ANTI CD-4 ANTIBODIES BLOCKING HIV-INDUCED SYNCYTIA

Abstract: Anti-CD4 antibody homologs, DNA sequences and recombinant DNA molecules encoding them, prophylactic, immunotherapeutic and diagnostic compositions comprising those antibody homologs, and methods for preventing or treating diseases in mammals, including humans, caused by infective agents whose primary targets are CD4<+> lymphocytes. Such diseases include acquired immune deficiency syndrome ("AIDS"), AIDS related complex, and human immunodeficiency virus infection.

Description: I Anti CD-4 antibodies blocking HIV-induced syncytia. TECHNICAL FIELD OF INVENTION 5 This invention relates to anti-CD4 antibody homologs, to DNA sequences encoding those homologs, to prophylactic, immunotherapeutic and diagnostic compositions comprising those homologs, and to methods for preventing or treating diseases in mammals, 10 including humans, caused by infective agents whose primary targets are CD4 + lymphocytes. Such diseases include acquired immune deficiency syndrome ("AIDS"), AIDS related complex, and human immunodeficiency virus infection. 15 BACKGROUND OF THE INVENTION CD4 is a cell surface glycoprotein of CD4 + T lymphocytes (helper/inducer cells) . CD4 + lymphocytes are critical regulatory cells of the human immune system. They mediate T cell proliferation, lympho ine 20 release and helper cell interactions affecting immunoglobulin release. The primary targets of certain infective agents, including the human immunodeficiency virus ("HIV"), are cells bearing the CD4 glycoprotein.* * This application uses the generic term human 25 immunodeficiency virus ("HIV") to refer to independent isolates from AIDS patients and to laboratory strains (continued... ) Such cells include CD4 + lymphocytes, acrophages and certain brain cells. Upon infection with HIV, CD4 + lymphocytes are rendered non-functional and become depleted. This T cell depletion has been attributed both to recurrent cycles of infection resulting from lysis of infected cells and to fusion (syncytia formation) between CD4 infected and uninfected cells [J. Sodroski et al., "Role Of The HTLV-III/LAV Envelope In Syncytium Formation And Cytopathicity", Nature, 322, pp. 470-74 (1986)]. The depletion of CD4 + lymphocytes leads to immunosuppression, with the patient becoming susceptible to a wide range of opportunistic infections and malignancies. Such immunosuppression is seen in patients suffering from acquired immunodeficiency syndrome ("AIDS") . In some cases, AIDS is accompanied by central nervous system disorders, thought to be directly caused by HIV infection of CD4 + brain cells. Complete clinical manifestation of AIDS is usually preceded by AIDS related complex ("ARC"), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss. HIV is thought to be the etiological agent for AIDS and its precursor, ARC [M. G. Sangadharan et al., "Detection, Isolation And Continuous Production Of Cytopathic Retroviruses (HTLV-III) From Patients With AIDS And Pre-AIDS", Science. 224, pp. 497-508 (1984)]. *(...continued) derived therefrom. The term HIV includes viruses elsewhere identified as human T cell lymphotrophic virus type III ("HTLV-III"), lymphadenopathy-associated virus ("LAV") and AIDS-associated retrovirus ("ARV") . The HIV terminology was adopted by the human retrovirus subcommittee of the International Committee On Taxonomy Of Viruses. The major surface (envelope) protein of HIV is produced as a precursor polypeptide (gpl60) which, in mature form, is cleaved into a large heavily glycosylated exterior membrane protein having about 481 amino acids — gpl20 — and a smaller transmembrane protein of about 345 amino acids, which may be glycosylated — gp41 [L. Ratner et al., "Complete Nucleotide Sequence Of The AIDS Virus, HTLV-III", Nature. 313, pp. 277-84 (1985)]. It is believed that HIV gpl20 selectively binds to CD4 epitope(s), thus targeting HIV to CD4 + cells [A. G. Dalgleish et al., "The CD4 (T4) Antigen Is An Essential Component Of The Receptor For The AIDS Retrovirus", Nature. 312, pp. 763-67 (1984); D. Klatzmann et al., "T-Lymphocyte T4 Molecule Behaves As The Receptor For Human Retrovirus LAV", Nature, 312, pp. 767-68 (1984)]. The binding of HIV gpl20 to cell surface CD4 is thought to initiate infection of the CD4 + cell. It is also thought to initiate membrane fusion of infected CD4 + cells with uninfected CD4 + cells (i.e., syncytia formation), which contributes to cell- to-cell transmission of the virus and to its cytopathic effects [J. A. Habeshaw and A. G. Dalgleish, "The Relevance Of HIV env/CD4 Interactions To The Pathogenesis Of Acquired Immune Deficiency Syndrome", J. AIDS. 2, pp. 457-68 (1989) ; ' J. D. Lifson and E. G. Engleman, "Role Of CD4 In Normal Immunity And HIV Infection", Immunol. Rev.. 109, pp. 93-117 (1989)]. Mature CD4 (also known as T4) is a 433 amino acid glycoprotein displaying a molecular mass of 55,000 to 62,000 daltons, having an extracellular domain (approximately AA -AA ) , a membrane spanning domain (approximately AA 3?6 -AA 395 ) and a cytoplas ic tail (approximately (AA -AA ) . CD4 is synthesized as a pre-protein with a 25 amino acid signal sequence. The - A - nucleotide sequence and deduced amino acid sequence for cDNA encoding full length human CD4 have been reported [P. J. Maddon et al., "The Isolation And Nucleotide Sequence Of A cDNA Encoding The T cell Surface Protein T4: A New Member Of The Immunoglobulin Gene Family", Cell. 42, pp. 93-104 (1985); D. R. Littman et al., "Corrected CD4 Sequence", Cell. 55, p. 541 (1988)]. The CD4 extracellular domain consists of four tandem regions having homology to immunoglobulin V regions — VI (spanning approximately AA 1 -AA 10Q ) , V2 (spanning approximately AA 101 -AA lg0 ) , V3 (spanning approximately « AA 181 -AA 2g0 ) and V4 (spanning approximately AA 2gι -AA 375 [see Maddon et al. , Cell, supra; J. Wang et al., "Atomic Structure Of A Fragment Of Human CD4 Containing Two Immunoglobulin-Like Domains", Nature. 348, pp. 411-18 (1990)]. The CD4 VI region has been identified as the binding site of HIV gpl20 [J. Arthos et al., "Identification Of The Residues In Human CD4 Critical For The Binding Of HIV", Cell. 57, pp. 469-81 (1989); T. Mizukami et al., "Binding Region For Human Immunodeficiency Virus (HIV) And Epitopes For HIV- Blocking Monoclonal Antibodies Of The CD4 Molecule Defined By Site-Directed Mutagenesis" , Proc. Natl. Acad. Sci. USA. 85, pp. 9273-77 (1988); A. Peterson and B. Seed, "Genetic Analysis Of Monoclonal Antibody And HIV Binding Sites On The Human Lymphocyte Antigen CD4", Cell. 54, pp. 65-72 (1988); N. R. Landau et al., "The Envelope Glycoprotein Of The Human Immunodeficiency Virus Binds To The Immunoglobulin-Like Domain Of CD4", Nature. 334, pp. 159-62 (1988); L. K. Clayton et al., "Substitution Of Murine For Human CD4 Residues Identifies Amino Acids Critical For HIV-gpl20 Binding", Nature. 335, pp. 363-66 (1988)]. The possible ability of anti-CD4 antibodies to prevent or treat HIV infection by blocking HIV gpl20 binding to CD4 has led a number of workers to explore the ability of certain anti-CD4 antibodies to block HIV-induced syncytia formation between CD4 + cells, as well to study the immunosuppressiveness of some of those antibodies. For example, the CD4 Vl-specific antibodies Leu3A and OKT4A have been reported to be effective blockers of HIV-induced syncytia formation [Q. J. Sattentau, "Epitopes Of The CD4 Antigen And HIV Infection", Science. 234, pp. 1120-23 (1986); B. A. Jameson et al. , "Location And Chemical Synthesis Of A Binding Site For HIV-1 On The CD4 Protein", Science. 240, pp. 1335-39 (1988) ; Peterson and Seed, Cell. supra1. However, these antibodies have serious drawbacks for use as a pharmaceutical for treatment of HIV infection. For example, they can not bind to or act on a CD4 molecule which is already bound to HIV gpl20, because OKT4A and Leu3A recognize CD4 epitopes that overlap with the gpl20 binding site [see, e.g., P. A. Bates et al., "A Predicted Three-Dimensional Structure For The Human Immunodeficiency Virus Binding Domains Of CD4 Antigen", Prot. Enσnσ.. 3, pp. 13-21 (1989); J. S. McDougal et al., "Binding Of The Human Retrovirus HTLV-III/LAV/ARV/HIV To The CD4 (T4) Molecule: Conformation Dependence, Epitope Mapping, Antibody Inhibition, And Potential For Idiotypic Mimicry", J. Immunol.. 137, pp. 2937-44 (1986); Landau et al., Nature, supra; A. G. Dalgleish et al., "Neutralisation Of HIV Isolates By Anti-Idiotypic Antibodies Which Mimic The T4 (CD4) Epitope: A Potential AIDS Vaccine", Lancet, 2, pp. 1047-50 (1987)]. Also, OKT4A has been reported to be quite immunosuppressive, which is not a desirable characteristic for a putative AIDS therapeutic [D. Lamarre et al. , "Class II MHC Molecules And The HIV gpl20 Envelope Protein Interact With Functionally Distinct Regions Of The CD4 Molecule", EMBO J.. 8, pp. 3271-77 (1989); W. E. Biddison et al., "Possible Involvement Of The OKT4 Molecule In T Cell Recognition Of Class II HLA Antigens", J. Exp. Med.. 156, pp. 1065- 76 (1982)]. Anti-CD4 monoclonal antibodies that are specific for other CD4 epitopes or domains have been studied, but the published reports on these antibodies also evidence drawbacks for use as AIDS therapeutics. One such antibody is OKT4B, which has been reported to be specific for the V2 domain of CD4 [T. Kieber-Emmons et al., "The gpl20-CD4 Interface: Structural, Immunological And Pathological Considerations", Biochim. Biophys. Acta. 989, pp. 281- 300 (1989)]. There have been conflicting reports as to whether OKT4B significantly interferes with HIV gpl20 binding to CD4 [McDougal et al., J. Immunol., supra; K. Lundin et al., "A Specific Assay Measuring Binding Of 125 I-Gpl20 From HIV To T4 + /CD4 + Cells", J. Immunol. Methods. 97, pp. 93-100 (1987); Lamarre et al. , EMBO J.. supra] . And, OKT4B has been reported to be significantly more immunosuppressive than OKT4A [Lamarre et al., EMBO J.. supra1. Moreover, OKT4B is a relatively weak blocker of HIV-induced syncytia formation, as compared to 0KT4A [Sattentau et al. , Science, supra] . Other anti-CD4 antibodies that have been reported to have some effect on HIV-induced syncytia formation, and also have been reported to bind to CD4 epitopes distinct from the epitopes bound by OKT4A and Leu3A, include MT151, VIT4 and MT321 [Sattentau et al., Science, supra] . However, several more recent independent studies indicate that these closely related antibodies recognize conformational-dependent CD4 epitopes that overlap with the CD4 epitope involved in gpl20 binding [Q. J. Sattentau et al., "Structural Analysis Of The Human Immunodeficiency Virus-Binding Domain Of CD4", J. EXP. Med.. 170, pp. 1319-34 (1989); Bates et al., Prot. Enqnq. , supra; Landau et al., Nature, supra. M. Merkenschlager et al., "Functional Epitope Analysis Of The Human CD4 Molecule", J. Immunol.. 9, pp. 2839-45 (1990)]. Another anti-CD4 antibody that has been studied is OKT4, which is specific for the V3V4 domain of CD4 [E. A. Berger et al., "A Soluble Recombinant Polypeptide Comprising The Amino-Terminal Half Of The Extracellular Region Of The CD4 Molecule Contains An Active Binding Site For Human Immunodeficiency Virus", Proc. Natl. Acad. Sci. USA. 85, pp. 2357-61 (1988)]. OKT4 has even greater drawbacks as a therapeutic agent for HIV infection than 0KT4A, Leu3A, OKT4B and other known anti-CD4 antibodies. For example, 0KT4 has been reported to be a "nonblocker" of HIV-induced syncytia formation [Sattentau, Science, supra]. Before our invention, no anti-CD4 antibody had been reported to be capable of both not significantly blocking the binding of HIV gpl20 to human CD4 and effectively blocking HIV-induced syncytia formation. Such an antibody would clearly offer advantages for therapeutic intervention in AIDS, ARC and HIV infection, as it could be used to intervene after HIV binding to CD4, or in combination with agents that do block the HIV gpl20-CD4 binding event. Thus, the need exists for anti-CD4 antibodies having such a highly desirable combination of properties, for use in the treatment and prevention of AIDS, ARC and HIV infection. SUMMARY OF THE INVENTION The present invention generally solves many of the problems referred to above by providing, for the first time, antibody homologs, preferably monoclonal antibodies, that bind to human CD4 without significantly blocking binding of HIV gpl20 to human CD4 and that display one of the following sets of properties: (1) block HIV-induced syncytia formation between CD4 + cells at least about as well as OKT4A (a commercially available CD4 Vl-specific anti-CD4 monoclonal antibody) ; (2) block HIV-induced syncytia formation between CD4 + cells better than OKT4 (a commercially available CD4 V3V4-specific anti-CD4 monoclonal antibody) and are less immunosuppressive than OKT4A in an in vitro tetanus toxoid-specific proliferation assay; or (3) block HIV-induced syncytia formation between CD4 + cells at least about as well as OKT4A and are less immunosuppressive than 0KT4A in an in vitro tetanus toxoid-specific proliferation assay. Certain of the anti-CD4 antibody homologs of this invention will bind to a human CD4 fragment consisting of CD4 AA ±-AAX-o on U (i.e., they are V1V2- specific) , but will not bind to a human CD4 fragment consisting of CD4 AA -AA (i.e., they are not solely Vl-specific) . Similarly, certain antibody homologs of this invention do not significantly inhibit the binding of CD4 Vl-specific antibodies to human CD4. The preferred anti-CD4 antibody homologs of this invention also inhibit infection of CD4 + cells by HIV. Other preferred antibody homologs of this invention display one or more characteristics selected from causing no significant (a) decrease in the number of circulating CD4 + cells in vivo, (b) modulation of CD4 from the surface of CD4 + cells in vivo, (c) decrease in peripheral white blood cell counts in vivo, and (d) decrease in the antibody titer elicited in response to foreign antigens in vivo. The present invention provides anti-CD4 antibody homologs of many types. These include monoclonal antibodies, recombinant antibodies, recombinant chimeric antibodies and recombinant humanized antibodies. The provided antibody homologs preferably are intact immunoglobulin molecules having two each of heavy and light chains, but may consist of one or more light chains, one or more heavy chains or combinations thereof. In addition, the anti-CD4 antibody homologs of this invention may be in the form of Fab fragments, Fab* fragments, F(ab) fragments, F(v) fragments or any other immunoglobulin fragment having the above-described properties. Provided as preferred anti-CD4 antibody homologs of this invention are the mouse monoclonal antibodies designated 5A8, 1F8 and 5F2. 5A8 is most preferred. This invention provides DNA sequences encoding the 5A8 heavy chain variable region and the 5A8 light chain variable region. Also provided are DNA sequences encoding 5A8-chimeric and 5A8-humanized recombinant antibodies utilizing those DNA sequences, or portions thereof, as well as the polypeptides encoded by those DNA sequences. Recombinant DNA molecules comprising those DNA sequences and expression control sequences operatively linked thereto are also provided. This invention provides 5A8-mimetic agents, which are peptides, semi-peptidic compounds or non-peptidic compounds that significantly block binding of monoclonal antibody 5A8 to human CD4. 5A8-mimetic agents of this invention inhibit HIV-induced syncytia formation between CD4 + cells, inhibit infection of CD4 + cells by HIV, or both. Preferably, a 5A8-mimetic agent displays the properties of an antibody homolog of this invention. The present invention also provides anti-CD4 antibody homologs that are linked to one or more substances selected from antibody homologs and 5A8-mimetic agents of this invention, detectable agents, cytotoxic agents and pharmaceutical agents. Also provided are cells that produce the antibody homologs of this invention, a process for producing the antibody homologs by culturing those cells, and a process for producing hybridoma cells of this invention by immunizing a non-human mammal with CD4 + cells expressing CD4 on their surface which are produced by transforming CD4 " tissue culture cells with DNA encoding full-length human CD4. The properties of the anti-CD4 homologs and 5A8-mimetic agents of the present invention make them especially useful in the detection, prophylaxis and treatment in humans of diseases caused by infective agents whose primary targets are CD4 + cells, for example, the HIV-related diseases ARC and AIDS. Accordingly, the present invention provides diagnostic, prophylactic and therapeutic compositions comprising the above-described anti-CD4 antibody homologs and 5A8- mimetic agents, useful for detecting, preventing and treating in humans diseases caused by infective agents whose primary targets are CD4 + cells, for example, the HIV-related diseases ARC and AIDS, as well as methods using these compositions. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts fluorescence activated cell sorter ("FACS") profiles of human peripheral blood lymphocytes stained with the CD4 Vl-specific monoclonal antibody Leu3A labelled with fluorescein isothiocyanate ("Leu3A-FITC") in the presence of buffer (Figure IA) , unlabelled Leu3A (Figure IB) , the CD4 Vl-specific monoclonal antibody OKT4A (Figure IC) , the CD4 V3V4- specific monoclonal antibody OKT4 (Figure ID) or monoclonal antibody 5A8 of this invention (Figure IE) . Data are plotted as log fluorescence intensity (y-axis) as a function of forward scatter (x-axis) . Figure 2 depicts immunofluorescent staining of the human CD4 + cell line H9 with an antibody homolog of this invention (5A8) and the anti-CD4 monoclonal antibodies Leu3A, OKT4A and OKT4, with and without preincubation with excess HIV gpl20. The dotted lines signify staining with an anti-CD4 monoclonal antibody and the solid lines signify staining with irrelevant negative control mouse antibodies in the absence (left profiles) or presence (right profiles) of excess HIV gpl20. Figure 3 depicts percent inhibition of syncytia formation (quantified as 51 Cr release) as a function of antibody concentration (0.026-2,000 ng/ml) for a monoclonal antibody of this invention (5A8) and two CD4 Vl-specific monoclonal antibodies (Leu3A and OKT4A) . Figure 4 depicts percent inhibition of syncytia formation (quantified as 51 Cr release) as a function of antibody concentration (3.2-10,000 ng/ml) for a monoclonal antibody of this invention (5A8) , two CD4 Vl-specific monoclonal antibodies (Leu3A and 0KT4A) and an "OKT4-like" monoclonal antibody specific for CD4 V3V4 (2-103-D11) . Figures 5-6 depict the inhibition of tetanus toxoid ("TT")-induced proliferation of human peripheral blood lymphocytes (quantified as 3 H-thymidine incorporation and identified as "cpm x 10E3 (Thousands)") caused by an antibody homolog of this invention (monoclonal antibody 5A8) and various control antibodies (the CD4 Vl-specific antibodies OKT4A and Leu3A and the isotype-matched control antibodies MOPC 21 and UPC 10) on days four (Figure 5) and five (Figure 6) of the assay. The bars labelled "TT Control" show the baseline growth of the cells without TT stimulation (open bar) and the TT response without any antibody (solid bar) . The effect on proliferation of antibody only, without TT stimulation, is indicated by the bars with large spots. Figures 5-6 also show the effect on proliferation after TT stimulation (i.e., inhibition of TT response) caused by the various antibodies at concentrations of 10 μg/ml (bars with dots) (MOPC 21 and 5A8 only) , 1 μg/ml (bars with diagonal stripes) (every antibody) and 0.1 μg/ml (bars with crosshatching) (every antibody) . Figure 7 depicts the peripheral white blood cell count of rhesus monkeys at various time points before, during and after a course of treatment with 5A8 (solid lines, Mn 261-85 and Mn 251-87) or the isotype- matched control monoclonal antibody MOPC21 (dashed lines, Mn 265-85 and Mn 265-87) . The y-axes depict white blood cells (in thousands) per microliter of blood. The x-axes depict days, where 5A8 or MOPC21 was injected on days 0, 2 and 4. Figure 8 depicts the number of peripheral CD4 + lymphocytes in rhesus monkeys at various time points before, during and after a course of treatment with 5A8 (solid lines, Mn 261-85 (top panel) and Mn 251-87 (bottom panel) ) or the isotype-matched control monoclonal antibody MOPC21 (dashed lines, Mn 265-85 (top panel) and Mn 265-87 (bottom panel) ) . CD4 + cell number is quantitated by FACS analysis after staining with the fluorescently labelled CD4 V3V4-specific monoclonal antibody FITC-OKT4 (open and closed circles) or by FACS analysis after incubating isolated cells with excess 5A8 in vitro and then staining with fluorescently labelled goat anti-mouse Ig (open and closed triangles) . The y-axes depict CD4 + cell number per microliter. The x-axes depict days, where 5A8 or MOPC21 was injected on days 0, 2 and 4. Figure 9 depicts the anti-tetanus toxoid titers of rhesus monkeys at various time points before, during and after treatment with 5A8 (solid lines, Mn 261-85 and Mn 251-87) or the isotype-matched control monoclonal antibody MOPC21 (dotted lines, Mn 265-85 and Mn 265-87) . The y-axis depicts units per milliliter blood of anti-tetanus toxoid antibodies established relative to a standard anti-tetanus toxoid immune serum. The x-axis depicts days, where 5A8 or M0PC21 was injected on days 0, 2 and 4 and tetanus toxoid was injected on days 3 and 21. The bar beneath days 0-9 indicates the time period during which there was saturation coating of CD4 by 5A8 in vivo. DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein, "CD4" means any CD4 protein encoded by a naturally occurring CD4 gene. As used herein, "CD4 + cells" are cells that present the CD4 glycoprotein on their surface. Such cells include CD4 + T lymphocytes and CD4 + mammalian tissue culture cells, e.g., H9 and C8166 cells. As used herein, "CD4 VI" is the region of CD4 spanning AA -AA . As used herein, "CD4 V1V2" is the region of CD4 spanning AA 1-AAl-o on . As used herein, "CD4 V3V4" is the region of CD4 spanning AA . -AA 37g . As used herein, "recombinant soluble CD4" or "rsCD4" is a polypeptide consisting of AA 1 -AA 375 (i.e., regions VI-V4) of human CD4. As used herein, a "CD4 Vl-specific antibody" is an antibody that binds to an epitope in the VI region of CD4. As used herein, a "CD4 V3V4-specific antibody" is an antibody that binds to an epitope in the V3V4 region of CD4. As used herein, an "antibody homolog" is a protein comprising one or more polypeptides selected from immunoglobulin light chains, immunoglobulin heavy chains, and antigen-binding fragments thereof, which are capable of binding to one or more antigens. The component polypeptides of an antibody homolog composed of more than one polypeptide may optionally be disulfide-bound or otherwise covalently crosslinked. Accordingly, antibody homologs include intact immunoglobulins of types IgA, IgG, IgE, IgD, IgM (as well as subtypes thereof) , wherein the light chains of the immunoglobulin may be of types kappa or lambda. Antibody homologs also include portions of intact immunoglobulins that retain antigen-binding specificity, for example, Fab fragments, Fab 1 fragments, F(ab') fragments, F(v) fragments, heavy chain monomers or dimers, light chain monomers or dimers, dimers consisting of one heavy and one light chain, and the like. As used herein, a "humanized recombinant antibody homolog" is an antibody homolog initially derived from a nonhuman mammal in which recombinant DNA technology has been used to substitute some or all of the amino acids not required for CD4 binding with amino acids from corresponding regions of a human immunoglobulin light or heavy chain. As used herein, a "chimeric recombinant antibody homolog" is an antibody homolog derived initially from a nonhuman mammal, in which recombinant DNA technology has been used to replace all or part of the hinge and constant regions of the light chain, the heavy chain or both, with corresponding regions from an immunoglobulin light chain or heavy chain of a mammal of a different species, preferably a human. As used herein, an antibody homolog that "does not significantly block binding of a CD4 VI- specific antibody to human CD4" is one that causes no more than a 30% reduction in the binding of the CD4 Vl-specific antibody either to human rsCD4 (CD4 V1-V4) or to human CD4 displayed on a CD4 + cell. As used herein, an antibody homolog that "does not significantly block binding of HIV gpl20 to human CD4" is one that causes no more than a 30% reduction in the binding of HIV gpl20 either to human rsCD4 (CD4 V1-V4) or to human CD4 displayed on a CD4 + cell. As used herein, "OKT4" is the anti-CD4 mouse monoclonal antibody commercially available from Ortho Diagnostic Systems, Raritan, NJ under catalog number 7042. As used herein, "OKT4A" is the anti-CD4 mouse monoclonal antibody commercially available from Ortho Diagnostic Systems, Raritan, NJ under catalog number 7142. As used herein, a "5A8-mimetic agent" is a compound that causes at least a 30% reduction in the binding of monoclonal antibody 5A8 either to human rsCD4 (CD4 V1-V4) or to human CD4 displayed on a CD4 + cell. As used herein, an antibody homolog "causing no significant decrease in the number of circulating CD4 + cells in vivo" is an antibody homolog which, within 24 hours after administration to a mammal having normal immune function, causes less than a 50% decrease in the number of circulating CD4 + cells, as compared either to the pre-administration number for that mammal or to the number in a control mammal to whom an isotype-matched antibody homolog of irrelevant specificity has been administered instead of an antibody homolog of this invention. As used herein, an antibody homolog "causing no significant modulation of CD4 from the surface of CD4 + cells in vivo" is an antibody homolog which, within 24 hours after administration to a mammal having normal immune function, causes less than a ten-fold decrease in the number of CD4 molecules on the surface of the mammal's CD4 + cells, as compared either to the pre-administration number for that mammal or to the number in a control mammal to whom an isotype-matched antibody homolog of irrelevant specificity has been administered instead of an antibody homolog of this invention. As used herein, an antibody homolog "causing no significant decrease in circulating peripheral white blood cell counts in vivo" is an antibody homolog which, within 24 hours after administration to a mammal having normal immune function, causes less than a 50% decrease in the ' number of circulating peripheral white blood cells, as compared either to the pre- administration number for that mammal or to the number in a control mammal to whom an isotype-matched antibody homolog of irrelevant specificity has been administered instead of an antibody homolog of this invention. In this context, "peripheral white blood cells" include B lymphocytes, T lymphocytes (CD4 + or CD8 + ) and monocytes. As used herein, an antibody homolog "causing no significant decrease in the antibody titer elicited in response to foreign antigens" is an antibody homolog which, upon administration to a mammal having normal immune function, causes less than a ten-fold decrease in the antibody titer elicited in response to a subsequently administered foreign antigen, as compared to the antibody titer elicited by the foreign antigen in a control mammal to whom an isotype-matched antibody homolog of irrelevant specificity has been administered instead of an antibody homolog of this invention. In this context, a "foreign antigen" is a molecule (e.g., a viral or bacterial polypeptide) that is not encoded by the genome of that mammal. Antibody Homologs According To This Invention The antibody homologs according to one embodiment of the present invention (a) bind to human CD4; (b) do not significantly block binding of HIV gpl20 to human CD4; and (c) block HIV-induced syncytia formation between CD4 + cells at least about as well as 0KT4A. Another embodiment of the present invention relates to antibody homologs that (a) bind to human CD4; (b) do not significantly block binding of HIV gpl20 to human CD4; (c) block HIV-induced syncytia formation between CD4 + cells better than OKT4; and (d) are less immunosuppressive than OKT4A in an in vitro tetanus toxoid-specific proliferation assay. A further embodiment relates to antibody homologs that (a) bind to human CD4; (b) do not significantly block binding of HIV gpl20 to human CD4; (c) block HIV-induced syncytia formation between CD4 + cells at least about as well as OKT4A and (d) are less immunosuppressive than OKT4 in an in vitro tetanus toxoid-specific proliferation assay. Certain of the antibody homologs of this invention bind to a polypeptide consisting of human CD4 V1V2 (i.e., they are VlV2-specific) , but do not bind to a polypeptide consisting of human CD4 VI (i.e., they are not solely Vl-specific) . Similarly, certain antibody homologs of this invention do not significantly block the binding of CD4 Vl-specific antibodies, such as OKT4A and Leu3A, to human CD4. The preferred antibody homologs of this invention inhibit infection of CD4 + cells by HIV. Other preferred antibody homologs of this invention display one or more characteristics selected from: (a) causing no significant decrease in the number of circulating CD4 + cells in vivo; (b) causing no significant modulation of CD4 from the surface of CD4 + cells in vivo; (c) causing no significant decrease in circulating peripheral white blood cell counts in vivo; (d) causing no significant decrease in the antibody titer elicited in response to foreign antigens in vivo; and (e) causing no consistent or persistent inhibition ex vivo of T cell proliferative responses to mitogens and xenogeneic cells. The most preferred antibody homologs of this invention display all of the above-described properties. Specific antibody homologs according to the present invention include the mouse monoclonal antibodies designated 5A8 (IgG 1 ) , 1F8 (IgG 2 ) and 5F2 (IgG ) , described infra. 5A8 is preferred. While not wishing to be bound by theory, we believe that the antibody homologs of this invention are prophylactic and therapeutic for AIDS, ARC and HIV infection because they inhibit HIV-induced syncytia formation between CD4 + cells, thus slowing spread of the virus to uninfected cells. We believe the antibody homologs of this invention to be particularly useful because they should prevent syncytia formation even after HIV gpl20 has bound to CD4 displayed at the surface of CD4 + lymphocytes. The antibody homologs of this invention that also inhibit infection of CD4 + cells by HIV are particularly useful. Furthermore, because the antibody homologs of this invention are noncompetitive blockers of virus binding, we believe their therapeutic and prophylactic effects to be independent of plasma virus levels. Screening Assays For Antibody Homoloαs According To This Invention The ordinary skilled worker may easily determine, using well known methods, whether a particular antibody homolog (or preparation comprising an antibody homolog) displays the properties described above, and thus may identify antibody homologs according to the present invention. To determine whether a particular antibody homolog binds to human CD4, any conventional binding assay may be used. Useful CD4 binding assays include FACS analysis, ELISA assays, radioimmunoassays and the like, which detect binding of antibody homologs to human CD4. Full-length and soluble forms of human CD4 useful in such assays are described in PCT patent application PCT/US88/02940, which is herein incorporated by reference. Reference should also be made to D. R. Littman et al. , Cell. 55, p. 541 (1988), which describes the correct signal sequence cleavage site of pre-human CD4 and which was published after the filing date of PCT/US88/02940. The binding of an antibody homolog to CD4, or to soluble fragments thereof, such as rsCD4, may conveniently be detected through the use of a secondary antibody specific for immunoglobulins of the species from which the antibody homolog was derived. To determine whether a particular antibody homolog does not significantly block binding of HIV gpl20 to human CD4, any suitable competition assay may be used. Useful assays include, for example, ELISA assays, radioimmunoassays and the like that quantify the ability of the antibody homolog to cross block with HIV gpl20 for binding to human CD4. Preferably, the ability of excess HIV gpl20 to block binding of labelled human rsCD4 to immobilized antibody homolog is measured. Preferably, the ability of an antibody homolog to bind to human CD4 is evaluated by testing its ability to bind to human CD4 + cells. The preferred CD4 + cells for use in determining whether a particular antibody homolog binds to human CD4 are mammalian tissue culture cells transformed with DNA encoding full-length human CD4 and expressing the CD4 on their surface. Such cells include, for example, the CHO cells transformed with DNA encoding full-length CD4 which are described in R. A. Fisher et al., "HIV Infection Is Blocked In vitro By Recombinant Soluble CD4", Nature. 