active ingredient in a suitable high molecular weight alcohol, such as propylene glycol or polyethylene glycol. Those skilled in the art will readily recognize that the foregoing is merely a detailed description of some preferred embodiments of the invention. Various modifications and alterations to the above-described components and methods can be readily achieved using the expertise available in this art, and all such modifications and alterations are within the scope of this invention. Experimental Example 1: Representation of a Structure This example describes the design of a performance construct inserted into a performance vector for recombinant production of a fusion protein. Anti-VEGF bevacizumab-Galacorin fusion heavy chain gene sequence (SEQ ID NO:1): Signal peptide coding sequence is shown in bold. Heavy chain coding sequence is shown with a straight line and underline. Linker coding sequence is shown in italics. Galacorin coding sequence is shown with a wavy line and underline. Bevacizumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:2): Signal peptide sequence is shown in bold. Heavy chain sequence is shown with a straight line and underline. Linker sequence is shown in italics. Galacorin sequence is shown with a wavy line and underline. Bevacizumab light chain gene sequence (SEQ ID NO:3): Signal peptide coding sequence is shown in bold. Light chain coding sequence is shown with a straight line and underline. Bevacizumab light chain protein sequence (SEQ ID NO:4): Signal peptide sequence is shown in bold. Light chain sequence is shown with a straight line and underline. Component amino acid sequences: Signal sequences of heavy and light chains (SEQ ID NO:5): MMSFVSLLLVGILFHATQA Linker sequence between core proteoglycan and heavy chain (SEQ ID NO:6): SGGGGS Core proteoglycan (SEQ ID NO:7): Bevacizumab heavy chain protein sequence (SEQ ID NO:8): Bevacizumab light chain protein sequence (SEQ ID NO:9): Anti-CTLA-4 ipilimumab-Galacorin fusion heavy chain gene sequence (SEQ ID NO:10): Signal peptide coding sequence is shown in bold. Heavy chain coding sequence is shown with a straight line and underline. Linker coding sequence is shown in italics. Galacorin coding sequence is shown with a wavy line and underline. Ipilimumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:11): Signal peptide sequence is shown in bold. Heavy chain sequence is shown with a straight line and underline. Linker sequence is shown in italics. Galacorin sequence is shown with a wavy line and underline. Ipilimumab light chain gene sequence (SEQ ID NO:12): Signal peptide coding sequence is shown in bold. Light chain coding sequence is shown with a straight line and underline. Ipilimumab light chain protein sequence (SEQ ID NO:13): Signal peptide sequence is shown in bold. Light chain sequence is shown with a straight line and underline. Component amino acid sequences: Signal sequences of heavy and light chains (SEQ ID NO:5) Linker sequence between core proteoglycan and heavy chain (SEQ ID NO:6) Core proteoglycan (SEQ ID NO:7) Ipilimumab heavy chain protein sequence (SEQ ID NO:14): Ipilimumab light chain protein sequence (SEQ ID NO:15): Anti-PD-L1 atezolizumab-Galacorin fusion heavy chain gene sequence (SEQ ID NO:16): Signal peptide coding sequence is shown in bold.Heavy chain coding sequences are shown with straight lines and underlines. Linker coding sequences are shown in italics. Galacorin coding sequences are shown with wavy lines and underlines. Atezolizumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:17): Signal peptide sequence is shown in bold. Heavy chain sequence is shown with straight lines and underlines. Linker sequence is shown in italics. Galacorin sequence is shown with wavy lines and underlines. Atezolizumab light chain gene sequence (SEQ ID NO:18): Signal peptide coding sequence is shown in bold. Light chain coding sequence is shown with straight lines and underlines. Atezolizumab light chain protein sequence (SEQ ID NO:19): Signal peptide sequence is shown in bold. Light chain sequence is shown with straight lines and underlines. Component amino acid sequences: Signal sequences of heavy and light chains (SEQ ID NO:5) Linker sequence between core proteoglycan and heavy chain (SEQ ID NO:6) Core proteoglycan (SEQ ID NO:7) Atezolizumab heavy chain protein sequence (SEQ ID NO:20): Atezolizumab light chain protein sequence (SEQ ID NO:21): Anti-PD-L1 avermab-Galacorin fusion heavy chain gene sequence (SEQ ID NO:22): Signal peptide coding sequence is shown in bold. Heavy chain coding sequence is shown with a straight line and underline. Linker coding sequence is shown in italics. Galacorin coding sequence is shown with a wavy line and underline. Avermab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:23): Signal peptide sequence is shown in bold. Heavy chain sequence is shown with a straight line and underline. Linker sequence is shown in italics. Galacorin sequence is shown with a wavy line and underline. Acimetidine light chain gene sequence (SEQ ID NO:24): The signal peptide coding sequence is shown in bold. The light chain coding sequence is shown with a straight line and underline. Acimetidine light chain protein sequence (SEQ ID NO:25): The signal peptide sequence is shown in bold. The light chain sequence is shown with a