WO1988009370A1

WO1988009370A1 - Separation of specific biological substances by a biochemical filter

Info

Publication number: WO1988009370A1
Application number: PCT/US1987/001229
Authority: WO
Inventors: Rabindra N. Ghose
Original assignee: Ghose Rabindra N
Priority date: 1983-09-06
Filing date: 1987-05-22
Publication date: 1988-12-01

Abstract

Apparatus and methods for selective removal of specific biological cells or specific antigens or antibodies, from fluid containing their mixture with other biological cells and particulates are described. Filtration by this biochemical filter system is effected in a continuous closed-loop fluid flow path. The apparatus described herein comprises a source (1) of fluid containing specific biological cells, antigens or antibodies to be removed; a source (2) of complementary cells or complementary antibodies for the antigens and complementary antigens for the antibodies which can form large agglutinates following a biochemical reaction; a reaction chamber (3) providing conditions favorable for fast clump formation following the reaction; a filter (4) for trapping large agglutinates; one or more pumps (23) to regulate various flow rates; and necessary connecting links to form a closed-loop fluid flow path that includes the sources of biological cells, antigens or antibodies and complementary cells, reaction chamber, and filter chamber.

Description

SEPARATION OF SPECIFIC BIOLOGICAL SUBSTANCES BY A BIOCHEMICAL FILTER

BACKGROUND OF THE INVENTION

The inventive apparatus and method described herein utilizes the concep of highly selective biochemical reactions between two types of complementary bio logical substances leading to the formation of large clumps or agglutinates and separation concept based on different dimensions of the clumps and the biologica cells and particulates not involved in the reaction. Antigens and corresponding specific antibodies, for example, are two such types of complementary biological substances, which when reacted, lead to the formation of large agglutinates.

In general, the antigen-antibody reaction occurs in two stages¹. In th first stage, an individual antigen combines with a complementary antibody. If specific antibodies are selected for a particular type of antigen to be removed or separated from a fluid, such as blood, the first stage reaction may take plac in a fraction of a second. Furthermore, the antibodies will react specifically with antigen cells which are complementary to each other and not with other cell of different species. Numerous papers have been published to demonstrate the extremely selective affinity between specific antibody and antigen. This selec¬ tivity in reaction is utilized in this invention.

The second stage antigen-antibody reaction involves the formation of large agglutinates or clumps, containing a large and often interconnected chain of antigen-antibody molecules. As early as in 1934, Marrack² described the reaction between antigen and antibody cells resulting in precipitation in terms of the building up of aggregates of large sizes. Marrack pointed out that if th antibody has more than one valency, it will be possible for antigens and anti¬ bodies to be bound together in the form of a coarse lattice.

The study in the field of second state antigen-antibody reaction leadin to precipitation or agglutination was also made long ago by Heidelberger³ who originally made use of purified capsular polysacharide of the type III pneumo--. coccus s antigens. The reactions were observed when an increasing amount of ant gens were added to a constant amount of antiserum or antibody. After a time, sufficient for the complete reaction to occur, the precipitates were washed free of uncombined reactant and the total antigen content was estimated. It was seen that the amount of antibody precipitate increased to a maximum with the increasin addition of antigen and then suddenly this amount declined so that in the extrem antigen-excess case , no precipi tate was formed. For a given anti gen and the cor respondi ng compl ementary anti body, then , there appears to be an optimal proporti of- antigen to antibody whi ch yiel ds the l argest aggl uti nates .

The second stage antigen-anti body reaction i s util ized i n this inventio so that physical ly l arge aggluti nates or cl umps can be obtained . The formation of l arge cl umps of antigen and anti body mol ecul es is bel ieved to resul t from mul tipl e reactions which can be descri bed as fol l ows :

A + S — AS

AS + A — ASA

ASA + A ~ ASA A ASA

ASA + S — AS AS

where A and S denote respectively the antigen and antiserum (antibody) molecules Indeed other reactions, besides those shown above, are possible.

The formation of large clumps of antigen and antibody has been observe by a large number of researchers. From such observations it appears that the dimensions of the antigen-antibody clump and the rate of clump formation depend on several factors such as antigen-antibody ratio, electrolyte concentration of the solution, temperature, antibody valency, etc. A polarizing electromagnet field¹* and stirring can also affect clump sizes and their formation rates.

