Title of Invention: Transgenic mice expressing heterologous complement receptor type 1 (CR1) molecules on erythrocytes and uses therefor Abstract: The present invention is directed, at least in part, to mice which express exogenous complement receptor type 1 (CR1) on red blood cells. The invention also pertains to genetic constructs encoding heterologous CR1 for expression on red blood cells. Methods of using the transgenic animals of the invention to identify and/or evaluate compositions that can reduce the concentration of an agent, e.g., a biologic agent, in the serum, circulation and/or tissues of a subject are also provided. Detailed Description: Part general_description_paragraphs: Part RELATED APPLICATION: This application claims priority to U.S. provisional application Ser. No. 60/469,262 filed May 9, 2003, the contents of which are entirely incorporated by reference. Part BACKGROUND OF THE INVENTION: The complement system is composed of many different proteins that are important in the immune system's response to foreign antigens. The proteins of the complement system constitute about 10% of the globulins in normal serum. The complement system becomes activated when its primary components are cleaved, and the resulting products, either alone or with other proteins, activate additional complement proteins, resulting in a proteolytic cascade. Activation of the complement system leads to a variety of responses including increased vascular permeability, chemotaxis of phagocytic cells, activation of inflammatory cells, opsonization of foreign particles, direct killing of cells and tissue damage. In the classical pathway, activation of the complement system is triggered by antigen-antibody complexes. In an alternative pathway, the complement system may be catalyzed, for example, by lipopolysaccharides present in cell walls of pathogenic bacteria. Complement receptor type I (CR1) is a membrane glycoprotein that has been shown to be present on erythrocytes (E), monocytes/macrophages, granulocytes, B cells, some T cells, splenic follicular dendritic cells, and glomerular podocytes. CR1 mediates the binding of particles or immune complexes that contain activated complement to the surface of these cells. More specifically, CR1 binds to the complement activation products C3b and C4b, and has thus also been referred to as the C3b/C4b receptor. The consequences of these interactions depend upon the cell type bearing the receptor (Fearon, D. T. and Wong, W. W. (1983) Ann. Rev. Immunol. 1:243). CR1 on the surface of erythrocytes binds immune complexes for transport to the liver (Cornacoff, J. B. et al. (1983) J. Clin. Invest. 71:236; Nedof, N. E. et al. (1982) J. Exp. Med. 145:1739). CR1 on neutrophils and monocytes internalizes bound complexes, either by adsorptive endocytosis through coated pits or by phagocytosis after activation of the receptor by phorbol esters, chemotactic peptides or proteins that are present in the extracellular matrix, such as fibronectin and laminin (Newman S. L. et al. (1980) J. Immunol. 124:2236; Wright, S. D. and Silverstein S. C. (1982) J. Exp. Med. 145:1149; Wright S. D. et al. (1983) J. Exp. Med. 148:1338). Phosphorylation of CR1 may have a role in the acquisition of this phagocytic activity (Changelian P. S. & Fearon D. T. (1986) J. Exp. Med. 163:101). The function of CR1 on B lymphocytes is less defined, although treatment of these cells with antibody to CR1 enhanced their response to suboptimal doses of pokeweed mitogen (Daha, M. R. et al. (1983) Immunobiol. 164:227 (Abstr)). CR1 on follicular dendritic cells may serve an antigen presentation role (Klaus G. G. B. et al. (1980) Immunol. Rev. 53:3). In addition to serving as a receptor, CR1 also has complement regulatory functions. For example, in the classical and alternative complement pathways, CR1 can inhibit the C3/C5 convertases and can also act as a cofactor for the cleavage of C3b and C4b by factor I (Fearon D. T. (1979) Proc. Natl. Acad. Sci. U.S.A. 76:5867; Liida X. & Nussenzweig V. (1981) J. Exp. Med. 153:1138). In the classical pathway of complement activation, the complex C4b, 2a is a C3 activating enzyme, or convertase. CR1 can bind to C4b and promote the dissociation of C4b,2a. This binding renders C4b susceptible to irreversible proteolytic inactivation by factor I through cleavage to the inactivated complement proteins C4c and C4d. In the alternative pathway of complement activation, the complex C3b, 4b is a C3 convertase. CR1 can bind to C3b and can also promote the dissociation of C3b, 4b. Formation of C3b, CR1 renders C3b susceptible to irreversible proteolytic inactivation by factor I, resulting in the formation of the inactivated complement protein C3b (iC3b). CR1 is a glycoprotein composed of a single polypeptide chain. Four allotypic forms of CR1 have been found, differing in molecular weight by increments of ˜40,000-50,000 daltons. The two most common forms are the F and S allotypes (also termed the A and B allotypes), having molecular weights of 250,000 and 290,000 daltons (Dykman, T. R. et al. (1983) Proc. Natl. Acad. Sci. U.S.A. 30:1698; Wong, W. W. et al. (1983) J. Clin. Invest. 72:685), respectively. There are also two rarer forms having molecular weights of 210,000 and >290,000 daltons (Dykman, T. R. et al. (1984) J. Exp. Med. 159:691; Dykman, R. R. et al. (1985) J. Immunol. 134:1787). These differences apparently represent variations in the polypeptide chain of CR1, rather than glycosylation state (Wong W. W. et al. (1983) J. Clin. Invest. 72:685). All four CR1 allotypes have C3b binding activity (Dykman, T. R. et al. (1983) Proc. Natl. Acad. Sci. U.S.A. 30:1698; Dykman, T. R. et al. (1984) J. Exp. Med. 159:691; Dykman, T. R. et al. (1985) J. Immunol. 134:1787; Wong W. W. et al (1983) J. Clin. Invest. 