JPH04503008A - Common idiotype-reactive anti-idiotype antibodies expressed by human lymphomas and autoantibodies - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Common idiotype-reactive antibodies expressed by human lymphomas and autoantibodies biotype antibody Description of related applications This application is filed on January 31, 1989, United States Application No. 30. This is a CIP application No. 4745.

field of invention The present invention relates to immunodiagnosis and immunotherapy. Specifically, the present invention provides treatment for autoimmune diseases. , HIV associated with B-cell lymphoma, and prevention of single-cell lymphoma in general. , relating to the discovery of antibodies that can be used for diagnosis, observation, treatment and improvement.

Background of the invention Immune system and immune diversity Antibodies (immunoglobulins) help the host recognize and eliminate foreign substances found in mammals. produced by B-cells (B-lymphocytes) of an animal's immune system to help fight . Typically, proteins as well as foreign substances that elicit such antibody responses by the host are It is called an antigen. In response to antigen stimulation, mature B-cells produce antigen-specific antibodies in their serum. Proliferate and differentiate into secreting plasma cells.

Immunoglobulins are Y-shaped, with two relatively long points called heavyweights (H). Consisting of two shorter polypeptide chains called the lipeptidyl chain and the light chain (L) It is a mercantile molecule. Each pair of arms of the Y-shaped structure has a specific antigen binding ability, Each arm contains an antigen-binding fragment (antigen-binding agment: F a b area). Tail part (base part) of Y-shaped structure ) is a crystallizable fragment : Fc region) and is a binding site for activating cell lytic ability.

Immunoglobulin molecules have variable regions that are responsive to their specific antigen recognition.

The characteristics that distinguish one immunoglobulin from another can be collectively referred to as the antibody 'idiotope'. It is called ip, which comes from the Greek word for "private type." classification and at the next stage of naming, variable region idiotypes are referred to as idiotobes. It includes and is defined by multiple determinants. These idioms The three-dimensional structure of the various peptides forming the polypeptide chain of the Fab region Consists of body structure. Like foreign protein antigens, each idiotope is immunogenic and has anti-inflammatory properties. − idiotypic immune response (to each idiotope or group of idiotobes) It is possible to induce specific antibodies). (e.g., Kunkel, H.G., et al., Saie 140, p. 1218 (1963): Woojin, J., and Michael, Mo. , (Cr, Acad, 5ci) (Paris), vol. 257, p. 805 (1963). ).

The variable regions are for the heavy chain, VN, D and J, gene segments, and for the light chain. It is encoded by the VL and JL gene segments. (Tonegawa, S9, Ne Ichar, Vol. 302, p. 575 (1983)) within the immunoglobulin variable region. It is these genes that create different antigenic determinants, or idiotopes. It is a combination of child segments. Idiotopes may be common (e.g. For example, rpr ivareJ). These common idiotope terms and concepts are explained below. Ru.

Antibodies, the formation of which are stimulated by the administration of an antigen, are bound to the antigen by non-covalent bonds. Can be combined. This binding occurs due to topographical complementarity between the antigen binding site and the antibody binding site. considered to be based on gender. (However, it is not possible to do this by any specific means.) I don't think such a join is actually happening). Binding of antigen recognized by antibody The site is called an "epitope" and the binding site on an antibody is called a "paratope". Ru. (Gerne, N1, Ann, Immunol, (Institut Pasteur) 125 C: 373 pages (1974)). Paratopes also act as idiotopes . That is, paratopes stimulate anti-idiotypic responses. There, originally Anti-idiotypic antibodies bind to paratopes as well as epitopes. if , if the anti-paratope anti-idiotope antibody is structurally similar to the antigen, It is called the internal image of the antibody. The conformation of the original antigen In addition to these anti-paratope anti-ideotypes that represent Idiotypic antibodies are antibodies and T-cell receptors involved in the regularity of immune responses. Identify the target idiotype. These idiotypes are regular idiotypes. These are not necessarily the original This is not an internal image of a conventional antibody. (e.g. Baputt, S., and Schwartz, Ro, Niney England Journal of Medicine, 3 (See Vol. 17, p. 219 (1987)). Internal image in immunotherapy The use of anti-idiotypes has been demonstrated experimentally. For example, internal Image anti-idiotypes against viral, bacterial and parasitic infections and tumors It has been used as a surrogate for antigen to generate a specific immune response against it. (for example , Berlin, D. et al., Science, 2322100 (1986); Gieduri, S. et al., Journal of Immunology, 137:1743. (1986)’).

There are many types of antibodies that bind to one specific antigen. Some of this diversity There is a reason. First, there are hundreds of types of VM and VL gene segments. Ru. Different gene segments exhibit different antigenic features in different combinations. can be done. Second, vH or VL genes are associated with various D and J gene sets. can be combined with a component. Third, various VH and VL tablets are can be combined by law. These factors contribute to the immunoglobulin expression observed in mammals. This is the reason for diversity. Somatic mutations that further increase diversity occur within B cells.

Even at the level of a specific epitope, the human body has one or more molecules that can react with that epitope. antibody molecules. These antibodies can be used to target light or heavy chain constant regions or variable Different in area. Within a species, differences can be seen in key constant regions.

These differences are known as isotypes, and the immune system uses different immunoglobulins. Classes and subclasses of phosphorus, e.g. IgG1, IgG2, IgG in humans G3, IgG4, IgM, IgAl, IgA2 and IgE. these Structural differences contribute to the ability to bind complement and increase phagocytosis by macrophages. Which specific effector actions confer different immunoglobulin molecules. specific pieces Within different antibody isotopes, additional genetic differences in the structure of the key constant regions occur. , is called an "allotype." The allotype region of the important constant region is the It comes from genes inherited from parents. Antibody molecules found in immunoglobulin variable regions The difference is that when B cells differentiate into antibody-producing plasma cells, specific v8 and and as a result of the use of VL genes. That is, the characteristics present on the antigen Antibodies that react with a given epitope have different heavy chain constant regions, different light chain constant regions ( either kappa or lambda) can be used. That is, various VL or 7M Gene segments may be selected. Maintain proper complementarity and reactivity with the epitope. Various combinations of these variable region gene segments can be constructed.

Anti-idiotype antibodies target specific compartments (idiotypes) of immunoglobulin variable regions. reacts with Antibodies that react with a given epitope are randomly selected antibodies. It is possible that more specific ■, or vL gene segments are utilized than in the body.

Specific antigenic determinants within the variable region identified by anti-idiotypic antibodies, i.e. An "epitope" is also known as an "idiotope."

That is, a large number of idiotobes are involved in immunoglobulin variable light chain and variable heavy chain segments. Exists within the ment. i.e., defined by the ternary flanking regions of the heavy and light chains. It will be done. Because of the tremendous diversity that occurs within the immunoglobulin gene system, anti- Idiotypic cross-reactivity is rare but not expected. Various antibodies A cross-reactive idiotype occurs when two molecules react with the same antigenic determinant (epitope). is more often observed. This is a structure that is complementary to an antigenic determinant (epitope). Based on the need to select suitable VL and ■8 gene segments with It is. That is, the discovery of a common anti-idiotype indicates that these antibody molecules are similar. may react with epitopes (idiotopes in the case of immunoglobulins) It suggests that there is no. However, similar V and ■H gene segments It can be utilized for reactions with other antigenic determinants. In these cases, anti-idiotypic may cross-react with antibodies that do not have similar antigen-binding specificities. i.e. Now that it has been discovered that lymphomas share idiothes, these If any of the othobes reacts with similar antigenic determinants (e.g., antigens associated with pathogenic bacteria) In the process of becoming defective, defective B cells develop specific vH or VL genes. It is suggested that the child segment be pre-sequenced to select it.

Antibodies are just one component of an animal's immune response system. Antibodies bind to foreign proteins. Whenever an antigen is recognized, it produces a wide range of phenomena that can ultimately lead to the destruction of the recognized antigen. let Antibodies are produced by B-cells, which are a type of lymphocyte. B-Thin The cells carry a sample of specific antibodies that the cell produces on the surface of its cell membrane. Already As discussed in Plasma cells secrete serum antibodies during the positive foot cycle. Secrete. For example, when an antigen enters the bloodstream, it comes into contact with existing circulating serum antibodies. I might. In such cases, the antigen does not reach the specific B-cell and stimulation It also does not cause differentiation. However, if the introduced antigen is in excess of the effective circulating antibody, If so, then further stimulation of antibody production may occur by this mechanism.

Immune diseases and immunotherapy B-cells are antibody-producing cells, each expressing a different antibody on its membrane surface . The human body has the capacity to express a huge number of antibodies (i.e. 10'-10 ``Individuals''. B-cell lymphocytes are added to tumor cells caused by the proliferation of specific B-cells. I have a tumor. As a result of B-cell diversity, two or more B-cell lymphomas It expresses the same antibody idiotype on its cell membrane.

AIDS is a deadly disease caused by the HIV virus, which is often an opportunistic infection. It is associated with tumors such as B-cell lymphoma and B-cell lymphoma. In AIDS, these lymphomas are common It is a severe lymphoma, with little predictability due to its rapidly progressive clinical course, and Most patients survive less than 6 months. In general, B-cell lymphomas are associated with AIDS. The properties of cell membrane surface antibodies produced by AIDS associated with B-cell lymphoma are It is expected that there will be a lot of interest. That is, these antibodies have antigenic determinants. They are not expected to have common features (referred to as groups).

In B-cell lymphoma, the defective B-cells, like their normal counterparts, have an immune system on their membrane surface. A unique idiot that can be used as a “tumor-associated antigen” marker in therapy expresses type determinants. (Stevensin, G. T., et al., Nature, 254 Volume 714 (1975); Stevenson, G., T., et al., Federicine. ・See Proceedings, Vol. 36, p. 2268 (1977)). B-Lymphoma treatment The effectiveness of anti-idiotypes in treatment has been demonstrated in several animal models (e.g. Horton et al., Journal of Immunology, Vol. 121, p. 2353 (19 78): Krolick, K., A., et al., Journal of Experimental ・Medicine, Vol. 155, p. 1797 (1982); Maloney, D., G., et al. Hybridoma, Vol. 4, p. 191 (1987); Stephenson, F., K., et al. , Journal of Immunology, vol. 130, p. 9709 (1983); Ku, Y. et al., Journal of Immunology, vol. 131, p. 1600 (1983 ): Stephenson 1, F., et al., British Journal of Canada. Sur, vol. 50, p. 495 (1980).

Here, we present a monoclonal anti-idiotype for the treatment of human B-cell lymphoma. The activity was investigated. In these early clinical trials, anti-idiotypes were It showed remarkable clinical responses and reproducible anti-tumor effects in many patients (see: Hamplin, T. J., et al., British Journal of Cancer, 42. Volume 495 (1980); Miller, R.A., et al., New England Japan. Null of Medicine, vol. 306, p. 527 (1982); Meeker, T. C., Roeder et al., Blood, Vol. 65, p. 1349 (1985); Brown, S. Lo, Miller, R. A., Holling, S. J., Cervinski, D.9. To, S9, Matsukeburi, Ro, Iram, To, Wolunke, R1, Meliga N, T., C., Levi, R.1, “Anti-idiotypes only and alpha-in "Treatment of B-cell lymphoma in combination with terferon", Blood, Vol. 73, 651. Page (1989); Rankin, E. M. et al., Blood, Vol. 65, p. 1373 (19 85); and Loder 1J, N., et al., Blood, vol. 69, p. Year)). Despite these encouraging results, the use of anti-idiotypes Effective anti-idiotype therapy for lymphoma is limited by multiple factors. One of the inherent problems in immunotherapy research is that tumors react with administered antibodies. or the presence of a circulating idiotype in the patient's serum derived from either normal B-cells. It is present.