straight line and underline. Component amino acid sequences: Signal sequences of heavy and light chains (SEQ ID NO:5) Linker sequence between core proteoglycan and heavy chain (SEQ ID NO:6) Core proteoglycan (SEQ ID NO:7) Acimetidine heavy chain protein sequence (SEQ ID NO:26): Acimetidine light chain protein sequence (SEQ ID NO:27): Anti-PD-L1 durvalumab-Galacorin fusion heavy chain gene sequence (SEQ ID NO:28): The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is shown with a straight line and underline. The linker coding sequence is shown in italics. The Galacorin coding sequence is shown with a wavy line and underline. Duvalib-Galacorin fusion heavy chain protein sequence (SEQ ID NO:29): The signal peptide sequence is shown in bold. The heavy chain sequence is shown with a straight line and underlined.Linker sequences are shown in italics. Galacorin sequences are underlined with wavy lines. Duvalib light chain gene sequence (SEQ ID NO:30): Signal peptide coding sequence is shown in bold. Light chain coding sequence is underlined with straight lines. Duvalib light chain protein sequence (SEQ ID NO:31): Signal peptide sequence is shown in bold. Light chain sequence is underlined with straight lines. Component amino acid sequences: Signal sequences of heavy and light chains (SEQ ID NO:5) Linker sequence between core proteoglycan and heavy chain (SEQ ID NO:6) Core proteoglycan (SEQ ID NO:7) Duvalib heavy chain protein sequence (SEQ ID NO:32): Duvalib light chain protein sequence (SEQ ID NO:33): Anti-PD-1 nivolumab-Galacorin fusion heavy chain gene sequence (SEQ ID NO:34): Signal peptide coding sequence is shown in bold. Heavy chain coding sequence is underlined with straight lines. Linker coding sequence is shown in italics. Galacorin coding sequences are shown with wavy lines and underlines. Nivolumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:35): Signal peptide sequence is shown in bold. Heavy chain sequence is shown with straight lines and underlines. Linker sequence is shown in italics. Galacorin sequence is shown with wavy lines and underlines. Nivolumab light chain gene sequence (SEQ ID NO:36): Signal peptide coding sequence is shown in bold. Light chain coding sequence is shown with straight lines and underlines. Nivolumab light chain protein sequence (SEQ ID NO:37): Signal peptide sequence is shown in bold. Light chain sequence is shown with straight lines and underlines. Component amino acid sequences: Signal sequences of heavy and light chains (SEQ ID NO:5) Linker sequence between core proteoglycan and heavy chain (SEQ ID NO:6) Core proteoglycan (SEQ ID NO:7) Nivolumab heavy chain protein sequence (SEQ ID NO:38): Nivolumab light chain protein sequence (SEQ ID NO:39): Anti-PD-1 pembrolizumab-Galacorin fusion heavy chain gene sequence (SEQ ID NO:40): Signal peptide coding sequence is shown in bold. Heavy chain coding sequence is shown with a straight line and underline. Linker coding sequence is shown in italics. Galacorin coding sequence is shown with a wavy line and underline. Pembrolizumab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:41): Signal peptide sequence is shown in bold. Heavy chain sequence is shown with a straight line and underline. Linker sequence is shown in italics. Galacorin sequence is shown with a wavy line and underline. Pembrolizumab light chain gene sequence (SEQ ID NO:42): The signal peptide coding sequence is shown in bold. The light chain coding sequence is shown with a straight line and underline. Pembrolizumab light chain protein sequence (SEQ ID NO:43): The signal peptide sequence is shown in bold.Light chain sequences are shown with straight lines and underlines. Component amino acid sequences: Signal sequences of heavy and light chains (SEQ ID NO:5) Linker sequence between core proteoglycan and heavy chain (SEQ ID NO:6) Core proteoglycan (SEQ ID NO:7) Pembrolizumab heavy chain protein sequence (SEQ ID NO:44): Pembrolizumab light chain protein sequence (SEQ ID NO:45): Anti-TGF-β avermab-Galacorin fusion heavy chain gene sequence (SEQ ID NO:50): Signal peptide coding sequence is shown in bold. Heavy chain coding sequence is shown with straight lines and underlines. Linker coding sequence is shown in italics. Galacorin coding sequence is shown with wavy lines and underlines. Avermab-Galacorin fusion heavy chain protein sequence (SEQ ID NO:51): Signal peptide sequence is shown in bold. Heavy chain coding sequence is shown with straight lines and underlines. Linker sequence is shown in italics. Galacorin sequence is shown with wavy lines and underlines. Acimenba light chain gene sequence (SEQ ID NO:52): The signal peptide coding sequence is shown in bold. The light chain coding sequence is shown with a straight line and underline. Acimenba light chain protein sequence (SEQ ID NO:53): The signal peptide sequence is shown in bold. The light chain sequence is shown with a straight line and underline. Anti-TGF-β. In some embodiments, the construct comprises a single entity or two or more copies of two or more copies of galacorin or other core proteoglycan molecules linking each C heavy chain gene, or a portion of a galacorin molecule linking the heavy chain gene (e.g., a TGF-β binding domain). Multiple TGF-β binding domains are present in the Galacorin / core proteoglycan molecule. These