72:685). While CR1 is found on various hematopoietic cells, the vast majority of CR1 in the blood is present specifically on erythrocytes. This CR1 plays a predominant role in the processing and clearance of circulating immune complexes. Once a pathogen adheres to the erythrocyte, the immune-complexed pathogen is efficiently transferred to acceptor phagocytic cells, such as fixed tissue macrophages in the liver and spleen. Interestingly, the pathogen in this transfer reaction is apparently stripped from the erythrocyte without any discernible damage to the erythrocyte (Lindorfer M. A. et al. (2001) Immun. Reviews 183:10-24). The detailed mechanism of the transfer reaction has not yet been fully elucidated. Studies suggest, however, that the in vivo transfer reaction is facilitated by a process that is unlikely to depend upon Factor I-mediated release (Lindorfer et al. (2001) Immun. Reviews 183:10-24). An important goal in the pharmaceutical industry is the development of novel therapeutic modalities that can target and clear pathogens from tissues or the bloodstream. Several approaches undertaken to address this problem are aimed at taking advantage of the immune adherence function of primate erythrocytes. In one approach, bispecific monoclonal antibodies complexes (heteropolymers, HP) are designed to bind and immobilize a target pathogen to CR1 of a primate erythrocyte (Lindorfer M. A. et al. (2001) Immun. Reviews 183:10-24). For example, heteropolymers can consist of a monoclonal antibody specific for CR1 that is chemically cross-linked with a monoclonal antibody specific for the target pathogen. In this way, the antibody specific for CR1 serves as a surrogate for the natural CR1 ligand, C3b. One advantage of this approach is that while the natural affinity of C3b for CR1 is low, thus requiring robust complement activation and the capture of multiple C3b molecules to insure erythrocyte binding, several mouse monoclonal antibodies have been raised that possess very high affinity for CR1. Crosslinking these antibodies to a high-affinity pathogen-specific monoclonal antibody should allow for virtually any target pathogen to be bound by erythrocytes in the absence of complement. This strategy has been successfully applied to a number of bacteria and viruses (Powers J. H. et al. (1995) Infect. Immun 63:1329-1335; Kuhn S. E. et al. (1998) J. Immunol. 160:5088-5097; Nardin A., et al. (1998) 211:21-31; Hahn C. S. et al. (2001) J. Immunol 166:1057-1065). In a related approach, the use of erythrocytes and bispecific reagents to target molecules in the serum and/or circulation can be extended to target the numerous autoantibodies associated with autoimmune diseases, such as the IgG anti-dsDNA antibodies in systemic lupus erythematosus (SLE). The autoantibodies can be targeted for erythrocyte-mediated clearance by using antigen-based heteropolymers (AHP) (Lindorfer M. A. et al. (2001) Immun. Reviews 183:10-24). Antigen-based heteropolymers consist of an autoantigen chemically cross-linked to an anti-CR1 monoclonal antibody. The erythrocyte-bound antigen-based heteropolymer captures autoantibodies and directs the newly formed erythroycte-bound immune complex into the transfer reaction for ultimate clearance to the liver. There is a clear need in the art for animal models that can be used to test the ability of bispecific compositions, such as heteropolymers which bind CR1, to clear targeted molecules from tissues, serum and/or the circulation. Such animal models would be useful in evaluating both the efficacy and safety of bispecific compositions and bispecific composition-based therapies. Unfortunately, while mice are an excellent model for drug testing, mice do not express CR1 on their erythrocytes (Kalli and Fearon. 1994. J. Immunol. 152:2894). Part SUMMARY OF THE INVENTION: The present invention is based, at least in part, on the generation of mice expressing human complement receptor type 1 (CR1) and the observation that these animals express CR1 on red blood cells. Accordingly, the invention features genetic constructs and non-human animals in which a heterologous CR1 gene is expressed. Methods of using the transgenic animals of the invention to identify and/or evaluate compositions that can reduce the concentration of an agent, e.g., a biologic agent, in the tissues, serum and/or circulation of a subject are also provided. In one aspect, the invention is directed to a genetic construct for expression in a non-human animal consisting of a nucleotide sequence encoding a human complement receptor 1 (CR1) polypeptide operably linked to a promoter, wherein the construct directs the functional expression of human CR1 on erythrocytes. In another aspect, the invention is directed to a non-human animal whose genome includes a polynucleotide encoding human complement receptor 1 (CR1) operably linked to a promoter, wherein the human CR1 molecule is functionally expressed on the erythrocytes of the animal. Preferably, the human CR1 molecule is preferentially expressed on erythrocytes. In preferred embodiments, the promoter is a GATA-1 promoter. More preferably, the promoter comprises the GATA-1 promoter and an upstream control region activating expression on erythrocytes. In preferred embodiments, the non-human animal is homozygous or heterozygous for the polynucleotide. Preferably, the animal is a transgenic mouse. In another aspect, the invention features a method for screening for a bispecific compound capable of reducing the concentration of an agent in the serum and/or circulation of a subject. This method includes the steps of: (a) administering a plurality of test compounds to a non-human animal whose genome comprises a polynucleotide encoding human complement receptor 1 (CR1) operably linked to a promoter, wherein the human CR1 is functionally expressed on erythrocytes of the non-human animal; (b) determining the ability of a bispecific compound to reduce the concentration of the agent in the serum and/or circulation of the non-human animal; and (c) selecting a bispecific compound that reduces the concentration of the agent in the serum and/or circulation of the non-human animal to thereby identify a bispecific compound capable of reducing the concentration of an agent in the serum and/or circulation of a subject. In a related aspect, the invention provides a method for evaluating the ability of a bispecific compound to reduce the concentration of an agent in the serum and/or circulation of a subject. This method includes the steps of: (a) administering the bispecific compound to a non-human animal whose genome comprises a polynucleotide encoding human complement receptor 1 (CR1) operably linked to a promoter, wherein the human CR1 is functionally expressed on erythrocytes of the non-human animal; and (b) determining the