Such circulating antibodies neutralize administered anti-idiotypic antibodies and Preventing the antibody from reaching the tumor target, thereby impeding its therapeutic efficacy. meeker et al., Blood, Vol. 65, p. 1349 (1985), the concentration of circulating idiotypes. It is stated that if the is too high, an anti-tumor response cannot be achieved. i.e. book One of the objectives of the invention is to develop a method that does not react with common idiotopes expressed at high concentrations in plasma. The goal is to develop new anti-idiotypes. This is why the anti-idiopathic drug is used in therapy. This is because it prevents the use of IP.

A further practical feature is the widespread and economical use of anti-idiotypic immunotherapy. is a hybrid that produces anti-idiotypic antibodies for an individual patient's tumor. Limited by current requirements for custom production of dormers. Order-based resistance - The time required to produce the idiotype may occur in late stages of the disease or in rapidly progressive disease. This prevents patients from receiving treatment. Additionally, patients order anti-idiotypic treatments related to Expenses may limit its application. Therefore, expressed by a related group of lymphomas Anti-idiotypes that recognize common idiotopes (common anti-idiotypes) It is an object of the present invention to develop. Reacts collectively with lymphoma in the majority of patients The development of a panel of anti-idiotype antibodies that can be used for diagnostic and therapeutic purposes during lymphoma treatment This greatly facilitates the use of anti-idiotypes as therapeutic and therapeutic agents.

Related to the concept of a common idiotype, various studies in animal and human systems have A number of antibodies with cross-reactive idiotypes are shown. These systems include: Human B-cell tumors (see: Kamen, D. A., et al., Molecusi Immunology , Vol. 20, p. 1081 (1983): Rankin, E. M. et al., Blood, Vol. 68. 430 pages (1986), Kunkel, H.G., et al., Journal of Experiments. Rementa/L/-Medicine (J, EXI, Med) Volume 137, Page 1453 (1977): Mayumi, M. et al., Journal of Immunology-129, 9. 04 pages (1982); Kiyotaki, M. et al., Journal of Immunology 1 Vol. 38, p. 4150 (1987): Kipps, T. J., et al., Blood, Vol. 72, 4. 22 (1988)); Murine Immunoglobulin Idiotype (Makela, 0. et al., Immunological Review, Vol. 34, p. 119 (1977)); Cold agglutinin Antibodies (Williams, R.C., et al., vol. 161, p. 379 (1968)); Umachi Factor (Kabato, E, A, et al., Experimental Immunochemistry) -, Thomas Publishing, Springfield, IL (1961); Basgari, J. L.

et al., European Journal of Immunology, vol. 13, p. 197 (198 3 years); human anti-thyroglobulin antibody (Matsuyama, J et al., Clinical Ann. Experimental Immunology, Vol. 51, p. 381 (1983); complete Antibodies in patients with systemic lupus erythematosus (Solomon, G. et al., Proceedings of ・National Academy of Sciences, USA, Volume 80, Page 850 (19 83); Zienfeldt, Y., et al., Journal of Experimental Medicine, Vol. 158, p. 718 (1983)) and T-cell tumors (Maue Le, S., C., et al., Journal of Experimental Medicine, 157 Volume 705 (1983): Bigsey, R1 et al. Mental Medicine, Vol. 158, p. 1000 (1983)).

Stephenson et al. An attempt was made to identify anti-idiotypes for use in the treatment of. So The study of anti-idiotopes that react with idiotobes present in normal human serum This suggests that there is a great deal of potential for reactions with common idiotopes. but However, looking at the limited number of antibodies, Stephenson et al. Only a few antibodies react with a very small proportion of B-cell lymphomas. I stopped at checking the diotype. The present results demonstrate that normal human serum and anti-ideal These antibodies will cross-react with common idiotopes. This shows that it is not enough to just predict. Aggregates, the majority of lymphomas There are many types of antibodies that react with a common idiotope that would react with Stephenson et al. do not disclose or suggest that he is deaf.

In a study by Stephenson et al., the anti- Approximately 15% of idiotype antibodies have been shown to react with normal serum immunoglobulins. It's clear. In this study, it was even more common in lymphoma idiotypes. Approximately 24% of anti-idiotypes produced against normal serum immunoglobulin Reacted with several components. Stephenson et al. each tested B-cell tumor idiotypes. Two anti- I discovered an idiotype. Some of these idiotypes are known self-replicants. It is noteworthy that this myeloma protein is responsive. As mentioned, different Cross-reactivity occurs when antibody molecules react with the same antigenic determinant (epitope). Otype is more often observed. The anti-idiotype of Stephenson et al. One type is reactive with a common idiotope expressed on bloating lymphoma, and is a tumor. It may discolor only some combinations of cell groups and may not be effective for treatment as a whole. Dew. This antibody reacted with two of the 12 types of saturation lymphoma, but the second antibody did not react with any of the saturated lymphomas in test 12. normal serum immunoglobules Anti-idiotype antibodies that cross-reacted with phosphorus may also cross-react with other tumor idiotypes. It turned out that it was compatible. In other words, in our experience, out of 44 such antibodies, Only 32 from 1 to 3 were cross-reactive with the tumor idiotype. i.e. normal serum Anti-idiotypic reactivity with lymphoma alone does not predict reactivity with lymphoma. or certain. On the contrary, this cross-reactive anti-idiotide The samples were selected based on the widespread discoloration of the tumor cell population (Figure 4). ).

Kipps et al., Blood, Vol. 72, pp. 422-248 (1988), chronic lymphocytic investigated surface antibodies associated with leukemia (ffCLLJ). CLL cells are patients More than 90% of CD-5+ lymphocytes are derived from CD-5+ lymphocytes. This is probably due to B-cell Any of the very wide changes that could have turned malignant It is different from other lymphomas such as Hodgkins lymphoma (rHNL). Kipps et al. The results show that 25% of the Vk region of cell membrane surface antibodies in CLL is the same. did. CLL cells are derived from a specific subset of B-cells, namely CD5+. It is not surprising that these are closely related. other On the other hand, no such identity was found in the tested NHL B-cells. That is, It is inconceivable that a common idiotype would be discovered among non-CLL B-cell lymphomas. Not possible.

Kipps et al., Leukemia, vol. 2, p. 194 (1988); Kipps et al., Jhana Le of Experimental Medicine, Vol. 67, pp. 840-852, 847. (1988). Kipps et al., Blood, Vol. 72, p. 422 (1988) and Kiyotaki et al., Journal of Immunology, vol. 138, p. 4150 (1 (987) are cross-reactive idiotynes that occur in chronic lymphocytic leukemia. reported a high incidence of depression. Conserved kappa light chain variable region for CLL The high frequency of expression of region genes explains the high incidence of crossed idiotypes. kips As also pointed out, this idiotype is frequently expressed in saturated lymphomas. stomach. It is possible that CLL cells represent a special case in which they are CD5 positive. be. CD5-positive cells have autoreactive antibodies that also have cross-reactive idiotypes. known to be related. (See Blood, Vol. 72, p. 422 (1988)) (see).

systemic lupus erythematosis ff5LEJ) and rheumatoid arthritis (rRAJ). All autoimmune diseases are associated with antibodies that react with the host's own antigens. self like this Reactive antibodies, or autoantibodies, are Protein, RNA, calciolipin, thyroglobulin, red cell antibody, platelet antibody or may react with other autoantigens. Is the 16.6 antibody originally a patient with SLE? This is a DNA-reactive autoantibody isolated from 16.6 antibodies are found in patients with SLE and Identification frequently expressed by autoantibodies found in some patients with and RA. Including biotypes. That is, the 16-6 idiotype has these diseases. commonly seen in patients. 16.6 Serum and tissue concentrations of related idiotypes correlates with disease activity. In the past, rabbit polyclonal antiserum It has been used to measure the concentration of the 16°6 idiotype. Therefore, the purpose of the present invention is to 16.6 to identify common idiotypes associated with autoantibodies.

Rheumatoid factor (fRFJ) reacts with immunoglobulin constant region antigenic determinants. It is an autoantibody that RFs are associated with many autoimmune diseases, especially RF autoimmune diseases. This is particularly important in rheumatoid arthritis, where body concentrations are correlated with disease activity. destination The current literature indicates that RFs are polyclonal mixtures of many antibodies, i.e., the main This suggests that it may not express a particular idiotype.

Therefore, common antibodies expressed by lymphoma and autoantibodies with disease antigen reactivity Discovery of the idiotype would normally not be possible. However, lymphoma and The discovery of anti-idiotypic antibodies that react with common idiotypes in autoimmune diseases Facilitate the use of antibodies in the diagnosis and treatment of autoimmune and lymphoma diseases. present invention Previously, due to the tremendous diversification of the B-cell population, anti-idiotypic antibodies on a custom-made basis for use in the diagnosis or treatment of lymphoma or autoimmune diseases. It had to be manufactured using This is difficult, time-consuming, and expensive. stomach. Therefore, a secondary object of the present invention is to treat lymphoma and/or autoimmune diseases. Common idiotypes and predicted reactions that can be used more effectively for testing, diagnosis and treatment development of anti-idiotypic antibodies formulated for

Summary of the invention In broad terms, the present invention relates to autologous lymphoma associated with B-cell lymphoma and autoimmune diseases. A common idiotype expressed with variable frequency in different histological subsets of antibodies Based on the findings of a panel of at least 32 anti-idiotypic antibodies that react with It's a spider. See Table 2. Further, specifically, 332 B-cell lymphomatosis 108 (32.5%) cases, of which 3 from 116 small cleavage lymphomas. 2 (30%) are reactive with at least one of the 32 anti-idiotypic antibodies. It turned out that it was compatible. Five anti-idiots for AIDS-related lymphoma It was found that the antibody reacted with 12 of 15 such lymphoma cases.

See Table 3. In addition, a small number of antibodies that also bind to selected autoantibodies (all 7 types of anti-B- Cellular lymphoma antibodies were confirmed. See Table 6. The degree of cross-reactivity is high and certain This is something that cannot be predicted. This time, here are these, and autoimmune diseases, AIDS - useful in the treatment, diagnosis and/or monitoring of and non-AIDS related lymphomas Other novel anti-antibodies are disclosed and claimed.

Brief description of the drawing Fig. l is monoclonal that reacts with a common idiotope in normal human serum. Competitive inhibition ELISA used as primary selection of antibodies is shown. Comparison with horse serum Then, human serum has a common idiotope derived from the tumor and the idiotype. More than 4-fold inhibition of binding of monoclonal anti-idiotypic antibody C33-13-8 caused harm.