The concentration of antigens and antibodies in the solution, perhaps, affect the clump formation most markedly. It is well known, for example, that t precipitation or agglutination varies in composition according to the proportio of antigen and antibody in the reacting mixture. If antibody is present in exces the precipitation will contain relatively more of this component and vice versa It is seen that if the valency of the antigen is N and that of the antibody is there will be increasing chances of building large aggregates up to a point whe S/A ratio is about N/2. It may be recognized that this combination of two sub¬ stances to form a compound of variable composition according to the proportions in which they are mixed has no counterpart in chemical reactions of small molecul but it is more akin to the polymerization of plastics. It is, of course, essen tial that the antigen be multivalent and the antibody be at least bivalent for the latice hypothesis to work in this way. An application of time-varying electromagnetic field shows possibili of enhancing the rate of agglutination process. For example, large aggregat nonspherical dielectric particles including biological cells have been made the application of a time-varying electromagnetic field. This process is of referred to as pearl-chain formation. The formation of large aggregates of a gen and antibody molecules could be obtained by similar techniques. The pea chain formation is regarded as a direct consequence of increasing the free en of the biological cells in solution by a nonther al energy source such as the electromagnetic field. Since the energy that can be imparted byan electromag field to the biological cells depends on the coupling mechanism, which in tu depends on the frequency and polarization of the electromagnetic field for a g set of antigens and antibodies, the average time required to form a clump of given dimension can be considerably reduced if an appropriate electromagnetic field is impressed on the solution.

In addition, adaptation of complement fixation procedures, provision stirring and a reduction of hapten concentration in the antibody solution tha normally terminates the antigen-antibody chain could be used to increase the agglutination and reduce the time required for the second stage antigen-antib reaction.

Besides antibodies, agglutinins have been developed such that clumps be formed following a highly specific reaction of such agglutinins with certa complementary biological cells in a solution. Burger⁵ for example, reported agglutinin prepared from wheat germ lipase which reacted with tissue culture lines that were transformed by a tumor virus, while under identical condition their untransformed parent cell lines did not agglutinate. These and similar agglutinins including monoclonal antibodies can be used to form clumps and to separate specific biological substances.

Once large clumps containing the biological cells to be removed or s ated are formed, a filter, that discriminates the filtrate against the residu based on their grossly different sizes, can be used for the final separation the cells. Various mechanizations of the selective cell separation or cell re in a closed-loop fluid flow path, containing the source of fluid, a reaction chamber where clumps of the cells to be removed are formed through a highly s ific biochemical reaction, and a filter chamber where the clumps are retained permitting the fluid along with nonreacted cells and particulates to return t source, are embodied in the invention. SUMMARY OF THE INVENTION

The invention described herein comprises an apparatus and method for selectively removing specific biological substances from a fluid containing suc substances without affecting other cells and particulates also contained in the same fluid. The separation or selective removal of such substances is effected by first forming large clumps of the substances to be removed by adding biochem cally complementary substances which biochemically react almost exclusively wit such substances and then filtering the fluid so that the clumps containing the substances to be removed are trapped in the filter. The filtration is effected bvy discriminating clumps of larger dimensions against other cells and particu¬ lates of smaller dimensions, which do not participate in the biochemical reacti The filtrate, without the clumps, is returned to the original source of the flu and the filter containing the clumps is removed periodically to complete the s aration process. The process of separation or selective removal of substances conducted in a continuous closed-loop fluid flow path such that the substances which escape the biochemical filtering in one cycle, are subjected to the same filtering process again and again in subsequent cycles, until they are trapped.

When the fluid is blood and its source is a living system, the biochemi filter of the invention described herein may constitute an extracorporeal bloo circulatory system where specific antigens, such as specific bacteria, viruses, fungi, or parasites contained in the blood can be selectively removed. For th clump formation, as is essential in this invention, certain quantities of compl mentary antibodies need to be added to the blood only while it flows through t extra-corporeal blood circulatory system. Such a selective separation of antig from blood may constitute an alternative form of therapy. The volume of blood per unit time in the extra-corporeal blood circulatory system need not be as la as in a kidney dialysis machine, since, in most cases, the rate of growth of antigens in blood is relatively slow. Thus, if the antigens are removed at a r faster than their growth rate, the blood could be made almost free of the speci antigens eventually. The process will be similar to that encountered in a swi ming pool filter where only a small volume of water is processed in a given per but the rate of processing or filtering is a little faster than the growth rat the pollutants. One advantage of this form of therapy by a selective removal specific antigens is that no rejection or side effects of drugs can occur, sin no foreign substances, such as drugs are introduced into the body. Also, unli in many chemotherapies, where desired cells and tissues in the blood stream ca be damaged or destroyed while the undesired cells or antigens are destroyed, effective therapy through the selective removal of antigens cannot harm the c and tissues not participating in the highly specific biochemical reaction.