ability of the bispecific compound to reduce the concentration of the agent in the serum and/or circulation of the non-human animal, to thereby evaluate the ability of the bispecific compound to reduce the concentration of the agent in the serum and/or circulation of a subject. In one embodiment, these methods further include the step of administering the agent to the non-human animal. In preferred embodiments, the agent is a pathogen, a virus, a toxin, a polynucleotide, a bacterium, or an auto-antibody associated with an auto-immune disease. In preferred embodiments, the bispecific compound binds to human CR1. Preferably, the bispecific compound is a heteropolymer or an antigen-based heteropolymer. In preferred embodiments, the non-human animal is a transgenic mouse. In other preferred embodiments, the promoter comprises a GATA-1 promoter or the GATA-1 promoter and an upstream control region activating expression on erythrocytes. The invention further features a method for treating a subject that has been exposed to a biologic agent. This method includes administering a bispecific compound that is identified in methods provided by the invention to the subject, such that the subject is treated. In a related aspect, the invention provides a method for treating a subject that is at risk of exposure to a biologic agent. This method includes administering a bispecific compound that is identified in methods provided by the invention to the subject, such that the subject is treated. In yet another related aspect, the invention provides a method for treating a subject with an infection or auto-immune disease. This method includes administering an agent that was identified in methods provided by the invention to the subject, such that the subject is treated. The invention further features a method for making a transgenic mouse expressing human CR1 on the surface of its erythrocytes. This method includes the steps of: a) introducing a polynucleotide encoding a human CR1 polypeptide into an egg or an embryo of a mouse, the polynucleotide operably linked to a promoter which causes human CR1 to be expressed on mouse erythrocytes; and b) allowing the egg or embryo comprising the CR1 polynucleotide to develop to term to thereby produce the transgenic mouse. In a related aspect, the invention provides a method of producing a transgenic mouse. This method includes breeding two transgenic mice, each comprising a diploid genome comprising a polynucleotide encoding a human CR1 polypeptide, wherein the polynucleotide is expressed to produce a human CR1 polypeptide on mouse erythrocytes, to thereby produce an offspring transgenic mouse. Part DETAILED DESCRIPTION OF THE INVENTION: The present invention is based, at least in part, on the generation of mice whose genome contains a polynucleotide encoding human complement receptor 1 (CR1) operably linked to a promoter, and the observation that herologous CR1 molecules are functionally expressed on the red blood cells of the animal. Accordingly, the present invention features genetic constructs comprising CR1 and non-human animals in which CR1 is expressed on erythrocytes. The invention provides methods of using the non-human animals for identifying bispecific compounds capable of reducing the concentration of a target agent in the serum and/or circulation of a subject. The invention further features methods of treating subjects having diseases or disorders that could benefit from administration of such bispecific compounds. So that the invention may be more readily understood, certain terms are first defined. I. Definitions As used herein, the term “transgene” refers to a heterologous or foreign gene or recombinant nucleic acid construct that has been incorporated into an animal. The transgene may be a wild-type or mutant gene, or one which has been altered so that it is expressed in an aberrant pattern. As used herein, the term “transgenic cell” refers to a cell containing a transgene. As used herein the term “heterologous gene” or “foreign gene” includes genes that are not found naturally as part of the genome into which they are introduced or which are found in a location or locations in the genome that differ from that in which they occur in nature. Heterologous DNA is not endogenous to the cell into which it is introduced, but has been obtained from another cell. As used herein, the term “genetic construct” includes non-naturally occurring nucleic acid molecules in which nucleotide sequences that are not normally present in the same molecule are engineered to be joined. The constructs of the invention are in a form suitable for expression of the nucleic acid molecule in a host cell. Preferably, the constructs include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operatively linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term “regulatory sequence” is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). As used herein, the term “upstream control region” includes regulatory elements that are 5′ of the gene to be expressed, e.g., promoters or upstream enhancers. As used herein, the term “promoter” includes regions of DNA involved in binding of RNA polymerase to initiate transcription. As used herein, the term “preferentially expressed” with reference to the expression of a particular protein or a particular cell type includes expression which is greater on that cell type than on other cell types, but which is not necessarily exclusive to that particular cell type. For example, proteins that are preferentially expressed on erythrocytes are expressed at levels at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold or higher on erythrocytes than on other cell types. As used herein, the term “functionally expressed” includes expression of a protein such that biological activity of the protein is maintained. For example, CR1 is functionally expressed on a cell when it is capable of binding to a natural ligand, e.g., C3b, or to an antibody. As used herein, “transgenic animals” refers to those animals which have a heterologous or foreign gene incorporated into their genome. The term “transgenic animal” includes an animal, e.g., a non-human mammal, e.g., a swine, a monkey, a goat, or a rodent, e.g., a mouse, in which one or more, and preferably essentially all, of the cells