domains are configured in any suitable configuration. In some embodiments, each of the above options is linked to a bispecific or multispecific antibody against two or more targets. Exemplary sequences are shown below. Acimetab-Galacorin2x fusion heavy chain gene sequence (SEQ ID NO:54): The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is shown with a straight line and underlined. The linker coding sequence is shown in italics. The Galacorin coding sequence is shown with a wavy line and underlined. Acimetab-Galacorin2x fusion heavy chain protein sequence (SEQ ID NO:55): The signal peptide sequence is shown in bold. The heavy chain sequence is shown with a straight line and underlined. The linker sequence is shown in italics. Galacorin sequences are shown with wavy lines and underlines. Acitumb-Galacorin / Core Proteoglycan (Full-length Endogenous Human Core Proteoglycan Asp45-Lys359) TGF-β Binding Domain Fusion Heavy Chain Gene Sequence (SEQ ID NO:56): Signal peptide coding sequence is shown in bold. Heavy chain coding sequence is shown with straight lines and underlines. Linker coding sequence is shown in italics. Galacorin / Core Proteoglycan (Asp45-Lys 359) coding sequence is shown with wavy lines and underlines. Acitumb-Galacorin / Core Proteoglycan (Full-length Endogenous Human Core Proteoglycan Asp45-Lys359) TGF-β Binding Domain Fusion Heavy Chain Protein Sequence (SEQ ID NO:57): Signal peptide sequence is shown in bold. Heavy chain sequence is shown with straight lines and underlines. Linker sequence is shown in italics. The Galacorin / core proteoglycan (Asp45-Lys 359) sequence is shown with a wavy line and underlined. Acitumab-Galacorin / core proteoglycan (full-length endogenous human core proteoglycan Asp45-Lys359) TGF-β binding domain 2x fusion heavy chain gene sequence (SEQ ID NO:58): The signal peptide coding sequence is shown in bold. The heavy chain coding sequence is shown with a straight line and underlined. The linker coding sequence is shown in italics. The Galacorin / core proteoglycan (Asp45-Lys 359) coding sequence is shown with a wavy line and underlined. Acitumab-Galacorin / core proteoglycan (full-length endogenous human core proteoglycan Asp45-Lys359) TGF-β binding domain 2x fusion heavy chain protein sequence (SEQ ID NO:59): The signal peptide sequence is shown in bold.Heavy chain sequences are shown with straight lines and underlines. Connector sequences are shown in italics. Galacorin / core proteoglycan (Asp45-Lys 359) sequences are shown with wavy lines and underlines. Acitumab-Galacorin / core proteoglycan (full-length endogenous human core proteoglycan Leu155-Val260) TGF-β binding domain fusion heavy chain gene sequence (SEQ ID NO:60): signal peptide coding sequence is shown in bold. Heavy chain coding sequences are shown with straight lines and underlines. Connector coding sequences are shown in italics. Galacorin / core proteoglycan (Leu155-Val260) coding sequences are shown with wavy lines and underlines. Acitumab-Galacorin / core proteoglycan (full-length endogenous human core proteoglycan Leu155-Val260) TGF-β binding domain fusion heavy chain protein sequence (SEQ ID NO:61): signal peptide sequence is shown in bold. Heavy chain sequences are shown with straight lines and underlines. Linker sequences are shown in italics. Galacorin / core proteoglycan (Leu155-Val260) sequences are shown with wavy lines and underlines. Acimetab-Galacorin / core proteoglycan (full-length endogenous human core proteoglycan Leu155-Val260) TGF-β binding domain 2x fusion heavy chain gene sequence (SEQ ID NO:62): Signal peptide coding sequence is shown in bold. Heavy chain coding sequences are shown with straight lines and underlines. Linker coding sequences are shown in italics. Galacorin / core proteoglycan (Leu155-Val260) coding sequences are shown with wavy lines and underlines. Acimetab-Galacorin / core proteoglycan (full-length endogenous human core proteoglycan Leu155-Val260) TGF-β binding domain 2x fusion heavy chain protein sequence (SEQ ID NO:63): Signal peptide sequence is shown in bold. Heavy chain sequences are shown with straight lines and underlines. Connector sequences are shown in italics. Galacorin / core proteoglycan (Leu155-Val260) sequences are shown with wavy lines and underlines. Example 2. This example describes the generation of a cell line that produces the fusion protein described in Example 1. Reverse transcription vector generation: The phenotype constructs described above were introduced into the HEK 293 cell line, which constitutively produced MLV gag, pro, and pol proteins. The envelope containing the phenotype was also co-transfected with bevacizumab light chain (see vector map in Figure 2) or bevacizumab heavy chain-galacorin fusion (see vector map in Figure 3) gene constructs. Two co-transfections result in a non-replicating, high-valence reverse transcription vector for light or heavy chain-galacorin, which is concentrated by ultracentrifugation and used for cell transduction (see, for example, Bleck, GT 2005 An alternative method for the rapid generation of stable, high-expressing mammalian cell lines (Technical Review). Bioprocessing J. Step / October pp. 1-7; Bleck, GT, 2010. GPEx® A Flexible Method for the Rapid Generation of Stable, High Expressing, Antibody Producing Mammalian