331, pp. 76-78 (1988) ("r-CD4-CHO cells") . Suitable r-CD4-CH0 cells were deposited with the In Vitro International, Inc. culture collection in Linthicum, MD, under accession number IVI-10260 and transferred to the American Type Culture Collection, Rockville, MD, under accession number CRL 10884. Binding of the antibody homolog to the CD4 + cell preferably is detected by staining the cells with a fluorescently labelled secondary antibody specific for immunoglobulins of the same species from which the antibody homolog being tested is derived. A fluorescence activated cell sorter ("FACS") is used to detect and quantify any binding. See generally H. M. Shapiro, Practical Flow Cvtometrv. Alan R. Liss, Inc., New York, New York (1985). Most preferably, the ability of an antibody homolog to block binding of HIV gpl20 to human CD4 is determined by preincubating excess HIV gpl20 with CD4 + cells, and quantifying the degree to which the bound HIV gpl20 blocks binding of the antibody homolog to the cells. Binding of the antibody homolog to the CD4 + cells is quantified by FACS analysis, using a fluorescently labelled secondary antibody specific for immunoglobulins of the same species from which the antibody homolog being tested is derived. The HIV gpl20 used in the above assays may be provided by cells infected with HIV, by HIV itself, by host cells transformed with the gene for HIV gpl20, or by isolated gpl20. Preferably, a purified, soluble HIV gpl20 isolated from a unicellular host transformed with a truncated HIV gpl60 gene encoding HIV gpl20 will be used. Purified, recombinant HIV gpl20 is commercially available, for example, from Repligen (Cambridge, MA) and from Celltech (Berkshire, United Kingdom) . Cells producing recombinant gpl20 are described, for example, in Lasky et al., "Neutralization Of The AIDS Retrovirus By Antibodies To A Recombinant Envelope Glycoprotein", Science. 233, pp. 209-12 (1986) . Suitable soluble, recombinant HIV gpl20 polypeptides are produced by Spodoptera frugiperda cells transformed with recombinant baculovirus carrying the DNA sequence defined by SEQ ID NO:3. To determine whether a particular antibody homolog blocks HIV-induced syncytia formation between CD4 + cells better than OKT4 or at least about as well as OKT4A, any known syncytia assay may be used. Preferably, an HIV laboratory isolate or HIV-infected CD4 + tissue culture cells (e.g., H9) are added to cultures of C8166 cells, and varying amounts of the antibody homolog are added to all but the control cultures. To control cultures are added similar varying amounts of OKT4 or OKT4A. Some control cultures (negative controls) are supplemented with nothing, or with an irrelevant antibody of the same isotype as the antibody homolog. After incubation, all the cultures are scored by visual inspection for syncytia. In this way, the ability of the antibody homolog to block syncytia formation is compared to the syncytia blocking abilities of OKT4 and OKT4A. An alternative method for comparing the syncytia blocking abilities of an antibody homolog with that of OKT4 and OKT4A is the following. Transformed tissue culture cells expressing recombinant HIV envelope glycoprotein (i.e., HIV gpl20/gp41 after post- translational cleavage of " HIV gpl60) on their surface are incubated with human CD4 + cells containing a detectable substance (e.g., Jurkat cells labelled with 51 Cr) in the presence of OKT4, OKT4A, antibody homolog to be tested or no antibody. After incubation, the culture supernatants are assayed for the detectable substance (e.g. , measuring τ-irradiation for 51 Cr) . Cell lysis is an inevitable sequela to HIV-induced syncytia formation. Therefore, the amount of detectable substance released into a culture supernatant as a consequence of cell lysis is directly proportional to syncytia formation. In this way, the degrees to which OKT4, OKT4A and a particular antibody homolog block syncytia formation are easily quantified and compared. The most preferred transformed tissue culture cell for the above assay is a CHO cell expressing recombinant HIV envelope glycoprotein on its surface ("r-gpl60-CHO cell") . Such r-gpl60-CHO cells are exemplified by cultures which were deposited in the In Vitro International, Inc. culture collection, Linthicum, MD, under accession number IVI-10261 and transferred to the American Type Culture Collection, Rockville, MD, under accession number CRL 10885. The deposited cells are transformed with the DNA sequence defined herein by SEQ ID NO:l. To determine whether a particular antibody homolog is less immunosuppressive than 0KT4A in an in vitro tetanus toxoid-specific proliferation assay, the general protocol described in E. G. Engleman et al., "Activation Of Human T Lymphocyte Subsets: Helper And Suppressor/Cytotoxic T Cells Recognize And Respond to Distinct Histocompatibility Antigens", J. Immunol.. 127, pp. 2124-29 (1981) is preferred. In such a tetanus toxoid assay, the ability of antibody homologs and OKT4A to reduce tetanus toxoid-induced T cell proliferation is quantified. Typically, proliferation is measured by 3 H-thymidine incorporation by the T cells. To determine whether a particular antibody homolog either does not bind to a polypeptide consisting of the human CD4 VI region or whether it does bind to a polypeptide consisting of the human CD4 V1V2 region, ELISA assays, radioimmunoassays (RIAs) , FACS analysis or the like are useful. In such assays, the ability of the antibody homolog to bind to either of those polypeptides may be detected through use of a secondary antibody specific for immunoglobulins of the species from which the antibody homolog was derived. Preferably, binding is determined through inhibition studies with CD4 VI and CD4 V1V2 polypeptides as competitors for binding of the antibody homolog to human CD4 displayed on the surface of a CD4 + cell, using FACS analysis to quantify any inhibition. Alternatively, determining whether a particular antibody homolog binds or does not bind to a CD4 VI polypeptide or CD4 V1V2 polypeptide is accomplished using an RIA competition assay in which the antibody homolog is bound to. the plate (directly or indirectly) , and the CD4 VI polypeptide or CD4 V1V2 polypeptide simultaneously competes with detectably labelled rsCD4 for binding to the antibody homolog. The amount of bound rsCD4 is compared with the amount of rsCD4 bound in the absence of the CD4 VI or CD4 V1V2 polypeptide, allowing calculation of the percent inhibition of rsCD4 binding caused by the CD4 VI or CD4 VIV2 polypeptide. The preferred polypeptides consisting of the human CD4 VI or CD4 V1V2 regions are CD4 AA.-AA. n _ or CD4 A -AA.-., respectively, of the CD4 sequences set forth in PCT patent application PCT/US88/02940 or in Maddon et al.. Cell, supra. Using the corrected numbering system of Littman et al.. Cell, supra. these polypeptides correspond respectively to human CD4 AA χ -AA 113 and human CD4 AA -AA 8Q . A suitable CD4 VI polypeptide is described in B. H. Chao et al., "A 113- Amino Acid Fragment Of CD4 Produced In Escherichia coli Blocks Human Immunodeficiency Virus-Induced Cell Fusion", J. Biol. Chem.. 264, pp. 5812-17 (1989). A suitable CD4 VIV2 polypeptide is described in R. L. Garlick et al., "Escherichia coli Expression, Purification, And Biological Activity Of A Truncated Soluble CD4", AIDS Res. Hum. Retroviruses. 6, pp. 465- 79 (1990) . To determine whether a particular antibody homolog inhibits infection of CD4 + cells by HIV, any indication of HIV infection could be monitored. Useful indicators of HIV infection include, for example, secretion of HIV core antigen p24 by cells chronically infected by HIV and HIV-induced syncytia formation. Preferably, inhibition of HIV infection is determined by comparing HIV p24 levels in the presence and absence of the antibody homolog in HIV-infected CD4 + cell cultures. To determine whether a particular antibody homolog causes no significant decrease in the number of circulating CD4 + cells in vivo, the number of circulating CD4 + cells isolated from a mammal within 24 hours after administration of the antibody homolog to a mammal having normal immune function is quantified, and compared to the pre-administration number or the number in a control mammal to whom an isotype-matched antibody homolog of irrelevant specificity has been administered instead of an antibody homolog of this invention. Quantification of CD4 + cells may be accomplished, for example, by staining the cells with fluorescently labelled anti-CD4 antibodies that do not cross block with the antibody homolog for binding to CD4 (e.g., 0KT4) , followed by FACS analysis. To determine whether a particular antibody homolog causes no significant modulation of CD4 from the surface of CD4 + cells in vivo, the number of CD4 molecules on CD4 + cells isolated from a mammal within 24 hours after administration of the antibody homolog to a mammal having normal immune function is quantified, and compared to the pre-administration number in that mammal or the number in a control mammal to whom an isotype-matched antibody homolog of irrelevant specificity has been administered instead of an antibody homolog of this invention. Quantification of cell surface CD4 may be accomplished, for example, by staining the cells with fluorescently labelled anti- CD4 antibodies that do not cross block with the antibody homolog for binding to CD4 (e.g., OKT4) , followed by FACS analysis. To determine whether a particular antibody homolog causes no significant decrease in circulating peripheral white blood cell counts in vivo, blood drawn within 24 hours after administration of the antibody homolog to a mammal having normal immune function is fractionated by conventional means and white blood cell counts are obtained (e.g., by staining blood smears). That number is compared to the pre-administration number for that mammal or to the number in a control mammal to whom an isotype-matched antibody of irrelevant specificity has been administered instead of an antibody homolog of this invention. To determine whether a particular antibody homolog causes no significant decrease in the antibody titer elicited in response to foreign antigens in vivo, the antibody titer elicited in a mammal having normal immune function by a foreign antigen is determined after administration of the antibody homolog, and compared to the titer elicited in a control mammal to whom an isotype-matched antibody homolog has been administered instead of an antibody homolog of this invention. The antibody titer for the foreign antigen may conveniently be determined, for example, by performing an ELISA using microtiter plates coated with the foreign antigen. To determine whether a particular antibody homolog causes no significant inhibition in vitro of T cell proliferative responses to mitogens and xenogeneic cells the proliferative responses of T cells isolated before and at various time points after administration of antibody homolog is measured. Useful mitogens for this purpose include Concanavalin A and phytohemagglutinin. Useful xenogeneic cells include any cells (e.g., lymphocytes) derived from a species other than the species of the mammal to which the antibody homolog was administered. Proliferative response may be measured, for example, by 3 H-thymidine incorporation into the various T cell samples after incubation in vitro with mitogens or irradiated xenogeneic cells, which cannot proliferate. Types Of Antibody Homologs According To This Invention And Their Production Antibody homologs according to the present invention may be of many types, the critical criterion being that the antibody homolog display one of the combinations of properties described above. For example, antibody homologs of this invention may be intact monoclonal antibodies, intact recombinant antibodies, intact chimeric recombinant antibodies, intact humanized recombinant antibodies, or antigen- binding portions of the foregoing antibodies. A. Monoclonal Antibodies The most preferred antibody homologs of the present invention are intact monoclonal antibodies produced by hybridoma cells. The technology for producing monoclonal antibodies is well known [see generally E. A. Lerner, "How To Make A Hybridoma", Yale J. Biol. Med.. 54, pp. 387-402 (1981); M. L. Gefter et al., "A Simple Method For Polyethylene Glycol-Promoted Hybridization Of Mouse Myeloma Cells", Somatic Cell Genet.. 3, pp. 231-36 (1977)]. Briefly, an immortal cell line (typically myeloma cells) is fused to lymphocytes (typically splenocytes) from a mammal immunized with a preparation comprising human CD4 or a VIV2-containing fragment thereof, and the culture supernatants of the resulting hybridoma cells are screened as described above for antibody homologs according to this invention. Useful CD4-comprising preparations include human CD4-bearing cells (e.g., CD4 + lymphocytes), fractions of such cells comprising CD4, partially purified or substantially pure human CD4 isolated from natural sources, and unpurified, partially purified or substantially pure human CD4 or V1V2-containing fragments thereof derived from recombinant host cells. Recombinant host cells expressing VlV2-containing fragments of CD4 are described, for example, in PCT patent application PCT/US88/02940. The preferred immunogen is CD4 + cells produced by transforming CD4~ mammalian tissue culture cells with DNA encoding full-length human CD4. Most preferably, the immunogen is a CHO cell transformed with the DNA sequence encoding CD4 A -.-AA.- set forth in Maddon et al. , Cell, supra (i.e., CD4 AA -AA. 3 _ using the corrected numbering system set forth in Littman et al. , Cell, supra) . Such a cell, referred to herein as an "r-CD4-CHO cell", was deposited with the In Vitro International, Inc. culture collection, Linthicum, MD, under accession number IVI-10260 and transferred to the American Type Culture Collection, Rockville, MD, under accession number CRL 10884 [see also Fisher et al. , Nature, supra] . While not wishing to be bound by theory, we believe that using r-CD4-CHO cells as the immunogen, rather than "natural" CD4 + cells, isolated CD4 or truncated forms of CD4 (e.g., rsCD4) , increases the likelihood of obtaining anti-CD4 antibody homologs according to the present invention from a particular fusion. We believe this increased likelihood as compared to "natural" CD4 + cells to be due possibly to the fact that there are no naturally occurring T cell surface molecules other than CD4 displayed on the surface of the r-CD4-CHO cells which, if present, might associate with the CD4 and by virtue of that association render certain CD4 epitopes inaccessible. We believe this increased likelihood as compared to isolated CD4 or fragments thereof to be due possibly to a more favorable conformation assumed by the CD4 on the surface of the r-CD4-CHO cells than that assumed by isolated CD4 and fragments thereof. Immunization may be accomplished using standard procedures. The unit dose and immunization regimen depend on the species of mammal immunized, its immune status, the body weight of the mammal, and the CD4 content of the CD4 preparation administered. Typically, the CD4 preparation will be administered with an adjuvant, such as complete or incomplete Freund's adjuvant. In the preferred embodiment, each dose of the CD4 preparation used for immunization of mice contains at least about 2 x 10 5 cells, preferably about 3 x 10 6 to 2 x 10 7 r-CD4-CHO cells. Most preferably, a unit dose contains about 5 x 10 6 r-CD4-CHO cells. Typically, the mouse is immunized intraperitoneally on day 0 with r-CD4-CHO cells in complete Freund's adjuvant. The mouse is given a first boost intraperitoneally with r-CD4-CHO cells without adjuvant, 14 days to 6 months after the initial immunization, and preferably 15 to 20 days after the first immunization. Additional boosts may be administered if desired. Three days before fusion, the final boost (r-CD4-CHO cells without adjuvant) is administered intravenously. Typically, this final boost is administered 1 to 6 months, and preferably 39-44 days, after the initial immunization. Three days after the final boost, the mammal is sacrificed, its spleen removed and the splenocytes (including lymphocytes) are prepared for fusion with the immortal cell line. The immunized mammals may be bled between boosts and the serum from each blood sample assayed for antibody homologs according to the present invention using the screening assays described above. The lymphocytes used in the production of hybridoma cells typically are isolated from immunized mammals whose sera have already tested positive for the presence of antibody homologs according to this invention. Any of the many well known protocols used for fusing lymphocytes and immortalized cell lines would be useful for the purpose of generating antibody homologs of this invention [see, e.g., G. Galfre et al., "Antibodies To Major Histocompatibility Antigens Produced By Hybrid Cell Lines", Nature. 266, pp. 550- 52 (1977); Gefter et al., Somatic Cell Genet. , supra; Lerner, Yale J. Biol. Med.. supra] . Moreover, the ordinary skilled worker will appreciate that there are many variations of such methods which also would be useful. Typically, the immortal cell line (e.g., a myeloma cell line) is derived from the same mammalian species as the lymphocytes. Useful mammals include mice and rats. Most preferably, both the immortal cell line and the lymphocytes are derived from an inbred mouse of strain BALB/c (Jackson Labs, Bar Harbour, ME) . Preferred immortal cell lines are mouse myeloma cell lines that are sensitive to culture medium containing hypoxanthine, aminopterin and thymidine ("HAT medium") . The most preferred mouse myeloma cell line is P3X63-AG8.653 (ATCC, Rockville, MD, catalog no. CRL 1580) . Typically, HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol ("PEG"), preferably PEG-3350. Hybridoma cells resulting from the fusion are then selected using HAT medium, which kills unfused and unproductively fused myeloma cells (unfused splenocytes die after several days because they are not transformed) . Hybridoma cells producing an antibody homolog (monoclonal antibody) according to the present invention are detected by screening the hybridoma culture supernatants using the screening assays described above. Preferably, the primary screen will select antibodies that bind to human CD4 displayed on the surface of CD4 + cells. Such binding is detected by use of fluorescently labelled secondary antibodies specific for mouse immunoglobulins, and quantified by FACS analysis. To produce antibody homologs of this invention which are intact monoclonal antibodies, hybridoma cells that have tested positive in the above screening assays are cultured in a nutrient medium under conditions and for a time sufficient to allow the hybridoma cells to secrete the monoclonal antibodies into the culture medium. Tissue culture techniques and culture media suitable for hybridoma cells are well known [see, e.g., Lerner, Yale J. Biol. Med.. supra] . Conditioned hybridoma culture supernatant containing the antibody homologs is collected. Alternatively, the desired antibody homolog may be produced by injecting the hybridoma cells into the peritoneal cavity of an unimmunized mouse. The hybridoma cells proliferate in the peritoneal cavity, secreting the antibody homolog, which accumulates as ascites fluid [see Lerner, Yale J. Biol. Med.. supra1. The antibody homolog is harvested by withdrawing the ascites fluid from the peritoneal cavity with a syringe. It will be understood by the ordinary skilled worker that monoclonal antibodies which are antibody homologs according to this invention may be purified with ease from conditioned hybridoma culture supernatant or from ascites. B. Recombinant Antibodies And DNA Encoding Them Antibody homologs according to the present invention may be recombinant monoclonal antibodies produced by host cells transformed with DNA encoding immunoglobulin light and heavy chains according to this invention. Recombinant antibodies may be produced by well known genetic engineering techniques. See, e.g., United States patent 4,816,397, which is incorporated herein by reference. For example, recombinant antibodies may be produced by cloning cDNA or genomic DNA encoding the immunoglobulin light and heavy chains of the desired antibody from a hybridoma cell that produces an antibody homolog according to this invention. The cDNA or genomic DNA encoding those polypeptides is then inserted into expression vectors so that both genes are operatively linked to their own transcriptional and translational expression control sequences. The expression vector and expression control sequences are chosen to be compatible with the expression host cell used. Typically, both genes are inserted into the same expression vector. This invention provides DNA sequences encoding the 5A8 light chain variable region (SEQ ID NO:14) and the 5A8 heavy chain variable region (SEQ ID NO:9), portions thereof that encode an antibody homolog according to this invention, and DNA sequences degenerate to any of those DNA sequences. Also provided are recombinant DNA molecules comprising one or more of the foregoing DNA sequences and one or more expression control sequences operatively linked thereto. Prokaryotic or eukaryotic cells may be used as expression hosts. Expression in eukaryotic host cells is preferred because such cells are more likely than prokaryotic cells to assemble and secrete a properly folded and immunologically active antibody. However, any antibody produced that is inactive due to improper folding may be renaturable according to well known methods [P. S. Kim and R. L. Baldwin, "Specific Intermediates In The Folding Reactions Of Small Proteins And The Mechanism Of Protein Folding", Ann. Rev. Biochem.. 51, pp. 459-89 (1982)]. It is possible that the host cells will produce portions of intact antibodies, such as light chain dimers or heavy chain dimers, which also are antibody homologs according to the present invention. It will be understood that variations on the above procedure are within the scope of the present invention. For example, it may be desired to transform a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an antibody homolog of this invention. Recombinant DNA technology may also be used to remove some or all of the DNA encoding either or both of the light and heavy chains that is not necessary for CD4 binding. The molecules expressed from such truncated DNA molecules are antibody homologs according to this invention. In addition, bifunctional antibodies may be produced in which one heavy and one light chain are antibody homologs of this invention and the other heavy and light chain are specific for an antigen other than CD4, or another epitope of CD4. c. Chimeric And Humanized Recombinant Antibodies And DNA Encoding Them DNA encoding the recombinant antibodies described above may be used as the starting point for producing chimeric or humanized.recombinant antibodies. Chimeric recombinant antibodies are produced by transforming a host cell with a suitable expression vector comprising DNA encoding the desired immunoglobulin light and heavy chains in which all or some of the DNA encoding the hinge and constant regions of the heavy and/or the light chain have been substituted with DNA from the corresponding region of an immunoglobulin light or heavy chain of a different species. When the original recombinant antibody is nonhuman, substitution of corresponding human sequences is preferred. An exemplary chimeric recombinant antibody has mouse variable regions and human hinge and constant regions. See generally, United States patent 4,816,397 and S. L. Morrison et al., "Chimeric Human Antibody Molecules: Mouse Antigen-Binding Domains With Human Constant Region Domains", Proc. Natl. Acad. Sci. USA. 81, pp. 6851-55 (1984). In the preferred 5A8 chimeric recombinant antibody homologs of this invention, the amino acid sequence of the light chain variable region is SEQ ID NO:15 and the amino acid sequence of the heavy chain variable region is SEQ ID NO:10, respectively. Humanized recombinant antibodies are produced by transforming a host cell with a suitable expression vector comprising DNA encoding the desired nonhuman immunoglobulin light and heavy chains in which all or some of the DNA encoding amino acids not involved in CD4 binding have been substituted with DNA from the corresponding region of a desired human immunoglobulin light or heavy chain. See generally, P. T. Jones et al. , "Replacing The Complementarity-Determining Regions In A Human Antibody With Those From A Mouse", Nature. 321, pp. 522-25 (1986). The most preferred humanized recombinant antibodies of this invention have the 5A8 complementarity determining regions ("CDRs") . These include humanized recombinant antibodies wherein: (a) light chain CDR1 is AA 24 ~AA 40 of SEQ ID NO:15; (b) light chain CDR2 is AA 56 -AA 62 of SEQ ID NO:15; (c) light chain CDR3 is AA„-AA, n , of SEQ ID NO:15; (d) heavy chain CDR1 is AA -AA 3 of SEQ ID NO:10; (e) heavy chain CDR2 is AA -AA-, of SEQ ID NO:10; and (f) heavy chain CDR3 is AA 99 -AA ι of SEQ ID NO:10. Another preferred embodiment provides humanized recombinant antibody homologs having 5A8 CDRs wherein the amino acid sequence of the light chain variable region is AA -AA of SEQ ID NO:56 and the amino acid sequence of the heavy chain variable region is AA 1 -AA 122 of SEQ ID NO:45. A further preferred embodiment provides humanized recombinant antibody homologs having 5A8 CDRs wherein the amino acid sequence of the light chain is AA -AA 2 of SEQ ID NO: 56 and the amino acid sequence of the heavy chain is AA -AA of SEQ ID NO:45. This invention provides DNA sequences encoding a pre-5A8 humanized light chain (SEQ ID NO:55) and a pre-5A8 humanized heavy chain (SEQ ID NO:44), portions of the foregoing DNA sequences that encode antibody homologs according to this invention, and DNA sequences degenerate to the foregoing DNA sequences. Also provided are recombinant DNA molecules comprising one or more of the foregoing DNA sequences and one or more expression control sequences operatively linked thereto. Preferred recombinant DNA molecules include pMDR1007 (pre-5A8 humanized light chain) and pMDR1002 (pre-5A8 humanized heavy chain) , deposited with the American Type Culture Collection, Rockville, MD, under accession numbers ATCC 68846 and ATCC 68847, respectively. D. Antibody Homologs According To This Invention That Are Not Intact Antibodies The present invention also provides antibody homologs that are not intact antibodies. Such homologs may be derived from any of the antibody homologs described above. For example, antigen-binding fragments, as well as full-length monomeric, dimeric or trimeric polypeptides derived from the above-described antibodies are themselves antibody homologs according to the present invention. Useful antibody homologs of this type include Fab fragments. Fab' fragments, F(ab') fragments, F(v) fragments, heavy chain monomers or dimers, light chain monomers or dimers, dimers consisting of one heavy and one light chain, and the like. We believe that the foregoing fragments, other than Fab fragments of 5A8, generally are useful antibody homologs according to the present invention. Antibody fragments may be produced by chemical methods, e.g., by cleaving an intact antibody with a protease, such as pepsin or papain, and optionally treating the cleaved product with a reducing agent. Alternatively, useful fragments may be produced by using host cells transformed with truncated heavy and/or light chain genes. Heavy and light chain monomers may be produced by treating an intact antibody with a reducing agent, such as dithiothreitol, followed by purification to separate the chains. Heavy and light chain monomers may also be produced by host cells transformed with DNA encoding either the desired heavy chain or light chain, but not both. See, e.g., E. S. Ward et al., "Binding Activities Of A Repertoire Of Single Immunoglobulin Variable Domains Secreted From Escherichia coli". Nature. 341, pp. 544-46 (1989); L. Sastry et al., "Cloning Of The Immunological Repertoire in Escherichia coli For Generation Of Monoclonal Catalytic Antibodies: Construction Of A Heavy Chain Variable Region-Specific cDNA Library", Proc. Natl. Acad. Sci. USA. 86, pp. 5728-32 (1989). Derivatized Antibody Homologs According To This Invention In one embodiment, this invention provides derivatized antibody homologs in which any of the antibody homologs of this invention are functionally linked (by chemical coupling, genetic fusion or otherwise) to one or more members independently selected from the group consisting of antibody homologs of this invention, 5A8-mimetic agents of this invention, detectable agents, cytotoxic agents and pharmaceutical agents. One type of derivatized antibody homolog is produced by crosslinking two or more antibody homologs (of the same type or of different types) . Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate) . Such linkers are available from Pierce Chemical Company, Rockford, IL. Useful detectable agents include fluorescent compounds. Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-l-napthalenesulfonyl chloride, phycoerythrin and the like. The antibody homologs of this invention may also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, glucose oxidase and the like. When the antibody homolog is derivatized with a detectable enzyme, it is detected by adding additional reagents that the enzyme uses to produce a detectable reaction product. For example, when the detectable agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine leads to a colored reaction product, which is detectable. The antibody homolog may also be derivatized with biotin, and detected through indirect measurement of avidin binding. The present invention also provides antibody homologs linked to one or more pharmaceutical agents. Useful pharmaceutical agents include biologically active peptides, polypeptides and proteins, such as antibody homologs specific for a human polypeptide other than CD4. Other useful pharmaceutical agents include non-proteinaceous pharmaceutical agents such as HIV reverse transcriptase inhibitors (e.g., 3*-azido-2' ,3•-dideoxythymidine ("AZT") and 2' ,3'-dideoxyinosine ("DDI") and other antiviral compounds, or immunosuppressive agents (e.g., cyclosporin or FK506) . Cells That Produce Antibody Homologs According To The Present Invention The present invention also provides cells and cell cultures that produce the antibody homologs of this invention. Such cells include hybridoma cells that produce monoclonal antibodies which are antibody homologs of this invention, as well as transformed host cells that produce recombinant antibody homologs of this invention. Preferred cells according to this invention include those that produce the monoclonal antibodies referred to herein as "5A8", "1F8" and "5F2". The most preferred cell line produces monoclonal antibody 5A8. The hybridoma cell lines producing 5A8, 1F8 and 5F2 were deposited in the In Vitro International, Inc. culture collection in Linthicum, MD, under accession numbers IVI-10257, IVI-10258 and IVI-10259, respectively and transferred to the American Type Culture Collection, Rockville, MD, under accession numbers HB 10881, HB 10882 and HB 10883, respectively. Other preferred cells are host cells producing the 5A8 chimeric and humanized recombinant antibodies described supra. Eukaryotic host cells transformed with pMDR1007 (pre-5A8 humanized light chain) and pMDR1002 (pre-5A8 humanized heavy chain) are most preferred for producing 5A8 humanized antibodies. Moreover, the present invention provides a method of producing the antibody homologs of the present invention by culturing the cells of this invention, which produce the antibody homologs. Methods of culturing such cells and isolating the antibody homologs they produce are well known. These methods include tissue culture techniques, as well as the generation of ascites. Also provided is a method for producing cells of this invention which are hybridoma cells, comprising the step of immunizing a nonhuman mammal with CD4 + cells produced by transforming CD4 " mammalian tissue culture cells with DNA encoding full-length human CD4, which cells express the CD4 on their surface. Preferred cells to be used as an immunogen for this process are the r-CD4-CHO cells described above. 5A8-Mimetic Agents The present invention provides 5A8-mimetic agents, which are compounds that cause at least a 30% reduction in the binding of monoclonal antibody 5A8 either to human rsCD4 or to human CD4 displayed on the surface of a CD4 + cell. 5A8-mimetic agents may be peptides, semi-peptidic compounds or non-peptidic compounds. Preferred 5A8-mimetic agents inhibit HIV- induced syncytia formation between CD4 + cells, inhibit infection of CD4 + cells by HIV, or both. The most preferred 5A8-mimetic agents display the properties of one or more antibody homologs of this invention. 5A8-mimetic agents of this invention may be produced by synthesizing a plurality of peptides (e.g., 5-20 amino acids in length) , semi-peptidic compounds or non-peptidic, organic compounds, and then screening those compounds for their ability (1) to cross block with 5A8 for binding to human CD4, (2) to inhibit HIV- induced syncytia formation between CD4 + cells, and (3) to inhibit infection of CD4 + cells by HIV. See generally United States patent 4,833,092, J. K. Scott and G. P. Smith, "Searching For Peptide Ligands With An Epitope Library", Science. 249, pp. 386-90 (1990), and J. J. Devlin et al., "Random Peptide Libraries: A Source Of Specific Protein Binding Molecules", Science. 249, pp. 404-07 (1990), which are herein incorporated by reference. Pharmaceutical Compositions And Methods According To This Invention The antibody homologs and the 5A8-mimetic agents of this invention are useful in prophylactic and therapeutic compositions for preventing and treating diseases caused by infective agents whose primary targets are CD4 + lymphocytes. Such diseases include AIDS, ARC and HIV infection. Preferred pharmaceutical compositions of this invention for administration to humans include, as antibody homologs, one or more of the mouse monoclonal antibodies 5A8, 1F8 or 5F2, 5A8 mouse/human chimeric recombinant antibodies, 5A8 humanized recombinant antibodies or antigen-binding portions of those antibodies. Pharmaceutical compositions comprising 5A8 mouse/human chimeric recombinant antibodies or 5A8 humanized recombinant antibodies are most preferred. The pharmaceutical compositions of this invention may further comprise other therapeutics for the prophylaxis or treatment of AIDS, ARC and HIV infection. For example, the antibody homologs of this invention may be used in combination with anti- retroviral agents that block reverse transcriptase, such as AZT, DDI, HPA-23, phosphonoformate, suramin, ribavirin and dideoxycytidine, or with agents that inhibit the HIV protease. Additionally, the pharmaceutical compositions of this invention may further comprise anti-viral agents such as interferons, including alpha interferon, beta interferon and gamma interferon, or glucosidase inhibitors such as castanospermine, or immunosuppressive agents such as adrenal corticosteroids, azathrioprine, cyclosporin or FK506. Moreover, the antibody homologs of this invention may advantageously be administered in combination with agents that significantly block binding of HIV gpl20 to CD4. Such agents include, for example, anti-CD4 antibodies that are Vl-specific (e.g. , Leu3A) , CD4 VI polypeptides and antibodies (anti-idiotypic or otherwise) specific for HIV gpl20. Furthermore, one or more antibody homologs or 5A8-mimetic agents may be used in combination with two or more of the foregoing therapeutic agents. Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies. The pharmaceutical compositions of this invention comprise an immunotherapeutically effective amount of one or more antibody homologs or 5A8-mimetic agents according to this invention, or derivatized form(s) thereof and, preferably, a pharmaceutically acceptable carrier. By "immunotherapeutically effective amount" is meant an amount capable of lessening the spread, severity or immunocompromising effects of AIDS, ARC or HIV infection, or of other diseases caused by infective agents whose primary targets are CD4 + lymphocytes. By "pharmaceutically acceptable carrier" is meant a carrier that does not cause an allergic reaction or other untoward effect in patients to whom it is administered. Suitable pharmaceutically acceptable carriers include, for example, one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody homolog or 5A8-mimetic agent. The compositions of this invention may be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, pills, powders, liquid solutions, dispersions or suspensions, liposomes, suppositories, in ectable and infusible solutions. The preferred form depends on the intended mode of administration and therapeutic application. The preferred compositions are in the form of injectable or infusible solutions. The preferred pharmaceutical compositions of this invention are similar to those used for passive immunization of humans with other antibodies. The preferred mode of administration is parenteral. It will be apparent to those of skill in the art that the immunotherapeutically effective amount of antibody homolog or 5A8-mimetic agent of this invention will depend, inter alia, upon the administration schedule, the unit dose of antibody homolog or 5A8-mimetic agent administered, whether the antibody homolog or 5A8-mimetic agent is administered in combination with other therapeutic agents, the immune status and health of the patient, and the therapeutic activity of the particular antibody homolog or 5A8-mimetic agent administered. In monotherapy for treatment or prophylaxis of HIV infection, ARC or AIDS, immunotherapeutically effective amounts per unit dose of an antibody homolog which is an intact antibody range from about 0.1 to 10 mg/kg patient weight, preferably 2 mg/kg patient weight. Unit doses should be administered from twice each day to once every two weeks until an antiviral effect is observed, preferably once every two weeks. The antiviral effect may be measured by a variety of methods, including viral load, lymphocyte counts and clinical signs and symptoms. It will be recognized, however, that lower or higher dosages and other administration schedules may be employed. Treatment regimens for antibody homologs that are not intact antibodies and for 5A8-mimetic agents may differ, depending on their size and pharmaceutical properties. In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only, and are not to be construed as limiting the scope of the invention in any manner. EXAMPLES Production And Initial Screening Of Antibody Homologs Of This Invention The immunogen used to generate monoclonal antibodies 1F8, 5A8 and 5F2 was CHO cells transformed with DNA encoding full-length human CD4 expressed on the cell surface ("r-CD4-CHO cells") . The CD4 sequence used to transform the CHO cells is set forth in Maddon et al. , Cell, supra. These cells are described in R. A. Fisher et al., "HIV Infection Is Blocked In Vitro By Recombinant Soluble CD4", Nature, 331, pp. 76-78 (1988) , and were deposited with the In Vitro International, Inc. culture collection, Linthicum, MD, under accession number IVI-10260 and transferred to American Type Culture Collection, Rockville, MD, under accession number CRL 10884. The r-CD4-CHO cells were maintained at 37°C, under 5% CO , in a ' MEM media (Gibco, Grand Island, NY) supplemented with 10% dialyzed fetal calf serum ("FCS") (North American Biologies, Miami, FL, cat. no. 33189) and 30 nM methotrexate. Cells were prepared for injection by substituting the above culture medium with phosphate buffered (Ca + - and Mg + -free) saline ("PBS") supplemented with 5 mM EDTA, and harvesting the cells in that buffer. The harvested cells were pelleted by centrifugation at 500 x g for about 5 minutes, washed once by resuspending the pellet in PBS and centrifuging as before, counted, and adjusted to the appropriate volume for injection by resuspending the cell pellet in PBS. Two female BALB/c J mice, about 4-6 weeks old (Jackson Labs, Bar Harbour, ME) , were immunized with r- CD4-CH0 cells as follows. The first mouse was primed intraperitoneally (i.p.) on day 0 with a 1:1 emulsion of r-CD4-CHO cells in PBS with complete Freunds adjuvant ("CFA") (Colorado Serum Co., Denver, CO, cat. no. C51450) , boosted i.p. on day 20 with r-CD4-CH0 cells in PBS without adjuvant, and finally boosted intravenously on day 44 with r-CD4-CHO cells in PBS, without adjuvant. The other mouse was primed i.p. on day 0, boosted i.p. on day 15, and finally boosted intravenously on day 39 (all injections with r-CD4-CHO cells in PBS, without adjuvant) . For both mice, each injection contained approximately 3 x 10 6 to 2 x 10 7 r-CD4-CHO cells in a volume of approximately 250 μl. Three days after the last injection, both mice were sacrificed and each spleen was removed and placed in approximately 5 ml of serum-free DMEM (Gibco, cat. no. 430-2100) in a petri dish. The splenic capsules were cut and the spleen cells were teased out into the medium. The spleen cell suspensions were transferred to one 15 ml conical bottom tube and allowed to settle for about 5 minutes. The supernatant was removed to a fresh 15 ml conical bottom tube and placed in an incubator (37°C, 5% C0 2 ) until the fusion. The spleen cells from both mice were pooled. A 5-ml single cell suspension of control spleen feeder cells was prepared from an unimmunized mouse essentially as described above for the immunized spleen cells, and placed in an incubator (37°c, 5% CO ) until needed. The fusion partner for the immunized spleen cells was a hypoxanthine/aminopterin/thymidine ("HAT")- sensitive, non-secreting mouse myeloma cell line — P3X63-AG8.653 (ATCC, Rockville, MD, cat. no. CRL 1580). Prior to the fusions, the P3X63-AG8.653 cells were maintained in DMEM/10% FCS (37°C, 5% CO ) , ensuring that they were in a logarithmic growing phase on the day of the fusions. The fusion protocol used was a hybrid of the protocols set forth in Lerner, Yale J. Biol. Med.. supra and Gefter et al. , Somatic Cell Genet.. supra. Specifically, immediately before the fusions, the pooled spleen cells prepared as described above were washed three times with PBS, resuspended in approximately 10 ml of PBS and counted. Also immediately before fusion, the logarithmic phase P3X63- AG8.653 cells were washed three times with PBS and counted. The myeloma cells were resuspended to 1 X 10 7 cells/ml in PBS. For each fusion, 1.5 x 10 8 spleen cells were mixed with 3 x 10 7 myeloma cells in a 50 ml conical bottom polypropylene tube, and the cells were washed once with PBS. The ratio of spleen cells to myeloma cells was 5:1. The tubes were centrifuged at 500 x g for 5 minutes to pellet the cells. After aspiration of the supernatants, the pellets were gently resuspended by tapping the bottom of the tubes. The tubes were then placed in a beaker of 37°C water. All subsequent fusion steps were carried out in this beaker. Next, 0.8 ml of 37°C fusion medium (50 w/v % polyethylene glycol 3350 ("Baker" grade from J.T. Baker Co., Phillipsburg, NJ) in serum-free DMEM was slowly added to each cell pellet over the course of about 1 minute, while gently rocking the tube. One ml serum- free DMEM was added dropwise to each pellet over the course of another minute, and then 20 ml serum-free DMEM was added to each pellet over the next 5 minutes. Both tubes were centrifuged at 600 x g for 10 minutes at room temperature, and the supernatants were aspirated. Fifty ml of "HAT selection medium" containing 400 μl of the 5-ml suspension of control spleen feeder cells (prepared as described above) were added stepwise to each pellet, with occasional mixing. "HAT selection medium" was prepared by diluting a 50x HAT stock (Sigma Chemical Co., St. Louis, MO, cat. no. H-0262) 50-fold in DMEM/10% FCS (final concentrations: 10 μM hypoxanthine, 0.4 μM aminopterin, 16 μM thymidine) . Each 50-ml cell suspension was plated into 5 96-well flat-bottom microtiter plates, with -100 μl/well. The plates were kept in an incubator at 37°C, 5% CO . On day 2 post-fusion, the cells were fed by addition of 100 μl HAT selection medium per well. On day 10 post-fusion, the medium was aspirated and 200 μl HAT selection medium was added to each well. Supernatants were withdrawn for primary screening on days 12, 14, 16 and 19 post-fusion, from wells containing clones. The fusion efficiency was 34% (327 out of 960 possible wells developed clones that were screened) . The primary screen used was a radioimmunoassay (RIA) designed to detect antibodies that bind to human rsCD4. To perform the RIA, affinity-purified goat anti-mouse IgG (F fragment-specific) (Cappell, Cochranville, PA, cat. no. 22950) in PBS was added to 96-well PVC microtiter plates (50 μl/well) and incubated overnight at 4°C. The goat anti-mouse IgG was removed from the plates and the wells were blocked with 100 μl/well of 5% FCS/PBS for 1 hour at room temperature. After removing the blocking solution, neat hybridoma culture supernatant was added to the wells (50 μl/well) and incubated 1 hour at room temperature. The plates were washed 3 times with PBS/0.05% Tween-20. Next, 50 μl 125 I-rsCD4 (-20,000 cpm) in PBS/5% FCS (prepared as described below) was added to each well, and incubated 1 hour at room temperature. Finally, the wells were washed 3 times with PBS/0.05% Tween-20. After flicking out all the wash buffer, the wells were separated by cutting the plates and analyzed in a gamma counter. Wells to which 5% FCS/PBS had been added instead of culture supernatant served as background wells. The 125 l-rsCD4 used in the primary screening assay consisted of purified, 125 I-labelled human CD4 AA -AA„ of the CD4 sequence set forth in Maddon et al. , Cell, supra (i.e., human CD4 AA -AA according to the corrected numbering system of Littman et al. , Cell, supra) . The rsCD4 was produced by transformed CHO cells substantially as described in Fisher et al. , Nature. supra. The rsCD4 produced by those cells may be purified as described in Fisher et al. , Nature. supra. The purified rsCD4 was labelled with 125 I according to the Bolton-Hunter method, substantially as described by the supplier of the Bolton-Hunter reagent (New England Nuclear, Boston, MA) . The quality of the 125I-rsCD4 was routinely monitored by confirming that the labelling procedure did not destroy the epitopes recognized by the commercially available CD4 Vl- specific monoclonal antibodies Leu3A (Becton Dickinson, Mountain View, CA, cat. no. 7326) and OKT4A (Ortho Diagnostic Systems, Raritan, N.J., cat. no. 7124) and the CD4 V3V4-specific monoclonal antibody OKT4 (Ortho Diagnostic Systems, cat. no. 7024) . Clones were considered to be positive on primary screening if they were approximately 10-fold over background in the RIA. By this criterion, approximately 6% of the clones (21) were positive. The 21 positive clones were pulled and expansion was attempted; 13 clones survived expansion and were stored frozen. Many of these 13 clones were successfully subcloned, including 1F8, 5A8 and 5F2. Expansion, subcloning and freezing of the cells was conducted substantially as described in Lerner, Yale J. Biol Med.. supra. The 13 positive clones isolated after primary screening were subjected to the battery of tests described below. Based on those assays, we identified three hybridoma cell lines that produced antibody homologs according to the present invention — 1F8, 5A8 and 5F2. The results of the screening assays for clones 1F8, 5A8 and 5F2 are discussed below. The data for the other 10 antibodies are not shown. The first secondary screen we conducted was designed to determine whether the antibodies recognized native CD4 epitopes. This was accomplished by FACS analysis of cell surface CD4 displayed on CD4 + Jurkat cells and r-CD4-CHO cells stained with the monoclonal antibodies, visualizing binding with fluorescently labelled goat anti-mouse second antibody, substantially as described below. All 13 antibodies recognized cell surface CD4. Next, to localize the CD4 epitopes bound by our antibodies, we conducted competition assays as described below with a CD4 VI polypeptide and a CD4 V1V2 polypeptide, with commercially available CD4 Vl- specific and CD4 V3V4-specific antibodies, and with HIV gpl20. Many of the antibodies were then also assessed for their ability to inhibit HIV-induced syncytia formation between CD4 + cells and infection of CD4 + cells by HIV, as well as for their immunosuppressive activity in an in vitro tetanus toxoid-specific proliferation assay. Based on the competition assays, we determined that of the 13 positive clones, 3 secreted CD4 Vl-specific antibodies, 5 secreted antibodies that were CD4 V3V4-specific, and 5 secreted antibodies that were CD4 V1V2-specific. Of the CD4 VlV2-specific antibodies, only three — 1F2, 5A8 and 5F2 — did not significantly block HIV gpl20 binding to CD4. In a single fusion performed after immunization of a mouse with human rsCD4, none of the hybridomas was found to produce an antibody that was an antibody homolog of this invention, although other anti-CD4 monoclonal antibodies were produced. We believe that anti-CD4 antibody homologs according to this invention may be generated by immunization with rsCD4; however, using r-CD4-CHO cells as the immunogen increases the likelihood of obtaining such antibodies. Specificity For CD4 VI And CD4 V1V2 Polypeptides In order to characterize the CD4 epitopes recognized by the antibody homologs of this invention, we determined whether several antibody homologs recognized an epitope in the V1V2 region of human CD4, or an epitope defined solely by the CD4 VI region. Specifically, we studied the ability of polypeptides consisting of AA -AA and/or AA -AA of human CD4 ("CD4-V1") and AA -AA -on of human CD4 ("CD4-V1V2") to inhibit binding of human rsCD4 to three anti-CD4 antibody homologs of this invention (monoclonal antibodies 1F8, 5A8, and 5F2) , two CD4 Vl-specific monoclonal antibodies (Leu3A and OKT4A) and a CD4 V3V4- specific monoclonal antibody (OKT4) . Briefly, an RIA was performed in which each microtiter plate well was coated with an anti-mouse Ig, blocked, and then incubated with one of the hybridoma culture supernatants being tested. Next, a mixture of CD4-V1 or CD4-V1V2 and 125 I-rsCD4 was added. After incubation, the wells were washed and the bound 125 ι- rsCD4 was detected in a gamma counter. Specifically, microtiter plates (96-well) were coated overnight at 4°C with 50 μl/well of affinity-purified goat anti-mouse IgG (Fc fragment- specific) (Cappell) . Wells were washed 3 times with PBS/0.05% Tween-20, and then blocked by incubating 1 hour with 100 μl/well of 5% FCS/PBS. After removing the blocking buffer, the wells were incubated 1 hour at room temperature with 50 μl/well neat hybridoma culture supernatant (5-20 μg/ml Ig) . The control wells were incubated with 50 μl/well OKT4 (10 μg/ml in PBS/5% FCS) , OKT4A (500 ng/ml in PBS/5% FCS) or Leu3A (500 ng/ml in PBS/5% FCS) . The plates were washed 3 times with PBS/0.05% Tween-20. CD4-V1 and CD4-V1V2 (final concentrations 5 μg/ml) were separately pre- incubated with approximately 20,000 cpm 125 I-rsCD4 (prepared as described above) , for approximately 35-45 minutes at room temperature. Those pre-incubated mixtures were then incubated in the wells for 1-2 hours at room temperature. Following the incubation, the wells were washed 3 times with PBS/0.05% Tween-20 and then counted for radioactivity. The CD4-V1 used in this experiment consisted of AA 3 ~AA and/or AA -AA 3 of the CD4 sequence set forth in Figure 16 of PCT patent application PCT/US88/02940, which correspond respectively to CD4 AA -AA- 3 and AA 1 ~AA 111 according to the corrected numbering system of Littman et al.. Cell, supra. These CD4 VI polypeptides were produced and purified as described in B. H. Chao et al. , "A 113-Amino Acid Fragment Of CD4 produced In Escherichia coli Blocks Human Immunodeficiency Virus-Induced Cell Fusion", J. Biol. Chem.. 264, pp. 5812-17 (1989). The CD4-V1V2 used in this experiment consisted of AA 3 -AA _ of the CD4 sequence set forth in Figure 16 of PCT patent application PCT/US88/02940, which corresponds to CD4 AA -AA 8 _ according to the corrected numbering system of Littman et al., Cell. supra. The CD4 V1V2 polypeptide was bacterially produced using standard molecular biology techniques, in a manner analogous to the protocol used for production of the CD4 VI polypeptide described in Chao et al., J. Biol. Chem.. supra. A plasmid carrying DNA encoding the CD4 V1V2 polypeptide was transfected into E. coli, strain A89 [S. A. Goff et al., "Heat Shock Regulatory Gene htpR Influences Rates of Protein Degradation And Expression Of The Ion Gene In Escherichia coli". Proc. Natl. Acad. Sci. USA. 81, pp. 6647-51 (1984)]. The cells were fermented under standard conditions in a 10-liter fermenter, harvested using a Pelikon concentration system followed by centrifugation at 3000 rpm in a Beckman J-6M centrifuge. The cell pellet was stored frozen at -20°C until use. To purify the CD4-V1V2, the cells were thawed and suspended in 8 ml buffer (20 mM Tris-HCl, pH 7.7/1 mM Na 2 EDTA) per gram wet cell weight. The cells were broken by 3 passes through a french press. The insoluble material containing the CD4-V1V2 was pelleted by centrifugation. The pellets were washed 3 times with 1 M urea/15 mM sodium acetate, pH 5.5 (15- 20 ml per gram wet cell weight) , followed by 2 washes with 20 mM Tris-HCl, pH 7.7/1 mM Na 2 EDTA. The resulting washed pellet was extracted overnight at room temperature with 25 ml per gram of wet cell weight using 6 M guanidine-HCl/10 mM DTT/20 mM Tris-HCl, pH 7.7. The extract was clarified by centrifuging at 48,000 x g for 45 minutes at room temperature. To renature the CD4-V1V2, the clarified extract was diluted 1:60 v/v into cold (4°C) 20 mM Tris-HCl, pH 7.7, and bovine serum albumin ("BSA") was added to a final concentration of 0.5 mg/ml. All subsequent steps were performed at 4°C. The pH was lowered to 7.0 with 6 N HCl, and the suspension was clarified by passage through a 5 micron hydrophilic Minidisk filter (Millipore, Bedford, MA, cat. no. MCSC 40S 01) followed by passage through a Durapore 0.2 micron filter (Millipore, cat. no. CVGL 01T P3) . The clarified preparation was loaded onto an S-Sepharose Fast Flow column (Pharmacia LKB Biotechnology, Inc. , Piscataway, NJ) , pre-equilibrated with 20 mM Tris-HCl, pH 7.0, at a ratio of 1 volume S-Sepharose Fast Flow gel per 100 volumes load. The column was washed with 20 mM Tris-HCL, pH 7.0, and the bound proteins were eluted with 20 mM Tris-HCl, pH 7.7/300 mM NaCl. The eluate pool containing the CD4-V1V2 was diluted with an equal volume of 20 mM Tris-HCl, pH 7.7, and then loaded onto an anti-CD4 monoclonal antibody affinity column (described below) , pre-equilibrated with 20 mM Tris-HCl, pH 7.7/150 mM NaCl. The column was washed with 20 mM Tris-HCl, pH 7.7/150 mM NaCl followed by 20 mM Tris-HCl, pH 7.7/1 M NaCl. The bound proteins were eluted with 50 mM glycine/250 mM NaCl, pH 3.0. The eluted material was dialyzed into 20 mM HEPES, pH 6.8, and concentrated on a PM 10 membrane in an A icon ultrafiltration cell. The purified, concentrated CD4-V1V2 (approximately 0.5 - 3.0 mg/ml) was stored at -70°C until use. The anti-CD4 monoclonal antibody affinity column was prepared using one of the CD4 Vl-specific monoclonal antibodies produced from the fusions described above. The monoclonal antibody was purified from ascites by ammonium sulfate fractionation and anion exchange chromatography, concentrated by ultrafiltration, dialyzed into 0.1 M sodium borate (pH 8.0)/0.5-M sodium chloride, -and concentrated again by ultrafiltration to a concentration of approximately 5 mg/ml. The purified anti-CD4 monoclonal antibody (10 ml containing approximately 50 mg protein) was coupled to 4 g of CNBr-Sepharose according to the manufacturer's directions (Sigma Chemical Co., cat. no. C9142) , yielding 12 ml of derivatized resin. The results of these experiments are summarized in Tables I and II. * Because of the standard deviations encountered in assays of this type, we consider this figure to indicate that CD4-V1 caused no real inhibition of rsCD4 binding to the anti-CD4 monoclonal antibody indicated. * Because of the standard deviations encountered in assays of this type, we consider this figure to indicate that CD4-V1V2 caused no real inhibition of rsCD4 binding to the anti-CD4 monoclonal antibody indicated. The data displayed in Tables I and II demonstrate that monoclonal antibodies 1F8, 5A8 and 5F2 do not bind to a polypeptide consisting of human CD4 VI, and do bind to a polypeptide consisting of human CD4 V1V2. Cross Blocking With 5A8 and With Antibodies That Are CD4 Vl-Specific and CD4 V3V4-Specific To characterize further the CD4 epitopes recognized by the antibody homologs of this invention, we performed cross blocking experiments for rsCD4 with an antibody homolog, 5A8, and two CD4 Vl-specific antibodies (OKT4A and Leu3 ) , as well as with a CD4 V3V4-specific antibody (0KT4) . We also performed similar cross blocking experiments between 5A8 and other antibody homologs of this invention. In addition, we performed a cross blocking experiment with Leu3A and 5A8 for native CD4 displayed on the surface of human peripheral blood lymphocytes. The results of these cross blocking experiments are displayed in Tables III and IV, and in Figure 1. For the rsCD4 cross blocking experiment presented in Table III, an RIA was performed substantially as described above for the CD4-V1 and CD4-V1V2 crossblocking experiments. Specifically, each microtiter plate well was coated with anti-mouse Ig, blocked, and then incubated with 5A8 culture supernatant (5-20 μg/ml) , OKT4A (500 ng/ml) , OKT4 (10 μg/ml) or Leu3A (500 ng/ml) . The wells were then washed, and blocked with the 100 μl/well mouse Ig (50 μg/ml) in PBS for 30 minutes to 1 hour at room temperature. Competitor antibody (i.e., OKT4A, OKT4 or Leu3A at twice the above concentrations) was pre-m . cubated wi.th 125I-rsCD4, and each mixture was added to the wells at 50 μl/well. After incubating 1 hour at room temperature, the wells were washed and the bound 125I-rsCD4 was quantified i•n a gamma counter. Table III lists the percent inhibition of binding of I-rsCD4 to the immobilized antι-CD4 antibodies 5A8, 0KT4, 0KT4A and Leu3A by the soluble anti-CD4 antibodies Leu3A, OKT4A and OKT4. TABLE III Leu 3A, OKT4A and OKT4 Cross Blocking: Anti-CD4 onoclonal Antibodies Preincu a ed In olution With r CD4 * Because of the standard deviations encountered in assays of this type, we consider this figure to indicate that the anti-CD4 monoclonal antibody indicated at the top of the column caused no real inhibition of rsCD4 binding to the indicated anti-CD4 monoclonal antibody for that row. The data displayed in Table III demonstrate that Leu3A, OKT4A and OKT4 do not significantly block binding of rsCD4 to 5A8. These results imply that 5A8 recognizes different CD4 epitope(s) than those recognized by Leu3 , OKT4A and OKT4. For the rsCD4 cross blocking experiment presented in Table IV, an RIA was performed substantially as described above for the experiment presented in Table III, except that only 5A8 was immobilized, and the soluble competitor antibodies were 1F8 (5-20 μg/ml) , 5A8 (5-20 μg/ml) , 5F2 (-5 μg/ml) , OKT4 (10 μg/ml) and Leu3A (500 ng/ml) . In addition, the 125 I-rsCD4 used .in this experiment consisted of purified, 125 I-labelled human CD4 A 3 -AA 37? of the CD4 sequence set forth in Figure 16 of PCT patent application PCT/US88/02940 (rather than the sequence set forth in Maddon et al. , Cell, supra) . which corresponds to CD4 AA -AA according to the corrected numbering system of Littman et al., Cell, supra. Table IV lists the percent inhibition of binding of 125 I-rsCD4 to immobilized 5A8 by the soluble anti-CD4 antibodies 1F8, 5F2, 5A8, OKT4 and Leu3A. TABLE IV 5A8 Cross Blocking: Anti-CD4 Monoclonal Antibodies Pr b ted In Solution With rsCD4 The data displayed in Table IV demonstrate that 1F8 and 5F2 block binding of rsCD4 to 5A8, implying that 5A8, 1F8 and 5F2 recognize the same, overlapping, or proximate CD4 epitope(s) . Figure 1 displays the results of the cell surface CD4 cross blocking experiment. Human peripheral blood lymphocytes ("PBLs") were incubated with buffer (Figure IA) , Leu3A (Figure IB) , OKT4A (Figure IC) , 0KT4 (Figure ID) or 5A8 (Figure IE) . The cells then were washed and incubated with Leu3A labelled with fluorescein isothiocyanate ("Leu3A- FITC") . After washing again, the cells were analyzed using a FACStar fluorescence activated cell sorter. The results of the this FACS analysis are depicted in Figure 1. The data demonstrate that 5A8 does not significantly block binding of the Vl-specific antibody Leu3A to cell surface CD4. The protocol for this experiment follows. Specifically, human PBLs were isolated by diluting 10 ml blood two-fold with unsupplemented RPMI- 1640 media and layering the mixture over 10 ml of Lymphocyte Separation Media (Organon Teknika, Durham, NC, cat. no. 36427) in a 50-ml tube at room temperature. The tube was centrifuged at room temperature for 30 minutes at 400 x g . PBLs were collected from the interface, washed two times with unsupplemented RPMI-1640 media and counted. For each sample, 3 x 10 5 PBLs were suspended in 50 μl of staining buffer (PBS/1% BSA/0.02% sodium azide) per tube and washed one time with staining buffer. The staining buffer was aspirated from the pelleted cells, and antibody reagent was added to each pellet. For 5A8, the antibody reagent was 50 μl conditioned hybridoma cell culture supernatant containing approximately 5-20 μg/ml 5A8. The antibody reagents for the control antibodies were 2.5 μg/ml solutions in staining buffer: 60 μl/tube Leu3A; 30 μl/tube OKT4A; 30 μl/tube OKT4. As an additional control, one cell sample received 50 μl of staining buffer without antibody. Samples were incubated for 30 minutes on ice, then washed three times in 1 ml volumes of staining buffer. Next, 