of the animal include a transgene. The transgene is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, e.g., by microinjection, transfection or infection, e.g., by infection with a recombinant virus. The term “genetic manipulation” includes the introduction of a recombinant DNA molecule. This molecule is preferably integrated within a chromosome to ensure that it will be passed on to offspring, or it may be extrachromosomally replicating DNA. Preferred transgenic animals are mammals. According to the present invention, exemplary mammals include, without limitation, rodents (such as rats and mice), dogs, cats, pigs, sheep, cows, goats, horses and rabbits. Desirably the mammal is non-human. As used herein, the term “rodent” refers to all members of the phylogenetic order Rodentia. In a preferred embodiment, a rodent is a mouse. As used herein, “expression” includes the synthesis of a protein by a cell. Expression of a protein can be measured at various stages, e.g., transcription, post transcription, translation, and/or post translation. According to the present invention, transgenic animals misexpress a transgene. As used herein, the term “misexpression” includes a non-wild type pattern of gene expression. Misexpression includes: expression at non-wild type levels, i.e., a pattern of expression that differs from wild type in terms of the time or stage at which the gene is expressed, e.g., increased expression (as compared with wild type) at a predetermined developmental period or stage; a pattern of expression that differs from wild type in terms of increased expression (as compared with wild type) in a predetermined cell type or tissue type; a pattern of expression that differs from wild type in terms of the splicing size, amino acid sequence, post-transitional modification, or biological activity of the expressed polypeptide; a pattern of expression that differs from wild type in terms of the effect of an environmental stimulus or extracellular stimulus on expression of the gene, e.g., a pattern of increased expression (as compared with wild type) in the presence of an increase or decrease in the strength of a stimulus. Misexpression includes expression from a transgenic nucleic acid. Preferably, a transgene of the invention results in expression of the foreign gene on cells of the animal where the related endogenous gene was not previously expressed or was expressed at low levels. In one embodiment, the transgene is expressed on erythrocytes. In a preferred embodiment, the transgene is preferentially expressed on erythrocytes. As used herein, the term “marker sequence” refers to a nucleic acid molecule that (a) is used as part of a nucleic acid targeting construct to cause the expression of the gene of interest (e.g., the CR1 gene) and (b) is used to identify those cells that have incorporated the targeting construct into their genome. For example, the marker sequence can be a sequence encoding a protein which confers a detectable trait on the cell, such as an antibiotic resistance gene, e.g., neomycin resistance gene, or an assayable enzyme not typically found in the cell, e.g., alkaline phosphatase, horseradish peroxidase, luciferase, beta-galactosidase and the like, or other conveniently detectable proteins not typically found in the cell, e.g. green fluorescent protein, red fluorescent protein. As used herein, “administering” with respect to agents or bispecific compounds is intended to refer to dispensing, delivering or applying a composition to an animal or cell. The term “administering” is intended to refer to contacting or dispensing, delivering or applying the composition to an animal by any suitable route for delivery of the composition to the desired location in the animal, including, e.g., delivery by the parenteral or oral route, intramuscular injection, subcutaneous/intradermal injection, intravenous injection, buccal administration, transdermal delivery and administration by the intranasal or respiratory tract route. As used herein, the term “bispecific compound” includes any bispecific compound which can potentially reduce the concentration of an agent in the serum and/or circulation of a subject. A bispecific compound is a molecule consisting of two different binding moieties. Exemplary bispecific compounds include, e.g., bispecific antibodies and heteropolymers. In preferred embodiments, the bispecific compound is a heteropolymer or an antigen-based heteropolymer. Bispecific antibodies are single antibody molecules which have two specificities. Examples of bispecific antibodies are known in the art. Bispecific antibodies produced by a hybrid hybridoma or a trioma are disclosed in U.S. Pat. No. 4,474,893. Bispecific antibodies have been constructed by chemical means (Staerz et al. (1985) Nature 314:628, and Perez et al. (1985) Nature 316:354) and hybridoma technology (Staerz and Bevan (1986) Proc. Natl. Acad. Sci. USA, 83:1453, and Staerz and Bevan (1986) Immunol. Today 7:241). Bispecific antibodies are also described in U.S. Pat. No. 5,959,084. Fragments of bispecific antibodies are described in U.S. Pat. No. 5,798,229. Heteropolymers, as described herein, refer to molecules comprising two different binding moieties wherein at least one of the binding moieties of the heteropolymer is bivalent. For example, a heteropolymer can comprise two antibodies joined together. In one embodiment of the present invention, a heteropolymer consists of two distinct antibodies which are cross-linked by using any of a number of cross-linking techniques known in the art. In one embodiment, the heteropolymer binds human CR1. In one embodiment, a heteropolymer consists of distinct antibodies which are cross-linked by using any of a number of cross-linking techniques known in the art. In another embodiment, a heteropolymer is an antigen-based heteropolymer. An antigen-based heteropolymer, as described herein, refers to a heteropolymer containing a binding moiety which is an antigen recognized by a target antibody, e.g. an auto-antibody associated with an autoimmune disease or disorder, wherein the binding moiety is cross-linked to a second binding moiety using any of a number of cross-linking techniques known in the art. Preferably, a second binding moiety is an antibody that binds an antigen. In one embodiment, the