Cell Lines Chapter 4, Current Trends in Monoclonal Antibody Development and Manufacturing, Biotechnology: Pharmaceutical Aspects, edited by SJ Shire et al. © 2010 American Association of Pharmaceutical Scientists, DOI 10.1007 / 978-0-387-76643-0_4.). Overview. Overview of features of pCS-Bi-wayLC-WPRE (new ori), GDD2107.0003; Features of pFCS-BiwayGalacorin-WPRE-SIN (new ori), GDD2134.0001 Transduction of GCHO cells using a reverse transcription vector: Multiple cell transduction cycles of the GPEx® Chinese hamster ovary (GCHO) parental cell line were used to generate a combined cell line containing the bevacizumab-galacorin fusion antibody, with two light chain transductions performed weekly over 4 weeks, followed by two heavy chain-galacorin transductions. This transduction was performed to generate a combined cell line containing each of the two gene products. Bevacizumab-Galacorin fusion product was produced in batches from a pooled cell population: Following transduction, the pooled cell line for the bevacizumab-Galacorin fusion product was scaled up to the production levels observed in the batch feed studies in duplicate 250 mL shake flasks. Each shake flask was seeded with 300,000 viable cells per mL of 60 mL working volume of PF CHO LS medium (HyClone) and incubated in a humidified (70–80%) shaking incubator at 130 rpm, 5% CO2, and 37°C. The culture was fed four times with two different feed supplements during the production process. The culture was terminated when viability was ≤70%. Confirmation of fusion antibody production was achieved by SDS-PAGE gel analysis (Figure 4), and the amount of product produced was quantified by ELISA. The culture produced 360 mg / L of fusion antibody product. The product behaved as expected in SDS-PAGE, showing a dominant single band under non-reducing conditions and two bands (heavy chain-galacorin fusion and light chain) under reducing conditions. The approximately 80 kDa size of the heavy chain of the fusion matches the expected size of the product, and the normal size of the light chain is approximately 25 kDa. Example 3 This example describes the performance of the acitumab-Galacorin fusion. The gene construct of SEQ ID NO:50 was transiently transfected into ExpiCHO cells, and the fusion molecule was produced on a 250 ml scale. The titer of the fusion on the day of harvest was 377 mg / L. The fusion was purified using a MabSelectSuRe protein A column. The purified protein buffer was exchanged for pH 5.5 20 mM sodium citrate and 50 mM NaCl by tangential flow filtration. The obtained materials were examined using SDS-PAGE gel and SEC-HPLC. The product showed the expected size profile on the SDS-PAGE gel (Figure 5) and very low aggregation levels on SEC-HPLC (Figure 6). The materials produced in the above-described production process were used for evaluation in a mouse tumor model study. This study used C57BL / 6 mice and MC-38 human colorectal cancer cells. Forty C57BL / 6 mice were subcutaneously injected with MC-38 cells. Tumors were allowed to grow to approximately 100 mm³, and then 10 mice were each assigned to one of four different treatments. Each group received a single-dose IV treatment, and tumor size was measured over the following days. Treatment groups included mediator, 4 mg / kg Galacorin / core proteoglycan, 17 mg / kg avermab / anti-PD-L1, or 25 mg / kg avermab / anti-PD-L1-core proteoglycan / Galacorin fusion. Tumor growth was inhibited by both avermab / anti-PD-L1 and avermab / anti-PD-L1-core proteoglycan / Galacorin fusion therapy compared to either the mediator alone or Galacorin alone (Figure 7). Furthermore, avermab / anti-PD-L1-core proteoglycan / Galacorin fusion therapy also inhibited growth more effectively than avermab / anti-PD-L1 alone. All publications and patents mentioned in the foregoing specification are incorporated herein by reference. Various modifications and variations of the methods and systems described herein 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 conjunction with specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to these particular embodiments. Indeed, various modifications to the methods of carrying out the invention that will be apparent to those skilled in the art are intended to be within the scope of the appended claims. [Simplified Explanation of the Diagram] Figure 1 is a schematic diagram of the fusion protein of the present invention. Figure 2 is a diagram of the representation structure of the present invention. Figure 3 is a diagram of the representation structure of the present invention. Figure 4 shows the SDS-PAGE gel of the culture medium from the mixed CHO cell line expressing the bevacizumab fusion protein. Lane 10: Molecular weight standard. Lane 11: Non-reducing culture medium sample. Lane 12: Reducing culture medium sample. Figure 5 shows the SDS-PAGE gel of purified avelumab-galacorin fusion molecules. Lane 1: Molecular weight marker. Lane 2: Non-reduced purified avelumab-galacorin fusion. Lane 3: Reduced purified avelumab-galacorin fusion. Figure 6 shows the SEC-HPLC chromatogram of the purified avermab-galacorin fusion molecule. The monomer percentage is greater than 98%. Figure 7 shows tumor growth in the C57BL / 6 mouse MC-38 human colorectal cancer model after four treatments with a single IV dose.