Fig. 2 shows the relationship between immunoglobulin and anti-idiotype binding in collected human serum. The results of two stages of quantitative measurement are shown. Anti-idiotype C3 with collected human serum 3-13-8 serial dilutions of purified idiotype at a starting concentration of 25 μg/ml. By incubation of C33-13-8 monoclonal antibody with serial dilutions Competitive inhibition produced similar curves. Comparing the midpoints of the curves, blood The concentration of immunoglobulins with a common idiotype in the serum was 32 μg/ml. I understand that.

Fig. 3 schematically shows the idiotype structure of l;”a, Tr and Fu patients. Three large circles are used to illustrate this. individual idiotobes (pale nets) the idiotype structure (eye circles) and common anti-idiotypes (dark mesh circles) It is shown in Antibodies C33-13-8 and C53-23 were tested in these three patients. represents a common idiotobe expressed by tumor cells from other idiotobes Anti-idiotypes that are unique due to their lack of cross-reactivity with other patients It is expressed as Overlapping small circles indicate two or more anti-idiotypic antibodies The above idiotobes are identified by their reactivity with anti- The same or nearly the same as determined by idiotypic competitive binding experiments It's in the layout.

Fig. 4 shows Du (IgMK), Me (IgGK), ST (IgML) and Immunofluorescence staining and FAC performed with tumor cells from Ei (IgML) patients This shows the results of 8 analyses. Immunoglobulin-bearing cells are total B-cells and tumors. Anti-immunoglobulin light chain indicating proportion of B cells in population representing tumor clones Confirm by developing color with a reagent. Negative control color development was performed with incompatible light chain reagents. Matches the color development seen by color development. 537-48-6-26 (anti-common ID) iothobe) reacts with cells from Du, St and Ei patients. St and E Tumor cells from i patients are also colored with a unique anti-idiotype. S-37- , 48-6-2-6 shows no color development in patient Me cells, and 5 shows rheumatoid arthritis Concentration of L50-19 common idiotype over time in patient A with and the correlation between idiotype concentration and disease progression and regression.

Fig. 6 shows L50-19 over time in patient B with rheumatoid arthritis. Common idiotype concentration and the relationship between idiotype concentration and disease progression and regression. It shows a correlation.

Fig. 7 shows L50-19 over time in patient C with rheumatoid arthritis. Common idiotype concentration and the relationship between idiotype concentration and disease progression and regression. It shows a correlation.

Detailed description of preferred embodiments This time, we presented a small tumor-fighting drug for 67 patients with mild saturation B-cell lymphoma. At least 199 monoclonal anti-idiotypes were produced. Mild follicles B-cell lymphoma is one of the more common types of B-cell lymphoma. The diagnosis is Based on clinical appearance and histological findings. Anti-idiotypes that recognize common idiotypes To determine the frequency of deiotypes, Stephenson et al., Blood, Vol. 68, 4. anti-idiotypes using a modification of the technique described on page 30 (1986). The panel was selected. Using this technique, small components of normal serum immunoglobulin and select appropriate anti-idiotypes and target lymphoma and other proteins, e.g. autoantibodies. were selected and tested for cross-reactivity to a collection of bodies.

Additionally, anti-idiotypes produced against non-HIV-associated associated cotton follicle lymphoma Some common symptoms expressed in non-HIV-associated and HIV-associated cotton follicular lymphomas It was found that it reacts with the diotype. As mentioned above, the immune system has a huge number of gene and produce a common idiotobe, which is highly unlikely. This time, 10 Thirty-two anti-identifiers that could cross-react with B-cell lymphoma from eight different patients. Otype antibodies were found. This data outlines a panel of anti-idiotypic antibodies. used briefly to indicate that there is a therapeutic potential for B-cell lymphoma. There is. In fact, it could cross-react with B-cell lymphoma in 15 out of 381 patients. The anti-idiotype, 537-48-6-2-6, was isolated.

Furthermore, another object of the present invention is to provide a common method for immunotherapy of B-cell lymphoma. The use of these anti-idiotypes against Othobe. As a result of the present invention, common It is possible to create a panel of anti-idiotopes that can react with common idiotopes. Treatment of patients with one or more antibodies: Addressing problems with the prior art formal access to treatment; this has already been discussed. These novel anti- The body uses them for economical and practical use in disease, treatment, diagnosis and/or observation. It has an advantage over individual anti-idiotypes in that it is unique.

In addition, this time, AIDS-related B-cell lymphoma is associated with active HIV infection and/or It was found that they expressed antibodies that were useful in passive therapy. These lymphomas It was found that the antibodies produced recognized the HIV antigen. Lymphoma cells are examples For example, antibodies that secrete these antibodies can be induced by hybridoma technology. Ru. Antibodies produced in this way can then be used in the passive treatment of HIV infection. Ru. A cell line is produced from such AIDS-related lymphoma, and this cell line is infected with HIV. secreted human monoclonal antibodies that can react with the virus. One of these antibodies were isolated, tested, and immunologically reacted with the envelope glycoproteins of the HIV virus. (gp120). That is, these B-cell lymphomas are HI It is a source of antibodies that react with the V virus. Are they human monoclonal tumors? Because they are derived from It is preferable for certain applications to murine monoclonal antibodies. These human antibodies It can also be used to discover and identify the HIv virus.

These antibodies produced from AIDS-related lymphomas are associated with the production of anti-idiotypic antibodies. It can be used for. This anti-idiotype is an “internal image”. l image) J. That is, the antigen and species to which the antibody binds share the three-dimensional characteristics of That is, these anti-idiotypes are immunologically It is very similar to the HIV antigen. These are readily available and non-toxic to humans. similar to the relevant epitope of the original antigen without posing a viral threat to the patient. can elicit an immune response. This immune response is caused by a true virus. acts to protect the patient from infection. Additionally, carefully examine various anti-idioti By mixing the samples, the patient is exposed to different variants of the HIV virus. Generates a broad immune response. These anti-idiotypes can be used as vaccines. It is also effective as an immunotherapeutic agent for HIV infection.

Furthermore, in an additional aspect of the invention, some anti-common idiotype antibodies are It was found to cross-react with proteins other than those associated with B-cell lymphoma. Yo Specifically, proteins that react with anti-common idiotypes include the following: : Anti-DNA autologous antibodies typically associated with systemic lupus erythematosis (rSLEJ) Antibodies; rheumatoid factor (rRFJ), typically associated with rheumatoid arthritis autoantibodies: and autoantibodies to the autonuclear protein typically associated with Siegren's syndrome It is the body. A more preferred embodiment of the invention is L50-19 anti-common idiotype. is an antibody that cross-reacts with 16.6 autoantibodies associated with RF and SLE. child Using anti-idiotope antibodies, certain patient RFs can be identified as idiotypic. It turns out that there are limitations. Therefore, the L50-19 antibody provides active immunity. Useful in therapy and altering the production of pathogenic autoantibodies, such as 16.6 and RF. and will be regulated downward. In other therapeutic applications, solid-phase immunosorbents incorporating L50-19 The immunosorbent device is useful for in vitro extraction of autoantibodies from patient plasma. Furthermore, L5 0-19 antibody is autoantibody when L50-19 acts as an autoantibody detector. Useful in vitro tests for diagnosis, prognosis and observation of immune diseases.

In the context of SLH, we now present that 16.6 antibodies react with various antigenic determinants, At least three types of anti-idiotypic antibodies were identified. These antibodies are 16. 6 Identify common idiotypes that bind autoantibodies.

Idiotype preparation Generation of tumor idiotypes was performed according to previously described methods. (Ca Rolle, W. L. et al., Journal of Immunological Methods, 8. 9:61 (1986)). Simply put, EIV-related or non-HIV-related X6J16/B5, a HAT-susceptible heterohybridoma, (Stafford University). Another comparable fusion partner that could be used is 5P2 10^g14 (ATCC CRL 8287). Patients' tumors and severe and mild The chain immunoglobulin is enzymatically linked to a hybridomer that secretes the same type of immunoglobulin. Identified by immunosorbent assay (ELISA). Selections containing these hybrids Selected wells were grown separately and later pooled. Immunoa the idiotype Purified from cell culture supernatant by affinity chromatography.

Testing idiotypes derived from HIV-associated lymphoma Immediately before HIV-associated lymphoma Hybridomas generated as described in section were grown in tissue culture. . The supernatant containing the secreted idiotype was analyzed by Western blotting. were tested for IIIV binding activity. Western blotting is suitable for the following people: Hōnishitakatte, Kamiwo +1 [9/HTI7-IIIB (ATCC CRL 8 When cultured with cell lysates from an anti-HIV infected cell line known as 543) This was done by The extract obtained from I'19/HTLV-IIIB cells was 0,000,000 cells in 1 ml of virus disruption buffer (0.1% Tri in PBS) ton-X 100, pH-7, 2, diethylthiothreitol 0.15mg/ ml). After 10 minutes at room temperature, the lysate was Clarification was achieved by centrifugation at 0 g for 10 minutes. Add the supernatant at a ratio of 1=1. sample buffer and transfer 0.4 ml of this mixture onto a 14% dodecyl slab gel. Sodium sulfate polyacrylamide gel electrophoresis (hereinafter referred to as 5DSPA, GE) ). The protein bands on the gel were then transferred to nitrocellulose.

After electrophoretic transfer, the plots were incubated overnight at 4°C in PBS containing 20% calf serum. The cells were cultured in a transfer buffer (pH=7.2). After transfer, nitrocellulose The slot plot device (inch-rated separation system) Park, MA) and aligned it with the plotter's channel. hive Ridoma supernatant and positive and negative sera (1150x diluted in transfer buffer) 0.15 ml was analyzed in each channel for 2 hours at room temperature. continue channel Wash with 200ml of transfer buffer and add the conjugated antibody, i.e. goat anti-human Ig western horse Rust peroxidase (HRP) (1/250) on the plot for 2 hours at room temperature Cultured.

Wash the second antibody with 200 ml of transfer buffer and seal the nitrocellulose sheet. It was removed from storage and applied to the substrate 4-chloronaphthol. After 15 minutes at room temperature, the antibody The degree of reactivity is determined by the intensity of the blue band corresponding to the molecular weight of the positive serum protein. I put it out.

Generation of monoclonal anti-idiotypes Purified idiotypes from each patient's tumor Ba1b/c mice, C57/BL6 mice, or Fisher 34 One of the four rats was immunized as previously described (Tielmans, Ke. See I et al., Journal of Immunology, 133: 495 (1984). (see). Three days after the final boost, pancreatic cells were transformed into a non-secreting murine myeloma cell line, S It was fused with P210Ag 14 (ATCC CRL 8287). Fusion 10~ After 14 days, the patient's tumor idiotype and 6 idiotypes isolated from other patients ELISA using type panel (one of these isotype compatible) Screening tests hybridoma supernatants for anti-idiotype specificity. I tried it. Hybridoma supernatants were collected from frozen tissue sections of the patient's tumor tissue and from unrelated cells. Antibodies were tested for reactivity to human tonsils using immunoperoxidase staining techniques. It was further identified by testing. (Tielmans, Kay et al., Journal of ・See Immunology, 133: 495 (1984)). anti-idiotype an isotype-matched immunoglobulin or tonsil panel (from an unrelated donor) the patient's idiotype and the tumor histology, rather than the selected based on responsiveness. Anti-idiotype secreting hybrids by limiting dilution method The cells were then cloned and propagated by an in vitro route. Obtained culture supernatant or sperm The produced antibodies were used for the following discussion.