antigen-based heteropolymer binds to human CR1. As used herein, the term “agent” includes any substance or organism present in the serum and/or circulation of a subject that is associated with an infection, disorder or disease. Preferred agents are biologic agents include, e.g. pathogens, viruses, toxins, polynucleotides, antibodies or autoantibodies. As used herein, the term “biologic agent” also includes agents to which a subject could be exposed in biowarfare or terrorist activities, e.g. anthrax, smallpox, plague, Ebola, or Marburg virus. The present invention is described in further detail in the following subsections. II. CR1 Expression Constructs In one aspect, the invention features a nucleic acid molecules which, when introduced into a non-human animal, result in functional expression of the CR1 gene on the erythrocytes of the animal. Preferably, the CR1 gene is the human CR1 gene, although other mammalian CR1 molecules can be expressed. The nucleotide sequence of the wild type human CR1 gene is known in the art and is described in, for example, Wilson J. G. et al, (1986) J. Exp. Med. 164:50-59, U.S. Pat. No. 6,316,604, and U.S. Pat. No. 5,212,071 the contents of which are incorporated herein by reference. Variants of the above-referenced sequence can also be used in making the constructs of the invention. For example, different allotypes of CR1 have been described in the art. For example, such allotypes have been described by Wong et al. 1986. J. Exp. Med. 164:1531; Wong et al. 1989. J. Exp. Med. 169:847. Other human CR1 sequences are known in the art and can be found e.g., at GenBank accession No. AF169970; J. Immunol. 151: 6214(1993) or J. Biol. Chem. 265:974-980 (1990). Nucleic acid molecules encoding such allotypic forms of CR1 can also be used in the instant invention. Variant forms of CR1, e.g., variant forms of human CR1, can also be used. The production and use of nucleic acid molecules encoding portions of a CR1 gene, modified CR1 genes, or CR1 genes which comprise a polynucleotide sequence derived from the human CR1 gene and a portion of another nucleotide sequence (e.g. CR1 sequence from another organism or a non-CR1 sequence) i.e., chimeric CR1 genes, or CR1 genes related to the human CR1 gene can also be used. Such variant forms of CR1 are capable of being functionally expressed on erythrocytes of a non-human animal and are also capable of binding to human C3b or C4b and/or to an antibody which binds to human CR1. In one embodiment, mutations can be made to a CR1 nucleotide sequence to enhance or reduce the binding to molecules with which CR1 interacts, e.g., antibody molecules, C3b, etc. The production and use of other nucleic acid molecules encoding a CR1 gene heterologous to the non-human animal into which they are introduced is also provided for. For example, nucleic acid sequences encoding CR1 molecules which are highly homologous to human CR1, e.g., non-human primate forms of CR1, can also be used in the instant constructs provided that such CR1 molecules or portions thereof are capable of being functionally expressed on erythrocytes of an animal and are also capable of binding to human C3b or C4b and/or to an antibody which binds to human CR1. Variant forms of CR1 can be produced by various methods known in the art. For example, a cloned CR1 gene can be modified by any of numerous strategies known in the art (Maniatis, T., 1982, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.). Such variants can be made, e.g., to promote or reduce binding of CR1 to CR1 binding molecules. In the production of the gene encoding a CR1 variant, preferably the modified gene will remain within the same translational reading frame as CR1, uninterrupted by translational stop signals. In another embodiment, the CR1 gene can be mutated to create and/or destroy translation, initiation, and/or termination sequences, or to create variations in coding regions and/or form new restriction endonuclease sites or destroy preexisting ones, to facilitate further in vitro modification. Known techniques for mutagenesis known in the art can be used, including but not limited to, in vitro site-directed mutagenesis (Hutchinson, C., et al., 1978, J. Biol. Chem. 253:6551), use of TAB.RTM. linkers (Pharmacia), etc. In a preferred embodiment, changes to a nucleotide sequence encoding CR1 comprise conservative mutations to the sequence. In making the genetic constructs of the invention, an endogenous or exogenous promoter can be used. Preferably the CR1 gene is operably linked to a regulatory element (e.g., a transcriptional control element such as a promoter and/or an enhancer) which leads to expression or increased expression of CR1 on erythrocytes. The expression of CR1 need not be exclusively in erythrocytes. For example, promoters and/or enhancers that result in increased levels of expression in erythrocytes as compared to other cells may be used, even though expression on cells other than erythrocytes may result. Suitable promoters for use in the present invention include, but are not limited to, the regulatory sequences of the GATA-1 gene. In one embodiment, the regulatory element includes an upstream control locus that is identified by DNase I hypersensitivity and which confers the activation of expression in primitive erythroid cells (see, e.g., McDevitt, M. A. et al., (1997) Proc. Natl. Acad. Sci., USA, 94:7976-7981; Visvader J. E. et al., (1998) Genes & Dev. 12(4):473-479). Other regulatory elements are also known in the art, and include e.g., globin (see, e.g., Ristaldi et al. 1999. Proc Natl Acad Sci USA. 96:9654; Ristaldi et al. 1999 Blood Cells Mol. Dis. 25:193; Tewari et al. 1996. Development. 