Another advantage of the inventive apparatus and method is that undes or harmful antibodies in the blood can also be removed selectively by adding plementary antigens in the extracorporeal blood circulatory system, constitut the biochemical filter.

Still another advantage of the inventive apparatus and method is tha some undesired biological cells, such as T4 cells or neoplastic cells, which neither antigens nor antibodies, but have antigenic affinity for certain comp mentary agglutinins, can also be removed from the blood or bone marrow. The moval of certain biological substances, such as some retroviruses that can be used to cause fusion of other cells and thereby produce filterable clumps by inventive apparatus and method is yet another advantage.

Another advantage of the inventive apparatus and method is to preven permeation of cancerous cells into other parts of the body following a tumor s gery. To achieve this result, one or more units of the inventive apparatus c be inserted into the principal arteries and veins prior to the surgery so tha cancerous cells are trapped in the filter while blood with normal cells and tissues join the bloodstream.

Another advantage of the inventive apparatus and method is to comple drugs in therapy, particularly when the growth rate of certain bacteria or vir is too fast for drugs to provide a remedy in a timely manner. A simultaneous moval of some bacteria or viruses along with the destruction of other bacteri or viruses by drugs may, in some cases, accelerate the therapeutic process.

Still ^'another advantage of the inventive apparatus and method is to of therapeutic remedy for certain bacteria and viruses for which no drug exists is yet invented. It should be noted, however, that the application of the in tive apparatus and method described herein, need not be confined to the remov of antigens or antibodies from the blood.

The reservoir of knowledge of antigen-antibody reactions and the for tion of clumps of biological substances when appropriate complementary agglutin are added, may be regarded as prior art relevant to this invention. The art extracorporeal blood circulatory system, as is found in the dialysis machine, i also well known now and may be regarded as another prior art relevant to this i vention. Unlike these prior arts, however, the present invention teaches us ho to combine the related sciences and technologies associated with these arts in system engineering sense so that any specific antigens or antibodies or cells with antigenic sites can be removed from blood or similar fluids with a high de gree of specificity.

Further objects and advantages of the invention will become apparent from the study of the following portion of the specification, the claim, and th attached drawings.

REFERENCES

1. a. D. Pressman, "Molecular Complementariness in Antigen-Antibody Systems"

Molecular Structure and Biological Specificity, Ed. L. Pauling and H.A Itano, American Institute of Biological Science, Washington, D.C. b. L. Pauling, D.H. Campbell & D. Pressman, Physol . Rev., Vol. 23, pp 203- 219, 1943

2. G.R. Marrack, "The Chemistry of Antigens and Antibodies", Special Repo Series, Medical Research Council, London, No. 230, 1938

3. a. M. Heidelberger, Bacteriol Rev., Vol. 3, p. 49, 1939 b. J.H. Humphrey & R.6. White, Immunology for Students of Medicine, F.A. Davis Co., Phil a, pp 198-199

4. a. M. Saito & H.P. Schwan, "The Time Constants of Pearl-Chain Formation",

Proc. of Fort Ann, Tri-Serv. Conference on Biological Effects of Micro wave Radiation, Vol. 1, pp 85-97, Plenum Press, N.Y., 1960 b. L.D. Sher, "Technical Effects of AC Fields on Particles Dispersed in a Liquid", Biological Implications, 0NR Tech. Report, No.37, The Moore School of Electrical Engineering, Univ. of Penn., PA

5. M.M. Burger, "A Difference in the Architecture of the Surface Membrane of Normal and Virally Transformed Cells", Proc. National Academy of Science, Vol. 62, 1969 BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a conceptual schematic arrangement of a biochemical filter system which enables selective removal of specific biological substances from a fluid in a closed-loop fluid flow path.

FIG. 2 is a simplified schematic arrangement for the removal of bio¬ logical cells of relatively large dimensions.