Claims

1. A multifunctional protein molecule comprising at least one core proteoglycan core protein molecule having at least 95% sequence identity with SEQ ID NO:7, linked to an antibody molecule, wherein the antibody molecule is selected from the group consisting of: bevacizumab, ranibizumab, ipilimumab, atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.

2. The multifunctional protein molecule of claim 1, wherein the core proteoglycan core protein molecule lacks substantial modification by a glycosaminoglycan molecule at position 4 of the core proteoglycan core protein molecule.

3. A multifunctional protein molecule as claimed in claim 1 or 2, wherein the multifunctional protein molecule contains two or more copies of the core proteoglycan core protein molecule.

4. A multifunctional protein molecule as claimed in claim 1 or 2, wherein the functional portion of the core proteoglycan core protein molecule comprises a core proteoglycan domain that binds to one or more signaling molecules selected from the group consisting of: transformed growth factor-β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor 2 (VEGFR2), hepatocyte growth factor receptor (HGFR), insulin-like growth factor 1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), myosin, and C1q.

5. The multifunctional protein molecule of claim 4, wherein the TGF-β binding domain comprises amino acids Asp45-Lys359 of full-length endogenous human core proteoglycan, or amino acids Leu155-Val260 of full-length endogenous human core proteoglycan.

6. The multifunctional protein molecule of claim 4, wherein the multifunctional protein molecule comprises two or more copies of the functional portion of the core proteoglycan core protein molecule.

7. A multifunctional protein molecule as claimed in claim 1 or 2, wherein the core proteoglycan core protein molecule is operatively linked to the heavy chain of the antibody molecule.

8. A multifunctional protein molecule as claimed in claim 1 or 2, wherein the multifunctional protein molecule is a fusion protein.

9. A multifunctional protein molecule as claimed in claim 1 or 2, wherein the core proteoglycan core protein molecule is chemically linked to the antibody molecule.

10. A nucleic acid or nucleic acid genome encoding a multifunctional protein molecule as described in any one of claims 1 to 9.

11. One or more carriers comprising nucleic acids or nucleic acid genomes as requested in claim 10.

12. A host cell comprising one or more vectors as claimed in claim 11.

13. Use of a multifunctional protein molecule as claimed in any one of claims 1 to 9, a nucleic acid or nucleic acid group as claimed in claim 10, or one or more carriers as claimed in claim 11, for the preparation of a medicament for treating a disease characterized by angiogenesis or tumor growth.

14. As claimed in claim 13, 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.

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