Selection of anti-idiotype mAbs reactive with common anti-idiotypes Normal human serum to identify anti-idiotypes that exhibit detectable binding to intermediate immunoglobulins. Competitive inhibition ELISA was employed as the first screen. Concatenation of anti-idiotypes Serially diluted and undiluted normal human serum (pooled from 40 normal donors) (as a control) or horse serum as a control. After 1 hour, clean the sample. Add to the microtiter plate coated with the tumor idiotype and further The cells were cultured for 1 hour. Wash the plate and add horseradish peroxidase-conjugated goat anti- Mouse Immunoglobulin G (Tabo Incorporated, Burlingame, CA) ) was added. By adding ABTS hydrogen peroxide substrate, the conjugated anti-idiolide Determine type and absorbance at 405no+ by automated ELISA plate reader was measured. Binding to normal human serum immunoglobulin was determined by pooled human serum. anti-idiotypic reactivity with tumor immunoglobulins compared to control horse serum. It is considered to be significant if the inhibition is double or more.

Part Niscrini to Quantify the Levels of Common Idiotopes in Normal Human Serum We adopted the following analysis. Anti-idiotypes identified at saturating concentrations in the first screen a pool of purified tumor idiotypes and serial dilutions over a range of concentrations. The cells were cultured with normal human serum. After 1 hour of incubation, these samples were purified. tumor idiotype was added to the coated microtiter plate. join Anti-idiotypes were determined as described above. Next, plot the titration curve obtained. and dilutions of serum or purified tumor idiotype. The concentration of immunoglobulin in serum reactive with the otype was calculated.

Common idiotype expression by B-cell neoplastic cells and benign proliferative lymphoid tissue Tumor specimens were collected from patients diagnosed with lymphoma. International War A histopathological diagnosis was made using King formation. ("of Hodgkins Lymphoma Pathologic Classification Project National Cancer Institute, National Cancer Institute Sponsored Study of Classification of None (See Hodgkins Lymphomas, Cancer, 49: 212 (1982)) .

Immunofluorescence and/or immunovesting of fresh frozen cryostat sections or cell suspensions. Antibodies to common idiotoes can be detected in lymphomas and lymphomas by oxidase staining. Tested for reactivity with sex cell hypertrophic lymphocytic tissue (tonsils or lymph nodes) . (Tielmans, Kay et al., Journal of Immunology, 133: 4 95 (1984); Samok, M.K. et al., Hybridoma, 6: 6 05 (1987)). Immunofluorescence staining of cell suspensions can be performed using a fluorescence microscope or fluorescence activation method. Analyzed either by flow cytometry using a sex cell sorter (F ACS 440, Becton Mountain View, CA). table Fluorescein-conjugated goat anti-immunoglobulin expression Measured by staining with Brine heavy chain or light chain reagent (Tabo). The origin of the idiotype The second step was to use fluorescein-conjugated goat anti-mouse immunoglobulin (TABO) reagent. Determined by indirect immunofluorescence staining.

Generation of anti-idiotype antibodies One to five anti-idiotypes occurred in each of the 67 B-cell lymphoma patients. . 199 monoclonal antibodies were reduced from over 60 fusions. (1st table). These monoclonal antibodies are specific with respect to the immunizing idiotype. and was not reactive with a panel of idiotypes from six other lymphomas. 19 9 monoclonal antibodies due to their idiotype specificity and in patient biopsy specimens. Both were selected for their overall reactivity with tumor cell populations.

Common - Screening of anti-idiotypes for reactivity to idiotomes Group Initial screening assays identify anti-idiotypes that cross-react with normal human serum. It was impossible to determine. A representative analytical method is used for the anti-identifier designated C33-13-8. It is shown in FIG. 1 using the iotype. Undiluted normal human serum (excluding horse serum controls) ) is the corresponding common idiotype on the tumor idiotype of the anti-idiotype. was able to inhibit the binding. Individuals present on this tumor idiotype Anti-idiotypes reactive with determinants are inhibited by either human or horse serum. (data not shown). Using this analytical method, 152 anti-idiopathic type (76%) was found to be completely non-reactive with pooled normal human serum. It was. Such anti-idiotypes are not present in pooled normal human serum. Recognize the personal determinants expressed on lymphomas in corresponding patients. 199 mAbs Of these, 47 (24%) are present in pooled normal human serum immunoglobulins. was found to react with common idiotobes. (Table 1) Table 1 Anti-idiotype antibodies that recognize common idiotypes expressed on lymphomas choice Number of mAbs: 1 Number of patients: 1 Anti-idiotypes used in experiments 199 67 Initial screening 247 31 For tissue screening 37 26 Positive for other lymphoma idiotypes 2119 Tomotsukuro antibody count and type Number of lymphoma patients with diotypes 2. Number of anti-idiotypes reactive with pooled normal human serum (40 donors) 3: Due to low hybridoma antibody secretion rate, 10 antibodies were excluded from the next analysis. Ta.

The second step in the screening process is the determination of common idiotopes in normal human serum. The quantitative level was measured. A representative example of this analysis is shown in Figure 2 and summarized in Table 2.

Table 2 Anti-common idiotobic reaction with normal human serum, benign lymphocytosis and lymphoma responsiveness Hybridoma Common anti-common idiotope reactive clone in normal serum IDIO Benign lymph tissue 2 Lymphoma tope concentration (mg/ml) Positive (%) 3S37-48-6-2-6 2.1. <3.5% 5.5/381.3.9 %11B-76-6N/A <5% 1/28, 3,6%S 2-33-8 1 6 <5% 10/353.28% C33-13-832 negative 9/363.2 ．． 5%C33-23-7N/A N/^9/363.2.5%W2O-66- IN/A Negative 5/25.1.9% 530-47-9 75 Negative? /3 80.1.8%C59-300,6 negative 5/294.1.7%C52-22- 10100 negative 5/287.1.7%C45-23-769,8 negative 5/2 87.1.7%C39-25-256 negative 5/294.1.7%B48-16 10 <5% 5/381, 1.3% H27-17-11 26 <5% 5 /381, 1.3%L50-19-13 14 Negative 4/387.1.0%L 46-49-10-3 19<s% 4/387, 1.0%526-16N , D, Negative 3/363.0.8%W15-26-6 N/A <5% 5 /257, 0.78% H22-10-11 1.7 <5% 2/303, 0. 66%B4-11-2 1.6 negative 2/365.0.55%C22-43 negative Gender 2/365.0.55% B4-1-2-31 1.6 <5% 2/365 , 0.55% HIOI-2160 negative 2/380.0.53%W15-82- 3 N/A <5%! /257.0.39%C49-15-3575 negative 1 /2g? , 0.35% S6 Rho 76-23-9 0.6 Negative 1/294.0 ．． 34%571-157 8. D, <5% 1/355.0.28%B70 -9 1.9 Negative 1/363.0.28%H55-41,7<5% 1/3 65, 0.27% L50-5 40 <5% 1/381, 0.26% H2B- 48-11 25 Negative 1/387.0.26% 520-26 13 Negative 1/380.0.26%562-30 23 Negative 0/155S61-44 33 Negative 0/155H22-201,8 Negative 0/104 H22-151,5 negative 0/104 H70-116 negative 0/174 H55-60,9 negative 0/99 C49-6100 negative 0/41 C15-87-5-1517<5% O/165C49-24-109,7 negative O/411: Not measured.

2: Positive cell pattern measured by immunoperoxidase staining of frozen tissue sections -cent Negative: No positive cells observed.

5%: Few positive cells are observed.

3: Number of positive patients Total number of tests Used to propagate anti-idiotypes, and for that purpose Patients with idiotobes that have grown anti-idiotypes are not included.

Anti-idiotype human serum that binds to the corresponding generated tumor idiotype The inhibition of anti-idiotypes by horse serum was compared with that of anti-idiotypes by horse serum. mAb C3 3-13-8 is 32mg/ It was found that it reacted with ml of immunoglobulin. 47 monoclonal antibodies Common ID present in human serum at levels of 0.6mg/ml to 160a+g/ml It was found that it reacts with biotope.

Of these 47 anti-idiotypes, 90% reacted with <50 mg/ml; 78% were found to react with <25 mg/ml of the common idiotope.

Thirty-seven hybridomas were selected for further analysis. (See Tables 1 and 2. ).

Common idiotopes and opposites expressed in patients with AIDS-associated B-cell lymphoma Identification of responsive anti-idiotypes The present inventors identified 15 tested AIDS-related lymphomas. It was found that 12 of them reacted with 5 anti-idiotype antibodies. These anti Ideotype ATcc (o -) Kubir, MD) +::Deposit number S2 -33, ATCC #HB9981; L50-19-13, ATCC #9977 ; 530-47-9, ATCC#HB9980; B4-11-2, ATCC #9984.537-48-6-2-6, deposited with ATCC #HB10009 ing. The inventors have demonstrated that they do not produce anti-idiotypes that react with common idiotopes. The identity of the patient producing the hybridoma pair used to select the hybridoma The biotype has also been deposited. 52-33-8 is +121-12 (ATCC#HB 9955) and 7112-14 (ATCC #9953). reacts. As of now, 52-33-8 reacts in up to 50% of patients ( (unpublished results), common idiots expressed by AIDS-associated B-cell lymphomas This is the best antibody that has been identified to react with the probe. These anti-idio The reactivity with types of AIDS-related and non-AIDS-related lymphomas is described below. Ru.

Table 3 Anti-idiotypic antibodies reactive with HIV+ and HIV- high-grade lymphomas Number of positive patients/total number HIV+ HIV- S 2-33-8 5/15 0/15L 50-19-13 3/15 0/ 15S 30-47-9 2/15 0/15B 4-11-2 1/15 1 /15S 37-48-6-2-6 1/15 0/15 Total 12/15 ( 80%) 1/15 (13%) Response of tested non-HIV high-grade lymphomas It is considered a high-grade AIDS-related lymphoma because it is less sensitive (only 1 out of 15 responded). reactivity with these 5 antibodies is associated with BIT infection.

Unexpected findings in idiotypes expressed in BIV-associated lymphomas High idiotype restriction indicates reactivity with common antigens. This time it's this This suggests that lymphomas are produced in response to the presence of specific H. I understand (that is, lymphoma is antigen-derived). Similarly, non-HIV-associated lymphomas are also Possibly of original origin. For this reason, two Hv-related lymphomas have been isolated. The identified idiotypes were tested for reactivity with BIV. western blotte gp isolated from HIV in one patient, as measured using the It was found that the idiotype reacts with 120 proteins. (The data shows (not).

