DELIVERY OF BIOLOGICALLY ACTIVE COMPONENTS OF HETEROLOGOUS SPECIES INTERFERON ISOLATES

Abstract: Interferon glycoprotein isolates of heterologous species origin are subjected to treatment in a digestive environment and non-species-specific biologically active fractions thereof are administered, preferably through digestive tract tissue, to the circulatory system of mammals, including humans, to secure antiviral, antiproliferative (e.g., antineoplatic) and immunomodulatory (e.g. immunopotentiating) effects ordinarily associated only with parenteral administration of homologous species interferon.

Description: DELIVEBY OF BIOLOGICALLY ACTIVE COMPONENTS OF HETΞEDLOGOUS SPECIES . INTΞ.RFEHDN ISOIATΞS ' BACKGHOUND The present invention relates generally to therapeutic uses of interferon and more specifically to treatment of mammals, including humans, with isolates of iπterferon glycoprαtein derived from cells of heterologous mammalian species origin. "Interferon" is a term generiσally comprehending a group of vertebrate glycoproteins which are known to exert broad spectrum biological activity — including antiviral, aπtiproliferative and immuno- modulatory activities ~ in the species of animal from which the sub¬ stances are derived. • Since the* first descriptions of interferon by Isaacs and Liπdeman [See, Proc. Hoy. Soc. London (Ser. B), Vol. 147, pp. 258 et sec. (1957) and U.S. Patent No. 3,599,2223 , the material has been the subject of intensive research on a world-wide basis. Publications abound concern¬ ing th «e synthesis of interferon, its proposed molecular characterization, its clinical applications,- and proposed mechanisms of its an itumor, antiviral^ and immune system activities. See, generally, such review articles and collections as: DeMaeyer, et al., "Ihterferons" appearing as Chapter 5 in Comparative Virology, VoL 15, pp. 205-284, Plenum Press, N.Y., N.Y. (1979); CantreU, "Why Is Interferon Not In Clinical Use Today" appearing in Interferon 1979, I. Gresser, ed., Vol. I. pp. 1-23, Academic Press, London (1979); Stewart, "The Interferon System" Springer-Verlag, N.Y., N.Y. (1979); and Dunnick, et al., "Clinical Trials with Exogenous Interferon", J. Infect. Diseases, 139, No. 1, pp. 109-123 (1979). Owing to the disparate origins of the research contributing to the sum of the knowledge in the art concerning interferon, its characteristics and its uses, there exists a substantial lack of uniformity in such matters as classification of interferon types. There a ^ also numerous, sometimes contradictory, theories concerning the mode of action of interferon in producing clinical effects. The following brief summary is believed to provide a fair analysis of background information such as needed for understanding the present invention. A. Origins, Nomenclature and Physical Characteristics of Interieroπ Although originally isolated from cells of avian origin (chick allantoic cells), interferon production has been observed in cells of all classses of vertebrates, including mammals, amphibians, reptiles, etc. Interferon production by vertebrate cells is seldom spontaneous but is often readily "induced" by treatment of cells (in vivo or in vitro) with a variety of substances including viruses, nucleic acids (including those of viral origin as well as synthetic polynucleotides), Hpopolysaccharides and various antigens and mitogens. Inter eron is generally named in terms of correlation to the species of aiμ al cells producing the substance (e-g., human, murine, bovine, etc.) as well as to the type of cell involved (e.g. leukocyte, lymphoblastoid, fibroblast) and, occassionally, the type of inducer mate- rial responsible for interferon production (e-g,, virus, immune). Currently, inter eron is loosely classified by some researchers according to induction mode as either Type I or Type π, with the former classification compre¬ hending viral and nucleic acid induced interferon and the latter class including the material produced as a lymphokine through induction by antigens and mitogens. Various forms of interferon are distinguished by size, antigenicity, degree of glycosation and pH stability. Determination of precise molecular structures for inter¬ feron glycoprotein is presently beyond the capacities of the art. 3n the years since inter eron was first characterized as proteiπaceous on grounds of its inactivation by trypsin, attempts to purify and uniquely character¬ ize it have been frustrated by its high specific activity as well as its apparent heterogeneity, even in samples derived from a single cell type and using a single specific inducer. As one example, Thang, et al., P.N.A.S., VoL 76, No. 8, pp. 3717-3721 (1979) report that samples of human leukocyte interferon produced by challenge of leukocytes with Sendai virus can be separated into at least "two classes of subspecies" by c:.-r?ι Vv irO agarose-polynucleotide affinity chromatography with the two, in turn, displaying differing degrees of antiviral activity. interferon of human and murine origins is quantified by specific antiviral activity in terms International Units ("lϋ"), this despite knowledge that,e.g., the molecular- weight of human leukocyte and lym- phoblastoid interferon ranges between 13,000 to 25,000 daltons. B. Biological Activities of Interferon I its earliest applications, interferon was employed exdu- sively as an antiviral agent and the most successful clinical therapeutic applications to date have been in the treatment of viral or virus-related disease states * It became apparent, however, that exogenous interferon was sometimes capable of effecting regression or remission of various metastatic diseases. A summary of clinical trials of interferon as an antiviral and antiproliferative therapeutic agent through late 1978 is contained in Duππick, et aL supra.. The