FIG. 3 is a simplified schematic arrangement for the removal of bio¬ logical substances of relatively small dimensions.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 shows the conceptual arrangement for the selective removal of tain specific biological substances from a fluid. The first source, 1, embod a mixture, in a fluid of biological substances to be removed and other cells particulates, which must remain unaffected by the cell removal process. This source is connected to a reaction chamber, 3, so that the fluid can flow into reaction chamber at a controlled rate. The reaction chamber is also connecte a second source, 2, of complementary biological agglutinins which react almos exclusively with the biological substances to be removed and form large clump following the reaction. For example, if the biological cells to be removed f the fluid are antigens, such as bacteria, viruses, fungi or parasites, the co plementary agglutinins will be corresponding antibodies or antisera which rea almost exclusively with the particular type of antigens which are to be remov Similarly, when the biological substances to be removed from the fluid are an bodies, the complementary agglutinins will be specific antigens which will re almost exclusively with the antibodies to be removed. If the cells to be remo are virally transformed neoplastic cells, the complementary biological substa will be certain specific agglutinin which can agglutinate with the neoplastic cells but not with other cells including parent cells from which the neoplasti cells are derived. The complementary agglutinins are made to flow into the reaction chamb also at a controlled rate. At the reaction chamber, clumps of biological sub¬ stances to be removed and the complementary agglutinins are formed, the dimen¬ sions of the clumps being considerably larger than other cells and particulates The fluid containing the newly formed clumps and other unaffected cells and par ticulates is led to a filter chamber, 4, which retains the clumps as residue, b cause of the large dimensions of the clumps with respect to other cells and par ticulates, and permits the filtrate containing the fluid and unaffected cells a particulates to return to the first fluid source, 1. The filtering arrangement thus described, then, constitutes a closed-loop continuous fluid flow path. The biological substances which escape the reaction in one cycle are subjected to conditions favorable for the reaction over and over again in subsequent cycles. If the rate of removal of the biological substances is faster than their growth rate, the fluid eventually becomes free or almost free of such substances.

FIG. 2 illustrates, by way of an example, an embodiment of the inven¬ tion where the dimension of the biological substances to be removed is compar¬ able with the cells and particulates in the fluid which must remain unaffected by the cell removal process. In this arrangement, the source, 11, of the bio¬ logical substances to be removed in a mixture with other cells and particulates is connected to the reaction chamber, 13, through a pump, 12, a fluid rate con¬ trol mechanism, which controls the rate of the flow of the fluid from the source 11, to the reaction chamber, 13. The source, 14, of the complementary biologic agglutinins which react almost exclusively with the substances to be removed is also connected to the reaction chamber, 13, through a pump, 15, a fluid rate co trol mechanism, which controls the flow rate of complementary agglutinins into t reaction chamber. Reactions of the biological substances to be removed and the complementary agglutinins take place at the reaction chamber leading to the fo mation of clumps, the dimensions of which are many times larger than those of other cells and particulates in the fluid in source 11 or 14. The fluid, inclu ing the clumps and other cells and particulates unaffected by the reaction, is then led to the input side of a filter chamber, 16 or 17. Each filter chamber may consist of a membrane type partition, 18 or 19, which separates the input output sides of the filter. The poresize of the membrane is so chosen that th large clumps are retained at the input side of the filter while the filtrate which does not contain any cell or particulate having a dimension more thanabo one third or one fourth of that of the pore size of the membrane, flows throug the membrane to the output side of the filter chamber. The filtrate, then is l to a reservoir, 20, where it is stored temporarily. Only one of the two filte chambers, 16 or 17, operates at any time. When the membrane in one filter is clogged up by clumps, the fluid is channeled into the second filter without in terrupting the closed-loop fluid flow path. After the second filter resumes it operation, the first filter chamber along with the clumps retained as residue i replaced by a new filter chamber. The process is repeated if the need exists. The rapidity with which the filter chamber needs replacement will depend on th concentration of the cells to be removed in the fluid.

Alternatively, the filter chamber may consist of a tube or similar co tainer filled with glass beads of such dimensions and packing density as to retain the large clumps inside the filter chamber and allowing the filtrate wi unaffected cells and particulates to flow through the tube and reach the reser¬ voir, 20.