The inventor's results were unpredictable because there are a huge number of different B cells in the body. It is. Our results show that AIDS lymphoma B cells react with normal antigens. I understand that it can be done. The idiotype obtained from one of these was isolated and the EI It was tested for reactivity with Polymer V. This idiotype is the HIV envelope sugar It was found that it reacts with protein (gp120). produced this idiotype. The resulting cell lines are cloned and propagated in vitro, allowing human monochrome A source of anti-HIV antibodies. This human monoclonal antibody develops into HIV. They have several advantages over other types of antibodies. For example, mouse monoclonal anti- The body is produced against the HIV virus. However, these immunotherapy treatments for HIV infection There are several problems when used in vivo. Therapeutic Mouse Monoku The main limitation of local antibodies is that they elicit anti-mouse antibody responses in humans. It is immunogenic. Once an anti-mouse antibody response occurs, the applied antibody therapeutic effect disappears. Human monoclonal antibodies have very low immunogenicity; As a result, neutralizing antibodies are not produced by the host. Furthermore, human antibodies Mouse monoclonal antibodies such as the ability to determine different cell-mediated cytotoxicity in the body or mediating antibodies Other host effector mechanisms not mediated by antibodies can be mediated.

Based on the present invention, cell lines can be established or derived from AIDS-related B-cell lymphoma. hybridomas can be produced. Such antibodies have recently been developed by Jackson (The Lancet, September 1988, 17:647 (1988)) Using immune sera from asymptomatic individuals who were seropositive for IIIV, as described in to treat established HIV infection or in individuals who have been exposed to HIV. may be administered passively to prevent seroconversion. A monologue on HIV and reactivity Another use for local antibodies is to treat patients exposed to BIV as a means of disease prevention. or passive immunotherapy in infected patients. These anti-HIV mono Clonal antibodies may be used to generate anti-idiotypic antibodies.

Anti-idiotypic antibodies are produced that mimic the epitope on the corresponding HIv antigen . Such anti-idiotypes stimulate anti-)IIV immune responses in active immunotherapy. Used to intensify. These anti-idiotypes are linked to carrier proteins and immune molecules. It is combined with a dejuvant to promote antibody responses reactive with [V].

Below are some examples of the use of monoclonal anti-HIV antibodies in passive immunotherapy. Describe it in Human monoclonal anti-HIV antibodies can be administered in doses ranging from 5mg to 500mg. The dosage can be administered by intravenous injection for 30 minutes to 4 hours (larger doses generally injection time). Monitor anti-HIV antibody levels in plasma to determine dosage and By adjusting the number of calls and frequency, we can obtain long-lasting circulating anti-111V antibodies and eliminate viral proteins. HIV antigen can be detected and measured at the same time. Repeated administration of anti-HIV antibody to achieve sustained antibody excess and penetration into HIV-infected tissues. like this Doses are administered over a period of several weeks or months to patients with established infections or recent infections. Can be applied to patients exposed to IV.

An anti-HIV monoclonal antibody isolated from AIDS lymphoma cells was used as an immunogen. can be used to generate “internal image” anti-idiotype antibodies. Wear. These anti-idiotypes can be developed in mice using established hybridoma technology. can be produced in These internal images anti-idiotypes are responsible for It conjugates to body proteins and is used with immunological adjuvants to stimulate immune responses. 0 ．． 5 to IQmg of the antiidiotype can be administered subcutaneously or intramuscularly.

After repeated immunizations, such patients may be exposed to HIV produced by several people through contact. It produces neutralizing immunoglobulins similar to anti-[IIV antibodies]. These anti-I Biotype vaccines or immunotherapeutic agents are used to prevent and/or establish BIV infection. Each plays a role in the treatment of certain diseases. AIDS B-cell lymphoma A further use of anti-idiotype antibodies against these Includes passive immunotherapy for B-cell lymphomas occurring in patients. Max 50hg Administer intravenously for up to several hours to reduce antibody overload and into lymphoma tissue. anti-idiotype penetration can be achieved. Anti-idiotypic tissue Penetration is associated with other types of tumor responses in human B-cell lymphomas.

Because of the effectiveness of pre-existing anti-idiotypes in these patients, Since the need to create anti-idiotypes is removed, more Anti-idiotypes can be used earlier. To implement the invention in diagnosis To achieve this goal, tumor cells from patients with HIV or non-IV-associated lymphoma were treated using the inventor's method. with this antibody panel using immunofluorescence or immunohistochemistry as described in Section 1. Test for reactivity. Diagnosing antibodies found to be reactive with lymphoma It can be used for diagnosis, monitoring and/or treatment.

Antibodies from the panel can be used to monitor or treat disease states. joy However, administration to any patient from the panel disclosed and claimed herein. The best antibodies to test for are immunofluorescence or immunohistochemistry (see above). Any individual test or previously described method (Meeker, Tee et al., Blood, 65 : 1349 (1985)) or determined by methods known to those skilled in the art. be able to.

Common idiotype-reactive non-AIDS-related antibodies expressed on B-cell lymphomas ideal type 44 anti-idiotypes reactive with common idiotypes present in normal human serum frozen tissue specimens obtained from 28 to 387 different patients with B-cell lymphoma. or on cell suspensions and specimens of benign follicular proliferative tissue (tonsils or lymph nodes). In contrast to the results of Stevenson et al. (cited above), these Thirty-two of the idiotypes interact with other lymphomas as shown in Tables 1 and 2. I reacted differently. Each of these idiotypes tested between 0.26% and 3.9% It reacted with B cells (Table 2). Common idiotype 537-48-6-2-6 and The reactive anti-idiotypes were positive in 5 out of 387 specimens tested. (3.9%). Common idiotopes and other reactive anti-idiotopes tested The positive rate among the number of patients tested is low.

Table 2 also shows the reactivity of each anti-idiotype with follicular proliferative tissue. Follicular proliferation is It is a histological phenomenon of lymph nodes being stimulated by foreign antigens. At least 28 anti-I No reactivity with these tissues was observed for the deiotypes. proliferative disease Other 16 cells have low reactivity with cells in lymphoid tissue (<5%), i.e., are difficult to isolate. was found to react with monoclonal antibodies. No. Figure 3 shows an example of a special cell with similar reactivity to antibody C33-13-8. Each anti-id Normal pooled serum immunoglobules of monoclonal antibodies with respect to iotype association with phosphorus or proliferative lymphoid tissue and common identity expressed in lymphomas. No relationship was found between the detection frequencies of the otypes. Non-HIV associated follicular proliferative In contrast, present in follicular proliferative tissue isolated from several HIV-infected patients A high percentage of the cells react with antibodies in the panel of antibodies disclosed in . The inventor's data At night, in the same patient, approximately 50% of the cells had these antibodies (S2-33- 8). Some of these progress to lymphoma. this child This means that these anti-IDs are follicular proliferative agents that may progress to AIDS lymphoma. This means that it can be useful for identifying patients with cancer.

Characteristics of non-AIDS-related common idiotobes 32 common idiotobic reactive antibodies idiotypes, each of which recognizes a different group of lymphomas. Therefore, 32 different determinants (idiotopes) were identified. these The anti-idiotype has the following accession number L50-5-14, ATCC #HB99 73; H2717-11, ATCC#HB9978; H48-16 (H48 -16), ATCC# HB9979; 537-48-6-2-6, ATCC# HB10009; H28-48-IL ATCC#HB9957; L46- 49-10-3, ATCC #HB9958; 52-33-8, ATCC #HB 9981; L50-19-13, ATCC#HB9977; 530-47- 9, ATCC#HB9980. B4-11-2, ATCC#HB9984; B 4-1-2-31, ATCC# HB9974; C33-13-8, ATCC# HB9985: C3l-145-12, ATCC#HB9983; H22- 10-11, ATCC #HB9982; C39-25-25, ATCC #HB 9951; S6 Low 76-23-9, ATCC#'HB9954; C49- 15-35, ATCC #HB9975; C49-24-10, ATCC #HB 9952; ATCC #HB9976, C45-23-7, ATCC #HB99 50; C52-22-10, ATCC#HB9956; H15-26-6, ATCC #HB10328 (#H10328); C33-23-7, ATC C# HB10346; J18-76-6, ATCC# HB10329; W2 O-66-1, ATCC# HB10338; HIOl-2-'1, ATCC# HB10331: C22-4-4, ATCC #HB10530 (#HB105 30); H15-82-3, ATCC#HB10327. H70-9-55,A TCC#HB10337; 526-16-1, ATCC#HB10347 (# 10347); C59-30 (C39-30), ATCC#HB10340 ;571-157, ATCC#HB10336;H55-4 (H55-4) , ATCC #HB10335; 520-26, ATCC #HB10339; and H48-3, ATCC #f (B10345 ATCC, Rockwil, Mery) Deposited in Iran. (Deposit made before January 31, 1990.

ATCC#S is given at the time of transfer). These anti-idiotypes The common idiotobes identified are associated with these lymphomas as shown in Figure 3. It can be used to group into different families. These charts are helpful for these patients. related to idiotobes identified by personal anti-idiotypes created against Diagrammatic representation of common ideologues. This time, again, common idiom patient cases producing hybridomas that produce anti-idiotypes that react with The diotype was deposited. C33-13-8 is HI24-8 (ATCC#HB1 0010) and Idiota from C18-1 (ATCC#HB 10008) Reacts with yip. C33-13-8 and 52-33-8 react with lymphoma Some preferred anti-idiotype antibodies in terms of sexual frequency. I already mentioned it The patient idiotype that generates the hybridoma pair for sea urchin 82-33-8 is also , also deposited.

Immunophenotypic and histological subtypes of lymphomas expressing common idiotobes Both are shown in Table 4. In 7 cases, the common idiotope was found in two different immunoglobulins. Expressed by tumor idiotype using phosphorus-heavy, in 8 cases, common idiotype The probe uses either kappa or lambda immunoglobulin light chains to target tumor antibodies. Expressed by type. The remaining anti-idiotypes are linked to specific immunoglobulin classes. Although we identified common idiotobes that exist on the internet, only a small number of them can be used for analysis. Obtained. Common idioms with immunoglobulins with different heavy and/or light chains Tobe expression determines whether these anti-idiotypes are allotyped or isotyped. He does not accept the possibility that he recognized the group.

Table 4 Identified by common cross-reactive anti-idiotype characteristic MAb Number of patients: 1 Immunoglobulin Brin histology cross-reactive isotype 2 anti-idiotype 52-33-8 11 6MK, IGL, 2, 5FSC, 4SNC2N, 0.4 537-48-6-2-6 15 3MK, 8ML, IGL, 2FSC, 4S C.L.

3ND 2FML, 4DSC.

l5NC, IDML.

1BL S30-47-9 7 4GL, 2GK, IG 2FSC, 2FML.

IFLC, ID5C.

1B H48-1652MK, IGK, IK, IML 4FSC, ID5CC33-1 3-893MK, 3ML, lGL, IK 3FSC, 2FML.

IND　IFLC,3SCL C31-145-12134MK, IK, 3ND 9FSC, ID5C.

IDML, 2SCL L50-19-13 4 IMK, IML, 2K IDML, 15NC.

5CL H4-11-22111, IL 11BL, 15NCL46-49-10-3 4 2MX, IX, IL 15NC, 3SCLL50-5-14 1 IMK IFML1122-10-11 2 2MK IFSC, IFMLS6 Low 7 6-23-9 1 IMK IF5CC39-25-255IML, IGL, S ND 2DSC, 3SCL1 Number of cases expressing common idiotobes, anti- Includes patients for whom the idiotype was developed.