66 μl of FITC-conjugated Leu3A (Becton Dickinson, cat. no. 7323) was added at a 1:10 dilution in staining buffer; then the samples were incubated for 20 minutes on ice, washed two times and analyzed on a FACStar fluorescence activated cell sorter (Becton Dickinson Immunocytometry Systems, Mountain View, CA) . HIV gpl20 Cross Blocking We used two approaches to determine whether antibody homologs of this invention block binding of HIV gpl20 to human CD4 — an RIA using human rsCD4 and FACS analysis with human CD4 + tissue culture cells. The soluble, recombinant, HIV gpl20 ("r-gpl20") used in these assays was produced using a baculovirus vector/insect cell culture system. The vector used to transfer the truncated HIV-1 gpl20 gene into Autographa californica nuclear polyhedrosis virus (baculovirus) was a derivative of vector pAc373 [G. E. Smith et al., "Modification And Secretion Of Human Interleukin 2 Produced In Insect Cells By A Baculovirus Expression Vector", Proc. Natl. Acad. Sci. USA. 82, pp. 8404-08 (1985)]. DNA sequences encoding the signal peptide and pro-peptide of human tissue plasminogen activator and a C-terminal methionine were ligated in-frame to HIV-1 DNA sequences encoding AA -AA of gpl60 (see SEQ ID NO:l and SEQ ID NO:2), followed by DNA encoding leucine and serine (SEQ ID NO:3), in the pAc373 vector. The resulting vector and wild type baculovirus were cotransfected into Spodoptera frugiperda (sf9) cells, and the recombinant baculovirus expressing the two HIV r-gpl20 polypeptides was isolated according to the methods described in M. D. Summers and G. E. Smith, in A Manual Of Methods For Baculovirus Vectors And Insect Cell Culture Procedures r Texas Agricultural Experiment Station Bulletin No. 1555. Recombinant viruses were identified by their ability to produce a protein that could be specifically immunoprecipitated by HIV-1 antisera. Expression of SEQ ID NO:3 in the Spodoptera frugiperda cells resulted in production of two different r-gpl20 polypeptides: 70% of the polypeptides extended from AA 33 to AA 4g8 of SEQ ID NO:4 and 30% of the polypeptides extended from AA 23 to AA _ of SEQ ID NO:4. All purification steps were performed at 4°C. The conditioned insect cell culture supernatant was clarified by filtration through a Millipore Durapore hydrophilic 2 micron filter cartridge. The clarified filtrate was diluted with an equal volume of 40 mM MES, pH 5.5 and loaded onto an S-Sepharose Fast Flow column (pre-equilibrated with 20 mM MES, pH 5.5) at a ratio of l ml resin per 100 ml conditioned culture supernatant. The column was washed with 20 mM MES, pH 5.5, followed by 20 mM Tris-HCl, pH 7.0. The bound proteins were eluted with 20 mM Tris-HCl, pH 7.0/300 mM NaCl. The eluate pool, containing HIV r-gpl20 was diluted with an equal volume of 20 mM Tris-HCl, pH 7.0 and applied to a human rsCD4 affinity column. The affinity column contained purified human rsCD4 (described above) immobilized on Affi-Gel 10 resin at 5 mg rsCD4 per ml resin, substantially according to the resin manufacturer's directions (Bio-Rad Laboratories, Richmond, CA, cat. no. 153-6046) . The column was washed with 5 column volumes of PBS, then with 5 column volumes PBS/500 mM NaCl, and then with 5 volumes PBS. The bound HIV r-gpl20 polypeptides were eluted with 50 mM sodium citrate, pH 3.0/250 mM NaCl. The eluted fractions were immediately neutralized by addition of one tenth volume of 1 M Tris-HCl, pH 7. The purified HIV r-gpl20 polypeptides (approximately 0.2-0.3 mg/ml) were stored at -70°C until use. The RIA competition experiment was conducted substantially as described above for the CD4-V1 and CD4-V1V2 competition experiments. Specifically, each microtiter plate well was coated with anti-mouse Ig, blocked and then incubated with hybridoma culture supernatant (1F8, 5A8 or 5F2) , 0KT4, OKT4A or Leu3A, as described above. The purified baculovirus r-gpl20 (final concentration 2.5 μg/ml) and 125 I-rsCD4 were pre-incubated together 0.5 hour and then the mixture was added to each well. After incubation, the wells were washed and the bound I-rsCD4 was detected using a gamma counter. The results of the ELISA cross blocking experiment are shown in Table V, which lists the percent inhibition of human rsCD4 binding to three antibody homologs of this invention (1F8, 5A8 and 5F2) , two CD4 Vl-specific monoclonal antibodies (Leu3A and OKT4A) , and a CD4 V3V4-specific monoclonal antibody (0KT4) caused by purified HIV r-gpl20. TABLE V HIV r-gpl20 Cross Blocking: Anti-CD4 Monoclonal Antibodies Preincubated In Solution With rsCD4 The data displayed in Table V demonstrate that pre-incubation of human rsCD4 with HIV gpl20 does not significantly block the binding of monoclonal antibodies 1F8, 5A8 or 5F2 to the r-gpl20/rsCD4 complex. In contrast, the r-gpl20 nearly abolished binding of the CD4 Vl-specific antibodies OKT4A and Leu3A to human rsCD4. In our second approach, we used immunofluorescent staining to determine whether purified HIV r-gpl20 would compete with 5A8, two CD4 Vl-specific antibodies (Leu3A and OKT4A) and a CD4 V3V4-specific antibody (OKT4) for binding to a CD4 + human cell line (H9) . Two parallel sets of cell samples were stained. One set was stained only with the anti-CD4 monoclonal antibodies. The other set was preincubated with saturating HIV r-gpl20 before staining with the anti-CD4 monoclonal antibodies. Specifically, for each sample, 2 x 10 5 H9 cells (gift of Dr. Robert T. Schooley, University of Colorado Medical School, Denver, CO) were suspended in 50 μl of staining buffer PBS/2% FCS/0.02% sodium azide and 50 μl of antibody reagent was added. For 5A8, the antibody reagent was conditioned hybridoma cell culture supernatant containing approximately 5-20 μg/ml 5A8. The antibody reagents for the control antibodies were 10 μg/ml solutions in staining buffer of Leu3A, 0KT4A or 0KT4. As negative controls, two cell samples received antibody reagents containing 10 μg/ml in staining buffer of an antibody of irrelevant specificity — purified mouse myeloma proteins from MOPC 21 cells (IgG ) (Litton Bionetics, Inc., Charleston, SC, cat. no. 8402-03) or from UPC-10 cells (IgG ) (Litton Bionetics, Inc., cat. no. 8402-24). Samples were incubated for 30 minutes on ice, then washed three times in 1 ml volumes of staining buffer. Next, 2 μl FITC-conjugated goat anti-mouse immunoglobulin (Jackson Immunoresearch, West Grove, PA, cat. no. 115-006-062) was added at a 1:50 final dilution in staining buffer (30 μg/ml) , and the samples were incubated for 20 minutes on ice, washed two times and analyzed on a FACStar fluorescence activated cell sorter. In a parallel experiment (also with 2 x 10 5 H9 cells per tube) , the cell samples were incubated with excess r-gpl20 (saturating the cell surface CD4 molecules) before staining with the anti-CD4 monoclonal antibodies as described above. Specifically, 50 μl staining buffer containing 10 μg r-gpl20 was added to each cell sample. After a 30 minute preincubation with r-gpl20 on ice, the above antibody reagents were added, and the staining procedure was continued as described above. The cells were analyzed on a FACStar, as above. Figure 2 displays the results of this experiment. Each profile displays relative cell number (linear scale, x-axis) versus log fluorescence intensity of the H9 cells. Log fluorescence intensity is directly proportional to the density of stained molecules per cell. The profiles in the left column relate to the set of experiments in which the anti-CD4 antibodies were added directly to the H9 cells. The profiles in the right column relate to the set of experiments in which the cells were preincubated with excess HIV r-gpl20 before adding the anti-CD4 antibodies. The dotted lines represent staining with the anti-CD4 monoclonal antibodies. The solid lines represent staining by the irrelevant negative control mouse IgG antibodies. The UPC-10 immunoglobulin (IgG 2 ) served as a control for OKT4A (IgG ) and OKT4 (IgG ) , and the MOPC-21 immunoglobulin (IgG ) served as a control for 5A8 (IgG^ . The results demonstrate that 5A8 binding to CD4 + H9 cells is unaffected by preincubating the cells with excess HIV r-gpl20. In contrast, the binding of the CD4 Vl-specific antibodies Leu3A and OKT4A was completely blocked by preincubating with excess HIV r-gpl20. As expected, the CD4 V3V4-specific monoclonal antibody OKT4 was unaffected by preincubating with HIV r-gpl20. Blocking of HIV-induced Syncytia Formation We studied the ability of antibody homologs of this invention to block HIV-induced syncytia formation between CD4 + cells in order to assess their potential therapeutic benefit in the prophylaxis and treatment of AIDS, ARC and HIV infection. In a first approach, we tested several antibody homologs of this invention for their ability to block syncytia formation between HIV-infected H9 cells and uninfected C8166 cells, as described in B. D. Walker et al. , "Inhibition Of Human Immunodeficiency Virus Syncytium Formation And Virus Replication By Castanospermine", Proc. Natl. Acad. Sci. USA. 84, pp. 8120-24 (1984). HIV-infected H9 cells and C8166 cells (see Walker et al. , Proc. Natl. Acad. Sci. USA. supra) are CD4 + human T cell lines. C8166 is a CD4 + transformed human umbilical cord blood lymphocyte cell line, described in J. Sodroski et al., "Role Of The HTLV-III/LAV Envelope In Syncytium Formation And Cytopathicity", Nature, 322, pp. 470-74 (1986). Both cell lines were a gift from Dr. Robert T. Schooley, University of Colorado Medical School, Denver, CO, and are also available from the AIDS Reference Reagent Program, National Institutes of Health, Bethesda, MD. Specifically, for each sample, we incubated 5 x 10 3 of the chronically HIV-infected H9 cells in 100 μl "R-20 media" (RPMI 1640 culture media containing 10 mM HEPES (pH 6.8) and 2 mM glutamine, supplemented with 20% FCS) , for 30 minutes at 37°C in a 5% CO atmosphere, with 50 μl hybridoma cell culture supernatant containing approximately 5-20 μg/ml of an antibody homolog of this invention. The culture supernatants were tested at serial two-fold dilutions in R-20 media from 1:2 to 1:256. We then added 15 x 10 3 uninfected C8166 cells in 100 μl R-20 media, to give a final volume of 200 μl in each well. The samples were incubated at 37°C in a 5% CO atmosphere after adding the C8166 cells, and the number of syncytia per well was then scored by visual inspection under a light microscope. The maximum number of syncytia per well was established in the absence of any added anti-CD4 antibody-containing culture supernatant. In one sample, 100 μl of culture supernatant containing approximately 5-20 μg/ml of an isotype-matched irrelevant mouse immunoglobulin (hybridoma culture supernatant) was added as a negative control for any non-specific blocking effects. As a positive control, the CD4 Vl-specific monoclonal antibody Leu3A was tested at a number of concentrations, ranging from 2.5 μg/ml down to 0.04 μg/ml. The results of this experiment are depicted in Table VI. Data are expressed as the reciprocal of the hybridoma culture supernatant dilution that resulted in 50% blocking of syncytia formation. TABLE VI * Greater than or equal to 80% blocking down to 0.04 μg/ml. In several independent experiments using the above assay, the concentration of OKT4 (a CD4 V3V4-specific antibody) required to cause 50% blocking of syncytia formation ranged from 1-10 μg/ml. The above assay was also performed several times with purified 5A8, purified Leu3A, and purified 5A8 together with purified Leu3A. When Leu3A and 5A8 were administered together, synergistic inhibition was observed. For example, in one experiment, both Leu3A and 5A8 inhibited syncytia formation 50% at a concentration of 0.02 μg/ml when used alone. At 0.008 μg/ml of either Leu3A or 5A8 alone, we obeserved 30% and 20% syncytia blocking, respectively. However, when Leu3A and 5A8 were administered together only 0.004 μg/ml of each was required for 50% inhibition. Similar synergistic effects were observed in 3 out of 4 additional experiments. In an alternative syncytia assay, we accurately quantified the ability of purified 5A8 to block HIV-induced syncytia formation between human CD4 + Jurkat cells and transformed CHO cells expressing recombinant gpl60 on their surface ("r-gpl60-CHO cells") . The Jurkat cells were a gift of Dr. Timothy Springer, Dana Farber Cancer Institute, Boston, MA, and are also available from American Type Culture Collection, Rockville, MD, cat. no. TIB152. The r-gpl60-CHO cells were deposited with the In Vitro International Inc. culture collection in Linthicum, MD, under accession number IVI-10261 and were transferred to the American Type Culture Collection, Rockville, MD, under accession number CRL 10885. The nucleotide sequence of the HIV gpl60 gene used to transform those cells is set forth in SEQ ID NO:l, and the amino acid sequence of the gpl20/gp41 polypeptides it encodes also is set forth in SEQ ID NO:l, as well as in SEQ ID NO:2. For the purpose of comparison, we also used this assay to test the syncytia-blocking ability of two CD4 Vl- specific monoclonal antibodies (OKT4A and Leu3A) and one CD4 V3V4-specific monoclonal antibody (2-103-D11, similar to 0KT4 in behavior) . The purified 5A8 antibody used in this assay was prepared as follows. 5A8 hybridoma cells (1 x 10 6 ) were injected intraperitoneally into Balb/c mice (primed with pristane) , to generate ascites. 5A8 ascites was stored frozen at -20°C until use. After thawing, the 5A8 ascites was centrifuged at approximately 500 x g for 20 minutes at room temperature. The supernatant was filtered through a 0.45 μM Millipore filter, and then diluted six-fold and purified according to the manufacturer's directions using an Affi-Gel Protein A MAPSII column (Bio-Rad Laboratories, cat. no. 1536159) . The sample was then dialyzed extensively against phosphate buffered saline at 4°C. The dialyzed 5A8 preparation was divided into aliquots and stored at -70°C until use. Specifically, r-gpl60-CHO cells were plated into 96-well (flat bottomed) microtiter plates at 1.5 x 10 4 cells/well in 100 μl media (αf MEM supplemented with 10% dialyzed FCS, 4 mM L-glutamine and 500 nM methotrexate) , and incubated overnight at 37°C in a 5% CO atmosphere. After incubation, the plates were flipped onto absorbent paper to remove the media from the wells and 100 μl of antibody reagent was added to each well (each antibody concentration was tested in triplicate); these samples yield "test cpm". As antibody reagent, we added purified 5A8, Leu3A, OKT4 or 2-103-D11 (purified as described above for 5A8) , at concentrations ranging from 0.026 to 10,000 ng/ml. We then added 6 x 10 4 51 Cr-labelled CD4 + Jurkat cells (prepared as described infra) in 100 μl RPMI media supplemented with 10% heat-inactivated FCS, 2 mM glutamine and 100 U/ml penicillin G and streptomycin. To control for nonspecific 51 Cr release from the Jurkat cells, we added to a well 6 x 10 4 51 Cr-labelled Jurkat cells in a volume of 200 μl; this sample yielded "background cpm". The microtiter plates were incubated at 37°C in a 5% CO atmosphere for 17-19 hours. After the incubation, the wells were visually inspected under a light microscope for syncytia lysis in the positive control wells and inhibition of lysis in the wells containing anti-CD4 antibodies expected to block syncytia formation. The plates were centrifuged three to four minutes at approximately 400 x g . Supernatant (100 μl) was withdrawn from each well without touching the bottom and placed in Titertube Microtubes (Bio-Rad Laboratories, cat. no. 223-9390) . The Microtubes were then transferred individually to counting vials and the cpm emitted by each vial was measured in a gamma counter (Beckman) . To determine the total counts added to each assay ("total cpm"), 6 x 10 4 of the 51 Cr-labelled Jurkat cells were added to a scintillation vial, and then lysed in the vial by adding 0.2 N NaOH and 1% sodium dodecyl sulfate in PBS. The cpm emitted by this control vial was then measured in the gamma counter. The 51 Cr-labelled Jurkat cells were prepared as follows. Jurkat cells from flasks were spun down, resuspended in fresh growth media (RPMI media supplemented with 10% heat-inactivated FCS, 2 mM L-glutamine and 100 U/ml penicillin G and streptomycin) and counted. Fresh 51 Cr was added to 50-ml conical bottom sterile tubes at the following ratios: (1) 100 μCi 51 Cr (100 μl) added to 900 μl media containing up to 5 x 10 6 cells; (2) 200-250 μCi 51 Cr (200-250 μl) added to 800-750 μl media containing from 5 x 10 6 up to 10 x 10 6 cells. The cells were incubated at 37°C under 5% C0 2 with loose caps for 45 minutes, with occasional gentle shaking. After incubation, the cells were washed three times in their growth media (30 ml per wash) . The washed cells were resuspended in 1 ml of growth media, counted, and added to the syncytia assays. The cells were used in the assay within 30 minutes of their preparation. Percent inhibition was calculated as follows. testcpm■backgroundcpm 1∞ = % ≠a , js totalcpm-backgroundcpm J J J %Inhibition = ( 1 -%syncytialysisinpresenceofanti-C-D4MAb } 1 ∞ %syncytialysisinabsenceofantι-CD4MAb ' Figures 3 and 4 display the results of these experiments, plotting percent syncytia inhibition (calculated as described above) versus concentration (ng/ml) of antibody. Figure 3 shows the effect on syncytia formation of 0.026 to 2,000 ng/ml of 5A8, Leu3A and 0KT4A. Unexpectedly, Figure 3 demonstrates that the efficacy of 5A8 is comparable to that of Leu3A and OKT4A, with 50% syncytia blocking achieved at approximately 10 ng/ml. Figure 4 shows the effect on syncytia formation of 3.2 to 10,000 ng/ml of 5A8, Leu3A, OKT4A and the "OKT4-like" monoclonal antibody 2-103-D11. Figure 4 demonstrates that the.CD4 V3V4- specific antibody (2-103-D11) blocked syncytia formation only at a concentration several orders of magnitude higher than that required by 5A8. Blocking Of HIV Infection Of CD4* Cells We studied the ability of antibody homologs of this invention to block infection of CD4 + cells by HIV in order to assess their potential therapeutic benefit in the prophylaxis and treatment of AIDS, ARC and HIV infection. For these measurements, we used a microassay based on the protocol described in M. Robert-Guroff et al., "HTLV-III-Neutralizing Antibodies In Patients With AIDS And AIDS-Related Complex", Nature, 316, pp. 72-74 (1985). In a first experiment, 200 TCID 5Q (200 times the lowest dilution of virus that reproducibly infects one half the cultures inoculated) of HIV isolate HTLV- III. [Robert-Guroff et al.. Nature, supra] in R-20 media was added to 20 μl of an undiluted hybridoma culture supernatant containing anti-CD4 monoclonal antibodies or an irrelevant mouse IgG -containing culture supernatant (as negative control) and 4 x 10 4 C8166 cells in 10 μl R-20 media. HTLV-III a_ was a gift from Dr. Robert T. Schooley, University of Colorado Medical School, Denver, CO, and is also available from the AIDS Reference Reagent Program, National Institutes of Health, Bethesda, MD) . Aliquots of each mixture were added to three wells (15 μl/well) and each well was brought to a total volume of 200 μl with R-20 media. In a second experiment, cells were preincubated with the hybridoma culture supernatant for 30 minutes at 37°C before adding 100 TCID Q of HIV. Preincubation had no obvious effect on 5A8 blocking of infection. The wells from both experiments were visually scored under a light microscope four to eight days later for the onset of infection, as evidenced by the presence of syncytia. A well was scored as positive for infection if it contained more than 5 syncytia, with each syncytium being greater than 3 cell diameters in diameter. We considered 2 to 3 positive wells to be indicative of a successful infection, whereas 0 or 1 positive wells was indicative of effective blocking. Table VII displays the effects of 5A8 (5-20 μg/ml) , 1F8 (5-20 μg/ml) , 5F2 (-5 μg/ml) , the CD4 V3V4-specific mouse monoclonal IgG 2-103-D11 (-5 μg/ml) and an irrelevant mouse IgG culture supernatant (5-20 μg/ml) on the infection by 200 TCID 5Q of HIV of CD4 + C8166 cells, without preincubation of the cells and the antibodies. Table VIII displays the effects of the same antibodies, at the same concentrations, on the infection by 100 TCID Q of HIV, with preincubation of the cells and the antibodies. TABLE VII Infection By 200 TCID HIV In The Presence Of Antibody Homologs Of This Invention: No Preincubation 10 irrelevant IgG 1 1 2 no antibody 3 3 15 TABLE VIII Infection By 100 TCID 5α HIV In The Presence Of Antibody Homologs Of T is v n i : Wi reincubation 20 25 30 Tables VII and VIII demonstrate that 5A8 was able to block reproducibly the establishment of HIV infection in CD4 + cells. 1F8 and 5F2 also showed evidence of being able to block HIV infection. We performed additional infectivity experiments using a recent patient HIV isolate (isolate 0108E, Massachusetts General Hospital Phase I Reception Clinical Trial: R. T. Schooley et al., "A Phase I/II Escalating Dose Trial Of Recombinant Soluble CD4 Therapy In Patients With AIDS Or AIDS-Related Complex", Ann. Int. Med.. 112, pp. 247-53 (1989)) instead of the laboratory strain (HTLV-III_) used in the experiments described above. In this experiment, 500 μl of antibody reagent was added to 250 μl of "R-3 media" (R-20 media supplemented with 25 U/ml recombinant T cell growth factor ("r-IL2" or "r-TCGF") manufactured by Biogen, Inc., Cambridge, MA) containing 5-10 TCID - of HIV isolate 0108E and 250 μl of R-3 media containing 1 x 10 6 phytohemagglutinin ("PHA")-activated human peripheral blood lymphocytes ("PBLs") (prepared as described below) . The antibody reagents used in the experiment presented in Table IX were 5A8-containing hybridoma culture supernatant (5-20 μg/ml) and an isotype-matched IgG -containing culture supernatant (5-20 μg/ml) as a negative control, both diluted in R-20 media. The antibody reagents used in the experiment presented in Table X were purified 5A8 (described above) , purified Leu3A as a positive control, and isotype-matched, purified mouse IgG MOPC- 21 as a negative control (Litton Bionetics, cat. no. 8402-031), all diluted in R-20 media. The PHA-activated human PBLs were prepared as follows. Whole Blood (Red Cross) was layered on Histopaque (Sigma Chemical Co., cat. no. 1077-1), and centrifuged at 400 x g for 40 minutes, at room temperature. PBLs were collected from the interface, washed three times in unsupplemented RPMI-1640 media, and counted. The PBLs were then resuspended at 4 x 10 6 cell/ml in R-3 media supplemented with 1 μg/ml PHA-P (Difco, Springfield, NJ, cat. no. DF 3110 56 4) , and incubated for 3 days. After the incubation, the cells were frozen (10% DMSO in R-20 media) and stored at -80°C until use. Before use, the activated PBLs were thawed and cultured in R-3 media for 5 days. In the experiment using purified 5A8 (Table X) , the PHA-activated PBLs were preincubated with the antibody reagents for 1 hour at 37°C before adding virus. In the other experiment (Table IX) , using 5A8 hybridoma culture supernatant, there was no such preincubation. In both experiments, the cells were incubated with the antibody reagents and the virus for 24 hours at 37°C, under 5% CO . Each sample of cells was washed three times with R-20 media, divided into two wells, and incubated at 37°C under 5% CO in R-3 media. Every 3-4 days, 450 μl of cell supernatant was withdrawn and assayed for the presence of HIV core antigen p24 (an indicator of HIV infection) . After each such withdrawal, 500 μl R-3 media was added to each well. We assayed for HIV p24 by solid phase ELISA using a commercially available kit that employs anti- p24 monoclonal antibody immobilized in microtiter plate wells to capture p24 core antigen present in the sample (NEN Research Products, E. I. DuPont de Nemours and Co., Inc., Boston, MA, "HIV Core Profile ELISA", cat. nos. NEK-060, NEK-060A, NEK-060B) . The kit was used as specified by the manufacturer, with the extended range standard curve indicated in Appendix C of the procedure booklet supplied with the kit. A well was classified as "infected" if it contained greater than 0.1 ng/ml HIV p24. The results of these experiments are shown in Tables IX and X. TABLE IX Infection By 5-10 TCID^ Of A Patient HIV Isolate m The Presence Of 5A8 Culture Supernatant TABLE X Infection By 5-10 TCID 5Q Of A Patient HIV Isolate In The Presence Of Purified 5A8, Leu3A And IgG- Control Antibodies Number Of Wells Infected On Day 12 (of 2 possible) Dose IgG- (ug/ml) control 2.5 2 1.25 1 0.62 2 0.31 2 0.16 2 0.08 1 Tables IX and X demonstrate that 5A8 is an extremely effective blocker of infection by an HIV patient isolate. 5A8-containing culture supernatant blocked infection even at a 1:16 dilution. Purified 5A8 blocked infection by the patient virus isolate at a concentration as low as 0.08 μg/ml, the lowest concentration tested, which was comparable to Leu3A. Immunosuppressiveness We compared the immunosuppressiveness of an antibody homolog of this invention (5A8) with that of two CD4 Vl-specific anti-CD4 antibodies (Leu3A and OKT4A) using a T cell proliferation assay modified after the protocol described in E. G. Engleman et al., "Activation Of Human T Lymphocyte Subsets: Helper and Suppressor/Cytotoxic T Cells Recognize And Respond To Distinct Histocompatibility Antigens", J. Immunol.. 127, pp. 2124-29 (1981) ("Tetanus Toxoid" or "TT" assay) . In this assay, human PBLs are treated with tetanus toxoid, which stimulates their proliferation. If an immunosuppressive substance is present when the tetanus toxoid is added, then proliferation will be impeded. Proliferation is quantified as 3 H-thymidine incorporation by the cells. Human PBLs were isolated by diluting 10 ml blood two-fold with unsupplemented RPMI-1640 media and layering the mixture over 10 ml of Lymphocyte Separation Media in a 50-ml tube at room temperature. The tube was centrifuged at room temperature for 30 minutes at 400 x g . PBLs were collected from the interface, washed two times with unsupplemented RPMI- 1640 media, counted, and used in the Tetanus Toxoid assay as described below. The Tetanus Toxoid assay was performed in 96- well flat bottom microtiter plates, with each well containing human PBLs and tetanus toxoid. Antibody reagents were added to some of the wells, with the total volume in each well being 200 μl. Wells containing only cells (no antibody reagent or tetanus toxoid) constituted the "background" for this assay. The assay was performed in triplicate. Assay components were added in the following order: (1) 50 μl "assay media" (RPMI-1640 supplemented with 10% heat-inactivated fetal bovine serum (Hazelton Biologies, Inc., Lenexa, KS, cat. no. 12-10378P) , 2 mM L-glutamine and 100 Units/ml penicillin G and streptomycin) ; (2) 50 μl assay media (for "background" wells) or antibody reagent (final TT assay concentrations ranging from 10 to 0.1 μg/ml purified 5A8, Leu3A, OKT4A, MOPC 21 or UPC 10; (3) 50 μl of 40 μg/ml tetanus toxoid diluted in assay media (final TT assay concentration was 10 μg/ml); and (4) 1.5 x 10 5 PHA-activated PBLs, prepared as described above. The tetanus toxoid was obtained as a concentrate from the Massachusetts Public Health Biologic Laboratory, Jamaica Plain, MA, and was dialyzed at 4°C against 4 L of PBS for over 48 hours before use. The CD4 Vl-specific antibodies OKT4A (isotype IgG 2 ) and Leu3A (isotype IgG ) were obtained from Ortho Diagnostic Systems and Becton Dickinson, respectively. The purified 5A8 (isotype IgG ) was produced as described above. The purified MOPC 21 control antibody (Litton Bionetics) is isotype matched to 5A8 and Leu3A. The purified UPC 10 antibody is isotype matched to OKT4A. Following the addition of all reagents to the assays, the plates were incubated at 37°C in a 5% CO atmosphere for four and five days. On the fourth and fifth days, the plates were pulsed with 1 μCi of H- thymidine (NEN Research Products, cat. no. NET-027) for 6-18 hours at 37°C, 5% CO . After incubation with label, the plates were harvested with a PHD Cell Harvester (Cambridge Technologies, Inc., Cambridge, MA) , and filters containing the radioactive DNA were transferred to scintillation vials, to which scintillation fluid was added (3 ml per vial) (Scintiverse, Fisher Scientific Co. , cat. no. SK12-4) . The radioactivity of the vials was counted in a β-counter (Beckman Model LS 3801) . The results of the TT assays are displayed in Figures 5 (day 4) and 6 (day 5) . Figures 5 and 6 show the effect on proliferation (identified as cpm x 10 3 ) of 5A8 and the various control antibodies. The bars labelled "TT Control" show the baseline growth of the cells without TT stimulation (open bar) and the TT response without any antibody (solid bar) . The effect on proliferation of antibody only, without TT stimulation, is indicated by the bars with large spots. The figures also show the effect on proliferation after TT stimulation (i.e., inhibition of TT response) of the various antibodies at concentrations of 10 μg/ml (bars with dots) (MOPC 21 and 5A8 only) , 1 μg/ml (bars with diagonal stripes) (every antibody) and 0.1 μg/ml (bars with crosshatching) (every antibody) . The data in Figures 5 and 6 demonstrate that 5A8 was less immunosuppressive than 0KT4A on both days four and five of the assay. The immunosuppressiveness of 5A8 was comparable to Leu3A in these assays. 5A8 Epitope Mapping As part of our effort to characterize 5A8's mechanism of action, we performed several studies to map the CD4 epitope bound by 5A8. The results of these studies are summarized below. 5A8 was found to recognize nonreduced, SDS- denatured CD4 on a Western blot. However, 5A8 did not bind to reduced CD4 or to proteolytic fragments of CD4 (five different proteases were used) . Thus, 5A8 appears to recognize a conformational epitope of CD4. This result is consistent with the fact that 5A8 was raised against r-CD4 + -CHO cells, which presumably display CD4 having its native conformation, rather than against denatured CD4 or CD4 fragments. We studied the binding of 5A8 to a panel of mouse/human chimeric CD4 molecules. 5A8 does not recognize mouse CD4. Accordingly, by studying the binding of 5A8 to various mouse/human chimeric CD4 molecules, we hoped to identify the human CD4 residues required for 5A8 binding. Gene constructs encoding the mouse/human CD4 chimeras were provided by Daniel R. Littman of the Howard Hughes Medical Institute, University of California, San Francisco, CA and are described in N. R. Landau et al., "The Envelope Glycoprotein Of The Human Immunodeficiency Virus Binds To The Immunoglobulin-Like Domain Of CD4", Nature, 334, pp. 159-62 (1988) . We transiently transformed COS-7 cells with expression vectors containing those constructs, and assessed 5A8*s ability to bind to the various expressed chimeras by FACS analysis. As controls we used the anti-human CD4 monoclonal antibodies Leu3a and OKT4, and the anti-mouse CD4 monoclonal antibody GK1.5. Antibody binding was assessed quantitatively by titering 5A8 or the control antibodies, at sub-saturating concentrations, for each chimeric form. The results of the 5A8/chimeric CD4 binding studies indicate that: (1) human CD4 V1V2 residues are both required and sufficient for 5A8 binding; (2) human VI residues (through amino acid 83) are not required for efficient 5A8 binding; (3) human residues of the rod-like β strand which connects VI and V2 (AA 83 -AA 1()5 ) significantly influence 5A8 binding [see J. Wang et al., Nature. 