122:3991) β spectrin (see, e.g., Sabatino et al. 1998 Mol Cell Biol. 18:6634; Gallagher et al. 1999 J. Biol. Chem. 274:6062), and band 3 (see e.g., Cox et al. 1985. J. Cell Biol. 100: 1548). Regulatory sequences that control expression of other genes which are preferentially expressed in hematopoietic cells, and preferentially erythrocytes, may also be used in the invention. Other suitable promoters can be identified, for example, by first carrying out differential expression analysis, e.g., using DNA microarray technology, to identify genes that are preferentially expressed in erythrocytes, and then identifying the corresponding regulatory sequences. For example, genes which are identified as being expressed preferentially, e.g. about 2-fold more, 5-fold more, or 10-fold more, in erythrocytes as compared to another reference cell or tissue, such as liver or heart, could be selected and their promoters identified and used in the present invention. Methods of performing differential expression analysis and DNA microarray technologies are known in the art. An exemplary genetic construct comprises the human CR1 gene under the transcriptional control of the GATA-1 promoter and is shown in FIG. 1. Other elements which can be used to express CR1 in hematopoietic cells are known in the art and can be found, e.g., in Okuno et al. 2002. Blood. 100:4420; Radomska et al. 2002. Blood. 100:4410; Gaines et al. 2000. J Biol Chem. 275:34114; and Wilcox et al. 1999. Proc Natl Acad Sci U S A. 96:9654. Preferably, regulatory elements which more specifically increase CR1 expression on erythroid cells are employed in the instant constructs. In one embodiment, a construct of the invention can comprise a marker gene, e.g., green fluorescent protein or an antibiotic resistance gene. Such a marker gene can be used to aid in identifying cells that express the construct. III. Construction of Transgenic Animals In one aspect, the present invention provides a non-human animal whose genome contains a polynucleotide encoding human complement receptor 1 (CR1) operably linked to a promoter such that the human CR1 is functionally expressed on the erythrocytes of the animal. The present invention further provides methods for making a transgenic non-human animal expressing human CR1 on the erythrocytes of the animal. The transgenic animal used in the methods of the invention can be, e.g., a mammal, a bird, a reptile or an amphibian. Suitable mammals for uses described herein include: rodents; ruminants; ungulates; domesticated mammals; and dairy animals. Preferred animals include: rodents, goats, sheep, camels, cows, pigs, horses, oxen, llamas, chickens, geese, and turkeys. In a preferred embodiment, the non-human animal is a mouse. Various methods of making transgenic animals are known in the art (see, e.g., Watson, J. D., et al., “The Introduction of Foreign Genes Into Mice,” in Recombinant DNA, 2d Ed., W. H. Freeman & Co., New York (1992), pp. 255-272; Gordon, J. W., Intl. Rev. Cytol. 115:171-229 (1989); Jaenisch, R., Science 240: 1468-1474 (1989); Rossant, J., Neuron 2: 323-334 (1990)). An exemplary protocol for the production of a transgenic pig can be found in White and Yannoutsos, Current Topics in Complement Research: 64th Forum in Immunology, pp. 88-94; U.S. Pat. No. 5,523,226; U.S. Pat. No. 5,573,933; PCT Application WO93/25071; and PCT Application WO95/04744. An exemplary protocol for the production of a transgenic rat can be found in Bader and Ganten, Clinical and Experimental Pharmacology and Physiology, Supp. 3:S81-S87, 1996. An exemplary protocol for the production of a transgenic cow can be found in Transgenic Animal Technology, A Handbook, 1994, ed., Carl A. Pinkert, Academic Press, Inc. An exemplary protocol for the production of a transgenic sheep can be found in Transgenic Animal Technology, A Handbook, 1994, ed., Carl A. Pinkert, Academic Press, Inc. Several exemplary methods are set forth in more detail below. A. Injection into the Pronucleus Transgenic animals can be produced by introducing a nucleic acid construct according to the present invention into egg cells. The resulting egg cells are implanted into the uterus of a female for normal fetal development, and animals which develop and which carry the transgene are then backcrossed to create heterozygotes for the transgene. Embryonal target cells at various developmental stages are used to introduce the transgenes of the invention. Different methods are used depending on the stage of development of the embryonal target cell(s). Exemplary methods for introducing transgenes include, but are not limited to, microinjection of fertilized ovum or zygotes (Brinster, et al., Proc. Natl. Acad. Sci. USA (1985) 82: 4438-4442), and viral integration (Jaenisch R., Proc. Natl. Acad. Sci. USA (1976) 73: 1260-1264; Jahner, et al., Proc. Natl. Acad. Sci.USA (1985) 82: 6927-6931; Van der Putten, et al., (1985) Proc. Natl. Acad. Sci. (USA) 82: 6148-6152). Procedures for embryo manipulation and microinjection are described in, for example, Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY., 1986, the contents of which are incorporated herein by reference). Similar methods are used for production of other transgenic animals. In an exemplary embodiment, production of transgenic mice employs the following steps. Male and female mice, from a defined inbred genetic background, are mated. The mated female mice are previously treated with pregnant mare serum, PMS, to induce follicular growth and human chorionic gonadotropin, hCG, to induce ovulation. Following mating, the female is sacrificed and the fertilized eggs are removed from her uterine tubes. At this time, the pronuclei have not yet fused and it is possible to visualize them using light microscopy. In an alternative protocol, embryos can be harvested at varying developmental stages, e.g. blastocysts can be harvested. Embryos are recovered in a Dulbecco's modified phosphate buffered saline (DPBS) and maintained in Dulbecco's modified essential medium (DMEM) supplemented with 10% fetal bovine serum. Foreign DNA or the recombinant construct (e.g. hCR1 expression construct) is then microinjected (100-1000 molecules per egg) into a pronucleus. Microinjection of an expression construct can be performed using standard micro manipulators attached to a microscope. For instance, embryos are typically held in 100 microliter drops of DPBS under oil while being microinjected. DNA solution is microinjected into the male pronucleus. Successful injection is monitored by swelling of the pronucleus. Shortly thereafter, fusion of the pronuclei (a female pronucleus and a male pronucleus) occurs and, in some cases, foreign DNA inserts into (usually) one chromosome of the fertilized egg or zygote. Recombinant ES cells, which are prepared as set forth below, can be injected into blastocysts using similar techniques. B. Embryonic Stem Cells In another method of making