2. Immunoglobulin isotype. Bold type entries are This shows the phenotype of lymphoma in which an anti-idiotype has appeared against lymphoma. M=Ig M, G = IgASK = Kappa, L = Nilamda, expresses a common idiotope. Histological subtypes of lymphoma.

FSC = saturated, clsaved cells; 5NC = small, uncleaved cells; DSC = small cut cell type, diffuse. S CL = small cell (CLL ); DLC = large cell type, dispersed.

4 Not done.

Table 5 shows common characteristics of different histological subtypes of non-HIV-associated B-cell lymphoma. To summarize the biotope expression. The co-species identified by these monoclonal antibodies Common idiotopes appear to be restricted to specific histological subtypes of lymphoma. do not have. Although the number of cases of non-rotating small cleavage cell lymphoma is small, it is a true form of lymphoma. This suggests that scientific subtypes vary with the frequency of expression of common idiotopes.

In aggregate, 20 different anti-idiotypes have a 30% saturation of small cut cell phosphorus. Recognized the paroma idiotype.

Table 5 Histological subtypes of non-HIV-associated lymphomas expressing common anti-idiotypes Common idiotope! Histology 1 expressing lymphoma subtype 3 and anti-inflammatory Number of cases with number of diotypes FSC35/116 20 DSC8/11 6 SCL 25/70 12 DLC1/22 1 SNC7/14 7 FML 15/49 12 FCC5/10 3 DML 5/13 5 IBL 5/11 5 PC/MM 2/15 2 Total number of positive cases: 108 Total number of B-cell tumors tested 332 32.5%1 Abbreviations are the same as in Table 2. be.

2 Number of cases with common idiotobes/cases of histological subtypes in the research plan number of sources. Not all MAbs were tested against all FSC cases.

Each MAb was tested on an average of 111 cases of FSC lymphoma.

3 Number of anti-idiotype aggregates that react with each histological subtype Lymphoma ID The utility of the large collection of anti-idiotypes generated against B-cell lymphoma selecting a subset that was found to be responsive to a varying number of biotypes. made possible. This discovery shows that rotting lymphoma also expresses a common idiotope. show that it is much less common than CLL or AIDS-related lymphoma. now Multiple common idiotopes were identified twice, but each was found to be less common in the bloating lymphoma group. (Table 2). Compared to CLL, the common idiotope of rotting lymphoma is It does not appear to be associated with immunoglobulin heavy or light chain types. Interestingly, These lymphomas are grouped into families based on their common idiotope expression. ly).

The discovery that common idiotopes exist in various subtypes of B-cell lymphomas This has important implications for immunotherapy using idiotypes. Anti-Ideology available (and can be used immediately) at the time of tumor diagnosis and/or recurrence. . Under these conditions, the practicality of using anti-idiotypes in diagnosis and treatment is It increases. Currently, 20 anti-idiotype panels collectively account for approximately 30% of Reacts with the bloating lymphoma idiotype. This panel of anti-common ideology Due to the usefulness of this method, it is now possible to determine the immunophenotypic type of the tumor (idiotyping). and select the appropriate antibody or combination of antibodies for use in diagnosis or treatment. can be done.

There are other advantages to anti-idiotypes directed against common idiots. Ru. For example, an important reason for tumor leakage from treatment with anti-idiotypes is It involves the selection of biotype-negative, immunoglobulin-positive mutant cells. These details Cysts arise due to extensive somatic mutations in immunoglobulin variable region genes (mi Kerr, Tee, New England Journal of Medicine, 3 12:1658 (1985)). Common idiotobes are Segments of may not be able to mutate very often. This is the vxmb legacy of CLL. It was shown that this is the case for genes. Kipps, Tee, Jay8. Author, Journal Of Experimental Medicine, 167.840 (1988). Both Common idiotobes do not mutate as easily as other idiotobes, and therefore these Treatment with anti-idiotypes that react with determinants may be more effective.

Anti-idiotypes against common idiotobes can be developed using techniques described in the specification. can be produced and selected. Many anti-idiotypes have a common idiotope Anti-ideotypes must be produced to find confirmation of this. Sara In addition, therapeutically useful anti-idiotypes have several other criteria that are useful in vivo. must match. For example, cross-reactive idiotopes present in serum The amount of anti-idiotope administered should be 50 g/m to achieve tissue penetration of the administered anti-idiotope. (Marker etc., Brad, 65.1349 (198 5)). Other important factors are those that express common idiotopes and The percentage of cells within the tumor that react with the biotope. Immunotherapy has big eyes on applicants Applicant has developed an anti-inflammatory drug that is reactive in a high proportion (>85%) of the cells in the tumor. I deliberately chose the deiotype.

Anti-common idiotype antibody screening method for reaction with autoantibodies.

Autoantibodies, such as anti-DNA and RF antibodies, can be heterogeneous as previously described. It can be isolated from patients with SLE and RA using hybridoma technology. in short , lysing blood lymphocytes from a patient with SLE into myeloma cell partners; The resulting hybridomas are DN. Screen for secretion of antibodies that react with A or other antigens. Also, immunoaffinity Autoantibodies can also be isolated from patient serum using ichromatographic techniques. Ru.

The autoantibodies are then purified using conventional ELISA techniques to identify anti-common idiotype antibodies. The reactivity with this panel will be tested. In short, using anti-idiotype antibodies , used to coat microtiter plates. Then autoantibodies Or add control antibodies to the wells at various concentrations. After washing the wells, enzyme-labeled anti-i d to the wells to detect bound autoantibodies.

The anti-common idiotype antibodies discovered this time are shown in Table 6. rheumatoid arthritis Clinical correlation of L50-19 idiotype concentration with disease progression and regression in The relationship is shown in Figures 5-7.

Table 6 Anti-8IDS reacts with autoantibodies Reactivity with anti-8ID autoantibody L50-19 (S-002) 5sDNAF La (SSB) cardiolipin C3l-145-12 (5006) 5sDNAmRNP polydT Hl 01-2s 5DNA L46-49 (5-005) 5sDNAH70-9 (5-009) La BEOO15-I La Cl3-87 Poly dT Continuous cell lines, or hybridomas, are screened for suitable antibody production. autoantibodies and reactive anti-common antibodies are determined by the presence or amount of autoantibodies in the liquid sample. It can be used for in vitro detection methods. In vitro detection method for the presence of autoantibodies at least one antibody that has specific reactivity with the autoantibody and the fluid sample obtained from the patient. by contacting one anti-idiotypic antibody and by immunoassay. Complexing of anti-idiotype antibodies to autoantibodies in the sample ). Alternatively, capacitive measurement of the amount of autoantibodies in a liquid sample The liquid sample is treated with at least one anti-idioantibody that has specific reactivity with the autoantibody. the amount of anti-idiotype antibody bound to the autoantibody; and correlate the amount bound with the amount of autoantibodies present in the sample. This can be done by in vitro methods including.

The presence or amount of anti-idiotype antibodies that bind to the detected autoantibodies is not detectable. This can be done by labeling the anti-idiotype antibody with a marker. Used in the present invention The labeled antibodies used are the same labeled as those used in prior art iminoassays. Get covered. Among these, fluorophore labels for detection by fluorometry are No. 3,940,475 and enzyme markers are described in U.S. Patent No. 3.940.475. 645 ．． I would like to mention what is stated in No. 090. Signs can also be used by hunters and groups, for example. The method described in Leanwood, Nature, 144,945 (1962), or David et al., Biochemistry, 13° 1014-1021 (1974). It may also be a radioactive isotope, such as 1-25, using the methods described. moreover, The label is biotin, which can be detected by interaction with enzymatically labeled avidin. I can do it.

Those skilled in the art will appreciate that the analytical method of the present invention is purely qualitative or quantitative and that It can be used to monitor patients with autoimmunity or to make an initial diagnosis of autoimmunity. You can understand that. Preferably, the autoantibodies are well detected in the liquid sample; , these can also be measured in tissue samples. Liquid sample used according to the invention includes whole blood, serum, plasma, urine, sweat, tears and saliva. specific for the autoantibody for detecting the presence or amount of autoantibodies containing at least one anti-idiotype. A diagnostic kit can be assembled.

Immunotherapy for detecting idiotype-positive RF using L50-19 antibody as a detection agent Atsushi A, 96-well Imuion (i+omuion) using a multichannel pipette Plate with human IgG, Fc section (accurate), 0.05M sodium bicarbonate. pH 9, at a concentration of 5.0 gg/ml (100 μL/well) diluted in Covered with 5.

B. Moisture-proof each plate with microplate sealer and store between 2°C and 8°C overnight. incubate with C. Microplates were washed with washing buffer (0,9 %'/vNaAC10,05% Tween-20) (×5).

D. Dispense 100 μL of dilution buffer to each well using a multichannel pipette. .

E. Add 100 IIL of test serum to the microplate, leaving wells designated as AI blanks. Rate introduced into a single well of the first column. Normal collection of 100 μL in the same column. The serum was then introduced into another well. Using a suitable pipette, move from left to right. , performing serial two-fold dilutions of serum across microplates.

F. Incubate plate for 1 hour at room temperature.

G, biotinylated anti-common idiotype at a concentration of 2ag/ml in dilution buffer. Preparation of dilutions.

H8 Repeat step C.

■ Using a multichannel pipette, add 100 μL of anti-common idiotype antibody. , dispense the test sample into the reacted wells.

Repeat J1 stage F.

K, 1 of horseradish peroxidase-conjugated avidin (Tabo) in dilution buffer: Adjustment of 1000 dilution.

Repeat L1 stage C.

M. Using a multichannel pipette, add 100 μL of diluted avidin to the sample well. Introduced to each.

Repeat N0 stage F.

0, ABTS (2,2'-azinobis(3-ethylbenziazine-6- Sulfonic acid), diammonium salt, Sigma Chemical Ix dilution adjustment.

Repeat P3 step.

Q. Using a multichannel pipette, add 100 μL of 1x ABTS to all first volumes. Distribute onto the tubes and allow the color to develop for at least 15 minutes.

R, read the absorption value of the plate at a wavelength of 405 mm on a microplate reader. Pick up. Plot the values on graph paper and connect the points. Interpretation of data...normal Comparison of absorption values and determination of positive titer for collected serum. Same dilution as normal serum Dilutions with absorbance exceeding this are considered positive.

Analysis of idiotype-positive complexes operation A, Using a multichannel pipette, transfer the 96-well Imron plate to clg (clg). Rubiochem) diluted in 0.5M sodium bicarbonate. Oag/ml (100aL/well) coated with a concentration of TpH 9.5.

B. Moisture-proof each plate with microplate sealer - night between 2C and 8C. incubate with C. Wash the microplate with washing buffer (0.9 %'/vNaC10,05% Tween-20) (x5).

D. Dispense 100 pL of dilution buffer to each well using a multichannel pipette. .

E, Microprepare 100 pL of test serum, leaving wells designated as AI blanks. into a single well in the first column of the cell. Same - 100 liters of normal collected blood in column Introduce the supernatant into another well. Using a suitable pipette, move from left to right, Performing serial 2-fold dilutions of serum across the clone plate.