348, pp. 411-18 (1990) for human CD4 crystal structure]; and (4) human CD4 V2 residues AA 10g - AA- 3 (strands B and C of V2) are absolutely required for 5A8 binding. We also studied the binding of 5A8 to various point and cluster mouse/human substitution mutants of rsCD4. The substituted amino acid positions of the mutants were as follows: AA gQ (VI) , AA 12 ι"" AA i2 ^ V2 - 1 ' ^127^13 < V2 > ' ^165 < V2 > ' ^220^226 < V3 > aIld ^240 * 2 - (V3) . Specifically, we assesed the ability of these mutants to block binding of 5A8 to CD4 + cells, in comparison to their ability to block binding of the CD4 V3V4-specific antibody OKT4 to CD4 + cells. At a concentration of 1 μg/ml, every mutant form blocked 0KT4 binding comparably (about 60%) . In contrast, mutants at AA 12 ι" AA i24 ( connect:Ln *? loop between strand B and C of V2) and AA 1.,.2,7-AA1,3,4,, ( x strand C of V2) failed to block 5A8 binding to CD4 + cells. These data localize residues within V2 which are critical for 5A8 binding, agreeing well with those identified using the mouse/human chimeras. In addition, residue 165 was identified as contributing to recognition of CD4 by 5A8, although it was considerably less important than AA 2 -AA- 24 and AA 12? -AA 13 . Immune System Effects Of 5A8 In Rhesus Monkeys Monoclonal antibody 5A8 or a control isotype- matched monoclonal antibody (MOPC21) was administered to rhesus macaque monkeys in order to assess the impact of 5A8 on normal immune function in vivo. Several indicia of immune function were examined before and at various time points after 5A8 or MOPC21 infusion. Specifically, we assessed whether 5A8 caused (a) a decrease in the number of circulating CD4 + cells in vivo, (b) a modulation of CD4 from the surface of CD4 + cells, (c) a decrease in the circulating peripheral white blood cell counts in vivo or (d) a decrease in the antibody titer elicited in response to a foreign antigen (tetanus toxoid) in vivo. We determined that 5A8 had no significant effect on any of those indicia of immunosuppression in vivo. Thus, it appears that 5A8 has no adverse effects on the immune system i,n vivo. 1. Injection And Sampling Protocols Two adult rhesus monkeys (Mn 261-85 and Mn 251-87) were infused intravenously with 3 mg/kg 5A8 purified as described above or with control MOPC21 (Mn 265-85 and Mn 265-87) (4 monkeys total) on days 0, 2 and 4. On days 3 and 21, 0.5 ml alum-adsorbed tetanus toxoid (Squibb-Connaught) (standard human dose) was administered intramuscularly. Blood was drawn from each monkey prior to the first 5A8 injection and on each of days 0-4, 6, 9, 14, 21 or 24, 28, 35 and 42, and analyzed as described below. 2. Peripheral White Blood Cell Counts We assayed blood samples from both groups of monkeys (5A8-injected and MOPC21-injected) for their counts of white blood cells using standard staining of blood smears. The results are displayed in Figure 7. As shown in Figure 7, there was no significant difference between the 5A8-injected and control groups with respect to their white blood cell counts, before or after injection of the monoclonal antibodies. 3. Circulating CD4 + Cell Counts And Modulation Of Cell Surface CD4 We assayed blood samples from both groups of monkeys (5A8-injected and MOPC21-injected) for their counts of CD4 + cells. CD4 + cell count was determined by FACS analysis, both after direct staining with FITC- OKT4 and after indirect staining with 5A8 (i.e., in vitro incubation with excess 5A8 followed by FITC- goat anti-mouse Ig) . The protocols used were analogous to the FACS protocols described above. The results of these experiments are depicted in Figure 8. As shown in Figure 8, the number of circulating CD4 + cells in the 5A8-injected animals and the control animals did not change significantly after injection of the antibodies. Moreover, the intensity of staining for CD4 was not significantly different between the 5A8-injected and control monkeys. All other blood cell parameters, including CD2, CD8 and CD20 staining, were similar between 5A8-injected and control animals (data not shown) . These results demonstrate that 5A8 did not significantly deplete CD4 + cells and did not singificantly modulate CD4 from the surface of circulating CD4 + cells. 4. Binding Of 5A8 To Rhesus CD4* Cells In Vivo Saturation for CD4 binding sites on the monkey CD4 + peripheral T cells was determined by (1) FACS analysis after staining with FITC-goat anti- mouse Ig, (2) FACS analysis after adding additional 5A8 plus FITC-goat anti-mouse Ig (no increase in staining intensity) , and (3) the inability of cells recovered from the 5A8-injected monkeys to bind measurable amounts of FITC-5A8. Saturation for CD4 binding sites on all circulating CD4 + cells of the 5A8-injected rhesus monkeys was observed by day 1 and persisted for at least 9 days. In addition, a lymph node biopsy of a 5A8-injected monkey on day 4 revealed complete penetration and coating by 5A8 of lymph node CD4 + cells. No CD4 + cell coating was observed in the control monkeys. CD4 + cell coating by 5A8, as measured by indirect staining with FITC-goat anti-mouse Ig, could not be detected after day 14. 5. 5A8 and Anti-5A8 Serum Levels Using an anti-mouse Ig sandwich ELISA, 5A8 levels were found to be high through day 9 (about 10- 100 μg/ml) , but dropped off sharply between days 9 and 14. Conversely, monkey anti-mouse Ig titers (detected by ELISA on 5A8-coated plates) appeared between days 9 and 14. It is not clear whether complexed 5A8 was present after day 9 because the anti- mouse Ig trap might fail to detect it. 6. Antibody Response To Tetanus Toxoid We assessed the possible effect of 5A8 on the monkeys' ability to generate antibodies upon infusion of a foreign antigen — tetanus toxoid. We immunized the 5A8-injected and control animals with tetanus toxoid adsorbed to alum (i.m.) on day 3, after complete coating of CD4 + cells had been achieved in the 5A8- injected animals, and on day 21. The anti-tetanus toxoid titers elicited in the monkeys over time are displayed in Figure 9. As shown in Figure 9, we observed anti- tetanus toxoid serum antibody responses in all monkeys with comparable kinetics and titers. Anti-tetanus toxoid titers were measured by ELISA using tetanus toxoid-coated plates, followed by detection with an enzyme-linked goat anti-human/monkey IgM+G. Thus, 5A8 did not affect B cell and helper T cell function. DNA Encoding 5A8 Heavy Chain Variable Region Genomic DNA was prepared from the murine hybridoma cell line 5A8 (ATCC accession number HB 10881) substantially as described in J. Sambrook et al. , Molecular Cloning, ch. 9 (Cold Spring Harbor Laboratory Press 1989) . DNA encoding the variable region of the 5A8 immunoglobulin heavy chain (5A8 V„ £1) was isolated from this genomic DNA library as described below. DNA encoding the 5A8 heavy chain variable region was amplified from the genomic DNA by polymerase chain reaction (PCR) using VH01 (SEQ ID NO:5) and VH02 (SEQ ID NO:6) as primers. These primers are identical to the VHIBACK and VH1FOR primers, respectively, described in Orlandi et al., "Cloning Immunoglobulin Variable Domains For Expression By The Polymerase Chain Reaction", Proc. Natl. Acad. Sci. USA. 86, pp. 3833-37 (1989), except that VH02 lacks the two 3' nucleotides of VH1FOR. VH01 and VH02 (400 pmoles each) were dried down and then resuspended in 50 μl lx Kinase Buffer (lOx Kinase Buffer is 0.66 M Tris-HCl, pH 7.6, 10 mM ATP, 10 mM spermidine, 100 mM MgCl 2 , 150 mM dithiothreitol, 2 mg/ml gelatin). T4 polynucleotide kinase (1 μl) (New England Biolabs, 10 U/μl) was added and the reaction was incubated at 37 β C for 30 minutes, and then at 70°C for 5 minutes. The PCR reaction mixture contained 50 pmoles of each kinased primer (VH01 and VH02), 1 μg genomic 5A8 DNA and 1.25 mM of each dXTP in lx PCR Buffer (lOx PCR Buffer is 100 mM Tris-HCl, pH 8.3, 500 mM KC1, 15 mM MgCl 2 , 0.01% gelatin). Taq polymerase (0.5 μl) (Perkin Elmer-Cetus, 5 U/μl) was added during the 72°C incubation of the first incubation cycle. The PCR reaction conditions were: 30 cycles of incubation at 94°C for 2 minutes, 65°C for 2 minutes, and 72°C for 2 minutes. The PCR reaction products were fractionated on a 1% agarose gel by standard methods and the band corresponding to the expected size of immunoglobulin variable region (330 bp) was excised. The DNA in that band was eluted by the GENECLEAN II® technique (BiolOl Inc., LaJolla, CA) , ethanol precipitated and subsequently resuspended in 10 μl TE buffer (10 mM Tris-HCl, 1 mM Na 2 EDTA) . The purified PCR fragment was incubated at room temperature for 20 minutes with the Klenow fragment of DNA polymerase I (1 μl) (New England Biolabs, 5 U/μl) and 0.125 mM of each dXTP in lx Ligation Buffer (lOx Ligation Buffer is 0.5 M Tris- HCl, pH 7.6, 100 mM MgCl 2 , 100 mM dithiothreitol, 500 μg/ml gelatin) , at a final reaction volume of 15 μl. The reaction was terminated by incubation at 65°C for 5 minutes. Next, the PCR fragment was ligated into vector pNN03. Vector pNN03 was constructed by removing the synthetic polylinker sequence of pUC8 (Pharmacia, Piscataway, NJ) by endonuclease cleavage, and replacing it with a novel synthetic polylinker (SEQ ID NO:57) . The DNA sequence of pNN03 is set forth as SEQ ID NO:7. Vector pNN03 was prepared for ligation by linearizing with EcoR5. dephosphorylating the 5 » ends with calf alkaline phosphatase, fractionating on a low melting temperature agarose gel, and excising the band corresponding to linearized pNN03 (2.7 kb) . The linearized, dephosphorylated pNN03 was then ligated to the Klenow-treated PCR 5A8 V„ fragment using T4 DNA ligase. The ligation mixture was used to transform E. coli JA221 (ATCC 33875) to ampicillin resistance. Colonies were grown up and mini-prep DNA was prepared. The recombinant plasmids were screened for the presence of an approximately 450 bp Sac2 insert. In addition, the amino acid sequence encoded by the PCR fragment was compared to the experimentally determined amino terminal amino acid sequence of the 5A8 heavy chain. By these means, the insert of vector pMDR904 was confirmed to contain a DNA sequence encoding AA -AA of the 5A8 heavy chain variable region. E. coli harboring pMDR904 have been deposited with the American Type Culture Collection, Rockville, MD, under accession number ATCC 68848. SEQ ID NO:8 sets forth the DNA sequence of the pMDR904 insert. Nucleotides 3 to 365 of SEQ ID NO:8 encode AA 2 ~AA 122 of the 5A8 V R sequence. Vector pMDR904 does not contain the codon for AA of 5A8 V.H.. This codon is "built back" using an oolliiggoo:nucleotide when a 5A8 V„ H expression vector is made. Although pMDR904 is missing the codon for AA χ of 5A8 V„π, we know the identity of that amino acid from amino acid sequence results. The complete amino acid sequence of 5A8 V„ (AA -AA,--) is set forth as SEQ ID NO:10. A DNA sequence (hypothetical as to AA 2 ) encoding the 5A8 V„n amino acid sequence is set forth as SEQ ID NO:9. By comparison to known complementarity determining region (CDR) and framework (FR) sequences, we identified the following as the CDRs of the 5A8 heavy chain: CDR1 is A 3 -AA 3 _, CDR2 is AA g0 -AA 66 , CDR3 is AA g9 -AA lllf all with respect to SEQ ID NO:10. DNA Encoding 5A8 Light Chain Variable Region Total RNA was prepared from the murine hybridoma cell line 5A8 (ATCC accession number HB 1088) according to a conventional guanidinium isothiocyanate protocol. Poly(A) + RNA was prepared from the total RNA using an oligo-d(T) column (Clontech) , also according to conventional procedures. cDNA was prepared from the poly(A) + RNA as follows. Oligonucleotides ACE149 (SEQ ID NO:11) and ACE150 (SEQ ID NO:12) (200 pmoles each) were incubated separately with l μl T4 polynucleotide kinase (New England Biolabs, 10 U/μl) in 100 μl of lx Kinase Buffer. 5A8 poly(A) + RNA (25 μg) was dried down, and then incubated 10 minutes at room temperature with a mixture " of: 5 μl of each kinased oligonucleotide, 2 μl ' 25 mM methylmercury hydroxide and 10 μl water. After that 10 minute incubation, 2 μl 50 mM dithiothreitol was added, and the mixture was incubated an additional 5 minutes at room temperature. Next, the following were added: 10 μl M-MLV reverse transcriptase (BRL 80255B, 200 U/μl), 20 μl 2.5 mM dXTPs, 26 μl water and 20 μl 5x Reverse Transcriptase Buffer (250 mM Tris- HCl, pH 8.3, 375 mM KCl, 50 mM dithiothreitol, 15 mM MgCl 2 ) . After incubating at 37°C for 1 hour, the reverse transcriptase reaction was terminated by freezing. DNA encoding the 5A8 light chain variable region was amplified from the 5A8 cDNA by PCR using ACE149 (SEQ ID NO:11) and ACE150 (SEQ ID NO:12) as primers. The PCR reaction mixture contained 50 pmoles of each kinased primer, 5 μl 5A8 cDNA, 8 μl 2.5 mM dXTPs, 0.5 μl Taq polymerase (5 U/μl) and 10 μl lOx PCR Buffer. The PCR reaction conditions were: 30 cycles of incubation at 94°C for 1 minute, 37°C for l minute, and 72°C for 2 minutes. The completed PCR reaction mixture was extracted once with ether, once with phenol:chloroform (1:1) saturated with TE buffer, and then ethanol precipitated. The ethanol precipitate was resuspended in 100 μl of buffer containing 0.5 mM dXTPs, 100 mM NaCl, 10 mM Tris-HCl, pH 8.0, 1 mM Na 2 EDTA, 100 μg/ml gelatin and 10 mM dithiothreitol. Klenow fragment of DNA polymerase I (1 μl, 5 U/μl) was added and the mixture was incubated at room temperature for 10 minutes. The reaction mixture was fractionated on a 2% agarose gel by standard methods and the band corresponding to the expected size of immunoglobulin variable region (350 bp) was excised. The DNA in that band was eluted by the GENECLEAN II® technique. Next, the PCR fragment was ligated into vector pUC19 (New England Biolabs) . Vector pUC19 was prepared for ligation by linearizing with Smal, dephosphorylating the 5- ends with calf alkaline phosphatase, fractionating on a low melting temperature agarose gel, and excising the band corresponding to linearized pUC19 (2.7 kb) . The linearized, dephosphorylated pUC19 was then ligated to the Klenow- treated PCR 5A8 V. fragment using T4 DNA ligase. The ligation mixture was used to transform £. coli JA221 to ampicillin resistance. Colonies were grown up and mini-prep DNA was prepared. The recombinant plasmids were screened for the presence of an approximately 400 bp EcoRI/Hind3 fragment. In addition, the amino acid sequence encoded by the PCR fragment was compared to the experimentally determined amino terminal amino acid sequence of the 5A8 light chain. By these means, the insert of vector pMDR927 was confirmed to contain a DNA sequence encoding AA - AA 112 of the 5A8 light chain variable region. E. coli harboring pMDR927 have been deposited with the American Type Culture Collection, Rockville, MD, under accession number ATCC 68849. SEQ ID NO:13 sets forth the DNA sequence of the pMDR927 insert. Nucleotides 4 to 336 of SEQ ID NO:13 encode AA 1 ~AA 111 of the 5A8 V L sequence. Vector pMDR927 does not contain the codon for AA of 5A8 V L . That codon is "built back" using an oolliiggoo:nucleotide when a 5A8 V. expression vector is made. Although pMDR927 is missing the codon for A χι2 of the 5A8 V , we know the identity of that amino acid from amino acid sequence results. The complete amino acid sequence of 5A8 V. is set forth as SEQ ID NO:15. A DNA sequence (hypothetical as to AA 112 ) encoding the 5A8 V amino acid sequence is set forth as SEQ ID NO:14. By comparison to known CDR and FR sequences, we identified the following as the CDRs of the 5A8 light chain: CDR1 is AA 24 ~AA 40 , CDR2 is AA 5g -AA 62 , CDR3 is AA 95 -AA 102 , all with respect to SEQ ID NO:15. Humanizing 5A8 Heavy And Light Chains The amino acid sequences of the 5A8 V H„ and VX.J regions were compared to the known human immunoglobulin sequences to find the human framework sequences most closely matching the murine 5A8 framework sequences. Humanized versions of the 5A8 heavy and light chain variable regions then were designed by grafting the CDRs of the 5A8 V„ and V_ onto the human frameworks. These humanized variable regions were then ligated to DNA encoding human IgG heavy chain and kappa light chain constant regions, respectively, and inserted into eukaryotic expression vectors. 1. Humanizing 5A8 Heavy Chain Variable Region The 5A8 heavy chain variable region was humanized by PCR mutagenesis. Three PCR reactions were carried out using three different pairs of oligonucleotide PCR primers: (a) primers 312-56 (SEQ ID NO:16) and 312-57 (SEQ ID N0:17); (b) primers 312-58 (SEQ ID N0:18) and 312-59 (SEQ ID NO:19); and (c) 312-60 (SEQ ID NO:20) and 312-61 (SEQ ID NO:21). Each PCR reaction contained 30 pmoles of each of the appropriate primers, l μg pMDR904 (insert sequence is SEQ ID NO:8), 16 μl 1.25 mM dXTPs, 0.5 μl Taq polymerase (5 U/μl) and 10 μl lOx PCR Buffer. The incubation conditions for PCR were 10 cycles of incubation for 3 minutes at 94°C, 2 minutes at 45°C and 2 minutes at 72°C. The PCR products were fractionated through a 2% agarose gel, and the bands corresponding to approximately 160 bp, 175 bp and 165 bp were excised. The three PCR fragments were eluted separately using GENECLEAN II®, into 100 μl aliquots of TE buffer. The three eluted PCR fragments (10 μl each) were combined and subjected to a second round of PCR using oligonucleotide primers 312-56 (SEQ ID NO:16) and 312-61 (SEQ ID NO:21) for 20 cycles of incubation for 3 minutes at 94°C, 2 minutes at 72°C and 2 minutes at 72°C, with the same reaction conditions used in the first round of PCR. The PCR products were fractionated through a 2% agarose gel, and the band corresponding to approximately 365 bp was excised. The PCR fragment was eluted using GENECLEAN II® and the eluate was ethanol precipitated. The ethanol precipitate was resuspended in 20 μl TE buffer, and treated with the Klenow fragment of DNA polymerase I as described above. Next, the PCR fragment was ligated into vector pNN03 (SEQ ID NO:7). Vector pNN03 was prepared for ligation by linearizing with EcoR5. dephosphorylating the 5' ends with calf alkaline phosphatase, fractionating on a low melting temperature agarose gel, and excising the band corresponding to linearized pNN03 (2.7 kb) . The linearized, dephosphorylated pNN03 was then ligated to the Klenow- treated PCR 5A8 humanized V fragment using T4 DNA ligase. The ligation mixture was used to transform E. coli JA221(Iq) to ampicillin resistance. E. coli JA221(Iq) cells were deposited with the American Type Culture Collection, Rockville, MD, and have been assigned accession number ATCC 68845. Colonies were grown up and mini-prep DNA was prepared. The recombinant plasmids were screened for the presence of an approximately 400 bp Sac2 fragment. DNA sequence analysis revealed that none of the plasmids had the correct sequence, but one plasmid — pMDR989-15 (insert sequence is SEQ ID NO:22) — had approximately 50% of the mutations necessary to convert the murine 5A8 V H sequence to the designed humanized sequence. Therefore, pMDR989-15 was subjected to a second two rounds of PCR as described immediately above. Thereafter, the insert of vector pMDR991 was identified by DNA sequence analysis to have the designed 5A8 V fl humanized sequence. SEQ ID NO:23 sets forth the DNA sequence of the pMDR991 insert. Nucleotides 1 to 357 of SEQ ID NO:23 encode AA 2 -AA 120 of the humanized 5A8 V R sequence. Vector pMDR991 does not contain codons for AA χ and AA 121 -AA 122 of humanized 5A8 V H . As described below, these codons were "built back" using oligonucleotides when the humanized 5A8 V„ eukaryotic expression vector was made. 2. Humanizing 5A8 Light Chain Variable Region The humanized 5A8 light chain variable region was prepared by ligating 10 oligonucleotides, which together span the entire humanized 5A8 V. region, and screening for constructs having the correct sequence. The protocol is described in more detail below. Oligonucleotides 312-62 through 312-71 (SEQ ID NO:24 through SEQ ID NO:33, respectively) (20 pmoles each) were dried down, and separately resuspended in 20 μl lx Kinase Buffer containing 1 mM ATP and 1 μl T4 polynucleotide kinase (10 U/μl) . The kinase reaction mixture was incubated for 1 hour at 37°C. The reaction was terminated by incubating at 70°C for 5 minutes. The kinase-treated oligonucleotides (0.4 μg each) were combined with each other and with 25 μl 10 mM ATP and 2 μl T4 DNA ligase (10 U/μl) , and the reaction mixture was incubated at room temperature for 6 hours. The ligation reaction mixture was extracted with phenol:chloroform (1:1) saturated with TE buffer, and then ethanol precipitated. The ethanol precipitate was resuspended in 50 μl lx 150 mM Restriction Enzyme Buffer (lOx 150 mM Restriction Enzyme Buffer is 100 mM Tris-HCl, pH 8.0, 1.5 M NaCl, 100 mM MgCl 2 , 1 mg/ml gelatin, 10 mM dithiothreitol) and incubated with restriction enzymes Bgl2 and Asp718 for 16 hours at 37°C. The digestion products were electrophoresed through a 2% agarose gel, and the band corresponding to 330 bp was excised. The fragment was eluted using GENECLEAN II® and the eluate was ethanol precipitated. The ethanol precipitate was resuspended in 20 μl TE buffer. Next, the 330 bp fragment was ligated into vector pNN03 (SEQ ID NO:7) . Vector pNN03 was prepared for ligation by linearizing with Asp718 and Bg_12, dephosphorylating the 5• ends with calf alkaline phosphatase, fractionating on a low melting temperature agarose gel, and excising the band corresponding to linearized pNN03 (2.7 kb) . The linearized, dephosphorylated pNN03 was then ligated to the 330 bp oligonucleotide fragment encoding the humanized V. XJ region using T4 DNA ligase. The ligation mixture was used to transform E. coli JA221(Iq) to ampicillin resistance. Colonies were grown up and mini-prep DNA was prepared. The recombinant plasmids were screened for the presence of an approximately 400 bp Sac2 fragment. DNA sequence analysis identified vector pMDR1003 as having the designed humanized sequence for the 5A8 kappa light chain variable region. SEQ ID NO:34 sets forth the DNA sequence of the pMDR1003 insert. Nucleotides 11 to 343 of SEQ ID NO:34 encode AA -AA,,, of the humanized 5A8 V. sequence. Vector pMDR1003 does not contain the codon for AA 1,X,2- of humanized 5A8 V_X>. As described below, that codon was "built back" using an oligonucleotide when the humanized 5A8 V. eukaryotic expression vector was made. 3. 5A8 Humanized Heavy Chain Expression Vector A eukaryotic expression vector carrying 5A8 humanized heavy chain (pMDR1002) was constructed by ligating intermediate plasmids pMDRlOOl, pBAGlOl and pSAB132, as described below. A. Intermediate Plasmid pMDRlOOl Intermediate plasmid pMDRlOOl was constructed to carry DNA encoding the human HG3 immunoglobulin heavy chain signal sequence (see Kabat, Sequence of Proteins of Immunological Interest, p. 460 (4th ed.) , 1 - A 122 of the humanized 5A8 heavy chain variable region, followed by an RNA 5' splice site. Plasmid pMDRlOOl was constructed from pLCB7 and pMDR991. Plasmid pLCB7, in turn, was constructed from pLCB6 and pMDR904. Plasmid pLCB6 was designed to carry DNA encoding the human immunoglobulin heavy chain signal sequence, an RNA 5' splice site and restriction sites for Pstl and BstE2. To make pLCB6, oligonucleotides 312-45 (SEQ ID NO:35) , and 312-50 (SEQ ID NO:36) and 312-46 through 312-49 (SEQ ID NO:58 through SEQ ID NO:61, respectively) were treated with polynucleotide kinase and ligated together as described above. Next, the ligated oligonucleotide was itself ligated into a 2701 bp Asp7l8/BamHl fragment of plasmid pNN03, giving pLCB6. The DNA sequence of the pLCB6 insert is SEQ ID NO:37. Plasmid pLCB6 was cleaved with Pstl and BstE2. and a 2820 bp fragment was isolated. That fragment was ligated to the 346 bp Pstl/BstE2 fragment of pMDR904. Plasmid pLCB7 was identified by the presence of a 397 bp Styl restriction fragment. The DNA sequence of the pLCB7 insert is SEQ ID NO:38. Plasmids pLCB7 and pMDR991 were individually cleaved with Pstl and BstE2. and 2820 bp (vector) and 337 bp (insert) fragments, respectively, were isolated following separate fractionation through low temperature melting agarose. These fragments were then ligated together. Plasmid pMDRlOOl was identified by the presence of a diagnostic Hae2 restriction pattern (1871 bp, 523 bp, 393 bp and 370 bp) . The DNA sequence of the pMDRlOOl insert is SEQ ID NO:39. Plasmid pMDRlOOl was cleaved with Notl and Hind3 and the 443 bp fragment containing the plasmid insert was isolated by fractionation through low temperature melting agarose. B. Intermediate Plasmid pSAB132 Intermediate plasmid pSAB132 was constructed to be a general purpose eukaryotic expression shuttle vector. It carries the human cytomegalovirus immediate early promoter and enhancer. The construction of pSAB132 is described at pages 55-56 of commonly assigned United States patent application 07/770,967. The entire sequence of pSAB132 is set forth as SEQ ID NO:40. Vector pSAB132 was linearized with Notl. The 7913 bp linearized vector then was dephosphorylated and isolated by fractionation through low temperature melting agarose. C. Intermediate Plasmid pBAGlOl Intermediate plasmid pBAGlOl was constructed to carry genomic DNA encoding the human IgG 4 heavy chain constant region. Genomic DNA was prepared from human placenta substantially as described in J. Sambrook et al. , Molecular Cloning, ch. 9 (Cold Spring Harbor Laboratory Press 1989) . DNA encoding the IgG constant region was amplified as described above from the genomic DNA by PCR using oligonucleotides 370-38 (SEQ ID NO:41) and 370-40 (SEQ ID NO:42) as primers. The approximately 2109 bp PCR fragment was isolated by gel electrophoresis and ligated into EcoR5 linearized pNN03. Plasmid pBAGlOl was identified by the presence of 3887 bp and 3896 bp Bgl2 restriction fragments. The DNA sequence of the pBAGlOl insert is SEQ ID NO:43. The DNA sequence encoding the human IgG heavy chain constant region in the pBAGlOl insert was obtained from the corresponding sequence of Genbank Accession Number K01316-PR:HUMIGCD2. Plasmid pBAGlOl was cleaved with Notl and Hind3 and the 2109 bp fragment containing the plasmid insert was isolated by fractionation through low temperature melting agarose. D. Final Construction Of Vector pMDR1002 Three fragments were ligated together to generate pMDR1002: (a) 443 bp Notl/Hind3 fragment of pMDRlOOl; (b) 7913 bp Notl linearized pSAB132; and (c) 2109 bp Notl/Hind3 fragment of pBAGlOl. The ligation mixture was used to transform JS. coli JA221(Iq) to ampicillin resistance. Colonies were grown up and mini-prep DNA was prepared. The recombinant plasmids were screened for the presence of approximately 1276 bp and 9160 bp EcoRl fragments, identifying pMDR1002. The DNA sequence of pMDR1002's insert is set forth as SEQ ID NO:44. The amino acid sequence encoded by that DNA sequence is set out as SEQ ID NO: 5. The pMDR1002 insert comprises DNA encoding, in 5' to 3' order, (1) the immunoglobulin signal sequence (nucleotides 12-68 of SEQ ID NO:44, corresponding to AA_ 19 -AA_ 1 of SEQ ID NO:45), (2) AA^AA^ of the designed humanized sequence for the 5A8 heavy chain variable region (nucleotides 69-434 of SEQ ID NO:44, corresponding to AA 1 -AA 122 of SEQ ID NO:45), followed by genomic DNA (nucleotides 27 to 2525 of Genbank accession number K01316) encoding AA 114 -AA 4?8 (Kabat numbering) of the human IgG 4 heavy chain (i.e., the heavy chain constant region) (nucleotides 712-1005, 1396-1431, 1550-1879, and 1977-2296 of SEQ ID NO:44, corresponding to AA.- -AA 48 of SEQ ID NO:45). E. coli harboring pMDR1002 have been deposited with the American Type Culture Collection, Rockville, MD, under accession number ATCC 68847. 4. 5A8 Humanized Light Chain Expression Vector A eukaryotic expression vector carrying 5A8 humanized light chain (pMDR1007) was constructed by ligating intermediate plasmids pMDR1006 and pSAB132. Plasmid pMDR1006 was in turn constructed by ligating intermediate plasmids pMDR985, pMDR986 and pMDRl003. The specific construction strategy is discussed below. A. Intermediate Plasmid pMDR985 Intermediate plasmid pMDR985 was constructed- to carry DNA encoding a prototypical human immunoglobulin kappa light chain signal sequence. To make plasmid pMDR985, oligonucleotides 360-81 (SEQ ID NO:46) and 360-82 (SEQ ID NO: 7) were treated with polynucleotide kinase and ligated together as described above. Next, the ligated oligonucleotide was itself ligated into a 2707 bp Hind3/EcoR5 fragment of plasmid pNN03 that had been dephosphorylated by calf alkaline phosphatase. The ligation mixture was used to transform _£. coli JA221(Iq) to ampicillin resistance. Colonies were grown up and mini-prep DNA was prepared. The recombinant plasmids were screened for the presence of approximately 461 bp and 2321 bp Eco0109 I fragments, identifying pMDR985. The DNA sequence of pMDR985's insert is set forth as SEQ ID NO:48. DNA sequence analysis confirmed pMDR985 to have the correct codons for the signal sequence (nucleotides 9 to 77 of SEQ ID NO: 8) ; however, due to a cloning artifact the designed Hind3 site (5 r of the insert) was not reconstituted in PMDR985. Plasmid pMDR985 was cleaved with Aat2 and EcoR5 and the 572 bp fragment containing the plasmid insert was isolated by fractionation through low temperature melting agarose. B. Intermediate Plasmid PMDR986 Intermediate plasmid pMDR986 was constructed to carry genomic DNA encoding AA. og -AA 2 (Kabat numbering) of a human kappa light chain (i.e., the light chain constant region) . Genomic DNA was prepared from human placenta [substantially as described in J. Sambrook et al., Molecular Cloning, ch. 9 (Cold Spring Harbor Laboratory Press 1989) . The genomic DNA was cleaved with EcoRI and a 2.5 kb EcoRI fragment comprising the kappa chain constant region (Genbank Accession Number J00241- PR:HUMIGKC3) was cloned into the EcoRI site of pUC8, generating pABδ. DNA encoding the kappa constant region (AA 10g - AA-..) was amplified as described above from pAB8 by PCR using oligonucleotides 370-54 (SEQ ID NO:49) and 370- 55 (SEQ ID NO:50) as primers. The approximately 1240 bp PCR fragment was isolated and ligated into EcoR5 linearized pNN03 that had been dephosphorylated. Plasmid pSAB153 was identified by the presence of a 1314 bp Xmnl restriction fragment. The DNA sequence of the pSAB153 insert is SEQ ID NO:51. Plasmid pMDR986 was constructed from pSAB153 as follows. The kappa constant region was amplified from pSAB153 by PCR using oligonucleotides 360-83 (SEQ ID NO:52) and 370-55 (SEQ ID NO:50) as primers. The approximately 1276 bp PCR fragment was isolated by GENECLEAN II® elution, followed by electrophoresis through agarose, ethanol precipitation and resuspension in 20 μl TE buffer. The purified PCR fragment was treated with the Klenow fragment of DNA polymerase I and ligated to EcoR5 linearized pNN03 that had been dephosphorylated by calf alkaline phosphatase. The ligation mixture was used to transform £. coli JA221(Iq) cells. DNA was prepared from ampicillin resistant colonies and screened by Eco0109 I restriction digestion. Plasmid pMDR986 was identified by the presence of a 1122 bp Ecoθl09 I restriction fragment. The pMDR986 plasmid then was used to transform E. coli GM2929, which does not methylate its DNA (a dam-13, dcm-6 strain). The DNA sequence of the pMDR986 insert is SEQ ID NO:53. DNA sequence analysis confirmed pMDR986 to have the correct exons to encode AAl,U_o-AA2-1,4. of the human kappa chain. However, due to a cloning artifact the designed Notl site 3* of the constant region was not reconstituted in pMDR986 and a Pvul site was created instead. Plasmid pMDR986 was cleaved with Aat2 and Bell, treated with calf alkaline phosphatase, and the 3443 bp fragment was isolated by fractionation through low temperature melting agarose. C. Intermediate Plasmid PMDR1003 The construction of plasmid pMDR1003 is described above. It carries DNA encoding humanized 5A8 kappa light chain variable region. The DNA sequence of the pMDR1003 insert is set forth as SEQ ID NO:34. Plasmid pMDR1003 was cleaved with EcoR5 and Bgl2 and the 326 bp fragment containing the plasmid insert was isolated by fractionation through low temperature melting agarose. D. Final Construction Of Vector pMDR1007 Vector pMDR1007 was constructed from pSAB132 (SEQ ID NO:40) and pMDR1006 (insert DNA sequence is SEQ ID NO:54). Three fragments were ligated together to generate pMDR1006: (a) 572 bp Aat2/EcoR5 fragment of PMDR985; (b) 3442 bp Aat2/Bcll fragment of pMDR986; and (c) 326 bp EcoR5/Bql2 fragment of pMDR1003. The ligation mixture was used to transform E. coli JA221(Iq) [source?] to ampicillin resistance. Colonies were grown up and mini-prep DNA was prepared. The recombinant plasmids were screened for the presence of diagnostic Eco0109 I restriction fragments (2741 bp, 767 bp and 461 bp, 243 bp and 129 bp) , identifying pMDR1006. The DNA sequence of pMDR1006's insert is set forth as SEQ ID NO:54. Plasmid pMDR1006 was cleaved with Notl and the 1693 bp fragment was isolated. The Notl fragment was ligated into Notl linearized pSAB132 (SEQ ID NO:40) that had previously been dephosphorylated by calf alkaline phosphatase. The dephosphorylated reaction mixture was fractionated through low temperature melting agarose, and then used to transform £. coli JA221(Iq) to ampicillin resistance. Colonies were grown up and mini-prep DNA was prepared. The recombinant plasmids were screened for a diagnostic ApaLl digestion pattern (fragments of 6249 bp, 1593 bp, 1246 bp, and 498 bp) , identifying pMDR1007. The DNA sequence of pMDR1007's insert is set forth as SEQ ID NO:55. The amino acid sequence encoded by that DNA sequence is set out as SEQ ID NO:56. The pMDR1007 insert comprises DNA encoding, in 5' to 3' order, (1) the immunoglobulin kappa chain signal sequence (nucleotides 35-100 of SEQ ID NO:55, corresponding to AA -AA of SEQ ID NO:56), (2) AA 1 -AA 112 of the designed humanized sequence for the 5A8 light chain variable region (nucleotides 101-436 of SEQ ID NO:55, corresponding to AA.