clinical agent of choice in this work has been human leukocyte interferon, "mass-produced" by procedures involving collection and purification of vast quantities of human buffy coat leukocytes, induction with virus and isolation ' from culture media.. The need for interferon of human source is, of course, consistent with the long-standing conclusion that interferon is "species specific", i.e., biologically active, in vivo, only in species homologous to the source cells. Interferon is administered parenterally, i.e., intramuscularly and intradermally, with some successul topical usages having been report¬ ed. It is seldom administered intravenously owing to substantial adverse effects attributable to "contaminants" in crude and even highly purified isolates. Parenthetically, while providing interferon dosages in the range g of 1 to 5 x 10 IU, interferon isolates employed in clinical studies actually contain less than about 0.1 percent iπterferon glycoprotein — the balance of the preparations comprising extraneous materials such as cellular debris, viral fragments and the like. To date, there have been no reports of therapeutically successful oral administration of interferon. This is consistent with the belief, widely held, that the glycoprotein will not withstand exposure to a digestive environment, such as found in mamma¬ lian therapy candidates. It is simply not expected that the biological C,.f?I activity of the glycoprotein could be retained after the molecules are subjected to the degradative effects of carbohydrases (e.g., amylase in saliva), or simple esterases, or the proteolytic hydrolytic enzymes in gastrointestinal secretions (e-g., trypsin, pepsin, chymotrypsin, carboxy peptidases A and B) and in cells of the intestinal mucosa (e-g. the aminopeptidases). These beliefs as to lack of oral efficacy are supported in large part by the prevailing understanding in the art that, while the digestive environment may not be hostile to all proteinaceous materials (proteolytic enzymes themselves being proteins), proteins are generally not transported across the gastrointestinal membrane. Thus, were inter¬ feron glycoproteiπs able to withstand a digestive environment, they would not be expected to be made available to the circulatory system by absorption through digestive tract tissue. Exceptions to the "rule 17 concerning intact absorption of macro molecular proteinaceous materials are. few. See, e.g., Wiseman, "Absorption from the Intestine", pp. 65-67, Academic Press, N. Y., N. Y. (1964); Bσckman, et aL, Anat. Res., VoL 155, " 603-622 (1966); Walker, et a , Gastroenterology, .Vol. 57, 531-550 (1974); Warshaw et al., Gastro- enterology, VoL 66, pp 987-992 (1974); Freeman, et aL, Aπn.Rev.IVfed.., VoL 29 pp. 99-116 0978); TJ.S. Patent No. 3,004,893 and U. S. Patent No 4,132,776. In general, the most substantial exception involves absorption of macromolecules by digestive tissue of neonatal animals prior to maturation of intestinal epithelial cell membranes. Indeed, the single known suggestion in the art that inter eron might be orally ef ective involved studies with neonatal mice [Schafer, et aL, Science, Vol. 176 pp. 1326-7 (1972)3.. In addition to use in antiviral and antitumor therapy, inter¬ feron has rather recently been noted to possess immunomodulatory effects, both immunopotentiating and immunosuppressive in nature. See, e.g., Sonnenfeid, et aL, "A Regulatory Role For Interferon In Immunity", Annals, N.Y. Acad. Sci., VoL 322, pp. 345-355 (1979). While no human clinical or in vivo animal work specifically directed to evaluation of immunological effects of interferon has been reported, it is proposed by some that the antitumor effects of interferon are at least in part related to immune stimulation or activation of so-called "natural killer ceils," - a - macrophages and T-lymphocytes. See, e.g., Kershner, "New Directions in Cancer Chemotherapy" A.S.M.News, VoL 46, No. 3, pp. 102 et see. (1980). Finally, "new" biological activities for exogenous interferon are consistently being ascertained. Cantrell, et al., New Eng. Jour. Med., VoL 302, No.18, p.1032 (1980) report an effect of interferon in transiently diminishing high density lipoprotein levels and total cholesterol values, suggesting that interferon in humans, may influence cardiovascular dis¬ ease. The absence of widespread clinical usage of interferon at the present time is attributable to a number of factors, but principally the shortness of supply of the material showing greatest clinical promise, i.e., human leukocyte interferon.- It has been estimated that in Finland — the country supporting the largest production of interferon — enough of the substance is prepared annually to treat either 10,000 cases of herpes keratitis or 200 case of chronic neoplastic disease. The- scarcity of human leukocytic interferon for clinical applications has prompted many researchers to re-examine the species specificity phenomenon in greater- depth with the hope that some means _,might be found to chemically modify the much more readuy available supplies of non-human interferon for use in humans. Generally at the forefront of these researchers is W.A. Carter. [See, e.g., "Minireview Glycosylation: Intraspecies Molecular Heterogeneity and Trans-species Activity of Mammalian Iπterferon", Life Sciences, VoL 25, pp. 717-28, Pergamon Press (1979); "Bypassing the 'Species Barrier' With Carbo- hydrate-Altered Interferon From Leukocytes", Cancer Research, VoL 39, pp. 3790-3795 0.979); and Carter, et aL, Molecular Pharmacology, Vol. 15_, pp. 685-690 0979).] Carter- has exhaustively reviewed the art teachings with respect to in ^ vitro activities of interferon in protecting ceils of heterologous species from infection by virus and proposes an integrative modei wherein the ability of iπterferon glycoprotein to