F. Plates were incubated at 37°C for 1.5 hours, then between 2°C and 8°C for 0.5 hours. Incubate.

G, biotin-labeled anti-common idiotype at a concentration of 2 μg/ml in dilution buffer. Preparation of dilutions.

Repeat H6 steps.

■ Using a multichannel pipette, add 100 μL of anti-common idiotype antibody. , dispense the test sample into the reacted wells.

J, Incubate microplates for 1 hour at room temperature.

K, 1 of horseradish peroxidase-conjugated avidin (Tabo) in dilution buffer: Adjustment of 1000 dilution.

Repeat the L8 steps.

M. Using a multichannel pipette, add 100 aL of diluted avidin to the test well. Introduced to each.

Repeat the N1 step.

0, ABTS (2,2°-azinobis(3-ethylbenziazine-6- Sulfonic acid), diammonium salt, Sigma Chemical Ix dilution adjustment.

Repeat P9 steps.

Q. Using a multichannel pipette, add 100 μL of 1x ABTS to all tests. Dispense into wells and allow color to develop for at least 15 minutes.

R, read the absorption value of the plate at a wavelength of 405 mm on a microplate reader. Pick up. Plot the values on graph paper and connect the points. Interpretation of data...normal Compare the absorption values for the collected serum and measure the positive titer. Same dilution as normal serum Dilutions with absorbance exceeding this are considered positive.

Extracorporeal treatment of autoimmune diseases The H50-19 antibody is mounted on a solid support such as sepharose, cellulose or polyamide. Covalently bond to crylamide, etc. Active disease and high plasma concentrations Patients with the H50-19 reactive idiotype are suitable for extracorporeal treatment. blood The fluid or plasma is continuously passed through a solid-phase immunosorbent device to remove H50-19 reactivity from the plasma. Remove idiotype. The adsorbed plasma can be reinfused into the patient or discarded. Replaced with normal plasma. One or more total plasma volume replacements can reduce disease binding. Remove most of the diotype. Treatments are given at intervals ranging from 1 day to 1 month. The biotype is at or below the concentration found when the disease is inactive. repeated until the disease decreases or disease mitigation occurs. Look at idiotype concentration detection and retreatment should be initiated when idiotype concentrations rise and disease progression occurs. . Removal of pathogenic autoantibodies from plasma prevents the development of these antibodies in tissues and Reduce the suffering of diseases.

FIG./.

Serum 1: 2C33-13-8 dilution F/G, 2゜ Serial dilution of serum and Id FIG. 4 L50-19 serum idiotype concentration sample collection date of rheumatoid arthritis patients L50-19 serum idiotype concentration of rheumatoid arthritis patients/□, 6° L50-19 serum idiotype concentration of patients with rheumatoid arthritis Amendment translation submission form (Article 184-8 of the Patent Act) Same as July 31, 1991

Claims (1)