transgenic mice, recombinant DNA molecules of the invention can be introduced into mouse embryonic stem (ES) cells. Resulting recombinant ES cells are then microinjected into mouse blastocysts using techniques similar to those set forth in the previous subsection. ES cells are obtained from pre-implantation embryos and cultured in vitro (Evans, M J., et al., Nature 292: 154156 (1981); Bradley, M. O. et al., Nature 309: 255-258 (1984); Gossler, et al., Proc. Natl. Acad. Sci. (USA) 83:9065-9069 (1986); Robertson et al., Nature 322: 445448 (1986)). Any ES cell line that is capable of integrating into and becoming part of the germ line of a developing embryo, so as to create germ line transmission of the targeting construct, is suitable for use herein. For example, a mouse strain that can be used for production of ES cells is the 129J strain. A preferred ES cell line is murine cell line D3 (American Type Culture Collection catalog no. CRL 1934). The ES cells can be cultured and prepared for DNA insertion using methods known in the art and described in Robertson, Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, E. J. Robertson, ed. IRL Press, Washington, D.C., 1987, in Bradley et al., Current Topics in Devel. Biol., 20:357-371, 1986 and in Hogan et al., Manipulating the Mouse Embryo: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1986, the contents of which are incorporated herein by reference. The expression construct can be introduced into the ES cells by methods known in the art, e.g., those described in Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., ed., Cold Spring Harbor laboratory Press: 1989, the contents of which are incorporated herein by reference. Suitable methods include, but are not limited to, electroporation, microinjection, and calcium phosphate treatment methods. The expression construct (e.g. hCR1) to be introduced into the ES cell is preferably linear. Linearization can be accomplished by digesting the DNA with a suitable restriction endonuclease selected to cut only within the vector sequence and not within the gene (e.g. hCR1 gene) or regulatory sequence (e.g. GATA-1 regulatory sequence). After introduction of the expression construct, the ES cells are screened for the presence of the construct. The cells can be screened using a variety of methods. Where a marker gene is employed in the construct, the cells of the animal can be tested for the presence of the marker gene. For example, where the marker gene is an antibiotic resistance gene, the cells can be cultured in the presence of an otherwise lethal concentration of antibiotic (e.g. G418 to select for neo). Those cells that survive have presumably integrated the transgene construct. If the marker gene is a gene that encodes an enzyme whose activity can be detected (e.g., β-galactosidase), the enzyme substrate can be added to the cells under suitable conditions, and the enzymatic activity can be analyzed. Alternatively, or additionally, ES cell genomic DNA can be examined directly. For example, the DNA can be extracted from the ES cells using standard methods and the DNA can then be probed on a Southern blot with a probe or probes designed to hybridize specifically to the transgene. The genomic DNA can also be amplified by PCR with probes specifically designed to amplify DNA fragments of a particular size and sequence of the transgene such that, only those cells containing the targeting construct will generate DNA fragments of the proper size. C. Implantation The zygote harboring a recombinant nucleic acid molecule of the invention (e.g. hCR1) is implanted into a pseudo-pregnant female mouse that was obtained by previous mating with a vasectomized male. In a general protocol, recipient females are anesthetized, paralumbar incisions are made to expose the oviducts, and the embryos are transformed into the ampullary region of the oviducts. The body wall is sutured and the skin closed with wound clips. The embryo develops for the full gestation period, and the surrogate mother delivers the potentially transgenic mice. Finally, the newborn mice are tested for the presence of the foreign or recombinant DNA. Of the eggs injected, on average 10% develop properly and produce mice. Of the mice born, on average one in four (25%) are transgenic for an overall efficiency of 2.5%. Once these mice are bred they transmit the foreign gene in a normal (Mendelian) fashion linked to a mouse chromosome. D. Screening for the Presence of the Transgenic Construct Transgenic animals can be identified after birth by standard protocols. DNA from tail tissue can be screened for the presence of the transgene construct, e.g., using southern blots and/or PCR. Offspring that appear to be mosaics are then crossed to each other if they are believed to carry the transgene in order to generate homozygous animals. If it is unclear whether the offspring will have germ line transmission, they can be crossed with a parental or other strain and the offspring screened for heterozygosity. The heterozygotes are identified by southern blots and/or PCR amplification of the DNA. The heterozygotes can then be crossed with each other to generate homozygous transgenic offspring. Homozygotes may be identified by southern blotting of equivalent amounts of genomic DNA from mice that are the product of this cross, as well as mice that are known heterozygotes and wild type mice. Probes to screen the southern blots can be designed based on the sequence of the human CR1 gene, or the marker gene, or both. Other means of identifying and characterizing the transgenic offspring are known in the art. For example, western blots can be used to assess the level of expression of the gene introduced in various tissues of these offspring by probing the western blot with an antibody against the protein encoded by the gene introduced (e.g., the human CR1 protein), or an antibody against the marker gene product, where this gene is expressed. In situ analysis, such as fixing the cells and labeling with an antibody, and/or FACS (fluorescence activated cell sorting) analysis of various cells, e.g. erythrocytes, from the offspring can be performed using suitable antibodies to look for the presence or absence of the transgene product. For example, to verify expression of hCR1 on erythrocytes, flow