To illustrate the filtering action by way of an example, let it be assumed that the biological cells to be removed are some specific bacteria havi an average diameter of 10 microns. Let the pore-size of the membrane in the filter be 40 microns, and the fluid is blood which contains other cells, such a the red and white cells and particulates, ranging in dimensions from 5 to 15 microns. When, as a result of the antigen-antibody reaction, clumps are formed and the minimum dimension of the clump is much bigger than 40 microns, the clum will be retained by the filter while the blood with all its desired cells and particulates will flow through the filter as filtrate. Since the clumps will contain the bacteria, periodic replacement of the filter will cause the removal of the bacteria from the blood.

As shown in FIG. 2, an outlet of the reservoir, 20, is connected to another filter, 21, which will allow the fluid containing only the desired cell and particulates to pass through the filter, retaining any broken clumps which escape the first filter. The pore-size of the membrane, 22, used in the filter 21, is smaller than the pore-size of the membrane, 18 or 19, but larger than an desired cell or particulate in the fluid. The output of the filter, 21, is con nected to the first fluid source, 11, through a pump, 23, a fluid rate control mechanism, the object of which is^" to regulate the flow rate of the fluid as it i reintroduced into the first fluid source. The reintroduction of the fluid into the first fluid source closes the fluid flow path loop. A constant volume of fluid is usually maintained at the reservoir 20. To compensate for any loss of fluid during the filtering operation, a priming burette, 24, containing the same type of fluid as in source 11, but free of the undesired substances may be connected to the reservoir. In addition, an appro¬ priate heat exchanger may be provided at the reservoir and at the reaction chamber. Also, a source of appropriate electromagnetic field to hasten clump for¬ mation may be introduced at the reaction chamber. Furthermore, bubble traps, 25, may be provided at convenient points in the closed-loop fluid flow path, such as the filters and at the reservoir,^"to make^" the^' system free of any undesired air.

FIG. 3 illustrates, by way of an example, another embodiment of the in¬ vention, where the dimensions of the biological substances to be removed from a fluid are significantly smaller than those of the cells and particulates which must remain unaffected during the removal process. Here, the source, 31, em¬ bodies the fluid containing the biological substances to be removed along with other cells and particulates. This source is connected to a filter chamber, 33, through a pump, 32, the purpose of the pump being the regulation of the flow rate of the fluid to be processed. The filter chamber, 33, comprises a tube, 34, or a. similar structure inside a fluid tight enclosure, 35. The tube is made of a porous membrane which permits a part of the fluid containing all cells and par¬ ticulates, having dimensions much smaller than those of the cells and particu¬ lates which should remain unaffected by the cell removal process, to flow through it as the filtrate. The filtrate is collected in the enclosure, 35. The remain¬ ing fluid with larger cells and particulates than those in the filtrate is led to the reservoir, 39. The filtrate collected in enclosure 35, is led to a reaction chamber, 36, which comprises a tube-like structure encased in a heat exchanger. The complementary biological agglutinins which can react specifically with the biological substances to be removed are introduced in the reaction chamber, 36, from their source, 37, through a pump, 38, which controls the flow rate of the complementary agglutinins into the reaction chamber.

Following the reaction in the reaction chamber, 36, clumps or agglutin¬ ates, containing the biological substances to be removed, are formed. The fluid containing the clumps and other nonreacted particles, if any, is then led to another filter chamber, 40 or 41. The clumps are retained at the membrane, 42 or 43, inside the filter chamber, 40 or 41, respectively, allowing the filtrate fluid to be collected at the reservoir, 39. Finally the fluid from the reser¬ voir is returned to the source, 31, through another filter chamber, 44, and a pump, 45. The purpose of this filter is to prevent any cells, particulates or or clumps, larger than those originally present in the fluid, to return to th source, 31. The purpose of the pump, 45, is to regulate the flow rate of the returning fluid.