-AA... of SEQ ID NO:56), followed by genomic DNA (nucleotides 1 to 1201 of Genbank Accession Number J00241- PR:HUMIGKC3) encoding AA 108 ~ AA 214 ( Kabat numbering) of the human kappa light chain (i.e., the light chain constant region) (nucleotides 437 and 782-1101 of SEQ ID NO:55, corresponding to AA- 13 -AA of SEQ ID NO:56) . E. coli harboring pMDR1007 have been deposited with the American Type Culture Collection, Rockville, MD, under accession number ATCC 68846. 5. Expression Of Humanized 5A8 In a preliminary experiment, COS7 cells were transfected with expression vectors pMDR1007 and PMDR1002 by electroporation and the cells were cultured for 48 hours. The cells were then radiolabelled with 35 S-methionine. Then, cell extracts and conditioned culture media were incubated with Protein A-Sepharose. The Protein A-Sepharose was washed and the bound proteins were eluted with SDS polyacrylamide gel electrophoresis (PAGE) loading buffer, and analyzed by PAGE. Assembled immunoglobulin molecules were detected in the conditioned media at very low yields, as evidenced by Protein A precipitation of immunoglobulin light chain. Deposits Cells and antibody homologs according to the present invention are exemplified by cultures deposited under the Budapest Treaty in the In Vitro International, Inc. culture collection in Linthicum, Maryland, U.S.A. on November 20, 1990, and identified as: "5A8-2F6" "7-27-1F8-2B4" "7-27-5F2-2C5" "CHO 379 clone 12.1" "CHO-160" These cultures were assigned accession numbers IVI-10257 to IVI-10261, respectively. These deposits were transferred on June 20, 1991 to the American Type Culture Collection, Rockville, Maryland, and are being maintained by the American Type Culture Collection under the Budapest Treaty under accession numbers HB 10881, HB 10882, HB 10883, CRL 10884 and CRL 10885, respectively. DNA sequences and recombinant DNA molecules according to the present invention, and a microorganism useful in preparing same, are exemplified by cultures deposited under the Budapest Treaty with the American Type Culture Collection, Rockville, Maryland, U.S.A. on November 21, 1991, and identified as: "E. coli K12 JA221(Iq)" "E. coli K12 JA221(Iq)/pMDR1007" "E. coli K12 JA221(Iq)/pMDR1002" "E.. coli K12 JA221(Iq)/pMDR904" "£. coli K12 JA221(Iq)/pMDR927" These cultures were assigned accession numbers ATCC 68845 to ATCC 68849, respectively. Sequences The following is a summary of the sequences set forth in the sequence library: SEQ ID NO:l DNA sequence of pre-HIV gpl60 SEQ ID NO:2 Amino acid sequence of pre-HIV gpl60 SEQ ID NO:3 DNA sequence of soluble HIV gpl20 SEQ ID NO:4 Amino acid sequence of soluble HIV gpl20 SEQ ID NO:5 DNA sequence of VH01 PCR primer SEQ ID NO:6 DNA sequence of VH02 PCR primer SEQ ID NO:7 DNA sequence of pNN03 SEQ ID NO:8 DNA sequence of pMDR904 insert (5A8 V R ) SEQ ID NO:9 DNA sequence of 5A8 heavy chain variable region SEQ ID NO:10 Amino acid sequence of 5A8 heavy chain variable region SEQ ID NO:11 DNA sequence of ACE149 PCR primer SEQ ID NO:12 DNA sequence of ACE150 PCR primer SEQ ID NO:13 DNA sequence of pMDR927 insert (5A8 V ) SEQ ID NO:14 DNA sequence of 5A8 light chain variable region SEQ ID NO:15 Amino acid sequence of 5A8 light chain variable region SEQ ID NO:16 DNA sequence of 312-56 PCR primer SEQ ID NO:17 DNA sequence of 312-57 PCR primer SEQ ID NO:18 DNA sequence of 312-58 PCR primer SEQ ID NO:19 DNA sequence of 312-59 PCR primer SEQ ID NO:20 DNA sequence of 312-60 PCR primer SEQ ID NO:21 DNA sequence of 312-61 PCR primer SEQ ID NO:22 DNA sequence of pMDR989-15 insert SEQ ID NO:23 DNA sequence of pMDR991 insert SEQ ID NO:24 DNA sequence of 312-62 oligonucleotide SEQ ID NO:25 DNA sequence of 312-63 oligonucleotide SEQ ID NO:26 DNA sequence of 312-64 oligonucleotide SEQ ID NO:27 DNA sequence of 312-65 oligonucleotide SEQ ID NO:28 DNA sequence of 312-66 oligonucleotide SEQ ID NO:29 DNA sequence of 312-67 oligonucleotide SEQ ID NO:30 DNA sequence of 312-68 oligonucleotide SEQ ID NO:31 DNA sequence of 312-69 oligonucleotide SEQ ID NO:32 DNA sequence of 312-70 oligonucleotide SEQ ID NO:33 DNA sequence of 312-71 oligonucleotide SEQ ID NO:34 DNA sequence of pMDR1003 insert SEQ ID NO:35 DNA sequence of 312-45 oligonucleotide SEQ ID NO:36 DNA sequence of 312-50 oligonucleotide SEQ ID NO:37 DNA sequence of pLCB6 insert SEQ ID NO:38 DNA sequence of pLCB7 insert SEQ ID NO:39 DNA sequence of pMDRlOOl insert SEQ ID NO:40 DNA sequence of pSAB132 SEQ ID NO:41 DNA sequence of 370-38 PCR primer SEQ ID NO:42 DNA sequence of 370-40 PCR primer SEQ ID NO:43 DNA sequence of pBAGlOl insert SEQ ID NO:44 DNA sequence of pMDR1002 insert (pre- 5A8 humanized heavy chain) SEQ ID NO:45 Amino acid sequence of pMDR1002 insert (pre-5A8 humanized heavy chain) SEQ ID NO:46 DNA sequence of 360-81 oligonucleotide SEQ ID NO:47 DNA sequence of 360-82 oligonucleotide SEQ ID NO:48 DNA sequence of pMDR985 insert SEQ ID NO:49 DNA sequence of 370-54 PCR primer SEQ ID NO:50 DNA sequence of 370-55 PCR primer SEQ ID NO:51 DNA sequence of pSAB153 insert SEQ ID NO:52 DNA sequence of 360-83 PCR primer SEQ ID NO:53 DNA sequence of pMDR986 insert SEQ ID NO:54 DNA sequence of pMDR1006 insert SEQ ID NO:55 DNA sequence of pMDR1007 insert (pre- 5A8 humanized light chain) SEQ ID NO:56 Amino acid sequence of pMDR1007 insert (pre-5A8 humanized light chain) SEQ ID NO:57 DNA sequence of pNN03 synthetic polylinker SEQ ID NO:58 DNA sequence of 312-46 oligonucleotide SEQ ID NO:59 DNA sequence of 312-47 oligonucleotide SEQ ID NO:60 DNA sequence of 312-48 oligonucleotide SEQ ID NO:61 DNA sequence of 312-49 oligonucleotide. While we have hereinbefore described a number of embodiments of this invention, it is apparent that our basic embodiments can be altered to provide other embodiments that utilize the compositions and processes of this invention. Therefore, it will be appreciated that the scope of this invention includes all alternative embodiments and variations which are defined in the foregoing specification and by the claims appended hereto; and the invention is not to be limited by the specific embodiments that have been presented herein by way of example. SEQUENCE LISTING (1) GENERAL _NK_RA_IION: (I) APPLICANT: BURKLV, LINDA C. OΠSHDLM, ROHICEA L. TH1«S, DAVID W. ROSA, MARGARET D. ROSA, JGSEEH J. (Ϋ) TEHE C INVENIICN: ANTI-CD4 ANTIBODY KM3LOGS USEFUL IN HRØEIAXIS AND TKEMMENT OF AIDS, ARC AND HIV INEEOTCN (v) OUBJJSR READABLE FCEM: (A) MEDIUM TOE: Floppy disk (B) G ME TER: IBM PC cαipatible (C) CfERffiDC SYSTEM: FCHES/MS-DOS (D) SOFTWARE: Rateπtln Release #1.0, Version #1.25 (vi) CURRENT AEH CKnC DATA: (A) APPLICATION NUMEER: WO (B) FHJNG DAJE: (C) CLASSlt'lCATTCN: (viii) ATICFNEV/AGENT INFCRRTICN: (A) NHiE: HALEY, JR. , JAMES F. (B) RElSISTRAϋlON NUMBER: 27,794 (C) REIΕKENCE DOCKET NtMBER: B148 CTP (ΪX) -TrTFrrrMHECAillCN INFC ftTICN: (A) TELEHENE: (212) 715-0600 (B) TELEFAX: (212) 715-0673 (C) TELEX: 14-8367 (2) ]_NFCR-ATION FCR SEQ ID NO: l: (i) SEQUENCE CHARACTERISTICS: (A) IENG fl: 2571 base pairs (B) TYPE: nucleic acid (C) STERANEEINESS: single (D) "KBDICGY: linear (ϋ) MDIECULE TYFE: cENA (iϋ) HYRJIHϋLlCftL: NO (iv) ANTI-SENSE: NO (ix) EEKrϋRE: (A) NAME^KEY: sig_peptide (B) IOCAHCN: 1..87 (ix) FΕXTURE: (A) NM4E/KEY: mat_pepti_de (B) LXAϋlCN: 88. -2568 (ix) FEATURE: (A) NAME/KEY: miscjEeature (B) ICCATICN: 1533..1534 (D) OIHER INFCfMATICN: /note= *w gpl20/gp41 cleavage site *wr (ix) FEATURE: (A) NAME/KEY: CDS (B) IOCAHCN: 1..2568 (ix) FEATURE: (A) NAME^KEY: misc_feature (B) IOCATICN: 1 (D) OIHER mFCEMffilCN: /hote= "pre-fflV gpl60» (xi) SEQUENCE EESCkL l'ICN: SEQ ID NO:l: AT5 AGA GIG MG <3G AAA TAT CPΩ CAC TIG TG3 A3 TGG QGG TGG A3A 48 Met Arg Val lys Glu lys Tyr Gin His Leu Trp Arg Trp Gly Trp Arg -29 -25 -20 -15 TGG GGC ACC AIG CTC CUT GGG MG TIG A1G MC TGT AGT GCT ACA GAA 96 Trp Gly Thr Met leu Iβα Gly Met leu Met lie Cys Ser Ala Thr Glu -10 -5 1 AAA TTG TGG GTC ACA GTC TAT TAT 033 GTA CCT GIG TGG AAG GAA GCA 144 lys Iai Trp Val T r Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala 5 10 15 ACC ACC ACT era. TΓΓ TGT GCA TCA GKΓ GCΓ AAA QCA TAT GAT PCΆ. GAG 192 Thr Thr Thr Le Ehe Cys Ala Ser Asp Ala lys Ala Tyr Asp Thr Glu 20 25 30 35 GTA CAT AAT GIT TGG GCC ACA CAT GCC TGT GTA CCC ACA GAC GCC AAC 240 Val His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro As 40 45 50 OC CAA GAA GTA GTA TIG GTA AAT GIG ACA GAA AAT TTT AAC AIG TGG 288 ■ Pro Gin Glu Val Val leu Val Asn Val Thr Glu Asn Phe Asn Mat Trp 55 60 65 - Ill - AAA AM GAC ATG GTA GAA CAG AIG CM GAG GM MA MC AGT TTA TGG 336 I^AΞnAΞp ^ ωGluGln _^Hi≤Gl A£p ne eSerI£u rp 70 75 80 GM CAA AGC CIA AAG CCA TGT GTA AAA TTA AX GCA CTC TGT GIT ACT 384 Asp Gin Ser leu lys Pro Cys Val Lys leu Thr Pro Leu Cys Val Ser 85 90 95 TTAAAGTGCACTGMTTGAAGAMGMA TAMAαCAMAGTAGTAGC 432 leu lys Cys Thr Asp leu lys Asn Asp Thr Asn Thr Asn Ser Ser Ser 100 105 110 115 GGG_M^A__D3A!IAMCGAGAAAGGAGAGATAAAAAACTG^ 480 Gly Ag Met He Met Glu lys Gly Glu He lys Asn Cys Ser Hie Asn 120 125 130 ATC AGC ACA AGC ATA AGA GST AAG GIG CAG AAA GAA TAT GCA TTT TTT 528 He Ser Thr Ser He Arg Gly lys Val Gin lys Glu Tyr Ala Phe Rie 135 140 145 TAT AAA CUT GM MA ATA OCA MA GM AM GM ACT ACC AGC TAT AAG 576 Tyr lys Leu Asp He He Pro He Asp Asn Asp Thr Thr Ser Tyr lys 150 155 160 TIG ACA AGT TGT AAC ACC TCA GTC ATT ACA CAG GCC TGT CCA AAG GIΑ 624 Lsu Thr Ser Cys Asn Thr Ser Val He Thr Gin Ala Cys Pro lys Val 165 170 175 TGC TTT GAG CCA ATT CCC ATA CM TAT TGT GCC CCG GCT GST TTT GQG 672 Ser Phe Glu Pro He Pro He His Tyr Cys Ala Pro Ala Gly Phe Ala 180 185 190 195 ATT C A AAA TGT AM AM AAG AGG TTC AM GSA ACA GGA GCA TGT ACA 720 He leu lys Cys Asn Asn lys Thr Hie Asn Gly Thr Gly Pro Cys Thr 200 205 210 AM GTC AGC ACA GTA CAA TGT ACA CM GSA ATT AGΞ CCA GTA GTA TCA 768 Aε Val SerThrVεd GlnCysThrHi≤Gly HeArgProValVal Ser 215 220 225 ACT CAA CIG CTG TTA AM GGC AGT CTA GCA GAA GAA GAG GTA GTA ATT 816 Thr Gin leu leu lsu Asn Gly Ser leu Ala Glu Glu Glu Val Val He 230 235 240 AGA TCT GTC AM TTC ACG GAC AM GCT AAA ACC ATA ATA GTA CΛ3 CTG 864 Arg Ser Val Asn Hie Thr Asp Asn Ala lys Thr He He Val Gin Leu 245 250 255 AACACATCTGmGAAATrAMTGTAAAC-AOXAAC 912 Asn Thr Ser Val Glu He Asn Cys Thr Arg Pro Asi Asi Asn Thr Arg 260 265 270 275 ^^MCOTMCCMrøQ^CC\QX^GCΑTITOT_»£AAI_A 960 lys Arg He Arg He Gin Arg Gly Pro Gly Arg Ala Hie Val Thr He 280 285 290 GGA AAA. ATA GGA. AAT AIG AGA CAA GCA CAT TGT AAC ATT AGT AGA GCA 1008 Gly lys He Gly Asi Met Arg Gin Ala His Cys Asn He Ser Arg Ala 295 300 305 AAA TGGAMAACACTTTAAAAC_^ATAGCTAGCAAATTAAGAGAACA^ 1056 lys Trp Asn Asn Thr leu lys Gin He Ala Ser lys leu Arg Glu Gin 310 315 320 TTT GGA AM AM AAA ACA ATA ATC TTT AAG CAA TCC TCA GGA GGG GAC 1104 Hie Gly As Asn lys Thr He He Hie lys Gn Ser Ser Gly Gly Asp 330 335 CCA GAA ATT GTA AOS CAC AGT TTT AM TGT GGA GGG GAA TTT TTC TAC 1152 Pro Glu He Val Thr His Ser Hie Asn Cys Gly Gly Glu Hie Hie Tyr 340 345 350 355 TGT AM TCA ACA CAA CTG TTT AM AGT ACT TGG TTT AM AGT ACT TGG 1200 Cys Asn Ser Thr Gin leu Hie As Ser Thr Trp Hie As Ser Thr Trp 360 365 370 AGTACTGAAGGGT^AMAACACTGAAGGAAGTGACACAATCACCCIC 1248 Ser Thr Glu Gly Ser Asi As Thr Glu Gly Ser Asp Thr He Thr Leu 375 380 385 CCATGCAC-AAi AAACAAAaTAIAAACAIGTGGCM 1296 Pro Cys Arg He lys Gin He He Asn Met Trp Gin Lys Val Gly lys 390 395 400 GCA ATG TAT GCC OCT CCC ATC AGT GGA CAA ATT AGA TGT TCA TCA AM 1344 Ala Met Tyr Ala Pro Pro He Ser Gly Gin He Arg Cys Ser Ser As 405 410 415 ATT ACA GGG CIG CTA TTA ACA AGA GM GST GST AM AGC AAC AM GAG 1392 He Thr Gly leu Leu Leu Thr Arg Asp Gly Gly As Ser As Asn Glu 420 425 430 435 TCC GAG ATC TTC AGA GCT GSA GSA GSA GM AIG AGG GAC AM TGG AGA 1440 Ser Glu He He Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg 440 445 450 AGT GAA TTA TAT AAA TAT AAA GTA GTAAAA ATT GAA CCATTA GA GTA 1488 Ser Glu leu Tyr lys Tyr lys Val Val lys He Glu Pro Leu GlyVal 455 460 465 GCACCCACCAAGGCAAAGAGAACAGIGGIGCAGAGAGA^ 1536 Ala Pro Thr lys Ala lys Arg Arg Val Val Gin Arg Glu Lys Arg Ala 470 475 480 GIG GGA ATA GSA GCT TIG TTC CIT GGG TTC TTG GSA GCA GCA GGA AGC 1584 Val Gly He GlyAla leu Hie Lai Gly Hie leu Gly Ala Ala Gly Ser 485 490 495 ACT ATG GGC GCA GGG TCAAIG ACG CIG ACE GTA CAG GCCAGA CAA TTA 1632 IhrMefcGlyAlaAlaSerMetThrL- * uThrValGlnA^ 500 505 510 515 TTG TCT GST ATA GIG CAG CAG CAG AAC AM TTG CIG AGG GCT ATT C-AG 1680 leu Ser Gly He Val Gin Gin Gin Asn Asn leu Leu Arg Ala He Glu 520 525 530 GCGCAACAGCATCTCTIGCAACICA_CAGICT^ 1728 Ala Gin Gin His Leu Leu Gin leu Thr Val Trp Gly He lys Gin leu 535 540 545 CAG GCA AGA ATC CTG GCT GIG GAA AGA TAC CTA AAG GM CAA 2G C C 1776 Gin Ala Arg He leu Ala Val Glu Arg Tyr ai Lys Asp Gin Gin Lai 550 555 560 CTA GGG AIT TGG GST TGC TCT GSA AAA CTC ATT TGC ACC ACT GCT GIG 1824 leu Gly He Trp Gly Cys Ser Gly lys leu He Cys Thr Thr Ala Val 565 570 575 GCT TGG AM GCT AGT TGG AGT AM AAA TCT CIG GAA CAG ATT TGG AM 1872 Pro Trp Asn Ala Ser Trp Ser Asn lys Ser Leu Glu Gin He Trp As 580 585 590 595 σ^ACGACCTGGA!IGGAGTGGGACAGAGAAAITAACAMT^ 1920 His Thr Thr Trp Met Glu Trp Asp Arg Glu He Asn Asn Tyr Thr Ser 600 605 610 TTA ATA GC TCC TTA ATT GAA GAA TOG CAA AAC CAG CAA GAA AAG AM 1968 leu He His Ser leu He Glu Glu Ser Gin As Gin Gin Glu lys Asn 615 620 625 GAA CAA GAA TTA TTG GAA TTA GM AAA TGG GCA AGT TTG TG AM TGG 2016 Glu Gin Glu Leu Leu Glu Leu Asp lys Trp Ala Ser Leu Trp Asn Trp 630 635 640 TTT AAC ATA ACA AM TGG CIG TGG TAT AϋA AAA TTA TTC MA MG MA 2064 Phe Asn He Thr Asn Trp leu Trp Tyr He lys leu Hie He Met He 645 650 655 GTA GSA GGC TTG GTA GST TTA AGA ATA GIT TTT GCT GTA CUT TCT ATA 2112 Val Gly Gly leu Val Gly leu Arg He Val Hie Ala Val leu Ser He 660 665 670 675 GIG AM AGA GTT AGG CAG GSA TAT TCA GCA TTA TOG TTT CAG A CPC 2160 Val Asn Arg Val Arg Gin Gly Tyr Ser Pro Leu Ser Hie Gin Thr His 680 685 690 CICXAAOCCOGAXGGACXGACAGGOXGAAGSAA^ 2208 Leu Pro Thr Ero Arg Gly Pro Asp Arg Pro Glu Gly He Glu Glu Glu 695 700 705 GSTGGAGTCAGAGACAGAGACAGATOCACTCGA-raGIG 2256 Gly Gly Glu Arg Asp Arg Asp Arg Ser He Arg Isu Val Asi Gly Ser 710 715 720 TTG GCA CIT AIC TGG GAC GM CIG 0DG A3C CIG TGC CTC TTC AGC TAC 2304 Leu Ala Leu He Trp Asp Asp Leu Arg Ser Leu Cys leu Hie Ser Tyr 725 730 735 CAC GGC TTG AGA GAC TTA CTC TTG ATT GTA ACS AGS A T GIG GAA CTT 2352 His Arg leu Arg Aεp leu leu leu He Val Thr Arg He Val Glu Leu 740 745 750 755 CIG GGA GSC AGS GΞS TGG GAA GGC CTC AAA TAT TGG TGG AM CTC CTA 2400 Leu Gly Arg Arg Gly Trp Glu Ala Leu Lys Tyr Trp Trp Asn Leu Leu 760 765 770 CPU TAT TG AGT CAG GAA CTA AAG AM AGT GCT GTT AGC TTG CTC AM 2448 Gin Tyr Trp Ser Gin Glu leu Lys As Ser Ala Val Ser leu Leu Asn 775 780 785 GCC PCh GCC ATA GCA GTA GCT GAG GGG ACA GM AGG GTT ATA GAA GTA 2496 Ala Ibr Ala ne A_l^ Val Ala Glu Gly Ihr Aεp Arg \^1 He Glu Val 790 795 800 GTA CAA GGA GCT TGT AGA GCT A T CGC CAC MA GCT AGA AGA ATA AGA 2544 Val Gin Gly Ala Cys Arg Ala He Arg His He Pro Arg Arg He Arg 805 810 815 CPC GCC TTG GAA AGG ATT TTG CTA TAA 2571 Gin Gly Leu Glu Arg He Leu Leu 820 825 (2) INFCfWATΪCN FOR SEQ ID NO: 2: (i) SEQUENCE vSAJtA IH- STICS : (A) LENGTH: 856 amino acids (B) TYPE: amino acid (D) TOEOLOSY: linear (ii) M3EH-UIE TYPE: protein (xi) SEQUENCE LXSCKCPITCN: SEQ ID NO: 2: Met Arg Val lys Glu lys Tyr Gin His leu Trp Arg Trp Gly Trp Arg -29 -25 -20 -15 Tr Gly Thr lfet lβu Lfiu Gly ϊfet L£u Ifet He <^ Ser Ala , I_tιr Glu -10 -5 1 Lys Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala 5 10 15 Thr Thr Thr Leu H e Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu 20 25 30 35 Val His Asi Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn 40 - 45 50 Pro Gin Glu Val Val Leu Val Asn Val Thr Glu Asi H*e Asi Met Trp 55 60 65 Lys Asn Aεp Met Val Glu Gin Mat His Glu Psp He He Ser leu Trp 70 75 80 Asp Gin Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Ser 85 90 95 Leu Lys Cys Thr Asp Leu Lys Asn Aεp Thr Asn Thr Asn Ser Ser Ser 100 105 HO 115 Gly Arg Met He Met Glu lys Gly Glu He lys Asi Cys Ser Hie Asn 120 125 130 He Ser Thr Ser He Arg Gly Lys Val Gin lys Glu Tyr Ala Hie Hie 135 140 145 Tyr Lys Leu Asp He He Pro He Asp Asn Asp Thr Thr Ser Tyr lys 150 155 160 leu Thr Ser Cys Asn Thr Ser Val He Thr Gin Ala Cys Pro lys Val 165 170 175 Ser Hie Glu Pro He Pro He His Tyr Cys Ala Pro Ala Gly Hie Ala 180 185 190 195 He Leu Lys Cys Asn Aεn Lys Thr Hie Asi Gly Thr Gly Pro Cys Thr 200 205 210 Asn Val Ser Thr Val Gln t-ys Thr His Gly He Arg Rro Val Val Ser 215 220 225 Thr Gin Lsu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Val He 230 235 240 Arg Ser Val Aεn Hie Thr Aεp Asn Ala Lys Thr He He Val Gin Leu 245 250 255 Aεn Thr Ser Val Glu He Asn Cys Thr Arg Pro Asi Asn Asn Thr Arg 260 265 270 275 Lys Arg He Arg He Gin Arg Gly Pro Gly Arg Ala Hie Val Thr He 280 285 290 Gly Lys He Gly Asi Met Arg Gin Ala His Cys Asn He Ser Arg Ala 295 300 305 Lys Trp Asn Asn Thr Leu Lys Gin He Ala Ser Lys Leu Arg Glu Gin 310 315 320 Hie Gly Asi Asi lys Thr He He He lys Gin Ser Ser Gly Gly Ptsp 325 330 335 Pro Glu He Val Thr His Ser Hie Asn Cys Gly Gly Glu Ehe Hie Tyr 340 345 350 355 Cys Asn Ser Thr Gin Leu Hie Asn Ser Thr Trp He Asn Ser Thr Trp 360 365 370 SerThrGlu Gly SerAsi Asn Thr Glu Gly Ser Asp Thr He Thr Leu 375 380 385 Pro Cys Arg He lys Gin He He Aεn Met Trp Gin Lys Val Gly Lys 390 395 400 Ala Met Tyr Ala Pro Pro He Ser Gly Gin He Arg Cys Ser Ser Asn 405 410 415 He Thr Gly Leu Leu Leu Thr Arg Aεp Gly Gly Aεn Ser Aεn Asn Glu 420 425 430 435 Ser Glu He HieArg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg 440 445 450 Ser Glu leu Tyr lys Tyr Lys Val Val Lys He Glu I-ro Leu Gly Val 455 460 465 Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gin Arg Glu Lys Arg Ala 470 475 480 Val Gly He Gly Ala Leu He Leu Gly Hie Leu Gly Ala Ala Gly Ser 485 490 495 T_hr Ms*t G la Ala Ser Met T_hr Ieu T^ 500 505 510 515 Leu Ser Gly He Val G n Gin Gin Asn Asn Leu Leu Arg Ala He Glu 520 525 530 Ala Gin G n His Leu Leu Gin Leu Thr Val Trp Gly He Lys Gin Leu 535 540 545 Gin Ala Arg He Leu Ala Val Glu Arg Tyr Leu Lys Aεp Gin Gin Leu 550 555 560 Leu Gly He Trp Gly Cys Ser Gly Lys Leu He Cys Thr Thr Ala Val 565 570 575 Pro Trp Aεn Ala Ser Trp Ser Aεn Lys Ser Leu Glu Gin He Trp Asn 580 585 590 595 His Thr Thr Trp Met Glu Trp Psp Arg Glu He Aεn Asn Tyr Thr Ser 600 605 610 Leu He His Ser Leu He Glu Glu Ser Gin Asn Gin Gin Glu lys Asn 615 620 625 Glu G n Glu Leu Leu Glu Leu A*=p Lys Trp Ala Ser Leu Trp Asn Trp 630 635 640 Hie Asn He Thr Asn Trp Leu Trp Tyr He Ivs Leu Hie He Met He 645 650 655 Val Gly Gly Leu Val Gly leu Arg He Val Hie Ala Val leu Ser He 660 665 670 675 Val Asn Arg Val Arg Gin Gly Tyr Ser Pro Leu Ser Hie Gin Thr His 680 685 690 Leu Pro Thr Pro Arg Gly Pro Asp Arg Pro Glu Gly He Glu Glu Glu 695 700 705 Gly Gly Glu Arg Aεp Arg Aεp Arg Ser He Arg Leu Val Asi Gly Ser 710 715 720 Leu Ala Leu He Trp Asp Aεp Leu Arg Ser Leu Cys Leu Hie Ser Tyr 725 730 735 His Arg Leu Arg Aεp Leu Leu Leu He Val Thr Arg He Val Glu Leu 740 745 750 755 Leu Gly Arg Arg Gly Trp Glu Ala Leu Lys Tyr Trp Trp Asn Leu Leu 760 765 770 Gin Tyr Trp Ser Gin Glu Leu Lys Asn Ser Ala Val Ser Leu Leu Asn 775 780 785 Ala Thr Ala He Ala Val Ala Glu Gly Thr Aεp Arg Val He Glu Val 790 795 800 Val Gin Gly Ala Cys Arg Ala He Arg His He Pro Arg Arg He Arg 805 810 815 Gin Gly Leu Glu Arg He Leu Leu 820 825 (2) INFCK4AITCN FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1497 base pairs (B) TYPE: nucleic acid (C) SIRANEEINESS: single (D) TOPOLOGY: linear (ϋ) M3LECUIE TYPE: cENA (iϋ) HXKJJwHETlCAL: NO (iv) MOT-SENSE: NO (ix) FEATURE: (A) NAME^KEY: CDS (B) IOCAIICN: 1. .1494 (ix) FEATURE: (A) NAME KEY: mi≤c_feature (B) IOCAIICN: 1 (D) OTHER INFCK-BITCN: /note *** "soluble HIV g ^O" (xi) SEQUENCE ΠES KIPHCN: SEQ ID NO: 3: ATG GM GCA ATG AAG AGA GGG CTC TGC TGT GIG CIG CTG CIG TGT GGA 48 Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 GCA GTC TTC GTT TOG CCC AGC CAG GAA ATC CM GCC 03A TTC AGA AGA 96 Ala Val Hie Val Ser Pro Ser Gin Glu He His Ala Arg Hie Arg Arg 20 25 30 GGA GCC AGA TCC ATG GTA GCT GIG TGG AAG GAA GCA AX AX ACT CTA 144 Gly Ala Arg Ser Met Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu 35 40 45 TTT TGT GCA TCA GM GCT AAA GCA TAT GM ACA GAG GTA CAT AM GTT 192 Hie Cys Ala Ser Aεp Ala Lys Ala Tyr Aεp Thr Glu Val His Asn Val 50 55 60 TGG GCC ACA CM GCC TGT GTA CCC ACA GAC CCC AAC CCA CAA GAA GTA 240 Trp Ala Thr His Ala Cys Val Pro Thr Aεp Pro Asn Pro Gin Glu Val 65 70 75 80 GTA TTG GTA AM GTG ACA GAA AM TTT AAC ATG TG AAA AM GAC AIG 288 Val Leu Val Aεn Val Thr Glu Asi Hie Aεn Met Trp Lys Asn Aεp Met 85 90 95 GTA GAA CAG AIG C GAG GM MA ATC AGT TTA TGG GM CAA AGC CTA 336 Val Glu Gin Met His Glu Asp He He Ser leu Trp Asp Gin Ser Leu 100 105 HO AAG GCA TGT GTA AAA TTA AX GCA CTC TGT GTT AGT TTA AAG TGC ACT 384 Lys Pro Cys Val Lys leu Thr Pro Leu Cys Val Ser Leu Lys Cys Thr 115 120 125 GMTTGAAGAMGMACTAMAΩ AMAGTAGTAXGGGA-ΑAIGAIA 432 Asp Leu Lys Asn Asp Thr Asn Thr Asi Ser Ser Ser Gly Arg Met He 130 135 140 ATGGAGAAAGGAC-AGATAAAAAACTGCTCT'TTCAMMCAGCA 480 Met Glu Lys Gly Glu He Lys Asn Cys Ser Phe Aεn He Ser Thr Ser 145 150 155 160 MA AGA GST AAG GTG CAG AAA GAA TAT GCA TTT TTT TAT AAA CTT GM 528 He Arg Gly lys Val Gin lys Glu Tyr Ala Hie Hie Tyr Lys Leu Asp 165 170 175 ATA ATA GCA ATA GM AM GM ACT AX AGC TAT AAG TTG ACA AGT TGT 576 He He Pro He Asp Asn Aεp Thr Thr Ser Tyr lys Leu Thr Ser Cys 180 185 190 AAC AX TCA GIC ATT ACA CAG GCC TGT CCA AAG GTA TCC TTT GAG OCA 624 Asn Thr SerVal HeThrGlnAlaCs Pro lysVal Ser Fhe Glu Ifco 195 200 205 AIT CCC ATA CM TM TGT GCC COG GCT GST TTT GGG ATT CTA AAA TGT 672 He Pro He His Tyr Cys Ala Pro Ala Gly Hie Ala He leu Lys Cys 210 215 220 AMAMAAGAOGTTCAMGGAACAα^Cr^TGTACAAMGICAXACA 720 Asn Asn Lys Thr Hie Asn Gly Thr Gly Pro Cys Thr Asn Val Ser Thr 230 235 240 GIA CAA TGT ACA CM GGA ATT AGG GCA GTA GTA TCA ACT CAA CTG CTG 768 ValGlnCysThrHisGlyHeArgRroValVal S^rTrιrG_lnLeuLeu 245 250 255 TTA AM GGC AGT CTA GCA GAA GAA GAG GTA GTA ATT AGA TCT GTC AM 816 Leu Asi Gly Ser Leu Ala Glu Glu Glu Val Val He Arg Ser Val Aεn 260 265 270 TTC AX GAC AM GCT AAA A ADA ATA GTA CAG CIG AAC ACA TCT GTA 864 Phe Thr Asp Asn Ala Lys Thr He He Val Gin leu Asn Thr Ser Val 275 280 285 GAA ATT AM TGT ACA AGA GX AAC AAC AM ACA AGA AAA AGA ATC GGT 912 Glu He Asn Cys Thr Arg Pro Asn Aεn Asn Thr Arg lys Arg He Arg 290 295 300 AIC CAG AGA GSA GCA GGG AGA GCA TTT GTT ACA AIA GSA AAA ATA GSA 960 He Gin Arg Gly Pro Gly Arg Ala Phe Val Thr He Gly lys He Gly 305 310 315 320 AM MG AGA CAA GCA CM TGT AAC ATT AGT AGA GCA AAA TGG AM AAC 1008 As Met Arg Gin Ala His Cys Aεn He Ser Arg Ala lys Trp Asi Asi 325 330 335 ACT TTA AAA CAG AIA GCT AGC AAA TTA AGA GAA CAA TTT GGA AM AM 1056 Thr Leu Lys Gin He Ala Ser Lys Leu Arg Glu Gn Hie Gly Aεn Asn 340 345 350 AAA ACA ATA ATC TTT AAG CAA TCC TCA GGA GGG GAC CCA GAA ATT GTA 1104 Lys Thr He He Hie lys Gin Ser Ser Gly Gly Asp Pro Glu He Val 355 360 365 AGG CAC AST TTT AM TGT GGA GGG GAA TTT TTC TAC TGT AM TCA ACA 1152 Thr His Ser Phe As Cys Gly Gly Glu Hie Hie Tyr Cys Aεn Ser Thr 370 375 380 CAA CIG TTT AM AGT ACT TG TTT AM AGT ACT TGG AGT ACT GAA GGG 1200 Gin Leu Hie Asn Ser Thr Trp Hie Asn Ser Thr Trp Ser Thr Glu Gly 385 390 395 400 TCA AM AAC ACT GAA GSA AGT GAC ACA ATC AX CTC GCA TGC AGA ATA 1248 Ser Asn Asn Thr Glu Gly Ser Asp Thr He Thr Leu Eto Cys Arg He 405 410 415 AAACAAAITAIAAACAIGTGSCAGAA C^C-tGAAAAGCAATC 1296 I^C^HeHeAsnMetTrpGlnlysVal GlylysAlatfetTyrAla 420 425 430 GCT GGC AIC AGT GSA CAA ATT AGA TGT TCA TCA AM ATT ACA GGG CTG 1344 Pro Pro He Ser Gly Gin He Arg Cys Ser Ser Asi He Thr Gly leu 435 440 445 CTA TTA ACA AGA GM GST GST AM AGC AAC AM GAG TGC GAG ATC TTC 1392 Leu Leu Thr Arg Aεp Gly Gly Asn Ser Aεn Aεn Glu Ser Glu He Hie 450 455 460 AGA CUT GGA GGA GSA GM ATG AGG GACAM TGG AGA AGT GAA TTA TAT 1440 Arg Pro Gly Gly Gly Aεp Met Arg Aεp Aεn Trp Arg Ser Glu Leu Tyr 465 470 475 480 AAA TAT AAA GTA GTAAAAATT GAA CCA TTA GGA GTA GCA CCCAX AAG 1488 lys Tyr Lys Val Val Lys He Glu Pro leu Gly Val Ala Efco Thr Lys 485 490 495 CTT AST TAA 1497 Leu Ser (2) INECK1ATTON FOR SEQ ID NO: 4: (i) SEQUENCE CHARACTERISTICS: (A) IFNGTH: 498 amino acids (B) TYPE: amino acid (D) -TOPOLOGY: l inpar (ii) M2LECUIE TYPE: protein (xi) SEQUENCE E-ES Xl i'lCN: SEQ ID NO: 4: Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu eu Cys Gly 1 5 10 15 Ala Val Hie Val Ser Pro Ser Gin Glu He His Ala Arg Phe Arg Arg 20 25 30 Gly Ala Arg Ser Met Val Pro Val Trp lys Glu Ala Thr Thr Thr Leu 35 40 45 Hie Cys Ala Ser Aεp Ala lys Ala Tyr Asp Thr Glu Val His Asn Val 50 55 60 Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro Gin Glu Val 65 70 75 80 Val leu Val Asn Val Thr Glu As Hie Asn !fet Trp lys Asn Asp Ifet 85 90 95 Val Glu Gin Met His Glu Asp He lie Ser Leu Trp Aεp Gin Ser leu 100 105 HO lys Pro Cys Val lys leu Thr Pro Leu Cys Val Ser leu lys Cys Thr 115 120 125 Asp Leu Lys Asn Asp Thr Asi Thr Asn Ser Ser Ser Gly Arg Met He 130 135 140 Ifet Glu Lys Gly Glu He Lys Asi Cys Ser Phe Asn He Ser Thr Ser 145 150 155 160 He Arg Gly Lys Val Gin Lys Glu Tyr Ala Phe Hie Tyr Lys Leu Aεp 165 170 175 He He Pro He Aεp Aεn Aεp Thr Thr Ser Tyr lys Leu Thr Ser Cys 180 185 190 Asn Thr Ser Val He Thr Gin Ala Cys Pro Lys Val Ser Hie Glu Pro 195 200 205 He Pro He His Tyr Cys Ala Pro Ala Gly Hie Ala He leu Lys Cys 210 215 220 Asn Asn Lys Thr Hie Asn Gly Thr Gly Pro Cys Thr Asn Val Ser Thr 225 230 235 240 Val Gin Cys Thr His Gly He Arg Pro Val Val Ser Thr Gin leu leu 245 250 255 leu Asn Gly Ser leu Ala Glu Glu Glu Val Val He Arg Ser Val Asn 260 265 270 Phe Thr Asp Asn Ala lys Thr He He Val Gin Leu Asn Thr Ser Val 275 280 285 Glu He Aεn Cys Thr Arg Pro Asi Asi Asi Thr Arg Lys Arg He Arg 290 295 300 He Gin Arg Gly fto Gly Arg Ala Hie Val Thr He Gly lys He Gly 305 310 315 320 Aεn Met Arg Gin Ala His Cys Aεn He Ser Arg Ala lys Trp Asn Asn 325 330 335 Thr Leu Lys Gin He Ala Ser lys Leu Arg Glu Gin Phe Gly Asn Aεn 340 345 . 