cytometry can be performed using antibodies specific for human CR1 (e.g. 1B4, HB8592 and 7G9 monoclonals, see U.S. patent application No. 20020103343) that are directly conjugated or used in conjunction with a secondary antibody that is fluorophore-conjugated and recognizes the antibody for hCR1. In this analysis, human erythrocytes can be used as a positive control and normal mouse erythrocytes can be used as a negative control for the presence of hCR1. E. Mice Containing Multiple Transgenes or an Additional Mutation Transgenic mice expressing hCR1 on their circulating erythrocytes as described herein can be crossed with mice that a) harbor additional transgene(s), or b) contain mutations in other genes. Mice that are heterozygous or homozygous for each of the mutations can be generated and maintained using standard crossbreeding procedures. Examples of mice that can be bred with mice containing a hCR1 transgene include, but are not limited to, mouse strains which are more prone to an auto-immune disease, such as mouse strains which are models for Lupus, e.g. mouse strains NZB/W, MRL+ or SJL. The invention further pertains to cells derived from transgenic animals. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. IV. Bispecific Compounds In one aspect, the invention provides a method for identifying candidate or test bispecific compounds which reduce the concentration of an agent in the serum and/or circulation of a non-human animal. Compounds selected or optimized using the instant methods can be used to treat subjects that would benefit from administration of such a compound, e.g., human subjects. Candidate compounds that can be tested in the methods of the present invention are bispecific compounds. As used herein, the term “bispecific compound” includes compounds having two different binding specificities. Exemplary bispecific compounds include, e.g., bispecific antibodies, heteropolymers, and antigen-based heteropolymers. Bispecific molecules that can be tested in the present invention preferably include a binding moiety that is specific for CR1, preferably human CR1, crosslinked to a second binding moiety specific for a targeted agent (e.g. a distinct antibody or an antigen). Examples of binding moieties specific for CR1 include, but are not limited to, CR1 ligands, e.g. C3b or, in preferred embodiments, antibodies to CR1. Examples of monoclonal antibodies specific for CR1 include, but are not limited to, any one of the following: 1B4, HB8592, 7G9, 3D9, E-11, 57F and YZ1. HB8592 and 1B4 are disclosed in Taylor et al., Proc. Nat. Acad. Sci., 88:3305-3309 (1991) and Reist et al., Eur. J. Immunol., 23:3021-3027 (1993). Antibodies 3D9 and E-11 are described in Edberg et al., (1992) Eur J Immunol. 22: 1333-9. In another embodiment, novel CR1 binding molecules can be identified based on their ability to bind to CR1. For example, libraries of compounds or small molecules can be tested cell-free binding assay. Any number of test compounds, e.g., peptidomimetics, small molecules or other drugs can be used for testing and can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the ‘one-bead one-compound’ library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, K. S. (1997) Anticancer Drug Des. 12:145). Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:6909; Erb et al. (1994) Proc. Natl. Acad. Sci. USA 91:11422; Zuckermann et al. (1994). J. Med. Chem. 37:2678; Cho et al. (1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061; and in Gallop et al. (1994) J. Med. Chem. 37:1233. Libraries of compounds may be presented in solution (e.g., Houghten (1992) Biotechniques 13:412-421), or on beads (Lam (1991) Nature 354:82-84), chips (Fodor (1993) Nature 364:555-556), bacteria (Ladner U.S. Pat. No. 5,223,409), spores (Ladner U.S. Pat. No. '409), plasmids (Cull et al. (1992) Proc Natl Acad Sci USA 89:1865-1869) or on phage (Scott and Smith (1990) Science 249:386-390); (Devlin (1990) Science 249:404-406); (Cwirla et al. (1990) Proc. Natl. Acad. Sci. 87:6378-6382); (Felici (1991) J. Mol. Biol. 222:301-310); (Ladner supra.). In many drug screening programs which test libraries of modulating agents and natural extracts, high throughput assays are desirable in order to maximize the number of modulating agents surveyed in a given period of time. Assays which are performed in cell-free systems, such as may be derived with purified or semi-purified proteins, are often preferred as “primary” screens in that they can be generated to permit rapid development and relatively easy detection of an alteration in a molecular target which is mediated by a test modulating agent. Moreover, the effects of cellular toxicity and/or bioavailability of the test modulating agent can be generally ignored in the in vitro system, the assay instead being focused primarily on the effect of the drug on the molecular target as may be manifest in an alteration of binding affinity with upstream or downstream elements. In another embodiment, phage display techniques known in the art can be used to identify novel CR1 binding molecules. In one embodiment, the invention provides assays for screening candidate or test compounds which bind to CR1 or biologically active portion thereof. Cell-based assays for identifying molecules that bind to CR1 can be used to identify additional agents for use in bispecific compounds of the invention. For example, cells expressing CR1 can be used in a screening assay. For example, compounds which produce a statistically significant change in binding to CR1 can be identified. In one embodiment of the invention CR1 or portions thereof can be used as “bait proteins” in a two-hybrid assay or three-hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al. (1993) Cell 72:223-232; Madura et al. (1993) J. Biol. Chem. 268:12046-12054; Bartel et al. (1993) Biotechniques 14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696; and Brent WO94/10300), to identify other proteins, which bind to or interact with proteins of the invention and are involved in their activity. The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for an protein is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo, forming a complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) which is
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