To further explain the operation of the process of removal of biolog cal substances in this case, let it be assumed that the biological substances to be removed are viruses, the dimensions of which are on the order of 0.1 micron. Let the fluid containing the viruses be blood which carries red and white cells and other particulates, the dimensions of which range from 5 to 1 microns. The porous tube, 34, in filter chamber 33, is so chosen that only t cells and particulates of dimensions less than 7*0.5 micron can flow through t pores into the enclosure 35. The contents of the enclosure, 35, then, will b the blood containing the viruses to be removed along with other cells and par ticulates, the dimensions of which are less than 0.5 micron. Such contents are then led to the reaction chamber, 36, where specific biological reactions take place among the viruses to be removed and the corresponding antibodies which are, in this case, the complementary biological agglutinins introduced into the chamber from the source, 37. If the pore-size of the membrane, 42 o 43, in the filter chamber, 40 or 41, is such that only cells and particulates of dimensions less than 0.5 micron can flow through it and if the minimum dim sion of the clumps is greater than 1 micron, the filtrate of the filter chamb 40 or 41, will be continuously freed from the viruses. If some viruses escap the reaction in one cycle, they will be subjected to conditions favorable for reaction over and over again until almost all the viruses are removed. As in FIG. 2, when one of the filter chambers, 40 for example, is filled with clump the fluid flow is routed through filter chamber 41 without interrupting the co tinuous fluid flow. Meanwhile, the filter chamber, 40, is replaced by a new one. This process is continued until all or most of the viruses are removed from the blood. Again, as in FIG. 2, a priming burette, 46, containing the same fluid as in the source, 31, is connected to the reservoir, 39, to compen sate for any loss of fluid during the cell removal process. Also, as in FIG. the filter chamber, 44, prevents reentry into the source, 31, of any cells, p ticulates, or clumps, the dimensions of which are larger than 20 microns.

In a living system, where specific antigens or antibodies are to be removed from the blood, the sources 11 in FIG. 2 and 31 in FIG. 3 will be re placed by the blood circulatory system of the living body. The above described embodiments and methods are furnished as illustra¬ tions of the principles of the invention and are not intended to define the only embodiments possible in accordance with the teachings of the invention. Rather, protection under the Patent Law shall be afforded to the inventor not only to the specific embodiments above, but to those falling within the spirit and terms of the invention as further defined in the following claims.

Claims

What is claimed is:

1. A biochemical filter system comprising:

(a) a chamber containing specific biological cells to be separated a fluid mixture of these cells, other biological cells and particulates;

(b) a complementary source storage chamber containing correspondin complementary agglutinins which can react specifically with the biological c to be separated to form clumps;

(c) a reaction chamber, where specific reaction occurs, leading to formation of clumps, said chamber having first and second inlets and an outl

(d) means for connecting said chamber containing said biological c to be separated to the first inlet of the reaction chamber and for introducin said specific biological cells into said reaction chamber;

(e) means for connecting said chamber containing complementary aggl tiijins to the second inlet of the reaction chamber and for introducing said complementary agglutinins into said reaction chamber;

(f) filter means coupled to said outlet of said reaction chamber fo filtering the fluid containing the clumps and other cells and particulates following the reaction in the reaction chamber so as to retain the clumps as filter residue;

(g) means for introducing the fluid containing the clumps and other cells and particulates following reaction in the reaction chamber into said filter means ; and

(h) means for returning the fluid filtrate following filtering to the chamber containing said biological cells.

2. A biochemical filter system as in Claim 1, wherein said chamber contain specific antigens to be separated and said complementary source storage chamber contains corresponding complementary antibodies which react specifically to sai antigens.

3. A biochemical filter system as in Claim 1, wherein said chamber contain biological cells with antigenie sites and said complementary source storage chamber contains corresponding antibodies having specific complementary sites and said reaction chamber promotes the biochemical reaction forming clumps.

4.. A biochemical filter system as in Claim 3, wherein the biological cell to be separated are leukemic leukocytes and the complementary antibodies com¬ prised of leukemic leukocyte antibodies.

5. A biochemical filter system as in Claim 1, wherein the fluid is blood comprising plasma, red cells, leukocytes and other particulates not participat¬ ing in said biochemical reaction.

6. A biochemical filter system as in Claim 5, wherein the source of fluid is an in vivo blood circulatory system.

7. A biochemical filter system as in Claim 1, wherein said chamber contain specific antibodies to be separated and said complementary source storage chambe contains corresponding complementary antigens which react specifically to said antibodies.

8. A biochemical filter system as in Claim 1, wherein the fluid filtrate is returned to the fluid chamber through a reservoir.

9. A biochemical filter system as in Claim 1, wherein said system in¬ cludes at least one pump in the fluid flow path, between said chamber and the reaction chamber, between complementary source storage chamber and the^' reaction chamber, and in the path of the fluid filtrate returning means, to control the fluid flow rate therethrough, thereby to facilitate filtering of said specific biological cells to be removed from said fluid mixture.