350 Lys Thr He He H e Lys Gin Ser Ser Gly Gly Asp Pro Glu He Val 355 360 365 Thr His Ser Phe Asn Cys Gly Gly Glu Hie Hie Tyr Cys Asn Ser Thr 370 375 380 Gin Leu His Asn Ser Thr Trp Hie Asn Ser Thr Trp Ser Thr Glu Gly 385 390 395 400 Ser Asn Asn Thr Glu Gly Ser Asp Thr He Thr leu Pro Cys Arg He 405 410 415 ^ Gl H He Asi Met Trp Gln lys Val Gly Lys Ala 420 425 430 Pro Pro He Ser Gly Gin He Arg Cys Ser Ser Asi He Thr Gly leu 435 440 445 Leu Leu Thr Arg Asp Gly Gly Asn Ser As Asi Glu Ser Glu He Hie 450 455 460 Arg Pro Gly Gly Gly Aεp Met Arg Ptsp Asi Trp Arg Ser Glu leu Tyr 465 470 475 480 lys Tyr Lys Val Val Lys He Glu Pro Leu Gly Val Ala Ifco Thr Lys 485 490 495 Leu Ser (2) INFORMMTCN FDR SEQ ID NO: 5: (i) SEQUENCE CHARACIIKESITCS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) STRANCEINESS: single (D) TOPOLOGY: lijpλr (ϋ) MTfrrmEE TYPE: CCNA (iii) HYPOTHETICAL: NO (iv) ANII-SENΞE: O (ix) FEATURE: (A) NAME^KEY: misc_feature (B) IOCAIICN: 1 (D) σiHER INECIWAIICN: /no _e= "WJOl PCR primer"'' (xi) SEQUENCE DESCRπTION: SEQ ID NO: 5: AGST5MARCT GCAGSAGTCW GG 22 (2) INFDEMAHCN FOR SEQ ID ND:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 32 base pairs (B) TYPE: nucleic acid (C) STRANCEINESS: single (D) TOPOIDGY: linear (ii) M3LECULE TYPE: cENA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NSME KEY: misc_feature (B) IOCAIICN: 1 (D) OTHER INFORMMION: /note= "-VKE PCR primer* (xi) SEQUENCE CESCRIPITCN: SEQ ID NO: 6: TGAGGAGACG GIGAXSTGG TOXTTGSX 32 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE OIARACIERISITCS: (A) LENGTH: 2755 base pairs (B) TYPE: nucleic acid (C) SIRANCECNESS: single (D) TOPOLOGY: circular (ϋ) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (ix) FEATURE: (A) NAME KEY: mi≤c_feature (B) IOCAIICN: 1 (D) OTHER INFCRJAITCN: "ςtXI03" (xi) SEQUENCE EESCRIPITCN: SEQ ID NO:7: 'lαJUUUUl'l CGSIGAIGAC G3IGAAAAX TCTGAQOT QCAGCIϋ UG GA3AD3GICA 60 CAGCTTGTCT GTAAGOGSM GOOGSGAGCA GACAAGOXG TCA-GGOGCG TCAGCGGGTG 120 TTGGGGSSTG H.UXIJLIU , C IAACTATG CG3CAICA3A GCAGATIGTA CTGAGAGIGC 180 AGCATAIGCG GIG GAAATA GOGCACAGM GCGTAAGGAG AAAATAXGC A__ CA3GCGGC 240 ATTCGOCAIT CA3GCTGCGC AA l TlUULi AA33GCGAIC (Jϋl lX-rayr TCTTCGCTM 300 TACGCCAXT GSϋGAAAGSS GSMUIUCIU CAAGSCGATT .AAGITG33TA AOSCCAGSST 360 TTTOCCAGIC ACGACGTTGT AAAACGACGG- CCPGICCCPA C^πAGCGGCC GOGGTCCAAC 420 CACOΛICTC AAAGCΓΓGST ACCCGGSAM TCAGAICTGC AGCAIGCICG AGCTCΓAGM 480 MΌGMTCCA TQGATOCICA CATCCTAATC axo aaG AΠDSIAAIC AIQGΓCΆTAG 540 CIUI II UI TGIGAAAITG TTAICCGCTC Pa TCCPC AaAOOACG AGCCOSAA3C 600 A3AAAGTGTA A OTi aG TGCCTAATGA GIGAGCTAAC TCACAITAM lUOJl'lUJUt 660 TO UπXU TlvJCfiGIC GSSAAAXIG TtXIGCCAX --DX T TG AMDGSCCAA 720 σXEOGGGSA GK-GCGGITT GOGTAΓIQGG (JLJ l'lUL i CTlU lULJ r CACIGACICG 780 CTGCGCIOGG HJmHJU GGGS0GA3GG GTAICAGCIC ACICAAA33C GSTAMAOGS 840 -ITA XAGAG AATCAGSSSA TAAGGCAGSA AAGAACAIGT GAGCAAAAGG CCAGCAAAAG 900 GCCA3GAAX GIAAAAAOGC GGCGITGCIG GCGTTTTTCC A__LAGSCTCOG COJGXIGAC 960 GAGCATCACA AAAAIGGAOG CTCAAGTCAG AGGTGGCGAA AXQGACAGS ACTATAAAGA 1020 TACCA230GT TK. U7IGG AAGCTCCCTC GTGUUCIVJHJ CIGTΪCOGAC u UJL l 1 1080 AOOGGAiaα: αmu m Γ TercrmcG GGAAGOGIGG UU I I ICA TPC TCPCGC H40 TGTAGGTAIC TOCIICGST GTAUJI UIT OXICCAAGC TQ33CTGIGT GCAXAAXC 1200 CGOSTTCAGC ra taCIG CGULTIMCC GSTAACTAIC GICTIGAGTC CAAXGGSTA 1260 AGACACGACT TATOGOCACT GQCAGCAGX ACTGSTAACA GΞATTAGCAG A30GA3GTM 1320 GTAGGGG TG CTACAGAGTT CITUAAGTGG TGGCCTAACT ACGGCIACAC TAGAAGAACA 1380 GIA TIUSIA I lUOXTCT GCTGAAGGCA ϋllAL-Jl'ivJG GAAAAAGAGT TGSTAS 'I T 1440 TGAICtl^yA AACAAAXAC OGCIGSTAGC ?l» L?lT iT TmiTlGLAA GCA3CAGATT 1500 AGGOGCAGAA AAAAAGGAIC TCAAGAAGM C TTIGAI TiTClAXGG GICTGACGCT 1560 CAGTGGAACG AAAACTCAOG TTAAGSSATT TTGGTCAIGA GATTA CAAA AAGGAICTTC 1620 ACOTAGATCC TTTTAAATTA AAAATGAAGT TTTAAATCAA TCIAAAGTAT AIAIGAGTAA 1680 ACΠGGTCIG ACAGTΓAXA AIGCTTAAIC ASIGAGGCAC CΠAICICAX GATCIGIUTA 1740 TTICCTICAT COOASRIGC CIGACTCΑX GICGTGTAGA TAACTACGM AOG3SA3GGC 1800 TTAXAICIG GOXCAGTGC TGCAAIGATA OXCGAGAX CAXCTCAX GGCTCCAGM 1860 TTAICA3CAA TAAAXA3X AGCCGGAAGS GCCGAGCGCA GAAGIGGTX TGCAACTTTA 1920 TCTJGUCIU-A lUJAJlL'lAT TAA IGIIUC CGGGAAGCTA GAGTAAGTAG TTDGCCAGIT 1980 AATAGTTTGC GCAAOGITGT TGCCAIT3CT ACA3GCATOG lUJlGlCAX CK.GTCGTTT 2040 GGTAIG CTT CAITCAGCTC CGGTTCCCAA CGAICAASGC GAGTTACAIG MCCCGCMG 2100 TIGTGCAAAA AAGCGSTTAG OCCΓICQGT CEKΌGMOG TTGICAGAAG TAAGΓIGGCC 2160 GCAGIGTTM CACICATGST TAIGSCAGCA CIGCMAATT CICTTACTGT CAIGGCMGC 2220 GIAAGATGCΓ T IULUIGAC TGSTGAGTAC TCAAXAAGT CA I I AGA ATASEGTAIG 2280 O330GAXGA GITGCTCTTG U.U-U IJllA AIAGQGGATA ATAOOGCGX ACAIAGCAGA 2340 ACITTAAAAG TGCTCMCM TGGAAAAGGT TCITOGQGGC GAAAAOTCIC AAGGAICTTA 2400 u LJUiuriiA GAICCAGΓΓC GAIGTAAXC ACIOGIGCAC CΓAACIGATC TICAGCAICΓ 2460 TTTACTTTCA OCAGOSTTTC TGSSTGAGCA AAAACAGGAA GSCAAAATGC GGCAAAAAAG 2520 GGAAmAΩG OGACAΩGGAA AIGTTGAATA CTOflACTCT TCCITTTTCA AIAmiTGA 2580 AXATTTAIC AGGGTTATTG TCICMGAGC GSAIACAIM TTGAATGTM TTAGAAAAM 2640 AAACAAATAG U Jl'lULUJ ; CACAITTOX OGAAAAGIGC CAOIDGACGT CTAAGAAAX 2700 AITATTAICA TGACAITAAC CTAIAAAAM AGGGSTAICA CGAJGUU TT TCJGTC 2755 (2) INFOFMATTCN FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 365 base pairs (B) TYPE: nucleic acid (C) STRANCEΣNESS: single (D) TOPOLOGY: linear (ii) MOLECUIE TYPE: CENA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME KEY: misc_feature (B) IOCAHCN: 1 (D) OTHER INFC KCICN: /note *** /* pMEP904 inse_rt' , (xi) SEQUENCE EESCRIPITCN: SEQ ID NO: 8: A33IGAAGCT GCA3GA3TCT QGACOTGAAC TGSIAAAGX TGSSGCTIC^ 60 CCIGCAAGGC TTCIGGAIAC ACATTCAC A GCTMGTTM ACACTGSSTG AGGCAGAAGC 120 CIGSSCAGGG CCTTGACIGS ATTGGAIATA TTAATXTTA CAATGATGGT AC GA IACG 180 AIGAGAAGTT CAAAGGCAAG C--XACACIGA CTTCAGACAA AICCICCAGC ACAGGCTA___A 240 TGGA3CICA3 CAGCCTGAX TCIC-AGGACT CTGCGSTCTA TTACIGIGCA AGA_3A3AAQG 300 ATAACTAOGC GAXGSSSX TQGITTGCTT ACTGGGGCCA AQGSACCAOG GICACQGTCT 360 CCICA 365 (2) INFC MTCN FOR SEQ ID NO:9: (i) SEQUENCE OlARACTERISriCS : (A) IΣNGTH: 366 base pairs (B) TYPE: rucleic acid (C) SΓRANE-ETNESS: single (D) TOPOLOGY: linpar (ϋ) MDIICULE TYPE: cENA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAMEKEY: CDS (B) LCCAHCN: 1..366 (ix) FEATURE: (A) NAME^KEY: misc_feature (B) IOCAIICN: 1 (D) CdHER INFCKflAITCN: /note= "5A8 heavy chain variable regiατ' r (xi) SEQUENCE EESCRLPITCN: SEQ ID NO: 9: GAG GIG AAG CIG CAG GAG TCT GGA OCT GAA CIG GTA AAG GCT GGG GCT 48 Glu Val Lys Leu Gin Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 TCA GIG PPG ATG TCC TGC AAG GCT TCT GGA TAC ACA TTC ACT AGC TAT 96 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 GTT ATA CAC TG GIG AGG CA3 AAG GCT GGG CAG GGC CTT GAC TGG ATT 144 Val He His Trp Val Arg Gin lys Pro Gly Gin Gly Leu Aεp Trp He 35 40 45 GGA TAT ATT AM GCT TAC AM GM GGT ACT GAC TAC GM GAG AAG TTC 192 Gly Tyr He Asn Ffco Tyr Asi Aεp Gly Thr Aεp Tyr Asp Glu lys Hie 50 55 60 AAAGGCAAGG ACACIGACTTCAGACAAATGCTXAGCACAG^ 240 Lys Gly lys Ala Thr leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 ATG GAG CTC AGC AGC CTCAXTCTGAGGACTCTGXGTCT TACTGT 288 Met GDLu leu Ser Ser Leu Thr Ser Glu Aεp Ser Ala Val Tyr Tyr Cys 85 90 95 GCA AGA GAG AAG G AACTACGXACGG3GGXTG3TTTGCTIACTCC 336 Ala Arg Glu lys Psp Asi Tyr Ala Thr Gly Ala Trp Hie Ala Tyr Trp 100 105 HO GGC CAA GGG AX ACS GTC AX GIC TCC TCA 366 Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 (2) INFCf»MATION FOR SEQ ID NO: 10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 122 amino acids (B) TYPE: amino acid (D) TCΦQLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE I-ESCRIPITCN: SEQ ID NO: 10: Glu Val lys Leu Gin Glu Ser Gly Pro Glu leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val lys Ifet Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Val He His Trp Val Arg Gin Lys Pro Gly Gin Gly Leu Asp Trp He 35 40 45 Gly Tyr He Asi Pro Tyr Asi Asp Gly Thr Aεp Tyr Asp Glu Lys Hie 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ser Asp lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Lys Aεp Asn Tyr Ala Thr Gly Ala Trp Phe Ala Tyr Trp 100 105 HO Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 (2) INFO-MAITON FOR SEQ ID ND:H: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 27 base pairs (B) TYPE: rucleic acid (C) SIRANEELNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: c£NA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME^KEY: ιtύ≤c_featu_re (B) IOCAIICN: 1 (D) OTHER INFCR-KEICN: /note= "ACE149 PCR primer* (xi) SEQUENCE DESCRIPTION: SEQ ID NO:H: OGSAIATOG TAATGACXA GKTCCA 27 (2) INFCK-KEICN FCR SEQ ID ND:12: (i) SEQUENCE CHARA LEKl TlCS : (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) STRANTFTHESS: single (D) TOPOLOGY: linear (ϋ) MOLECULE TYPE: cCNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) iα__ATICN: 1 (D) OTHER 3NFC 4AIΪ.ON: /note= * A-EL50 PCR primer* (xi) SEQUENCE DESCKEPITON: SEQ ID NO: 12: GITAGATCIC CA3CITGGTC X 22 (2) INFCREiπCN FCR SEQ ID ND:13: (i) SEQUENCE CHARACLERISTTCS: (A) IENGTH: 340 base pairs (B) TYPE: nucleic acid (C) SLRANEEINESS: single (D) TOPOLOGY: l inerir (ii) MOLECULE TYPE: cCNA (iii) HYPOTHETICAL: NO (iv) ANTI-SEN5E: O (ix) FEATURE: (A) NSME/KEY: misc_feature (B) IOCAIICN: 1 (D) OTHER INFC ft-LTCN: /note= "pMCR927 insert" (xi) SEQUENCE DESCRIPIICN: SEQ ID NO:13: CIGGMKDCG TA IGAXCA GICIO ΑTC TOTIAGCIG 'I T AjliU-. AfflGAMGFT 60 AClATGATCT GCAAGIOCAG TXSGPG L'L' TTATATAGIA CCAAICAAAA GAACTACTTG 120 GOCIGGTAGC AGCAGAAAX AGGGCAGTCT CCTAAACTSC TGATITACTG GGCAICCACT 180 AQGGAAICIG J l LUlLA TU- iACA GGCAGIGGM CIGSSACAGA TTTCACICIC 240 AXAICAGCA GIGTGAAGGC TGAACiACCTG GCAGTTTATT ACTGTCAGCA AIAITAIAGC 300 TATCGSAOGT TCGSIGGAGG GAXAAGCTG GAGAICTAAO 340 (2) πSCFMAITC FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 336 base pairs (B) TYPE: nucleic acid (C) SIRANHΣNESS: single (D) TCfEOLOGY: linear (ϋ) MOLECULE TYPE: CDNA (iii) HYPOTHETICAL: NO (iv) ANH-SENSE: NO (ix) FEATURE: (A) NMfl-ξ/KEY: CDS (B) IOCAIICN: 1..336 (ix) FEATURE: (A) NAME^KEY: misc_feature (B) IOCAIICN: 1 (D) OTHER INFCfWAIICN: /note= "SAB light chain variable region* (xi) SEQUENCE DESCRIPITCN: SEQ ID NO: 14: GM MC GTA AIG ACC CAG TCT GCA TCC TCC CTA GCT GIG TCA GTT GSA 48 A^HeVallfetThrGlnSerRroSerSerLeuAlaVal SerValGly 1 5 10 15 GAG AAG GTT ACT AIG AIC TGC AAG TCC AGT CAG AX CTT TTA TAT AGT 96 Glu Lys Val Thr Met He Cys lys Ser Ser Gin Ser Leu Leu Tyr Ser 20 25 30 AXAM<^A j^T CTTGGXTGGT CC GC GAAAC GQGCra 144 Thr Asi Gin lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45 TCT CUT AAA CIG CIG ATT TAC TGG GCA TCC ACT AGG GAA TCT GGG GTC 192 Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 GCT GM GGC TTC ACA GGC AGT GGA TCT GSS ACA GM TTC ACT CTC AX 240 Pro Asp Arg Hie Thr Gly Ser Gly Ser Gly Thr Asp Hie Thr Leu Thr 65 70 75 80 ATC AGC AGT GTG AAG GCT GAA GAC CTG GCA GTT TAT TAC TGT CAG CAA 288 He Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gin Gin 85 90 95 TM-IMAXTMOGSACGTTCGCTGSAGSSAGCAAGCIGGAGA_^ 336 Tyr Tyr Ser Tyr Arg Thr Hie Gly Gly Gly Thr Lys Leu Glu He lys 100 105 HO (2) IN -RMATTCN FCR SEQ ID NO: 15: (i) SEQUENCE CHARAO_ERISTICS: (A) LENGTH: 112 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPI'ICN: SEQ ID NO: 15: AspHeVal etTrarGlnSerProSerSerLeuAlaVal SerValGly 1 5 10 15 Glu Lys Val Thr Met He Cys Lys Ser Ser Gin Ser Leu Leu Tyr Ser 20 25 30 Thr Asn Gin lys Asi Tyr leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45 Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Hie Thr Gly Ser Gly Ser Gly Thr Asp Hie Thr Leu Thr 65 70 75 80 He Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gin Gin 85 90 95 Tyr Tyr Ser Tyr Arg Thr Hie Gly Gly Gly Thr lys Leu Glu He Lys 100 105 HO (2) INFCRKEICN FCR SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 58 base pairs (B) TYPE: r-ucleic acid (C) STRANΠEΓNESS: single (D) TOPOLOGY: linear (ii) MDϋCϋlE TYPE: cCNA (iii) HYPOTHEHCAL: NO (iv) ANIΪ-5EN3E: NO (ix) FEATURE: (A) NAME/KEY: mi≤c_feature (B) LOCAHCN: 1 (D) OTHER INFORMAIICN: /note= *312-56 PCR primer* (xi) SEQUENCE IXSCRIPTTCN: SEQ ID NO: 16: GIGCAGCTGC AGSAGICIGS AGCTGAAGTG AAAAAGCCTG GUU L'V PGT GAAGSTGT 58 (2) INFOEMAITCN FCR SEQ ID ND:17: (i) SEQUENCE CHARACTERISTICS: (A) IENΞTH: 49 base pairs (B) TYPE: nucleic acid (C) SIRMCECNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: c£NA (iii) HYPOTHETICAL: NO (iv) ANϋ-SENSE: NO (ix) FEATURE: (A) NAME KEY: misc_feature (B) ICCATICN: 1 (D) OTHER INFORMATICN: /note= *312-57 PCR primer* (xi) SEQUENCE IXSCRTPITCN: SEQ ID NO: 17: AGGATTAAIA TAICCAAICC ACICAAGGX CIGCTXA3GC GCCIGCCIC 49 (2) INFCRMAITCN FOR SEQ ID ND: 18: (i) SEQUENCE CHARACTERISTTCS: (A) LENGTH: 47 base pairs (B) TYHS: nucleic acid (C) Sπ»ANDECNESS: single (D) TCPOIOGY: linear (ϋ) MOLECULE TYPE: cCNA (iii) HΏΌ HEITCAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME^KEY: misc_feature (B) IOCAIICN: 1 (D) OTHER INFCfMAIICN: /note= *312-58 PCR primer* (xi) SEQUENCE EES RI l'lON: SEQ ID NO: 18: TGSS GAGGC AGGCGCCIGG GCA3GSGCTT GAGTG AITG GAIATAT 47 (2) INFGFMAHCN FOR SEQ ID NO: 19: (i) SEQUENCE CHARACHRISπCS: (A) IENGTH: 75 base pairs (B) -TYPE: nucleic acid (C) ST-RANTF TESS: single (D) TOPOLOGY: linear (ϋ) MOLECULE TYPE: dUA (iii) HYPOTHETICAL: NO (iv) ANH-SENSEr NO (ix) FEATURE: (A) NAME KEY: misc_feature (B) IOCATICN: 1 (D) OTHER INPO MAIICN: /note= *312-59 PCR primer* (xi) SEQUENCE EESCRIPITON: SEQ ID NO: 19: GAXGCAGTG TCCTCAGAX TCAGGCTGCT GAGCTGCAIG TAGGCIGTGT TQGIQGAIGG 60 GTCTAAAGTC ACTGT 75 (2) INECK-AIICN FCR SEQ ID NO: 20: (i) SEQUENCE CHARACIERISITCS: (A) IENGTH: 75 base pairs (B) TYPE: nucleic acid (C) STRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cCNA (iii) HYPCαHE-TTCAL: NO (iv) MJH-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feat-jre (B) IOCAIICN: 1 (D) OTHER INFC -KriCN: /nσte= "312-60 PCR primer* (xi) SEQUENCE EESCRIPITON: SEQ ID NO: 20: AGGCCACAGT GACITTAGAC GCMCCAGCA A3 GCCTA CP3ΩC3CCTC AGCAGO TGA 60 GGICIGAGSA CACIG 75 (2) INPOFMOTCN FCR SEQ ID NO: 21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 55 base pairs (B) TYPE: nucleic acid (C) STRAMDEΣNEΞS: single (D) TCfOLCGY: linear (ϋ) MOLECULE TYPE: cENA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME KEY: misc_feature (B) LOCAΠCN: I (D) OTHER INFOWAHCN: /note= *312-61 PCR primer* (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21: AGAOSSIGAC CAGGGICGCT 330CCCPGT AAGCAAAXA αrπ:u:.SrC GOSTA 55 (2) INFC JAΣTICN FCR SEQ ID NO: 22: (i) SEQUENCE CHARAC .' I ΗRlfa lGS : (A) LENGTH: 331 base pairs (B) TYPE: nucleic acid (C) STRANCEDNESS: single (D) TOPOLOGY: linear (ii) M3LECUIE TYΪE: cCNA (iϋ) HΪHJIHEI'ICAL: NO (iv) MJπ-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feat-jre (B) LOCATICN: 1 (D) OTHER INECf»MATTC-N: /net- * * ** * *pM[_R989-15 insert" (xi) SB3UENCE IESC-RTPTICN: SEQ ID NO: 22: AAGIGAAAAA aUUJ- .T TCAGIGAAGG lUlJCTGCAA U Cl'l- lUA TAGACAITCA 60 OTAGCTAIGT TATACACIGG GIGAGGCAGA AGCCIGGSCA GQGCCITGAC TOGAITGGM 120 A3ATTAATCC TTACAATGM C-GTACIGACr ACGAIGAGAA GTTCAAAGSC AAGGCCACAC 180 TGACTTCAGA CAAAT CTCC AXACAG T ACATGSAGCT CAGCAGGCTG ACCTCIGAQ3 240 ACTOTGCGST OTAITACIGT GCAAGAGAGA A3ΞATAACTA CGOGACGGGS GGCTGGTTTG 300 CTTACIGSSG GCAAGGSACT C-GICAXGTC T 331 (2) INFC IAIICN FOR SEQ ID ND:23: (i) SEQUENCE CHARACI LS'I'ICS : (A) IENGTH: 358 base pairs (B) TYPE: rucleir. acid (C) STRANEEIKESS: single (D) -ICKJLOGY: l in p ar (ii) MOLECULE TYPE: CCNA (iii) HYPOTHETICAL: NO (iv) MHI-SENSE: O (ix) FEATURE: (A) NAME KEY: miscjEeature (B) LOCATION: 1 (D) OTHER INFCRMAΠON: /note= "p}f_R991 insert* (xi) SEQUENCE DESC LPITON: SEQ ID NO: 23: GIGC?CCTGC A3G J1U1UJ AGCTGAAGIG AAAAAGOCTG (U.V 1- PGT GAAJ ?imU 60 TGCAAGGCTT CIGGAIACAC AITCACIAGC TMGTTATAC ACIGSSTGAG QCAGGCGCCT 120 QGGCAGGSOC TIGAGTGGM TQGATATAIT AAIUJI'IACA ATGATGSIAC TGAZCACGM 180 GAGAAGITCA AAQGCAAGGC CACAGTGA C TTAGACOCAT CCAXAACAC AGCC ACAIG 240 GAGCICAQCA GCOTGAGSTC TC-AGGACACT GCGSICTATT ACIGIGCAAG AGA3A3GM 300 AACTA3GCGA (JUajaAVIU GITTGCITAC TG3GGCCAA3 QGAαriGST CAQCGTCT 358 (2) INFOEMAIICN FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 66 base pairs (B) TYPE: n Klein acid (C) STPANDEENESS: single (D) TOPOLOGY: linear (ii) MOIECULE TYPE: CCNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME ΗEY: mi≤c_feature (B) IOCAIICN: 1 (D) OTHER INFC ftlTCN: /note= "312-62 cjliga-ixieσtide" (xi) SEQUENCE DESCRIPTICN: SEQ ID NO: 24: GTAOJXTGS ATATUG1AM GAOXAGTCT CCAGAC1CX' TAGCT TUIC ACTItGSAGAG 60 A3GGCT 66 (2) INFDFMAIICN FOR SEQ ID NO:25: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 62 base pairs (B) TYPE: rucleic acid (C) STRANCEINESS: single (D) TOPOLOGY: linear (ϋ) MOLECULE TYPE: c£NA (iii) HYPOTHETICAL: NO (iv) .MϊIT-SENSE: NO (ix) FEATURE: (A) NAME^KEY: misc_feature (B) IOCAIICN: 1 (D) OTHER INFCRftHCN: /note= "312-63 oligcr iLecitide" (xi) SEQUENCE 1__ESCRIPTI.CN: SEQ ID NO: 25: ACTATAAACT GCAAGTGGAG TGGΞAGGCTT TTATATMTA GCAAICCAAA C-AACTACTTG 60 GC 62 (2) INFC MICN FOR SEQ ID ND:26: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 69 base pairs (B) TYPE: nucleic acid (C) STRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cENA (iii) HYPOTHETICAL: NO (iv) ANH-SENSE: NO (ix) FEATURE: (A) NAMζ/KEY: mi≤c_feature (B) IOCAIICN: 1 (D) OTHER INFC BIION: /note= "312-64 oligorucLeotide" (xl) SEQUENCE IISCRIPTICN: SEQ ID ND:26: CTGGTAXAG C_AGAAAGCAG gg J CIl ' TAAACTGCIG AITTACIGSG CAIPCACTAG 60 GSAAICBGS 69 (2) INFCEM TON FCR SEQ ID ND:27: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 72 base pairs (B) TYPE: rucleic acid (C) SIPANEEDNESS: single (D) TCSCI03Y: linear (ii) MOLECULE TYPE: cCNA (iϋ) HYKJIH I'ICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME^KEY: misc_feature (B) IOCMION: 1 (D) OTHER INFCFMAITCN: /note *** "312-65 ol__igcπrleotide" (xi) SEQUENCE EESCRIPITCN: SEQ ID ND:27: GG1U IGM (JJCIU I ^G GCAGIPGAIC TOGGACAGM TTCA l I A CQICAGCAG 60 TTTGCAGQCT GA " 72 (2) INFC MION FCR SEQ ID N0:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 69 base pairs (B) TYPE: r deic acid (C) SIRANEEΣNESS: single (D) TOPOLOGY: linear (ϋ) MOLECULE TYPE: cCNA (iii) HYPOTHETICAL: NO (iv) _»ΪIT-5ENSE: NO (ix) FEATURE: (A) NBMEyKEY: misc_feature (B) IOCAIICN: 1 (D) OIHER INFCRftlTCN: /note= "312-66 oligcπccleotide" (xi) SEQUENCE CESCRIETICN: SEQ ID NO: 28: A3A0STGGCA GITIA-L'JACT GTCAGCAMA TTATAGCTM CGΞAJGITCG GTCAAGQSAC 60 CAA3CIGGA 69 (2) INFOFMAITCN FCR SEQ ID NO: 29: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 67 base pairs (B) TYPE: rucleic acid (C) STRANCEDNESS: single (D) TCaPQLpSY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANH-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) IDCMICN: 1 (D) OTHER 3NFCFMKIICN: /note= "312-67 c jjgσn-Cleotide" (Xi) SEQUENCE DESCFUL ΓION: SEQ ID NO: 29: GAICTCCAX TlUϋlUUUlT GAXGAACGT CCGATAXTA TAAUfflGCT GACA3IAATA 60 AACTGX 67 (2) INFORMAIICN FOR SEQ ID NO: 30: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 71 base pairs (B) TYIE: nucleic acid (C) STRANCEINESS: single (D) TOPOLOGY: linear (ϋ) MOLECULE TYPE: cENA (iϋ) HYPOTHETICAL: NO (iv) ^JIT-SENSE: NO (ix) FEAIURE: (A) NMffi^KEY: misc_feature (B) IOCAIICN: 1 (D) OIHER INFCRKEION: /note= "312-68 cuαgcπLxΛeαtide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30: JiqTR2C CUIUCAAACT GC'lϋaimiG AGAGIGAAM ClUl J - ^A TQS^TO I' 60 GMAAGCG C 71 (2) INFC MICN FCR SEQ ID N0:31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 69 base pairs (B) TYPE: rucleic acid (C) STRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEAIURE: (A) NAME 'KEY: misc_featurε (B) IOCAIICN: 1 (D OTHER INFORMMICN: /note= "312-69 oligcπx-leotide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31: AGGGAOXCA GAITUITAG -IQGATGOXA GIAAAICAGC AG1T1AGSAG GCT ϋOIG 60 I l UUlϋ 69 (2) INFC -BIICN FOR SEQ ID NO: 32: (i) SEQJ3ENCE CHARACTERISITCS: (A) LENGTH: 63 base pairs (B) TYPE: rucleic acid (C) STRANCEINESS: single (D) TOPOIOGY: linear (ii) MOLECULE TYPE: cCNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) BESIUPE: (A) NBME/KEY: miscjEeature (B) IOCAHCN: 1 (D) OTHER INFCCMAITCN: /note= "312-70 αligcruclecitide" (xi) SEQUENCE I H RL l'lCN: SEQ ID NO: 32: GTAGCAGSX AAGTAGl'l r 'lTlGA J - 1 ACTATATAAA AGGOTCDCAC TGSAOTIGCA 60 GTT 63 (2) INFCR1AITON FOR SEQ ID ND:33: (i) SEQUENCE CHARACTERISTTCS: (A) IENGTH: 68 base pairs (B) TYJE: nucleic acid (C) SIRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYffi: cCNA (iii) HYPOIHEEECAL: NO (iv) ANTT-SEN3E: NO (ix) FEAIURE: (A) NAME^KEY: misc_feature (B) IOCAIICN: 1 (D) OTHER INFOFMAITCN: /note= "312-71 oligcπucleotide" (xi) SEQUENCE LlώCRJJ- lCN: SEQ ID NO: 33: TA_I_AGIAGGC CTCTCICCAA GIGACACAX TAGGGAGTCT GGAC-ACIGSS IIAI'IAOGM 60 ATGCAGGG 68 (2) INFOFMAITCN FOR SEQ ID NO: 34: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 344 base pairs (B) TYΣE: nucleic acid (C) SIRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cCNA (iii) HYPOTHETICAL: NO (iv) MJIT-SEN5E: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) IOCAIICN: 1 (D) OIHER INFORMAITCN: /note= ' * pMI__KL003 insert" (xi) SEQUENCE EESCRTPIICN: SEQ ID ND:34: GGTa tXCIG GAUATUJIAA TGACOCAGTC TDGA-ACIOC CIAGCIGTOT CACTIQGAGA 60 GA3GSCTACT AIAAACIGCA A 1U A 1U GA3GCTTTTA TMA3IAXA AICAAAAGAA 120 CTACTIGGX TUGT&XAGC AGAAAXAGG GCAGOOTCCT AAACTGCIGA TTTACTGSSC 180 ATOCACrAGG GAATOIGSGG TXOTGATCG CTTCICA3GC AGIGSAICIG GSACAGATTT 240 CACTCTCAX AICAGCAGTT TC-QGGCIGA AGAOJCGGCA GITIA 'IACT GICAGCAATA 300 TTMAGCTM CGΞAOSTTCG GICGA3GGAC CAAGCTGSAG PITCT 344 (2) T-NECREIICN FOR SEQ ID NO:35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 base pairs (B) TYPE: rucleic acid (C) SIRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cCNA (iii) HYPOTHETICAL: NO (iv) .MJTI-SENSE: NO (ix) FEAIURE: (A) NAME KEY: misc_feature (B) IOCATICN: 1 (D) OIHER INFCHftllCN: /note= "312-45 oligcrucLeotide" (xi) SEQUENCE DESCRIPITCN: SEQ ID NO: 35: GIACCGCGSC CGCADCAIGS ACTGSAXTG C__A23GTCTTC TUL HJUHJ^ C 51 (2) INFCEWAIICN FCR SEQ ID NO: 36: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 44 base pairs (B) TYPE: nucleic acid (C) STRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cENA (iii) HYPOTHETICAL: NO (iv) .M-HI-SENSE: NO (ix) FEAIURE: (A) NMffi/KEY: misc_feature (B) IOCAIICN: 1 (D) OTHER INFOPMAITON: /note= "312-50 oHgcπLicdeotide" (xi) SEQUENCE CESCRIPITCN: SEQ ID NO: 36: GMCCAAGCT TA23ACTCAC CIGAGGAGAC GGIGAXCIC GAGG 44 (2) INFCFMAIICN FOR SEQ 3D NO:37: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 144 base pairs (B) TYPE: rucleic acid (C) SIRANDEDNESS: single (D) TCfOLOSY: linear (ϋ) MOLECULE TYPE: CDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: roiεc_feature (B) IOCAIICN: 1 (D) OTHER INFCFMAIICN: /note= "pLCBδ insert" (xi) SEQUENCE CESCRIPIICN: SEQ ID ND:37: GIACmCGGC CGCACCAIGG ACIGGAOCTG GAAJJILTI- 'lULT'lUCIGG CDGIAGCACC 60 AGGIGGGCAC TCCCPG3TCC AACIGCAGIC TAGAGICGAC CICGAGSSTC AXGICICCT 120 GAGGIGA3IC CTAA3CTTGG AICC 144 (2) INFCRftTTCN FCR SEQ ID NO: 38: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 461 base pairs (B) TYPE: nucleic acid (C) SIRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECUIE TYPE: cCNA (iii) HYPOTHETICAL: NO (iv) ANIT-SENSE: NO (ix) EEMURE: (A) NAME^KEY: misc_feature (B) XailCN: 1 (D) OTHER INFCFMAITCN: "pI£S7 insert" (xi) SEQUENCE CESCRHTTCN: SEQ ID NO: 38: CHAXGCGGC Q3CACCAIQG ACIGGACCTG GAJULrlCl'l 'HJCJl'lGCIGG C1U1AGCACC 60 A3GIGGC AC TCCCA3GICC AACTSCA2GA GTC1UGAOCT GAAOTGSTAA AXCIGSQGC 120 TTCAOTGAAG AIGIC GCA AGGCTICIGS ATACACA TC ACIAGCTAIG TTA ACACIG 180 OHGAGSCAG AAGCOG33C AGSGGCITGA CIGGATTGGA TAIAITAAIC CITACAAIGA 240 TGGTACTGAC TAOGAIGAGA AGTTCAAAGG CMGGCCACA CTGACITCAG AGAAAICCTC 300 CAXACAGOC TACAIGGAGC TCAGCAGCCT GAfXICIGAG GAOICTGCGG TCTAITA0TG 360 TGCAA3AGA3 AAGSA AACT AOXGACGGG UJUUiUm GCTTACIGSS GCCAAGQGAC 420 CAO-GICAX GI ECCICAG GIGAGIXTA AGCTTGGAIC C 461 (2) INFCfMKEICN FOR SEQ ID NO: 39: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 461 base pairs (B) TYPE: rucleic acid (C) STRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cCNA (iii) HYPOTHETICAL: NO (iv) ANH-SENSE: NO (ix) FEMURE: (A) NMffi KEY: miεc_feature (B) IOCSTIC-N: 1 (D) OTHER INFCFMAHCN: /note *** "fcMKLOOl insert" (xi) SEQUENCE DESCRIPIICN: SEQ ID NO: 39: C3_ACOGCGGC CGCAGCAIGG ACIGGAXTG GftGG I iT TG 11UC1UG LiiiflGCAX 60 AGSTGGCCAC TCDCAG31XX AACIGCAGGA GICTQGAGCT GAAGTGAAAA AXCIG GGC 120 TTCA3IGAAG GIGTGCIGCA A3GCITCIGG A3ACACAITC ACTA3CTAIG TTATACACIG 180 GGIGA33CAG GCGGCTGGSC AO UOJl'lLA GTC*3AITGGA TAIATTAAIC CTTACAATGA 240 TGGTAOIGAC TACGATGAGA AGITCAAAGG CAAGGGCACA GTGACI JAG ACO ATXAC 300 CAA-ACA3CC TA-AIGGA3C TCAGCAGCCT GfiOJDuIGAG G CTOCGS TCTATTACTG 360 TGCAAGAGAG AAGGAIAACT AOGCGACGSS (JLJLLTl-mTT GCTTACTSSS GCCAAGGGAC 420 OOTGGICAX GICiαCTCAG GIGAGICCTA AGCITGGAIC C 461 (2) INFOFMATTON FCR SEQ ID ND:40: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7892 base pairs (B) TYΪE: nucleic acid (C) επ_RANCEDNESS: single (D) TOPOLOGY: cirαilar (ii) M-tLECULE TYPE: cCNA (ϋi) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEAIURE: (A) NAMEyKEY: mi_3C_feature (B) IOCAIICN: 1 (D) OTHER INFORMMICN: /note= «pSAB132" (xi) SEQUENCE EESCRIPITGN: SEQ ID NO: 40: GAATΓOGAX TTGCAIGCCT G ? I I ΓΓ Aoα AcπA C-GSΓAAAIGG c taxiuuc 6o TC-AOTSCCCA AO-AXCOCG CtOCATTGACG TCAATAAIGA OGTAIGITCC CAilAGTAAGG 120 αCAAIAGSSA OTTTCCATTG AOGICAAIGG GTOGAGT T TA0GΞTAAAC TGCtXACTTG 180 GCASACAIC AAGIGTMCA TATGXAA3T AT CTXIXTA TIGACGICAA TGAOGSTAAA 240 T33C nGCCT GGCAITAIGC CCA3IACAIG AOCTTAIGGG ACTTTCCTAC TTGGCAGIAC 300 AICIACGTM TAGICAIΌGC TAITAXATG GIGAIGCGST TITGGCAGTA CAICAAIGGG 360 CGIGGMAGC GΞITTGACTC AOSSSGAITT CO-AGTCICC AOC-XMTGA CGTCAAIGGG 420 A ΠTGTΠT GGCAXAAAA TCAACGGGAC TTTΌCAAAM GICGTAACAA CICCGOOXA 480 TTGAOGCAAA TG33CG3IA3 GCGIGIACGG TC-OGAGSICT AIAIAAGCAG ASCTΌ ΠTA 540 GTOAACCGTC AGAIC3CCIG GAGAGGCCAT CCA0GLTG1T TTGACCICCA TAGAAGACAC 600 CΩGGAXGM CCPGXπXXli CHACICTAGAG GA__I_U3GGTAC TCGA3GAACT C3-AAAAXAG 660 AAAGITAACT GSTAAGITTA GKTITTTGT CTITTAITTC AG3ICCCG3A TCOGGTGSTG 720 GIGCAAATCA AAGAACIGCT CTICAGIGGA 'im'lUOJl'l ACITCTAG3C CIGTACG3AA 780 GIGT]_ACπ TGCTCLAAAA GCIKB5AAT TC^TAXCQCC GO JCOIUGA OISIGAOXC 840 to to to y H y H o to vo oo oo tj 8 8 § § K 8 8 δ TGAAIGGGAG CAGIGGIGGA AIRX TTAA TGAGSAAAAC CB5ITTTGCT CA3AAGAAM 2580 GCCAICTAGT GAIGAIGAGG CIACTGCIGA CTCTCAACM TCTACTCCIC CAAAAAAGAA 2640 GAGAAAGSTA GAAGAOXCA AGSACTTTX TTCAGAMTG CTAAGTHTT T AGTCATGC 2700 TU1U1T1AGT AATAGAACIC TlU TlϋClT TGCTATTTAC AOCACAAAGG AAAAAGCIGC 2760 ACIGCTAIAC AAGAAAATTA TGGAAAAATA TTCTGIAAX TTTAOAAGIA GGCATAACAG 2820 TTAIAAICM AACAIAZDGT THTI I'IAC TDCACACAGG CAIAGAGIGT CIG IAI'IAA 2880 TAACTAIGCT CAAAAAITGT GTACCTTTAG C TTTTAATT TGTAAAGΞSS TTAATAA3SA 2940 ATAITIGAIG TATAGIGCCT TGACTAGAGA TCATAATCAG C_OTAXACA TTIGTA5AGG 3000 TTTTACITGC TTTAAAAAAC CICtXACAX TC-XXIGAA GOTGAAACAT AAAATGAATG 3060 C-AATTGTTGT TGITAACTTG TTIATIGCAG CTTAIAAIGS TTACAAAIAA AGCAATAGCA 3120 TCACAAATTT CACAAATAAA GCATTTTTTT CACTGCMTC TAGITGTGST TTGTCCAAAC 3180 T ATCAAIGT ATCTTATCM GTCIGGAICC TCIACGCCGG ACGCAIGGTG G033GCATCA 3240 CCGGGQ33C AGOTGCGSTT ATATCGOOGA CAICACαG GG33AAGATC 3300 GGGCIOSCCA LTlU.Jm.TvJ AIGASOSCTT GlTlUJLJLIjr GGGEAIGGTG GCPCGCCCCG 3360 TO3 T333GG ACTGITGGGC GCOOCTCCT TGCAIGCAX AITCCπGOG Q33XGGIGC 3420 TCAAOGSCCT CAAXTACTA CIGQGCTGCT TtXTAAIGCA GGA3IGGCM AAGGSASMC 3480 GICGA5ACIC CAICICAAAA AIAAAAϋAAA AIAAAAATTA AAAAAAAAGG OLU TIUIU ! 3540 AAAGCIGACA GCTTGTAIGT TTCTGCIGIT GACAITTGTG OXJIUITIAC CAACACTICT 3600 GGAACACAGC AGIG AAGSG ACITOXAGA TATITTAAAA TTAOOCTTAG AAAGGGSTCT 3660 GIGAAAAAX ( XTAXTAM TTCCTTTTTG TTAAGIGAX TAAITAACAG GAGSACACAG 3720 AGGSTGSAIG GGCAGOCTM GAITGGAAIG TCCICICAA5 TAGA3GAGST TMGSTTTAT 3780 GAGSACACAG AGGAGCTTCC TGGΞSAICCA GACATGAOAA GATACATTGA TGAGTTIG A 3840 CAAACCACAA OTAGAATGCA GIGAAAAAAA TGCITTATTT GIGAAATTTG TGMGCTAIT 3900 QCTTTATΠG TAAOCATΓM AAGCIGCAM AAACAAGΓΓA ACAACAACAA TTGCATTCM 3960 TTTATOΓΠC AGSTΓCAGGS GGAGSIGTGG GMGITTTTT AAAGCAAGΓA AAACCTCΓA 4020 AAAOΠΠGGTΆ TGGCIGAITA TGAICICTAG TCAAGGCACT ATΆCAICAAA TATTCCΠAT 80 TAAOXCITT ACAAAITAAA AAGCTAAAGG TACA-AATTT' TTGAGCATAG T1AT1AAIAG 4140 OΏUΏCΪCT Aranσiur GSMIWEAA ΆAAA^HA GΓIMGMTΆ maπrmr 4200 GCCTACITAΓ AAAGGTTACA GAAIATTTTT GCMAAITIT CITGE&TAGC AGIGC-AGCTT 4260 TTICCTTTGT GSIGTAAAIA GCAAAGCAAG C_AAGAGπCT ATTACTAAAC A3 » -GCAIGAC 4320 TCAAAAAACT TAGCAAITCT GAAGGAAAGT < Tl ( rU *.-!l» TTCIACCITT QULIULTI 4380 TTGGAGGAGT AGAAIGITGA GK3ICAGCK5 TMCCTCAIC ATCACTAGM QGCAlT'ivJl 4440 CIGAGCAAAA CPGGTTTTCC TCATTAAAGG CATTXAXA CTGCTCCCAT TCATCAGITC 4500 CWA3GTTGS AAICTAAAM ACACAAACAA TTAGAAICAG TAGITTAACA C-ATTATACAC 4560 TLAAAAATTT TATATTTACC TTAGAGCTTT AAAICICTGT A3GIAGITTG TCCAATTAIG 4620 TCACACCACA GAAGTAAGGT TGCTTCACAA AGAICTAAAS GCAGCAAAAG TlXϊCAIQGTC 4680 TTATAAAAM GCAIAGCTTT AGSAGSSSAG CAGAGAACTT GAAAGCATCT -ICCTGTTAGT 4740 CTriUL'l l GIAGACTTCA AACITAIACT TGAIGCCITT TTDOTGCIQG AXICAGAGA 4800 GSAOGCCTGS GTA!l'l l3GS A_÷AAGTTTM ATTTOXCAA ATCAAITTCT QGGAAAAACG 4860 'iimca L ic AAAITDCIGC AIGMUL IG TΏ-_ΆAAGAG TCIGAGSIQG u imriG 4920 TCATOGCTTC CTGGTAAACA GAACIGGLTC CGALTAICCA AAXAIGTCI A LTIAZHG 4980 CCAATIUXS TTGITCAATA AOTCTTAAGG CMCAICC AOTTTIGGCA AGAAAAIGA5 5040 JUJXJJITJG 'iUm LLLTiU AGHCICIAC TGAGAACIAT AITAAITCIG lU iTlAAAG 5100 GIXXATTCTT OTCAGGAAIG GAGAAXAGG TTTTCCTAX CMAMCAX AGAITCTGTT 5160 TAOOTTCCAO TGAAGAGSTT GIC-GTCATIC TTTGGAAGTA CTIGAACTQG TTCCTGAGCG 5220 GAG3CCMGS TMSTCKEG TICTIGCC A TCtTXATAIT TTGSSACACG GGGAOGAIGC 5280 AJI'ILAAIGG TΌSAAXAIG AIGGCAGCGG GSATAAAAIC CTAXAGCCT TCA05CIA3G 5340 ATia JivA AGTΠGSCGC GAAATOGCAG axiGASciG τσ,τ.rπ:πτ CAAGCΠTTT 5400 GCAAAAGOCT A3GCC GCAA AAAAGGCICC TCACTACTTC TGGAATAGCT C_A5A3GQQGA 5460 GGCGGO TOS C<T_DCTGCM AAATAAAAAA AAITAGICAG CCATGSSSGG GPΩMOGGCC 5520 GGAACIGGGC G3GTTPG G GCGSSATGGG CZ5GA5TTAGG GGCGGSACTA TGGITGCTGA 5580 CTAATTGAGA TGCTGCCTCG GGGGITT GG TGATGAXGT GAAAACCTCT C3ACACAIGCA 5640 GOTCGCGSA5 AOSGTCACAG LT1U1- 1U1A AG035AIGCC CZS9GCA5AC AAGCtXGTCA 5700 C_0_XX5CGTCA f.-ϋ. .i-Jim'lG UUU _Jll2iU GGGGSCAXC AIGAOXAGT CSOΪIAGOGA 5760 TAGCGGAGIG TAITAZEGSCT TAACIAIGCG CXAICAGAX AGAITGTACT GPLGPGTECPC 5820 σflaiGCQjr GTGAAAIKE QCAQ-CftlGC GTAAGGAGAA AMMOGCAT C2GSCGCICT 5880 1-JUJLTTL- 1' CDCTCACIGA CICGCIGCGC T03GICGTTC G3CIU.Ua.T5 A3CG3IATCA 5940 G TCPCTCPA AGSOSSTAM A U I'IAIO ACAGAAICAG GGGATAAOGC AGGAAAGAAC 6000 AIGIGA5CAA AAQGCCA3CA AAAGGCCA3G AAXGTAAAA A3GUU JLUIT ULTLUULJITT 6060 TTCCAIA3GC TXrø π P TGAOGAGCAT CACAAAAAIC GACIXTLAAG TOEAGSIGS 6120 CGAAACCCGA CAGGACTATA AAGA__LAGCA5 GCGITTOXC CIGSAAGCTC ULlLUlvJUJL' 6180 TvjiujmriL' OGAOXIGX O_T___ACCGSA TAUJIUIUJG CEΠTCΓOX TTCGSSAAGC 6240 GIQGOGCITT OCKIAGCIC ACGCIGTA3G TAICICA3IT CGGIGTA3GT OJΓIUJL-IVJ-J 6300 AAGCIGSSCT GIΠLGCACGA AαX-OXGTT CA3X05AX om.-»J ( .L'.IT AICCGSTAAC 6360 TAIΌGTCITG AGICCAAOX C_GTAAGACAC GACTTAIOGC CACTGGCAGC A3CCACIGST 6420 AACA3GATTA GCPCPCU3C C3IATOIA3GC GGTGCT?V3C AGITCTTGAA GTU-JlUGOJl' 6480 AACTACGGCT ACACTAGAAG GACA LA IT GSIAICIGOG OTCTGCTGAA CXΣAGTΓAX 6540 TTOΞSAAAAA GA TlGϋlAG Cl l'ItGAlvX' GSCAAACAAA COOISCIQG TAGOIJIUGT 6600 TTITTTUI'IT GGAA3CA3CΑ GAITACGCQC AGAAAAAAAG GAICICAA5A A5A!l jαTlϋ 6660 MUITIT IA t liJ^lLTUA OJα TJG AACGAAAACT CAG3ITAAG3 GATITIGSTC 6720 ATGAGATTM O-AAAAGG CTTCACCTAG ATCCTTTTAA ATTAAAAAIG AAGTTI AAA 6780 TCAAICIAAA GTAT AIGA GTAAA TTGG TCTGACAGTT AXAMGCTT AAICAGTGAG 6840 GCAOCTAICT CA505AICTG TClift TlU l' Tv^ICCAIAG TTGCCIGACT CDXOTCGTG 6900 TAGAIAACTA C-GA_I_A3G3SA GS3CTTAXA 1LΕ35CU.TJA GIGCTGCAM GAIAGCGC-GA 6960 GAGCCAGGCT CAOI3GCICC AGMTTATCA GCAAIAAACC A3XAGGCGS AAGGSCOGA5 7020 CGCAGAAGTG GICCTGCAAC Tli UUG XJ TO-ATCCAGr OATTΑATTG TTGGCQGGAA 7080 GCTAGHSIAA GIA3ITCGX AGITAATAGT TIGCGCAAαG TTGITGCCM TC<TGCAGSC 7140 AIGGTG3IGT CACGCTOGTC GITIUUIAIG QCITCAITCA C-CIOOGGTIC CCAAOGAICA 7200 AGSσGASITA CATOAICCCC CAIGITGIGC AAAAAAGCGG TT 3CTCCTT OJSIUJI-XG 7260 AlϋGTlUlLA GAAGIAAGIT GGGOGCAGΓG TTA-TC_ACICA TGCSITAIGX AGCACIGCM 7320 AMTL'ILTJA CIGTCAIGX AICOGTAAGA TGLTITILIG TGACTGSTGA GIACICAAX 7380 AAGICAITCT GAGAATAGIG TAIGCG3CGA CDSAJ1TULT Cl'H J U.U Λ ' GTCAACA033 7440 CHAIAATAOOG CJGCXACATAG C_AGAACTTTA AAAC^IGCICA TCAITGSAAA ALXJI'I ITUG 7500 G3SCGAAAAC TCT2AA3GAT CTTA XTG TIGAGAICCA GTICGMGIA AXCACTCGT 7560 Gcaccc ACT GATCΓΓCAGC AICΠTTACΓ TTOKXAGCG TTTCIGSSIG AGCAAAAACA 7620 GC»AAGSCAAA AIGGCGCAAA AAAXGAATA AGGSG ACAC GGAAAIGTTG AAIACICATA 7680 Cl- l'lLL'lT TTCA ATTA TTGAAGCATT TATCA33GIT MTGTCTCM GA5GGSMAC 7740 A_IA_TITGAM OTMTTAGAA AAATAAACAA A3»3GGGITC αGCGCASIT TOCCCGAAAA 7800 GIGOCAXIG ACEICTAAΞA AACOflTAIT AICAIGACM TAAXTAIAA AAATAGGOGT 7860 AIIΩCGAGGC LL TimiCl 1 TCAAGAAITC OS 7892 (2) INFORMMION FOR SEQ ID NO: 41: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 33 base pairs (B) TYPE: rucleic acid (C) STRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYEOTHETICAL: NO (iv) ANΠ-SENSE: O (ix) FEAIURE: (A) NAME^KEY: misc_featurε (B) IOCAHCN: 1 (D) OTHER INEC βTION: /nσte= "370-38 PCR primer" (xi) SEQUENCE CESCRIPTICN: SEQ ID NO: 41: TGAGCTΓΓCT CΣΏGCAGSCC AGGXΓGAX TIG 33 (2) INFt-RM XCN FOR SEQ ID NO: 42: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 30 base pairs (B) TYPE: ruclei acid (C) SIRANCEINESS: single (D) TOPOLOGY: linear ( i) MOLECULE TYPE: c£NA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) EEAIURE: (A) NAME/KEY: mi≤c_feature (B) IOCAIICN: 1 (D) OTHER INEΌRMATICN: /note * - * - "370-40 PCR primer" (xi) SEQUENCE CESCRIPTICN: SEQ ID NO: 42: AGIGIUGSGA CAJlULJϋAX CGCTCi r 30 (2) INFORMMION FCR SEQ ID ND:43: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2029 base pairs (B) TYPE: rucleic acid (C) SIRANCEINESS: single (D) TOPOIOGY: linear (ii) MOLECULE TYPE: DNA (gerαnic) (iii) HYPCuHETICAL: NO (iv) ANII-SE_NSE: NO (ix) FEATURE: (A) NAME^KEY: misc_feature (B) IOCAIICN: 1 (D) OTHER INEOFMAHCN: /note= "pBfiGlOl insert" (xi) SEQUENCE CESCRIPTIC-N: SEQ ID NO: 43: TGAOJiTlUr C33GGCA3GOC iGUCTLaOC TlcJ lU JLJG GCA3G3A3SS GGCIAA3GIG 60 AC-GCAGSTGG GGGCAGCCAG GIGCACAXC AATGCGCAIG AGCGCAGACA CT iAGCCIG 120 CAIGSAXM 03CGGMAGA CAAGAAGOGA 0333XTCIG Cm mj CIA TCIGT 180 C-XACAOCGC QGTCACAIGS CACCAOCTCT CTIGCAGCTT GCACCAAGGG CCΩICCGTC 240 TiαXIXTUS (.t.->.U.TUCJlL' CAGSAXAX TCOGAGAGCA CPCCCGCCCT (333 ' TGCCIG 300 GICAAG3ACT A I LLUA ACOGGTGACG GTOIDGTGSA ACTCAGGCGC C-CIGAO AGC 360 GSCGTGCACA GCTICCOGSC TGTtXTACAG TCCICAGSAC TCTAOTOCCT CA3CA3CGTG 420 GTCA003TGC CCTXAGCAG CIΓGSSCACG AAGAXΓACA CXΠGCAAGGT A3AICACAAG 480 Cα_AGCAACA CCMCGTGCΆ CAAGAGAGIT GGIGAGA3GC CAGCACASSS AGG AGGGIG 540 'lLlUClOGAA eXTAGG T CMXT LTGC CTGGACGCAC U -JUGCTt ?l CTTrrrrAGC 600 C∑aGSGCAGC AAGQCAIGX eXAICIGTCT CCTCAαX05 AL-JUUlvJlvA OCAαXCACT 660 (GATGCICAGG GAGAGGGTCT TCTGSATTTT TOCAXAGGC TCCOGGCAX ACAGGCIGGA 720 TGGXCTAX CXAG CCCIG CXXAIACAGG GCAG3TGCTG OJLTCAGAX TGCCAAGA3C 780 C_AIAICCG3S AGGAXCIGC OXIGAXIA AGOXAOXC AAAGSCCAAA CICTCCA CC 840 OCTCAGCrCA GA3 .'lUl' (JIU HX AG AICTGAGIAA CTOXAAICT HJ1U1LT A 900 GA5I0CAAM K∑as∑axnz ATC CCATCA TGOOCA35IA AXCAAXCA O U- ILUCCC 960 T03-SCICAA GGCGSSACAG GIGQOCTAGA GIAGCCIGCA TCCAGGSAGA C3GCOXA3X 1020 GGSIGCIGAC GCAICCM T CCAI ILTIL' OTCAGGACCT GAGTICCIGG GGSSAXMC 1080 AJlvJl'lLUlG TTΌXOXAA AAOXAAGSA C-ACICTCAIG AICICCCGGA CCCCIGA3GT H40 CACGTGCGTG GTGSIGGACG TGAGGCAGΞA AGAXCDSA3 GTOCAALILA ACIGΞTACGT 1200 GGATGSCGTG GA3GIGCAIA AIGCCAAGAC AAAGCCGCGS GA3GA3CA3T TCAACA3CAC 1260 C3AC-3STGTG GTCA3CGTCC TCACOGTCCT GCAXAGGAC TGGCTGAAOG GCAAGGAGTA 1320 CAAGIGCAAG GICICCAACA AA3GCCICX GIOCTCCAIC GMSAAAX TC1U AAAGC 1380 CAAAGGIGSS AOXAOSSSS TGCGAGGSX AQ--CGGACAG A3GCCA3CIC GGCCCAXCT 1440 CIG XIUUG groA EG T GllJULAAXT A3 TA3 r OGA3A5CCAC 1500 Ajmma ac ULTUXUXA TOXAGGASG A5AIGAXAA GAAOCAGSTC A-LLTCJAXΓ lsβo GCCIGGrCAA AGGCITCΓAC CΣXΆ GGAC lU U lULA GTUOGAGAX AAIGGGCAGC 1620 CGSAGAACAA CIACAAGAX ACGCLTC-XG TGCTGGATIC OGACGSCICC TTLTTULT 1 1680 PCPΩCPG CT AAOCGTGSAC AAGAGCAGST GGCAGSA3GS GAATOT TTC ICAIUαOJ ' 1740 TGAIGCATGA GGCTCIGCAC AACCACIACA CACAGAAGAG CTICILU I 1U1 LU 1A 1800 AAIGAGIGCC AGSSCDGGCA AGCCOXGCT CπrnmCTC G3SAGSAIGC 1860 TTGGCACGTA CCOCGICLAC ATACTICGCA GGCAXCAX MGSAAAIAA AGCAXCAX 1920 AOGOXIGS (.