[Claims] 1. Epitopes expressed by at least one cell surface immunoglobulin present in at least two different patients with HIV-associated B-cell lymphoma or leukemia. anti-idiotypic antibodies, antibody fragments or antisera that are capable of reacting with the tape. 2. An anti-idiodine that can competitively bind to one of the antibody group consisting of S2-33-8, L50-19-13, S30-47-9, B4-11-2 and S37-48-6-2-6. type antibodies, antibody fragments or antisera, in which the binding occurs in at least two different patients with B-cell lymphoma or leukemia associated with HIV. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that it is directed against two or more human monoclonal antibodies collected from a human. 3. an anti-identifier capable of reacting with an epitope expressed by at least one cell surface immunoglobulin present in at least two different patients with B-cell lymphoma; Otype antibodies, antibody fragments or antisera. 4. L50-5-14, H27-17-II, H48-3, S37-48-6- 2-6, H28-48-II, L46-49-10-3, S2-33-8, L5 0-19 -13, 530-47-9, B4-11-2, B4-1-2-31, C 33-13-8, C31-145-12, H22-10-11, C39-25- 25, S66- 76-23-9, C49-15-35, C39-30, S71-157, C45-23-7, C52-22-10, J18-76-6, W15-26-6, C33-23-7, One of the antibody group consisting of W20-66-1, H101-2-1, C22-4-4, W15-82-3, H70-9-55, S26-16-1, H55-4 and 520-26 an anti-idiotypic antibody, antibody fragment or antiserum capable of competitively binding to a B-cell lymphocyte; Anti-idiotypic antibodies, antibody fragments or antisera, characterized in that they are directed against two or more human monoclonal antibodies, obtained from at least two different patients with neoplasia. 5. An anti-idiotypic antibody, antibody fragment or antiserum having a variable region, characterized in that said variable region cross-reacts with the H21-22 antibody and the JB2-14 antibody. or anti-blood Qing. 6. An anti-idiotypic antibody, antibody fragment or antiserum having a variable region, wherein the variable region cross-reacts with the H124-8 antibody and the C18-1 antibody. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that: 7. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody S2-33- 8 and its temptations (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody S2-33-8 to the pair of human monoclonal antibodies described above; (c) a polyclonal antibody derived from a species identified by its ability to competitively inhibit the binding of antibody S2-33-8 to the pair of human monoclonal antibodies described above; identified by reactivity with the anti-idiotypic antiserum; anti-idiotypic antibodies, antibody fragments, or antisera, characterized in that the antibody, antibody fragment, or antiserum is cross-reactive with a pair of human monoclonal antibodies as described above; or antiserum. 8. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody L50-19- 13 and its (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody L50-19-13 to the pair of human monoclonal antibodies described above; or (c) a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of antibody L50-19-13 to the pair of human monoclonal antibodies described above; Anti-idiotypic antibodies, antibody blocks The fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that: 9. an anti-idiotypic antibody, antibody fragment, or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, wherein the common idiotope is (a) monoclonal antibody S30-47-9; and derivatives thereof; or (b) compete the binding of antibody S30-47-9 with the human monoclonal antibody pair described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody S30-47-9 with the human monoclonal antibody pair described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 10. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody B4-11- 2 and its temptations (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody B4-I1-2 to the pair of human monoclonal antibodies described above; (c) a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of antibody B4-I1-2 to the pair of human monoclonal antibodies described above; and furthermore, the above-mentioned anti-idiotypic antibody, antibody flag that the antibody or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum characterized by: 11. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which (a) monoclonal antibody S37-48-6-2-6 and its derivatives; or (b) a combination of antibody S37-48-6-2-6 and the human monoclonal antibody described above. or (c) by the ability to competitively inhibit the binding of antibody S37-48-6-2-6 to the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from the specimen to be identified; further, said anti-idiotypic antibody, antibody fragment, or antiserum is cross-reactive with said pair of human monoclonal antibodies; An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that: 12. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotope competitively inhibits the binding of (a) monoclonal antibody H28-48-I1 and derivatives thereof, or (b) antibody H28-48-11 and the pair of human monoclonal antibodies described above. or (c) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody H28-48-11 to the pair of human monoclonal antibodies described above. The polyclonal antiserum derived from the antibody; The fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that: 13. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotope is (a) monoclonal antibody L46-49-10-3 and or (b) a combination of antibody L46-49-10-3 and the pair of human monoclonal antibodies described above; Specimen-derived monoclonal antibodies identified by their ability to competitively inhibit or (c) a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of antibody L46-49-10-3 to the pair of human monoclonal antibodies described above; identified by reactivity, and furthermore, the anti-idiotans anti-idiotypic antibodies, antibody fragments, or antisera, wherein the anti-idiotypic antibodies, antibody fragments, or antisera are cross-reactive with a pair of human monoclonal antibodies as described above. agent or antiserum. 14. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotope inhibits the binding of (a) monoclonal antibody B4-1-2-31 and its derivatives; or (b) antibody B4-1-2-31 and the pair of human monoclonal antibodies described above. a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit; or (c) competitively inhibit the binding of antibody B4-I-2-31 to the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from a specimen identified by the ability of the anti-idiotypic antibody; The fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that: 15. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotope is (a) monoclonal antibody C33-13-8 and its or (b) competes the binding of antibody C33-13-8 with the pair of human monoclonal antibodies described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody C33-13-8 with the human monoclonal antibody pair described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 16. An anti-idiotypic antibody, antibody fragment or antiserum characterized in that the antibody or antiserum is cross-reactive with a pair of human monoclonal antibodies as described above. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody C31-145- 12 and derivatives thereof; or (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody C31-145-12 to the pair of human monoclonal antibodies described above; or (c) Antibody C31-145-12 and one of the above human monoclonal antibodies Polychromes derived from specimens identified by their ability to competitively inhibit pair binding. and wherein said anti-idiotypic antibody, antibody fragment or antiserum crosses said pair of human monoclonal antibodies; Anti-idiotypic antibodies, antibody fragments or antisera characterized by differential reactivity. 17. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which (8) monoclonal antibody H22-10-11 and derivatives thereof; or (b) competitively inhibits the binding of antibody H22-10-11 and the pair of human monoclonal antibodies described above. or (c) a specimen identified by its ability to competitively inhibit the binding of antibody H22-10-11 to the pair of human monoclonal antibodies described above. polyclonal antiserum derived from The fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that: 18. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotope competitively inhibits the binding of (a) monoclonal antibody C39-25-25 and derivatives thereof, or (b) antibody C39-25-25 and the pair of human monoclonal antibodies described above. or (c) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody C39-25-25 to the pair of human monoclonal antibodies described above. The polyclonal antiserum derived from the antibody; The fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that: 19. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotope is (a) monoclonal antibody S66-76-23-9 and or (b) a combination of antibody S66-76-23-9 and the pair of human monoclonal antibodies described above; Specimen-derived monoclonal antibodies identified by their ability to competitively inhibit or (c) a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of antibody S66-76-23-9 to the pair of human monoclonal antibodies described above; identified by reactivity, and furthermore, the anti-idiotans anti-idiotypic antibodies, antibody fragments, or antisera, wherein the anti-idiotypic antibodies, antibody fragments, or antisera are cross-reactive with a pair of human monoclonal antibodies as described above. agent or antiserum. 20. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotope competitively inhibits the binding of (a) monoclonal antibody C49-15-35 and its derivatives, or (b) antibody C49-15-35 and the pair of human monoclonal antibodies described above. or (c) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody C49-15-35 to the pair of human monoclonal antibodies described above. The polyclonal antiserum derived from the antibody; The fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that: 21. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotopes are (a) monoclonal antibody C39-30-7 and its or (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody C39-30 to the pair of human monoclonal antibodies described above; or (c) an antibody a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of C39-30 to the pair of human monoclonal antibodies; type antibody, antibody fragment An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody or antiserum is cross-reactive with a pair of human monoclonal antibodies as described above. 22. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotope is (a) monoclonal antibody S71-57 and its inducer. or (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody S71-57 to the pair of human monoclonal antibodies described above; or (c) antibody S71. -57 and a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of said pair of human monoclonal antibodies; Antibodies, antibody fragments An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody or antiserum is cross-reactive with a pair of human monoclonal antibodies as described above. 23. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotopes are (a) monoclonal antibody C45-23-7 and its or (b) competes the binding of antibody C45-23-7 with the pair of human monoclonal antibodies described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody C45-23-7 with the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 2. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody or antiserum is cross-reactive with the pair of human monoclonal antibodies described above.24. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody C52-22- 10 and its or (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody C52-22-10 to the pair of human monoclonal antibodies described above; or (c ) a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of antibody C52-22-10 to the pair of human monoclonal antibodies; The above anti-idiotype antibody, antibody file The fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that: 25. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotopes are (a) monoclonal antibody L50-5-14 and its or (b) competes the binding of antibody L50-5-14 with the pair of human monoclonal antibodies described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody L50-5-14 with the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 2. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody fragment or antiserum is cross-reactive with a pair of human monoclonal antibodies as described above.26. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody H27-17- 11 and its or (b) competes the binding of antibody H27-17-B with the human monoclonal antibody pair described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) by reactivity with a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of antibody H27-17-11 to the pair of human monoclonal antibodies described above; and furthermore, the anti-idiotypic antibody, antibody file The fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that: 27. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotopes are (a) monoclonal antibody H48-3 and its derivatives; or (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody H48-3 to the pair of human monoclonal antibodies described above; or (c) antibody H48- 3 and a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of the above pair of human monoclonal antibodies; The above-mentioned anti-idiotypic antibodies, antibody fragments, etc. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody or antiserum is cross-reactive with a pair of human monoclonal antibodies as described above. 28. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotope is (a) monoclonal antibody W15-26-6 and its or (b) competes the binding of antibody W15-26-6 with the human monoclonal antibody pair described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody W15-26-6 with the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 29. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody C33-23- 7 and its derivatives; or (b) competes the binding of antibody C33-23-7 with the pair of human monoclonal antibodies described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody C33-23-7 with the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 3. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the anti-idiotypic antibody, antibody fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody J18-76- 6 and its derivatives; or (b) competes the binding of antibody J18-76-6 with the pair of human monoclonal antibodies described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody J18-76-6 with the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; Anti-idiotypic antibodies, antibody fragments or antisera, characterized in that the anti-idiotypic antibodies, antibody fragments or antisera are cross-reactive with a pair of human monoclonal antibodies as described above.31. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody W20-66- 1 and its derivatives; or (b) competes the binding of antibody W20-66-1 with the above pair of human monoclonal antibodies. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody W20-66-1 with the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 3. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the anti-idiotypic antibody, antibody fragment or antiserum is cross-reactive with a pair of human monoclonal antibodies as described above.2. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody W15-82- 3 and its derivatives; or (b) competes the binding of antibody W15-82-3 with the pair of human monoclonal antibodies described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody W15-82-3 with the above pair of human monoclonal antibodies. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 3. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above.3. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody C22-4- 4 and its temptations. (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody C22-4-4 to the pair of human monoclonal antibodies described above; (c) a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of antibody C22-4-4 to the pair of human monoclonal antibodies described above; and furthermore, the above-mentioned anti-idiotypic antibody, antibody flag that the antibody or antiserum is cross-reactive with the pair of human monoclonal antibodies described above. An anti-idiotypic antibody, antibody fragment or antiserum characterized by: 34. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotopes are (a) monoclonal antibody H70-9-55 and its or (b) a derivative that competes in the binding of antibody H70-9-55 with the pair of human monoclonal antibodies described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody H70-9-55 with the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 3. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody or antiserum is cross-reactive with the pair of human monoclonal antibodies described above.35. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody S26-16- 1 and derivatives thereof; or (b) compete the binding of antibody S26-16-1 with the pair of human monoclonal antibodies described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody S26-16-1 with the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 3. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody fragment or antiserum is cross-reactive with the pair of human monoclonal antibodies described above.36. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being: (a) monoclonal antibody H101-2; -1 and derivatives thereof; or (b) compete the binding of antibody H101-2-1 with the pair of human monoclonal antibodies described above. monoclonal antibodies derived from specimens identified by their ability to specifically inhibit or (c) compete the binding of antibody H101-2-1 with the pair of human monoclonal antibodies described above. a polyclonal antiserum derived from a specimen identified by its ability to specifically inhibit the anti-idiotype antibodies, antibody fragments; 3. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody fragment or antiserum is cross-reactive with a pair of human monoclonal antibodies as described above.37. An anti-idiotypic antibody, antibody fragment or antiserum capable of reacting with a common idiotope expressed by a pair of human monoclonal antibodies, the common idiotope being expressed by (a) monoclonal antibodies H55-4 and or (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody H55-4 to the pair of human monoclonal antibodies described above; or (c) antibody H55. -4 and a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of the above pair of human monoclonal antibodies; The above-mentioned anti-idiotypic antibodies, antibody fragments, etc. An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody or antiserum is cross-reactive with a pair of human monoclonal antibodies as described above. 38. A common idiotope expressed by a pair of human monoclonal antibodies a corresponding anti-idiotypic antibody, antibody fragment or antiserum, which The common idiotope is (a) monoclonal antibody S20-26 and its derivatives. or (b) a monoclonal antibody derived from a specimen identified by its ability to competitively inhibit the binding of antibody S20-26 to the pair of human monoclonal antibodies described above; or (c) antibody S20. -26 and a polyclonal antiserum derived from a specimen identified by its ability to competitively inhibit the binding of said pair of human monoclonal antibodies; Antibodies, antibody fragments An anti-idiotypic antibody, antibody fragment or antiserum, characterized in that the antibody or antiserum is cross-reactive with a pair of human monoclonal antibodies as described above. 39. An anti-idiotypic antibody, antibody fragment or antiserum having an antigen binding site, said site comprising at least one HIV antigen and a human idiotype expressed by a B-cell lymphoma in at least one AIDS patient. Connection with type anti-idiotypic antibodies, antibody flags, characterized in that they are capable of competing for binding; ment or antiserum. 40. Antibodies secreted by the hybridoma with accession number #HB9955 and deposited The small amount present on the antibody secreted by the hybridoma with accession number #HB9953 Anti-idiotypic antibodies, antibody fragments or antisera capable of cross-reacting with at least one common idiotype. 41. An anti-idiotypic antibody, antibody fragment or antiserum having an antigen binding site, said site being produced by the hybridoma of accession number #HB10010. and at least one common idiotype present on the antibody secreted by the hybridoma of accession number #HB10008. Anti-Impact, which is characterized by being an internal image of the original. Diotypic antibodies, antibody fragments or antisera. 42. Anti-idiotypic antibody, antibody fragment according to claims 39, 40, 41. A vaccine or active immunotherapeutic agent comprising at least one antiserum. 43. Steps: (a) isolating at least one type of cell derived from a lymph node of at least one AIDS-infected patient; (b) at least one type of cell derived therefrom; (c) capable of secreting antibody(s) capable of reacting with at least one AIDS-related infectious agent; (d) obtaining the antibody(s) from the hybridoma(s) selected above; method for producing antisera or antiserum. 44. 44. A product according to the method of claim 43. 45. Steps: (a) isolating at least one cell derived from a lymph node of an AIDS-infected patient with at least one AIDS-related lymphoma; (b) producing at least one hybridoma therefor; (c) ) capable of secreting antibody(ies) capable of reacting with at least one AIDS-related infectious agent. (d) obtaining antibody(s) from the hybridoma(s) selected above; anti-idiotypic antibodies against at least one AIDS-related infectious agent; Methods for producing antibody fragments or antisera. 46. 46. A product according to the method of claim 45. 47. Steps: (a) isolating at least one type of cell derived from a lymph node of at least one AIDS-infected patient; (b) at least one type of cell derived therefrom; (c) capable of secreting antibody(s) capable of reacting with at least one AIDS-related infectious agent; (d) obtaining antibody(s) from the hybridoma(s) selected above; (e) at least one anti-idiotype against said antibody(s) of step 3; producing an antibody; (f) identifying at least one anti-idiotypic antibody, antibody, antibody fragment, or antiserum that interferes with the binding of an AIDS-associated infectious agent to the antibody of step 3; (g) at least one anti-idiotypic antibody of step 6 capable of inducing a humoral anti-AIDS-related infectious agent response in a specimen other than the specimen from which the anti-idiotypic antibody, antibody fragment or antiserum was derived; 1. A method for producing an anti-idiotypic antibody, antibody fragment or antiserum against at least one AIDS-associated infectious agent, comprising: selecting an antibody fragment or antiserum. 48. 48. A product according to the method of claim 47. 49. At least one anti-idiota prepared by the method of claim 47. vaccines or immunotherapeutics, including immunotherapy antibodies. 50. Steps: (a) isolating at least one cell derived from a lymph node of an AIDS-infected patient with at least one AIDS-related lymphoma; (b) producing at least one hybridoma therefor; (c) ) selecting the hybridomas of step 2 whose antibody(ies) are capable of reacting with at least one AIDS-related infectious agent; and (d) obtaining the antibody(ies) from the hybridoma(ies) selected above; e) producing at least one anti-idiotype antibody against the antibody of step 3; and (f) at least one anti-idiotype antibody that interferes with the binding of the antibody of step 3 to an AIDS-associated infectious agent. Check for antibodies, antibody fragments, or antisera. (g) at least one anti-idiotypic antibody of step 6 capable of inducing a humoral anti-AIDS-related infectious agent response in a specimen other than the specimen from which the anti-idiotypic antibody, antibody fragment or antiserum was derived; 1. A method for producing an anti-idiotypic antibody, antibody fragment or antiserum against at least one AIDS-associated infectious agent, comprising: selecting an antibody fragment or antiserum. 51. 51. A product according to the method of claim 50. 52. At least one anti-idiota prepared by the method of claim 50. vaccines or immunotherapeutics, including immunotherapy antibodies. 53. Competitive with one of the antibody group consisting of L50-19-13, C321-145, H101-2, L46-49 (S-005), H70-9 (S-009), BE 0015-1 and C15-87 An anti-idiotypic antibody, antibody fragment or antiserum capable of binding to. 54. Anti-idiotypic antibody L50-19-13 and an antibody with the same immunological characteristics as the above antibody L50-19-13. 55. On deposit with the ATCC, Rockville, Maryland, under deposit number HB9977. A hybridoma cell line producing anti-idiotypic antibodies. 56. 58. A monoclonal antibody produced by the cell line of claim 57. 57. coating a solid support with a human IgG, Fc fragment; contacting a first section of the solid support with a liquid sample obtained from a patient; contacting a second section of the solid support with a control sample; 1st and 2nd cut above The fragment is labeled anti-common idiotype capable of reacting with rheumatoid factor (“RF”). and measuring the amount of the labeled antibody that has formed a complex with the RF; and correlating the amount of the labeled antibody that has formed a complex with the RF and the amount of RF in the sample. Investigating the presence or amount of RF present in a liquid sample obtained from a patient, including: Toro detection method. 58. coating a solid support with human Clq; contacting a first section of the solid support with a liquid sample obtained from a patient; contacting a second section of the solid support with a control sample; 2nd cut contacting the strip with a labeled anti-common idiotype antibody capable of reacting with an immune complex ("IC"); determining the amount of said labeled antibody complexed with said IC; and correlating the amount of the labeled antibody that has formed a body with the amount of IC in the sample; Vitro detection method.