10. A biochemical filter system as in Claim 1, wherein the means for con¬ necting the complementary source storage chamber to said reaction chamber in¬ cludes a flow rate control mechanism.

11. A biochemical filter system as in Claim 1, wherein the filtering is effected by a membrane having pore dimensions larger than the dimensions of sai specific biological cells, the complementary agglutinins, and other particulat in the fluid unaffected by the reaction, but smaller than the dimensions of the clumps formed by said biological reaction.

12. A biochemical filter system as in Claim 1, wherein the filtering is effected in a tube containing glass beads.

13. A biochemical filter system comprising:

(a) a chamber containing specific antigens to be separated in a fluid mixture wherein the dimensions of said antigens are sufficiently smaller than most of the cells and particulates in the fluid mixture;

(b) means for primary filtering the fluid mixture so that the primary filtrate comprises a portion of the fluid containing the specific antigens to b separated;

(c) means for introducing said fluid mixture into said primary filter ing means;

(d) a complementary source storage chamber containing complementary antibodies specific to said antigens to be separated from said fluid;

(e) a reaction chamber, where said reaction between said antigens and antibodies occurs leading to the formation of clumps, said chamber having first and second inlets and an outlet;

(f) means for conveying said primary filtrate into first inlet of the reaction chamber;

(g) means for connecting said complementary source storage chamber to second inlet of the reaction chamber;

(h) means connected to the outlet of said reaction chamber for second¬ ary filtering of the fluid containing the clumps and other cells and particulate following the reaction in the reaction chamber so as to retain the clumps as filter residue;

(i) a reservoir with a plurality of inlets and an outlet; (j) means for connecting the fluid filtrate following secondary filte ing to one inlet of the reservoir;

(k) means for connecting the fluid filtrate following primary filteri to another inlet of the reservoir; and

(1) means for returning the fluid accumulated at the reservoir to sai fluid chamber containing antigens to be separated.

14. A biochemical filter system as in Claim 13, wherein said chamber con¬ tains viruses to be separated from the fluid and said complementary source stora chamber contains antibodies specific to said viruses.

15. A biochemical filter system as in Claim 13, wherein the fluid is blood comprising plasma, red cells, leukocytes and other particulates nonreactive wit said complementary antibodies.

16. A biochemical filter system as in Claim 13, wherein at least one pump is inserted into the fluid flow path to control the fluid flow rate.

17. A biochemical filter system as in Claim 13, wherein the means for con¬ necting the complementary source storage chamber includes a flow rate control mechanism.

18. A biochemical filter system as in Claim 13, wherein the secondary filtering is effected by a membrane having pore dimensions larger than the di¬ mension of said specific antigens, the complementary antibodies and other par¬ ticulates in the fluid unaffected by the reaction, but smaller than the dimen¬ sions of the clumps of reacted specific antigens and antibodies.

19. A biochemical filter system as in Claim 13, wherein the source of flui is an in vivo blood circulatory system.

20. A method for selectively removing bacteria from an in vivo blood ci cu latory system which comprises:

(a) guiding the blood containing the bacteria from an in vivo blood circulatory system to an external reaction chamber;

(b) introducing complementary antibodies which can agglutinate with said bacteria into said reaction chamber; (c) allowing a bacteria-antibodies reaction to take place in said reaction chamber whereby clumps are formed of reacted bacteria and complement antibodies, said clumps having dimension filterably larger than those of the desired cells and particulates in the blood;

(d) filtering out the clumps by passage of the blood through a filt and

(e) returning the filtered blood to the in vivo blood circulatory system.

21. A method for selectively removing viruses from an in vivo blood circu latory system, the dimensions of the viruses being smaller than other desired cells in the blood, which comprises:

(a) diverting a portion of in vivo blood containing viruses from an vivo blood circulatory system into an alternate path;

(b) guiding the diverted blood containing the viruses from the in vi blood circulatory system to a primary filter which permits a portion of the diverted blood containing the viruses to be separated by filtration from the r maining portion of diverted blood containing larger cells and particulates and allowing the return of the diverted blood with larger cells and particulates t the in vivo blood circulatory system;

(c) combining complementary antibodies with that portion of the bloo containing the viruses whereby said viruses and complementary antibodies react and form clumps;

(d) maintaining the reacted viruses and antibodies together to allow the forming of clumps of reacted viruses and antibodies, said clumps having dimensions filterably larger than the dimensions of the viruses to be removed;

(e) filtering out the clumps by a secondary filter;

(f) collecting the secondary filtrate without the clumps; and

(g) returning the remaining diverted blood to the in vivo blood circ latory system.