-» U.t.'lUlLA GACIGTGAIG GITCTTTCCA CGGGTCAGSC OG lClv^G 1980 GCCTGAGIGA CMGAGS AG GCAGAGCGG 'ID OCTGTC GCCACACTA 2029 (2) INFOFMAIICN FCR SEQ ID NO: 44: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2560 base pairs (B) TYPE: nucleic acid (C) STRANCEINESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: CNA (gercmic) (iii) HΪPOTHETICAL: NO (iv) »m-SENSE: NO (ix) FEAIURE: (A) IWffi^KEY: sig_peptide (B) IOCAIICN: 12. .68 (ix) FEAIURE: (A) NAME/KEY: ιtat_peptide (B) IOCAIICN: join(69. .435, 712. .1005, 1396. .1431, 1550. .1879, 1977. .2296) (ix) FEAIURE: (A) NAMEyKEY: iπtron (B) IOCAIICN: 436. .7H (ix) FEAIURE: (A) NAME7KEY: iπtron (B) LOCAIICN: 1006. .1395 (ix) FEATURE: (A) NAKEKEY: iπtron (B) IOCAIICN: 1432..1549 (ix) FEAIURE: (A) NAME KEY: iπtron (B) IOCAIICN: 1880. .1576 (ix) FEAIURE: (A) NAME/KEY: miεc_feature (B) IOC TCN: 1 (D) OTHER INFC fillCN: /note= •fM-R1002 insert: pre-5A8 hunanized heavy chain" (ix) FEAIURE: (A) NAME/KEY: ex (B) IOCAIICN: 12. .435 (ix) FEAIURE: (B) IOCAIICN: 712..1005 (ix) FEAIURE: (A) NAME/KEY: ex (B) LOCAIICN: 1396. .1431 (ix) FEAIURE: (A) N&ME^KEY: exm (B) IOCAIICN: 1550..1879 (ix) FEAIURE: (A) NAME/KEY: exm (B) IOCAIICN: 1977. .2296 (ix) FEAIURE: (A) M-ME^KEY: CDS (B) IOCAIICN: join(12..435, 712..1005, 1396..1431, 1550..1879, 1977..2296) (xi) SEQUENCE DESCRJ TIC-N: SEQ ID ND:44: GCGSCCGCAC C AIG GAC TGG AX TGG AGG GTC TTC TGC TTG CTG GCT GTA 50 Ifet Asp Trp Thr Trp Arg Val Phe Cys leu Leu Ala Val -19 -15 -10 GCA GCA GST GX CAC TGC CAG GTC CAA CTG CAG GAG TCT GGA GCT GAA 98 AlaProGlyAlaHisSerGlnValGlnLeuGlnGluSerGlyAlaGlu -5 1 5 10 GIG AAA AAG GCT GGG GCT TCA GIG AAG GIG TGC TGC AAG GCT TCT GGA 146 Val_^I^ProGlyAlaSerVal ]_^ValServ^I^A]aSerGl TAC ACA TTC ACT AX TM GTT MA CAC TGG GIG AGS CAG GOG CCT GG 194 Tyr Thr Ehe Thr Ser Tyr Val He His Trp Val Arg Gin Ala Pro Gly 30 35 40 CAG GSC CTT GAG TGG ATT GSA TM ATT AM GCT TAC AM GM GST ACT 242 Gin Gly leu Glu Trp He Gly Tyr He Asi Pro Tyr Asn Asp Gly Thr 45 50 55 GAC TAC GM GAG AAG TTC AAA GSC AAG GCC ACA GIG ACT TTA GAC GCA 290 Asp Tyr Asp Glu lys Phe Ω/s Gly Lys Ala Thr Val Thr Leu Asp Pro 60 65 70 TDCACCAACACAGXTACATOGAGCTCAXAXCIGAXT^ 338 Ser Thr Aεn Thr Ala Tyr Ifet Glu Leu Ser Ser Leu Arg Ser Glu Asp 75 80 85 90 ACTGCGGTOTMTACTGTGCAAGAGA5AAGS^AAC 386 Thr Ala Val Tyr Tyr Cys Ala Arg Glu lys Asp Asn Tyr Ala Thr Gly 95 100 105 GCC TGG TTT GCT TAC TGG GSC CAA GGG AX CTG GTC AX GTC TCC TCA G 435 Ala Trp Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser HO 115 120 GIGAGTCCTA A3CITGSTAC GCGSSAMTC A5MOTUCA5 CMUCIGGAG CTCTAGA3KT 495 CA3CTTTCTG GGGCMGCCG GGCCTGACTT TGGCTGSSSS CAGGGA3GSS GCTAAGSTGA 555 GGCAGSTGSC GCCAGGCAGG TGCACAOXA AIGC-XMGA GGCCAGACAC TQ5AXCIGC 615 AIQSAXAIC GCGSATAGAC AAGAACOGAG ( X-tl-XXILTviC tJ ΩUmα? CA_XICIGTC 675 CCA-OAXSCG GDCACMGSC AXAXICTC TTGCAG CT TCC AX AAG GSC CCA 728 Ala Ser Thr I_ys Gly Pro 125 TXOTCTTCGXOXGCXECrrTGCTCC 776 Ser Val Phe Pro leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 GX GX CTG GGC TGC CIG GTC AAG GAC TAC TTC OX GAA GGG GTG AX 824 Ala Ala leu Gly Cys leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 GTG TGG TGG AAC TCA GSC GX CTG AX AX GGC GTG CAC AX TTC GOG 872 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Hie Pro 165 170 175 GCT GTC CTA CAG TCC TCA GSA CTC TAC TCC CTC AGC AGC GIG GIG ACC 920 Ala Val leu Gin Ser Ser Gly Leu Tyr Ser eu Ser Ser Val Val Thr 180 185 190 GIG OX TCC AGC AX TTG GGC AGG AAG AX TAC AX TGC AAC GTA GM 968 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 C_ACAAGCΣCAXAACAθ:AAGGIGGACAAGAGAGTT G GIGA5M3GX 1015 His lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 210 215 220 AGCACAGQGA GSSAGSSIGT CT3CTQGAAG OCAXCICAG (.U.-lU.ϋU.i; TGSACGCAX 1075 GCGSCTGIGC A3COXAGX CMS3CA3CA A3SCATGCCC CAIULUI IL' CTO¥XCGSA 1135 CX3CΣTCTGAC CPCCCCPCTC AIGCTCAGGG AGAGSSTCTT CTGGAIITTTT GCAXAGGCT 1195 QPCQQCAXA C_AGGCTGSM GCGCCTAXC CAGGCCCTGC GC3ΩACAGSS C2GGIQCIGC 1255 GCICAGAOCT GOCAAGAGOC AIA__DCOGGGA GGMOXIGCC OCIGAGCEAA GCOaCOCCA 1315 AAGGGCAAAC TCTtXACTGC CICAGCICAG ACAXI'I I TXTXCAGA TCIGASTAAC 1375 TOOCAAICIT CTOCLUCAG 1424 Glu Ser lys Tyr Gly Ffco Efco Cys Pro Ser 225 230 TGC CCA G GIAA3GCAAC OCAGGCCIGG CTX OCAGCT CAAGGCGSSA CAGGTGCCCT 1481 Cys Pro AGAGTAG3CT GCAIDCAGGS ACAGS03XA GσXGSIGCT GAOGCAICCA CX3CCATCIC 1541 TTDCTCAG C CCTGA5-rrcσGα_EG αC TC σrcTTC 1590 Ala Pro Glu Phe leu Gly Gly Pro Ser Val Phe Leu Phe Pro 235 240 245 α_ΑAAAαXAAGGACACTCTCAIGATCTlXCDGAXCCTC-^ 1638 Pro lys Pro Lys Psp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr 250 255 260 TCCGIGGIGGIGGACGIGAGCCAGGAAGACCXEC3AGCSXC-M 1686 Cys Val Val Val Asp Val Ser Gin Glu Aεp Pro Glu Val Gin Hie Asn 265 270 275 TGGTACGIGGMGXGTGGAGGIGCMAMGXAAGACAAAGC^ 1734 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr lys Pro Arg 280 285 290 GAG GAG CAG TTC AAC AGC AGG TAC CGT GIG GTC AGC GTC CTC AX GTC 1782 Glu Glu Gin Phe Aεn Ser Thr Tyr Arg Val Val Ser Val leu Thr Val 295 300 305 310 CTGCACCKJGTCTCCCIGAACGXAAGGAGTACAAGTGCAAGC^ 1830 leu His Gin Asp Trp Leu Asi Gly Lys Glu Tyr Lys Cys Lys Val Ser 315 320 325 AAC AAA G-X:CTCC- Tα Tα:ATCGGAAAα: G 1879 Asn Lys Gly Leu Pro Ser Ser He Glu lys Thr He Ser lys Ala lys 330 335 340 GΠXGAOXA 05GGSIGOGA GGGCTACACG GACAGAGGX AGCICGSUX ACtETCIGX 1939 CTGSSA3IGA ϋJULatflUOC AALXILIGI GCTA3AG G CA5 OX CGA GA5 CTA 1993 Gly Gin Pro Arg Glu Pro 345 CAGGIGTACAXCIGαXCCATvXCASGAGGAGAIGAXAAGAAOCAG 2041 (Gin Val Tyr Thr leu Pro Pro Ser Gin Glu Glu Met Thr Lys Aεn Gin 350 355 360 GTC AGC CTG AX TGC CTG GTC AAA GSC TTC TAC GX AGC GAO AIC GCC 2089 Val Ser Leu Thr Cys Leu Val Lys Gly Hie Tyr Pro Ser Asp He Ala 365 370 375 380 GTGC3AGTGSGA5AXAMC_QGσ^CrGC_∞AACAACTACAAGAα:ACG 2137 Val Glu Trp Glu Ser Asn Gly Gin Ffco Glu Asn Asn Tyr Lys Thr Thr 385 390 395 GCT GX GIG CIG GAC TCC GAC GSC TCC TTC TTC CTC TAC AGC AGS CTA 2185 Pro Pro Val Leu Asp Ser Aεp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 400 405 410 AX GIG GAC AAG AGC AGS TGG CAG GAG GSS AM GTC TTC TCA TGC TCC 2233 Thr Val Asp lys Ser Arg Trp Gin Glu Gly Asi Val He Ser Cys Ser 415 420 425 GIGAIGCMGAGC.Ω'CTGσ^AAOCAC-IACACACAG 2281 Val Ifet His Glu Ala Leu His Asn His Tyr Thr Gin lys Ser Leu Ser 430 435 440 CIG TCT CIG GST AAA TGA3B3CCAG GGO0S3CAAG (.IXUI-i-.TU αm'-Tld 2336 Leu Ser Leu (Gly Lys 445 GG3STCGCGC GA3GA_TGCTT GSCAOGTAX LUilLTACM A l'l -flGG CAGXAGCM 2396 C.GAAATAAA5 CACGCAXAC TGCGCIQGGC OXIGTGA3A CTGIGAIGGT TCITICCAOG 2456 GGTCAGXCG AGICIGAGGC CIGAGIGA A TGAGSSAGGC AGAGCG33TC OCAT ILIX 2516 αOCIGQGA TTCCAIGGM CCICACAICC CAAICCGCGS CXX3C 2560 (2) INFCI-M TON FOR SEQ ID NO:45: (i) SEQUENCE CHARA I -HhelSTlCS : (A) IENGTH: 468 amino acids (B) TYPE: amino acid (D) -ICfCLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE CESCKI I'ICN: SEQ ID NO: 45: Met Asp Trp Thr Trp Arg Val Hie Cys Leu Leu Ala Val Ala Pro Gly -19 -15 -10 -5 Ala His Ser Gin Val Gin Leu Gin Glu Ser Gly Ala Glu Val lys lys 1 5 10 Pro Gly Ala Ser Val lys Val Ser Cys lys Ala Ser Gly Tyr Thr Hie 15 20 25 Thr Ser Tyr Val He His Txp Val A_rg Gln Ala Pro Gly Gln Gly leu 30 35 40 45 Glu Trp He Gly Tyr He Asn Pro TyrAsnAsp Gly ThrAsp TyrAsp 50 55 60 Glu Lys Hie lys Gly lys Ala ThrVal Thr Leu Asp Pro Ser ThrAsn 65 70 75 ThrAla TyrMet Glu Leu Ser Ser LeuArg Ser GluAsp ThrAla Val 80 85 90 Tyr Tyr Cys Ala ArgGlu Lys Asp Asn TyrAla ThrGlyAla Trp Phe 95 100 105 Ala TyrTrp Gly Gin Gly Thr LeuVal ThrVal Ser SerAla SerThr HO 115 120 325 Lys Gly Pro SerVal Phe Pro Leu Ala Pro Cys SerArg Ser Thr Ser 130 135 140 Glu Ser ThrAla Ala Leu Gly Cys leu Val lys Asp Tyr Phe Pro Glu 145 150 155 Pro Val ThrVal Ser Trp Asn Ser Gly Ala leu Thr Ser GlyVal His 160 165 170 Thr Hie Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 175 180 185 Val Val ThrVal Pro Ser Ser Ser Leu Gly Thr lys Thr TyrThr Cys 190 195 200 205 Asn Val Aεp His lys Pro Ser Asn Thr lys Val Asp lys Arg Val Glu 210 215 220 Ser Lys Tyr Gly fto Fto Cys Pro Ser Cys Pro Ala Pro Glu Phe leu 230 235 Gly Gly Fro Ser Val Phe Leu Phe Pro Pro Lys Pro lys Asp Thr Leu 240 245 250 IfetHeSerArg-IhrProcauValTtøC^ValVa^ 255 260 265 Gin Glu Asp Pro (Glu Val Gin Phe Aεn Trp Tyr Val Asp Gly Val Glu 270 275 280 285 Val His Aεn Ala Lys Thr Lys Pro Arg Glu Glu Gn Hie Asn Ser Thr 290 295 300 Tyr Arg Val Va SerValLeu-rr^ValLeuHisC_αnAspTrpLeuAa 305 310 315 Gly Lys Glu Tyr lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 320 325 330 He Glu lys Thr He Ser Lys Ala Lys Gin Pro Arg Glu Pro Gn Val 335 340 345 Tyr Thr Leu Pro Pro Ser Gn Glu Glu Ifet Thr lys Asn Gin Val Ser 350 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 400 405 410 Asp Lys Ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met 415 420 . 425 His Glu Ala Leu His As His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 430 435 440 445 Leu Gly Lys (2) INFCEMAIICN FOR SEQ 3D N0:46: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 77 base pairs (B) TXEE: nucleic acid (C) STRANΓFTNESS: single (D) TOPOLOGY: linear (ii) MOIECULE TYPE: cCNA (iii) HYPOTHEIICAL: NO (iv) ANIT-SENSE: NO (ix) FEAIURE: (A) NAME KEY: miεc_feature (B) IOCAIICN: 1 (D) OTHER 3NFOFMAITCN: /note= "SβO-βl oligoru LeotidR" (xi) SEQUENCE CESCRIPITCN: SEQ 3D NO: 46: AXITAXM GGACAIGA3G ( J1UXU TL A3CTIXIU-J GCI XIGCIG IUIUJCH U 60 C_A3GIGOCA5 AGGIGM 77 (2) INFC fAIICN FOR SEQ ID NO: 47: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 73 base pairs (B) TYPE: nucleic acid (C) SIRANCEINESS: single (D) TOPOLOGY: I IΠRP-IΓ (ii) MOLECULE TYPE: cTNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEAIuRE: (A) NAME KEY: * αύsc_feature (B) IOCAIICN: 1 (D) OTHER INFCRMATICN: /note= "360-82 oligαir-leotide" (xi) SEQUENCE IESαvTPTTCN: SEQ ID NO: 47: ATCACCICIG GCAC GGCΆ GCCAGAGCAG CAGSAGOXC AGGAGCIGAG CG33GAXCT 60 CAIGTCCAIG GIA 73 (2) 3_NFCR!_AIICN FOR SEQ 3D ND:48: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 77 base pairs (B) TYPE: nucleic acid (C) SIRANCEINESS: single (D) TOPOLOGY: linear (ii) MOIBCϋLE TSE: cCNA (iii) HYHJlHhll'lCAL: NO (iv) ANH-SEΪBE: NO (ix) FEATURE: (A) NAME KEY: ιni_sc_feature (B) IOCAIICN: 1 (D) OTHER INFCRftllCN: /note *** *pJIF985 insert" (xi) SEQUENCE LESOU TICN: SEQ 3D NO: 48: AGCTiaCCM GGACAIGAGS GH.H.t 1 TC AXICdUGG GCI XlGClG ^UGCTUC 60 CAGGIGGCAG AGS GM 77 (2) INFORMATTCN FOR SEQ 3D NO: 49: (i) SEQUENCE C-HARACTERISTTCS: (A) IENGTH: 45 base pairs (B) TYPE: rι. * cleic acid ( SIRANCEINESS: single (D) TCPOIOGY: linear (ii) MOLECULE TYPE: cDNA (ϋi) HYPOΠEΓICAL: O (iv) ANII-SENSE: NO (ix) EEAIUPE: (A) NAME^KEY: πύsc_feature (B) IOCAIICN: 1 (D) OTHER INFCfWAIICN: /note= "370-54 PCR primer" (xi) SEQUENCE IΣSCRIPTICN: SEQ ID NO: 49: TC-0STOGACA AAOGTAAGIG CA ITIL'JAA AZICIGAGGS GΞTGG 45 (2) 3NFCEWMICN FOR SEQ 3D ND:50: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 30 base pairs (B) TYPE: nucleic acid (C) SIRANCECNESS: single (D) TDPOIOGY: linear (ii) MOIETOIE TYPE: cCNA (iii) HXKJiHtll'lCAL: NO (iv) ANH-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) IOCAIICN: 1 (D) OTHER 3NECRMAIICN: note= "370-55 PCR primer" (xi) SEQUENCE CESCRIPITCN: SEQ 3D NO: 50: TlϋGCBS re CAJ JiTlLTT CTITIGAAAA 30 (2) INFCRMAITON FOR SEQ 3D NO: 51: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1241 base pairs (B) TYPE: nucleic acid (C) SIRANCEINESS: single (D) TOPOLOGY: linmr (ii) MOLECULE TYPE: CNA (genαnic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEAIURE: (A) NAMξ KEY: πu_sc_feature (B) IOCAITCK: 1 (D) CHHER INFC ftllCN: /røte= "PSAB153 insert" (xi) SEQUENCE LESCRIPITCN: SEQ 3D NO: 51: TOGIOΞACAA AOGTAAGIGC ACHT iAAA CTCIGAGGSS GIOSSAIGAC C_ni3GCCAITC 60 TTIGCCTAAA GCAIIGAGIT TACIGCAAGS TCAGAAAAGC ATGCAAAGCC CICAaAIQG 120 CIGCAAAGAG CTCCAACAAA ACAAITTAGA ACITTMTAA GGAATAGGGG GAAGCTAGGA 180 AGAAACTCAA AACATCAAGA TITTAAATAC GLT'lLTTmJT CICCITGCTA TAAITAICIG 240 GGAIAA3C G LUITTILΓ GILTUILLL AACAlUαXT GIGAIΓAICC GCAAACAACA 300 caαxAAGss OEAACΓITG TTACITAAAC ACCAI CIGT TTGCΠCΠT OΠEAGGAAC 360 TC4IGGCIGCA CCAICTGICT ILA- -JriLLL 1 GCCAICIGM GAGCAGITGA AAICTGSAAC 420 TGULTLTU1T GlϋlULL'lUC TGAAIAACTT OAIC-XAGA Q-flGCCAAAG TACAGIGSAA 480 GGIGGAIAAC GOXTC AM α3GSTAACTC CCAGGAGAGT GICACAGAGC AGGACAGCAA 540 GGACAGCACC TACAcJU TLΑ QCAQCACCCT GAOGCTGAX AAAGCAGACr AOGAGAAACA 600 CAAAGTϋlg GOJlUG iAAG TθiUXAlCA cJ OJ -l MC 'lUL XUlCA CAAAgAGCTT 660 CAACAGΞSSA GAGIGTTAGA GSGAGAAGTG COCtXAOCTG CTCCTCPGTT QCAGCCIGAC 720 crxxroxM CCΠTGSCCΓ OΠGAH-LTΓΓ T Π^AGGS GAXTACOX TAΠGCGSTC 780 CICCAGCrCA TCTTTCAOCT C_A0DDCDCΓC LTL TL LIG GCΓITAATTA TGCTAAIGTΓ 840 GSAGSAGAM GAMAAMAA AGTGAAICTT TGCAOCIGTG GlTlULv iL'l 1 TTCCICAATT 900 TAATAAITAT TMUIUI'IU TTACCAACTA CTCAAi'l'l L' CTTATAAGSS ACTAAATATG 960 TAGTCAICCT AAGGCGCAIA AXATTTATA AAAAICAIOC TlLAl'lL AT TTTAXCTAT 1020 C A CTCTGC AAGACAGΓX TCCCΓCAAAC CCACAAGOCT TLIUILUILΆ C -W Γ G 1080 ( .«.M.-?1UL_J1A GGA5K5ACTT GLTT UlTUr T1'1 .TXI.'1LL' TCA3CAA3X CTCAIAGTX H40 TTTTTAAGss TGACAGSΓCΓ TAαssTCATA TAICCΠTGA TICAA IQX TGGSAATCAA 1200 (XAAGGCAAA TTTITCAAAA GAAGAAAXT 4. .lV.4.. A A 1241 (2) INFCRMAIICN FOR SEQ 3D NO: 52: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: rucleic acid (C) SIRANCEINESS: single (D) TCΪOLOGY: linear (ii) MOLECULE TYPE: cCNA (iii) HYPOTHETICAL: NO (iv) ANH-SENSE: NO (ix) FEAIURE: (A) NAME/KEY: mi≤c_feature (B) IOCATICN: 1 (D) OTHER 3NEC____WAII.CN: /note= "360-83 PCR primer" (xi) SEQUENCE CESCRIPTrON: SEQ 3D NO: 52: TCATGMCAA A0STAAGTGC 20 (2) INFC ffiHCN FCR SEQ 3D ND:53: (i) SEQUENCE OfiRATIERISTICS: (A) IENGTH: 1276 base pairs (B) TYPE: nucleic acid (C) SIRANCEINESS: single (D) TDP0L0GY: linear (ϋ) M3LECUIE TYPE LNA (genαnic) (iii) HYPOTHETICAL: NO (iv) ANH-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1 (D) OIHER INFCfMAIICN: /note= *p! R986 ineert" ( i) SEQUENCE CESCRIETICN: SEQ 3D NO: 53: T13HGAICAA AOGTAA3IGC A 1TTL1AAA CTCTGAGGSG GTCGGAIGAC GIGSUUMTC 60 TTTGCCΣAAA GCMTGA3TT TACIGCAAGG TCAGAAAAX AIGCAAAGX CTO-GAATGS 120 CIGCAAAGAG CICCAACAAA ACAAITTAGA ACTITATTAA GGAATAGGGS GAAGCTAGGA 180 AGAAACTCAA AACAICAAGA TTTTAAMAC u iLTlLLil 1 UϋlTULUA TAATIArCIG 240 GSAIAA3CM αaUlTl'lϋl' GlQϋiα AACAIGCCCT GIGATTAICC GCAAACAACA 300 CAGXAA3SS GASΛCITTG TTACTTAAAC AOCA1H 1U1' TICCITCTTT CπCMGAAC 360 ■ lUlLU IUJA GCAI GTCT 1UAILT1LUJ GGCAICIGM GA3CA3ITGA AATCTSSAAC 420 Tju iurr ( jmicJULjmu TGAAETAACTT CΠ GCCAGA GAGGCCAAAG TACAGIGSAA 48O GGIGGAIAAC OXTOAAT CGSSTAACTC CCAGSAGAGT GTCACAGAX A3GACAXAA 540 GGACAGCAX TACAGCTTCA CCAGCACCCT GAOGCTGA AAAGCAGACT AOGAGAAACA 600 CAAAGICTAC COJIGCGftAG TCAOXATCA GSSCCIGAX TOGOU 1 A CAAAGA3CTT 660 CAACAGGSSA GAGIGITAGA GSSAGAAGIG CDXCAXTG CDXICA3IT CCA CC'IGAC 720 L- αju M O HUJUL OGAXCΣTT TTCCACAGGG GAXΓACXC TAITGCGSTC 7βo CICCAGCTCA TCΠTCAOCT CAOXCCCTC CTCCTCCTTG GCTTTAATTΆ TUCIAAIGTT 840 GSAGSAGAM GAAIAAATAA AGDGAAICTT TGCAOCTGTG (JlTlv lLlLT TTTXICAAIT 900 TAATAATTM TAI lUlTUr TTTAXAACT ACTCAAITTC lUl'lAQAAGG GACTAAATM 960 GTAGTACICC TAAGGCGATA AXAITTATA AAAATCATCC TICAITCTAT TTTALTXTM 1020 (-AIC 1C1UC AAGACAGICC TvXCICAAAC CCACAAGCCT TOTGICCICA CAGTOXCIG 1080 GGCCAIGGTA GSAGAGACIT GLT'lLLTim' TT1LLLLTLL' TCASCAAGX CTCATWGICC H40 TTTTTAAGGS TGACAGGTCT TACAGICATA TATCCTTTGA TICAAIT C TGAGAATCAA 1200 αCAAAGCAAA TTTTTCAAAA GAAGAAAXT jf-U U AIC GM'ilXAlUG AICCTCACM 1260 αx icα c mππc 1276 (2) INFC BIICN FOR SEQ 3D NO: 54: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 1701 base pairs (B) TYPE: nucleic acid (C) SIRANCECNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: ENA (genomic) (iii) ffiPOTHFTTGAL: NO (iv) ANH-SENSE: NO (ix) FEATURE: (A) NAME/KEY: raisc feature (B) IOCAIICN: 1 (D) OTHER INFCFMMICN: hote= « !CR1006 insert" (Xi) SEQUENCE I-ESCRIPΠ0N: SEQ 3D NO: 54: . QTjaXBTS TCCAAXAX AAICICAXr TAXAIG3AC AIGAGSSTCC OOGCICAGCT 60 ( 'UX-t.-tJ 'lL' αUCIUCTCT GGOTGOCAGG TGCOEAGST GATAICGTAA TGAXCA3TC 120 TCCAGAC CC CTAGCTOIGΓ C_A0ITC-GAGA GAGGGCTACT AIAAACTGCA AGTGCAGIGG 180 GAGCEΓΠTA TAIAGTAXA AICAAAAGAA CTACΓIUULC TGGTAXA AGAAAXAGG 240 GC2GCCTCCT AAACIGCIGA 'I JΫM -I -HJ/ ATCCACE?_QΞ GAAT 3GGS TOCCTGAIDS 300 CllCl AGGC AGIH-AICTG GSACAGAITT CACTCTCAX AICfiGCAGIT TGCAGGCIGA 360 AGAOGIGSCA GITTATΓACT GTCAGCAAIA TTAIAGCIAT GGSAOGTΓCG GICGAGGSAC 420 CAAGCIG AG ATGAACGTA PGT33CTTT CTAAACICIG A33QQGTOGG AIGAX1UGC 480 CAITOTTTGC OTAAAGCAIT GASITTACIG CAAGGTCA5A AAAGCMGCA AAGOX CAG 540 AATOGCTGCA AAGAGCTIXA 600 TAGSAAGAAA CTCAAAACM CAAGAI'ITIA AATA.I.-ϊ.ϋ'l ITGSTCIϋCT lUϋlATAATT 660 AIOTGGSAIA AGCAIGCTGΓ T lUimL'l TOXTAACM GCCCIGTGM TATOCGCAAA 720 CSACACA-XC AAGQSCAGAA C1T1UΓ_1ACΓ TAAACAXM C lUlTlUCr 'ILlTIUϋlLA 780 GGAA IUIUG CTGCACCAIC TGTCITCAIC TTCCXI3XM CIGAIGAGCA GITGAAMCr 840 QSASQCCT urmmiG U IUL-IIJAAT AA LTCTAI OCMMMGC e x cx:- 900 TGGAA3SIG3 MAAJLJUUULl' G M Umr PΑAU PGG PGPUiUlHPC AGA3CA3GA0 960 A3CAAGSACA GCACCTACAG OCTCAGCAGC AXCIGAXC TGAGCAAAGC AC-ACTAGSAG 1020 AAACACAAAG TCTACGXIG CGAAGICAX CAKAGGGX TGAGCIOGCC OGTCACAAAG 1080 AGCTTCAACA GSSGA3A3BG TTAGMGGA5 AA3IG0X0C AOCIGCTGCT CAGTTCCAGC 1140 '. -r CIIGAXOXT XCMCCTTT GGOCΓCIGA: U ITTTIOA CAGSSSAOCT AXOCTATIG 1200 (JLUIvXICCA GαiAIL lT CACCTCAXC CX-CItXICCr LLT'IULXJIIT AAITMGCIA 1260 AIGTΓSSAGS A3AATGAAIA AATAAAGB5A ATCTITOCAC (JlUmillTL' 'ILTLTTILUI' 1320 CAATTTAATA ATTAITAICT GTIGTTTAX AACTAZECAA TTTCICITM AAGGGACTAA 1380 AIAIGTAGIC AICCTAAGX GCAIAAGCAT TTAIAAAAM CAICCITCM TCTAITTTAC 1440 CCTAICAICC TCTGCAAGAC AGTIXTOXT CAAAOCCACA AJUUITUIUI' CCICAQrølC 1500 (X .-HTπ TG3TA3GAGA GA ITU I'IL' Cl'lUl'l'l'lUϋ CL-'llLϋLAGC Sϋ TtaT 1560 AGIΌ ΓΠT AAGSSIGACA GSTOTTACGS TCATAOAICC TTIGMICAA TH I * U.UΆ 1620 AICAAOCAAG GCAAAITTTT CAAAA3AGA AACOGCGS€ CGMCGMTC CMGGAIOCI 1680 c_ACAiαxAA * __»τm ' i'_; c 1701 (2) INFClWKIieN FOR SEQ 3D NO: 55: (i) SEQUENCE CHARAL-'IVRlb lCS: (A) IENGTH: 1701 base pairs (B) TYPE: nucleic acid (C) STRANCECNESS: single (D) TOPOLOGY: l im-ir (ii) MOLEΣ-ULE TYPE: CNA (genαnic) (iii) HYPOTHETICAL: NO (iv) ANH-SENSE: NO (ix) FEAIURE: (A) NAME^KEY: sigjpεptide (B) IOCAIICN: 35..100 (ix) FEAIURE: (A) NMJE^KEY: raa_t_peptide (B) IOCAHCN: jθin(101. .437, 782. . HOI) (ix) FEAIURE: (A) NMffi^KEY: intrtn (B) LOCAIICN: 438. .781 (ix) FEAIURE: (A) IBME/I-EY: misc_fea±ure (B) IOCAIICN: 1 (D) OTHER 33*JFCf»MA_IICN: hDte= "pMCR1007 insert: pre-5A8 huαEtniεed l * _ ιt chain* (ix) FEATURE: (A) NAMEKEY: ex (B) IOCAIICN: 35..436 (ix) FEATURE: (A) NAME^KEY: exm (B) IOCMTON: 782.. HOI (ix) FEATURE: (A) NAME/KEY: CDS (B) IOCAIICN: jθin(35..437, 782.. HOI) (xi) SEQUENCE EESCKEPTICN: SEQ ID NO: 55: t-rmr π:ro TCCAAOCAX AMLILA L TAOC MG GAC AIG AGS GC OX 52 Ifet Asp Met Arg Val Pro -22 -20 GCT CAG CTC CIG GSS CTC CIG CTG CDC TGG CTG OCA GST GCC AGA GST 100 Ala Gin leu leu Gly leu leu leu Leu Trp leu Pro Gly Ala Arg Gly -15 -10 -5 GM MC GTA AIG AX CAG Id OCA GAC TCC CTA GCT GTG TCA CTT GSA 148 Asp He Val Met Thr Gn Ser Pro Asp Ser leu Ala Val Ser leu Gly 1 5 10 15 GAG AGS GCT ACT MA AAC TGC AAG TCC AGT GSS AX CUT TTA TAT AGT 196 Glu Arg Ala Thr He Asn Cys lys Ser Ser Gly Ser leu leu Tyr Ser 20 25 30 A AMCAAAAGAACTACT-roGX-lGGTACCAS∞ 244 Thr Asn Gin lys Asn Tyr leu Ala Trp Tyr Gin Gn Lys Pro Gly Gin 35 40 45 GCT GCT AAA CTG CG ATT TAC TGG GCA TCC ACT AGS GAA TCT GSS GTC 292 Pro Pro lys leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 GCT GM GGC TTC TCA GGC AGT GGA TCT GGG PCk GM TTC ACT CTC AX 340 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Hie Thr Leu Thr 65 70 75 80 AIC AGC AGT TTG CAG GCT GAA GAC GTG GCA GTT TM TAC TGT CAG CAA 388 HeSerSerl^uGlnAl GluA^ValAlaValTyrTyrC^canGln 85 90 95 TAT TM AGC TMCGGAαSTTCGGTCTGACGSACCAAGCTGCMATC C 437 Tyr Tyr Ser Tyr Arg Thr Phe Gly Arg Gly Thr lys Leu Glu He Lys 100 105 HO G3AAGIGCAC TT1LUAAACT CIGAGSSSST CGSAIGACST CZ3CCAITCIT TUC TAAAQC 497 ATTGAGΓΓΓA CΓGCAAGGTC AGAAAAGCM GCAAAGO Γ CACAAIGSCT GCAAAGAGCT 557 OCAACAAAAC AAITTAGAAO TTTATTAAGG AAIAGGGSSA A3CTA3GAAG AAACTCAAAA 617 CAICAAGAIT TTAAATAXC TI IUUIUT (X 1UC1AIA MJLAilLTUUG AIAA AIGC 677 'luri i iur CIUIDCCΓAA eaiuαnur GAITMOCGC AAACAA-ACA OCCAAGGSCA 737 GAACITHJIT ACπAAACAC CM XlLUlTT CJCITCITILL' TCAG GA ACT GIG GCT 792 Arg Thr Val Ala 115 GCA OCA TCT GTC TTC ATC TTC COS OCA TCT GM GAG CAG TTG AAA TCT 840 Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin leu lys Ser 120 125 130 GSA ACT GGC TCT GTT GTG TGC CTG CTG AM AAC TTC TM OX AGA GAG 888 Gly Thr Ala Ser Val Val Cys Leu Leu Aεn Asn Hie Tyr Pro Arg Glu 135 140 145 GX AAA GTA CAG TGG AAG GIG GM AAC GCC CTC CAA TOG GST AAC TCC 936 Ala lys Val Gin Trp Lys Val Asp Asi Ala leu Gin Ser Gly Asn Ser 150 155 160 CAG GAG AST G C ACA GAG CAG GAC AX AAG GAC AX AX TAC AX CTC 984 Gin Glu Ser Val Thr Glu Gin Asp Ser lys Asp Ser Thr Tyr Ser leu • 165 170 175 180 AX AX AαC -CTC ACD CTC AX AAA CCA GAC TA^ 1032 Ser Ser Thr Leu Thr Leu Ser lys Ala Asp Tyr Glu Lys His lys Val 185 190 155 TAC GX TGC GAA GTC AX CM CAG GGC CTG A TOG GX GTC ACA AAG 1080 Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys 200 205 210 AX T C AAC AGS GSA GAG TGT TAGA3GSAGA A3GCCOXA OClUαiJCTC 1131 Ser Phe Asn Arg Gly Glu Cys 215 PGTTCCPΩCC TGAXCCCTC CLAILULTTG ϋUCTCIGAX C1T1T1UJAC AGGQGAXTA 1191 oxcTMiσc osK π AG αi - m- AXICA X (XIIXICCIL' CTTGSCΠTA 1251 AITAIGC AA TGTIG3A3GA GAAIGAATAA AIAAAGIGAA TCITTGCAX TGTGSITTCT 1311 LT iTi cic AATΓΓAAIAA ■ ΠATTKΓCDG TTGΠTACCA ACTACΓCAM TICI I'IATΆ 1371 AGQGACIAAA "IAIGTAGICA TCCTAAGGOG CAIAA-XAIT TAIAAAAAIC AICtZETCAIT 1431 OATITTACC CIAICMCCT CDXAAGACA GTIXTUXT AAAOXACAA UUαiCILflL' 1491 OCACA3ICC OJlUJGOJSr G3TAGGMAG ALTIULTUX' TIUI HLUL CTαα_CA3CA 1551 α MA GTCCTΓΓΠA PGSSΠSCPG tiiiiiT-yirπ' CMMMCCΓ TTGATICAM i6H -DXCD3SSAA * K_AAXftA3G CAAMTTTTC AAAA3AAGAA AXDGCGSOC GMOGMTCC 1671 AIGGMCCΓC ACAICCΠAAT ,:n-t: A,ι iA: 1701 (2) DEFORMATION FCR SEQ 3D N0:56: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 241 aπino acids (B) TYPE: aαino acid (D) TCPOLCGY: linear (ii) MOT-ECULE TYPE: protein (xi) SEQUENCE I-ESCRIPIION: SEQ ID NO: 56: Met Asp Met Arg Val Pro Ala Gin Leu Leu Gly Leu Leu leu leu Trp -22 -20 -15 -10 Leu Pro Gly Ala Arg Gly Aεp He Val Met Thr Gin Ser Fro Asp Ser -5 1 5 10 Leu Ala Val Ser leu Gly Glu Arg Ala Thr He Asn Cys lys Ser Ser 15 20 25 Gly Ser leu Leu Tyr Ser Thr Asn G n lys Aai Tyr Leu Ala Trp Tyr 30 35 40 Gin Gin ys Pro Gly Gin Pro Pro Lys Leu Leu He Tyr Trp Ala Ser 45 50 55 Thr Arg Glu Ser Gly Val Pro Asp Azg Phe Ser Gly Ser Gly Ser Gly 60 65 70 Thr Asp Phe Thr leu Thr He Ser Ser Leu Gin Ala Glu Aεp Val Ala 75 80 85 90 Val Tyr Tyr Cys Gin Gin Tyr TVr Ser Tyr Arg Thr Phe Gly Arg Gly 95 100 • 105 Thr Lys Leu Glu He Lys Azg Thr Val Ala Ala Pro Ser Val Phe He HO 115 120 Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val 125 130. 135 Cys Leu Leu Asn Aai Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys 140 145 150 Val Asp Asn Ala Leu Gin Ser Gly Aεn Ser Gin Glu Ser Val Thr Glu 155 160 165 170 Gin Asp Ser lys Aεp Ser Thr Tyr Ser leu Ser Ser Thr Leu Thr Leu 175 ISO 185 Ser lys Ala Asp Tyr Glu Lys His lys Val Tyr Ala Cys Glu Val Thr 190 195 200 His Gin Gly Leu Ser Ser Pro Val Thr lys Ser Phe Asn Azg Gly Glu 205 210 215 Cys (2) INFC ffillCN FCR SEQ 3D NO: 57: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 115 base pairs (B) TYPE: .rucleic acid (Q STRAMEDNESS: single (D) -DOPOLOGY: linear (ii) MOLECULE TYPE: cCNA (iii) HYPOTHETICAL: NO (iv) Nn-SENSE: O (ix) FEAIURE: (A) NAME/KEY: misc_feature (B) IOCATICN: 1 (D) OTHER INFOFMAITCN: / cte * *p_NN03 εyπthetic polylinker" (xi) SEQUENCE CESCRHTTCN: SEQ 3D NO: 57: GCOGCOGCQS TDC AO JC A 60 TGCICGA3CT CTAGATBICG AITCCATGSA TCCICACAIC OCAATCCGOG OUGGC 115 (2) INFCRKT N FOR SEQ ID ND:58: (i) SEQUENCE CHARAOTEKESTICS: (A) IENGTH: 44 base pairs (B) TYPE: rucleic acid (C) STRANCEIUEΞS: single (D) TCfOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) H€VKEY: -α ec Eβerture (B) IOCMION: 1 (D) OTHER INFCRffillCN: (xi) SEQUENCE LESCRIPITQN: SEQ ID NO: 58: TGTA3CAOCA GGTGCΣXACT (XCAGGICCA AJIG AGTCT A3G 44 (2) INFORMATION FCR SEQ 3D NO: 59: (i) SEQUENCE CHARACJiK &llCS: (A) LENGTH: 44 base pairs (B) TYPE: nucleic acid (C) SIRANCEINESS: single (D) TDPCCOSY: linear (ii) M IBCT.TIE TYPE: £NA (iϋ) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEAIURE: (A) NBMyKEY: misc_£eature (B) LOCATKN: 1 (D) OTHER INEOMΩION: /note= *312-47 oligcraJCleotide-* * (xi) SEQUENCE TES STPπaHi SEQ 3D NO: 59: TCSAXICGA GGSICAOCGT CIULTCAGGT GALJI UIAAG CITG 44 (2) 33*ΪFORMAIIDN FCR SEQ 3D NO: 60: (i) SEQUENCE CHARSC11R1S1ICS: (A) IBdH: 46 base pairs (B) TYPE: nucleic acid (C) STRAΪCELNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: CCNA (iii) HYPOTHETICAL: NO (iv) ANIT-SENSE: NO (ix) FEAIURE: (A) NAM KEY: _αisc_feature (B) τsxxπatz 1 (D) OTHER INFCBβαiCN: rote *** "312-48 oligcπjclecfcide"- " (xi) SEQUENCE EESCRIPITGN: SEQ 3D NO: 60: GCAAQCAGAA GAOXTCt-AG ( JltXAJlUA lUilUULUlJ GOGSTA 46 (2) INFCRftlTCN FOR SEQ 3D NO: 61: (i) SEQUENCE CHARACTERISTICS: (A) IENGTH: 52 base pairs (B) TYPE: rucleic acid (C) STRAI ECNESS: single (D) TOPOLOGY: linear (ϋ) M3LECULE TYPE: C∑NA (iii) HYHJlHt-lICAL: NO (iv) ANΠ-SENSE: NO (ix) FEAIURE: (A) NAME KEY: π sc_ βature (B) LOCAITCN: 1 (D) OTHER INFΗβΣXCN: hots- "312-49 cligcnclec ide" (xi) SEQUENCE IOΞSσπPITON: SEQ ID NO: 61: TOGA T IAG ACDGCAGITG GAOCTGSSAG TOQGCAXIG GIULUACAX CA 52

Claims: CLAIMS We claim: 1. An antibody homolog that (a) binds to human CD4; (b) does not significantly block binding of HIV gpl20 to human CD4; and (c) blocks HIV-induced syncytia formation between CD4 + cells at least as well as OKT4A. 2. An antibody homolog that (a) binds to human CD4; (b) does not significantly block binding of HIV gpi20 to human CD4; (c) blocks HIV-induced syncytia formation between CD4 + cells better than OKT4; and (d) is less immunosuppressive than OKT4A in an in vitro tetanus toxoid-specific proliferation assay. 3. An antibody homolog that (a) binds to human CD4; (b) does not significantly block binding of HIV gpl20 to human CD4; (c) blocks HIV-induced syncytia formation between CD4 + cells at least as well as OKT4A; and (d) is less immunosuppressive than OKT4A in an in vitro tetanus toxoid-specific proliferation assay. 4. The antibody homolog according to any one of claims 1-3, wherein the antibody homolog does not bind to a polypeptide consisting of human CD4 VI. 5. The antibody homolog according to claim 4, wherein the antibody homolog binds to a polypeptide consisting of human CD4 V1V2. 6. The antibody homolog according to any one of claims 1-3, wherein the antibody homolog does not significantly block the binding of CD4 Vl-specific antibodies to human CD4 7. The antibody homolog according to any one of claims 1-3, wherein the antibody homolog inhibits infection of CD4 + cells by HIV. 8. The antibody homolog according to any one of claims 1-3, wherein the antibody homolog displays one or more characteristics selected from: (a) causing no significant decrease in the number of circulating CD4 + cells in vivo; (b) causing no significant modulation of CD4 from the surface of CD4 + cells in vivo; (c) causing no significant decrease in circulating peripheral white blood cell counts in vivo; and (d) causing no significant decrease in the antibody titer elicited in response to foreign antigens in vivo. 9. An antibody homolog derived from a hybridoma selected from the group of hybridomas having accession numbers HB 10881 (5A8) , HB 10882 (1F8) and HB 10883 (5F2) . 10. The antibody homolog according to claim 9, derived from the hybridoma having accession number HB 10881 (5A8) . 11. The antibody homolog according to any one of claims 1-3 or 9-10, wherein the antibody homolog is an intact monoclonal antibody. 12. The antibody homolog according to any one of claims 1-3 or 9, wherein the antibody homolog is selected from the group consisting of Fab fragments, Fab' fragments, F(ab') 2 fragments and F(v) fragments. 13. The antibody homolog according to any one of claims 1-3, which is a humanized recombinant antibody homolog. 14. The humanized recombinant antibody homolog according to claim 13, wherein the amino acid sequences of the CDRs are as follows: (a) light chain CDR1 is AA 24 ~AA 40 of SEQ ID NO:15; (b) light chain CDR2 is AA 56 -AA g2 of SEQ ID NO:15; (c) light chain CDR3 is AA 95 -AA 102 of SEQ ID NO:15; (d) heavy chain CDR1 is AA. -AA-_ of SEQ ID NO:10; (e) heavy chain CDR2 is AA 0 -AA- g of SEQ ID NO:10; and (f) heavy chain CDR3 is AA g -AA-. of SEQ ID NO:10. 15. The humanized recombinant antibody homolog according to claim 14, wherein: (a) the amino acid sequence of the light chain variable region is A -AA... of SEQ ID NO:56; and (b) the amino acid sequence of the heavy chain variable region is AA.-AA 22 of SEQ ID NO:45. 16. The humanized recombinant antibody homolog according to claim 15, wherein: (a) the amino acid sequence of the light chain is AA -AA... of SEQ ID NO:56; and (b) the amino acid sequence of the heavy chain is AA -AA 448 of SEQ ID NO:45. 17. The antibody homolog according to any one of claims 1-3, which is a chimeric recombinant antibody homolog. 18. The chimeric recombinant antibody homolog according to claim 17, wherein: (a) the amino acid sequence of the light chain variable region is SEQ ID NO:15; and (b) the amino acid sequence of the heavy chain variable region is SEQ ID NO:10. 19. A derivatized antibody homolog comprising an antibody homolog according to any one of claims 1-3 and 9-10, linked to one or more members independently selected from the group consisting of antibody homologs of claims 1-3 and 9-10, 5A8-mimetic agents of claims 37-39, detectable agents, cytotoxic agents and pharmaceutical agents. 20. The derivatized antibody homolog according to claim 19, wherein the pharmaceutical agent is selected from the group consisting of immunoglobulins and portions thereof that bind to human peptides, polypeptides or proteins. 21. A composition for preventing or treating a disease in a mammal caused by an infective agent whose primary target is CD4 + cells comprising an immunotherapeutically effective amount of one or more members selected from the group consisting of the antibody homologs of claims 1-18, the derivatized antibody homologs of claims 19-20 and the 5A8-mimetic agents of claims 37-39, and a pharmaceutically acceptable carrier. 22. The composition according to claim 21, wherein the mammal is a human and the infective agent is HIV. 23. The composition according to claim 21 or 22, further comprising one or more agents which significantly block binding of HIV gpl20 to CD4. 24. The composition according to claim 23, wherein the agent is selected from CD4 Vl-specific antibody homologs, CD4 VI polypeptides and anti-HIV gpl20 antibody homologs. 25. A method for preventing or treating a disease in a mammal caused by an infective agent whose primary target is CD4 + lymphocytes comprising administering to the mammal an immunotherapeutically effective amount of one or more members selected from the group consisting of the antibody homologs of claims 1-18, the derivatized antibody homologs of claims 19-20 and the 5A8-mimetic agents of claims 37- 39, and a pharmaceutically acceptable carrier. 26. The method according to claim 25, wherein the mammal is a human and the infective agent is HIV. 27. A DNA sequence selected from the group consisting of: SEQ ID NO:14 (5A8 light chain variable region), SEQ ID NO:9 (5A8 heavy chain variable region), SEQ ID NO:55 (pre-5A8 humanized light chain) and SEQ ID NO:44 (pre-5A8 humanized heavy chain); portions of any of the foregoing DNA sequences that encode an antibody homolog according to claims 1-3; and DNA sequences degenerate to any of the foregoing DNA sequences. 28. A recombinant DNA molecule comprising one or more DNA sequences according to claim 27 and one or more expression control sequences operatively linked thereto. 29. The recombinant DNA molecule according to claim 28, which is selected from pMDR1007 (ATCC 68846) and pMDR1002 (ATCC 68847). 30. A cell that produces an antibody homolog selected from the antibody homologs of claims 1-18. 31. The cell according to claim 30, which is a hybridoma cell. 32. The cell according to claim 31, which is selected from the group of cells having accession numbers HB 10881 (5A8) , HB 10882 (1F8) and HB 10883 (5F2) . 33. The cell according to claim 30, which is a host cell transformed with one or more recombinant DNA molecules according to claim 28 or 29. 34. A method for producing an antibody homolog selected from the antibody homologs of claims 1-18 comprising culturing a cell selected from the cells of any one of claims 30-33. 35. A method for producing a cell according to claim 31, comprising the step of immunizing a non- human mammal with CD4 + cells produced by transforming CD4~ mammalian tissue culture cells with DNA encoding full-length human CD4, which CD4 + cells express the CD4 on their surface. 36. The method according to claim 35, wherein the CD4 + cells have accession number CRL 10884. 37. A 5A8-mimetic agent which inhibits HIV- induced syncytia formation between CD4 + cells. 38. A 5A8-mimetic agent which inhibits infection of CD4 + cells by HIV. 39. A 5A8-mimetic agent displaying the properties of an antibody homolog selected from the antibody homologs of claims 1-8.

Inventors: BURKLY LINDA C, CHISHOLM PATRICIA L, ROSA JOSEPH J, ROSA MARGARET D, THOMAS DAVID W, BURKLY, LINDA, C., CHISHOLM, PATRICIA, L., ROSA, JOSEPH, J., ROSA, MARGARET, D., THOMAS, DAVID, W.
Applicants: BIOGEN INC, BIOGEN, INC.
Application year: 1991
Main classification: C12P21
IPC codes: A61K38, A61K39, A61P31, C07K14, C07K16, C07K19, C12N5, C12N15, C12P21, C12R1, G01N33