22. A method for selectively removing specific biological cells, the dime sions of which are comparable to red and white cells, contained in a fluid mixture in an in vivo system which comprises:

(a) diverting a portion of in vivo fluid containing the specific bio logical cells from the in vivo system into an alternate path;

(b) introducing the diverted fluid containing said biological cells along with other cells and particulates present in the fluid into an external reaction chamber;

(c) introducing complementary agglutinins which react with said bio¬ logical cells to form clumps into said reaction chamber;

(d) maintaining the specific biological cells and complementary agglutinins in said reaction chamber to allow a reaction to occur and the form ing of clumps of reacted cells having dimensions filterably larger than other constituents of said fluid;

(e) filtering out the clumps of reacted biological cells and agglu¬ tinins by a filter; and

(f) returning the resulting filtrate without the clumps to the in vivo system.

23. A method for selectively removing specific antibodies, the dimensions of which are significantly smaller than the red and white cells in blood from an in vivo blood circulatory system which comprises:

(a) diverting a portion of in vivo blood containing specific anti¬ bodies from a circulatory system into an alternate path;

(b) introducing said diverted blood into a primary filter whereby th separation of that portion of diverted blood containing the antibodies to be r moved from the remaining portion of diverted blood containing blood constituen which are filterably larger in dimension than the antibodies to be removed;

(c) conveying that portion of the blood with antibodies as detained following said primary filtering to a reaction chamber;

(d) conveying the remaining blood containing red and white cells and other particulates following said primary filtering to a reservoir; (e) introducing into said reaction chamber complementary antigens react with said antibodies to form clumps;

(f) maintaining the specific antibodies and complementary antigens said reaction chamber to allow an antigen-antibody reaction to occur and the forming of clumps, having dimensions filterably larger than those of the ant bodies to be removed by secondary filtration after discharge from said react chamber;

(g) filtering out the clumps by a secondary filter; and

(h) returning the filtrate without clumps to the in vivo blood cir latory system.

24. The method as in Claim 21 including storing the filtrate and the s of returning said secondary filtrate for reintroduction into said in vivo bl circulatory system.

25. A biochemical filter as in Claim 13, wherein the chamber contains specific antibodies to be separated, in a fluid mixture wherein the dimensio of said antibodies are sufficiently smaller than most of the cells and parti lates in the fluid mixture and the complementary source storage chamber cont complementary antigens specific to said antibodies with means for primary fil ing the fluid mixture so that the primary filtrate comprises a portion of th fluid containing the specific antibodies to be separated.

26. A biochemical filter system for selectively separating certain speci biological materials selected from the group consisting of biological cells, antigens, antibodies, viruses, fungi and parasites, from a mixture of these materials and particulates in a fluid comprising:

(a) a first storage chamber containing at least one of said group o specific biological materials in a fluid mixture;

(b) a second storage chamber containing corresponding complementary biological materials which can react specifically with one of said group to b separated to form clumps;

(c) a reaction chamber, where specific reaction occurs, leading to formation of clumps, said chamber having first and second inlets and an outle (d) means for connecting said first storage chamber to the first inl of the reaction chamber and for introducing one of said group into said reacti chamber;

(e) means for connecting said second storage chamber to the second inlet of the reaction chamber and for introducing said complementary material into said reaction chamber;

(f) filter means connected to said outlet of said reaction chamber f filtering the fluid containing the clumps and other substances and particulate following the reaction in the reaction chamber so as to retain the clumps as filter residue;

(g) means for introducing the fluid containing the clumps and other materials and particulates following reaction in the reaction chamber into sai filter means to produce a fluid filtrate; and

(h) means for returning the fluid filtrate following filtering to th first storage chamber.

27. A biochemical filter system as in Claim 26, wherein the biological materials to be separated are antigens and the complementary material which reacts with the biological materials to be separated are antibodies specific t said antigens.

28. A biochemical filter system as in Claim 26, wherein the biological materials to be separated are antibodies and the corresponding complementary biological materials are antigens.