cross or not cross species lines lies in the carbohydrate moiety and the cross-species biological activity is the function of the poiypeptide portion. See also, Braude, et al., "Differential Ihactivation and Separation of Homologous and Heterologous Antiviral Activity of Human Leukocyte Interferon 3y A Proteolytic Enzyme", Biochem. Biophys. Res. Comm., Vol. S9_, No. 2, pp. 612-619 (1979) and Thang, et aL, supra. To date, however, there have been no reports of the successful use of heterologous species interferon in vivo to develop those antiviral, antiproliferative or immunomodulatory ef ects ordinarily associated with administration of homolgous species interferon. In sum, interferon glycoprotein is presently recog-nized in the art as possessing enormous therapeutic potentiaL Interferon is as yet incompletely characterized as to biologically active components and precise mode of action. Species specificity characteristics impose severe limits on the range of its therapeutic utilities and concurrently severely restrict availability of interferon for clinical application. SUMMARY According to the present invention, mammals, including humans, are treated with therapuetically ef ective amounts of interferon glycoprotein isolated from cells of heterologous mammalian species origin. More specifically, antiviraL antiproliferative and/or immuno¬ modulatory effects heretofore ordinarily obtained only upon parenterai administration of isolates of homologous species interferon are obtainable through administration of more readily available isolates of interferon glycoprotein having heterologous mammalian species origins. Heterolo¬ gous species interferon preparations are first subjected to a digestive environment wherein non-species-specific biologically active fractions thereof are substantially freed from extraneous polypeptides and/or carbohydrates with which the biologically active fractions are ordinarily associated. The active components are administered to the circulatory system of the recipient animal, preferably through digestive tract tissue. In the most preferred procedures of the invention, heterolo¬ gous species interferon is administered to the alimentary canal of the recipient mammal, whereby the digestive materials in the canal operate on the isolate. Within such a digestive environment, extraneous carbo¬ hydrate and/or polypeptide materials which are not essential to the activity of biologically active fractions of interferon (but which are normally associated therewith when isolated) are degraded without de¬ tectable inactivation of the biologically active fractions. Such active fractions are thereafter absorbed through digestive tract tissues and enter the circulatory ' system of the recipient. Alternatively, the heterologous species interferon isolate may be treated in_ vitro under conditions substantially duplicating the digestive environment of the recipient mam¬ mal and thereafter administered to the mammal, either orally or, after suitable isolative procedures, parenterally. Mammals treatable according to the invention and suitable as cell sources for interferon production include those of the human, eline, bovine, equine, laprine and porcine species. The preferred types of interferon for use in the invention include fibroblast interferon as well as immune type interferon. Presently preferred practices of the invention include oral administration of bovine fibroblast and/or immune type interferon to human patients suffering from neoplatsie and/or viral diseases, including, e.g., malignant melanomas and benign papillomas of probable viral origin.. Further aspects and advantages of the invention will become apparent upon consideration of the following detailed description includ¬ ing the illustrative examples. DETAILED DESCRIPTION As employed herein, "interferon" and "interferon glyco¬ protein" shall be synonymous and shall have the meaning ordinarily attributed thereto in the art, including, but not limited to the meaning ascribed thereto in U.S. Patent No. 3,699,222. The term "isolated from cells of heterologous mammalian species origin" as applied to interferon shall designate derivation not only from in vitro mammalian cell growth media and in ^ vivo mammalian cellular exudates or secretions, but also from other suitable cellular sources. As such, the term is intended to designate interferon such as may be obtained as an in vitro isolate from media supporting growth of non-mammalian cells which have been the object of genetic transforma¬ tion involving mammalian DNA. "Isolate" shall compre end preparations- resulting from attempted purification of interferon present in cell growth media, cell exudates and ceil secretions, with no specific limitation as to precise concentration of interferon. "Digestive environment" shall mean and include conditions substantially duplicating those commonly present within the digestive tract of a recipient mammal, including, but not limited to, pH and temperature conditions and the presence of one or more hydrolytic, phosphoryiytic, oxidation-reduction, transferring, decarboxylating, hy- drating or isomerizing enzymes. As employed herein, "alimentary canal" and "digestive tract" shall be essentially synonymous and shall mean and include that anatom¬ ical portion of a mammal, e.g., the mouth, pharynx, stomach, duodenum, jejunum, ileum and large intestine in humans, wherein digestive processes occur. Parenterai administration" .shall mean and include administration to a mammal by means other than introduction into the alimentary canal. "Circulatory system" shall mean and include the hematic and/or lymphatic system of a mammal. The following* examples serve to illustrate practice of the invention wherein an interferon glycoprotein isolate from cells of heter¬ ologous mammalian species origin is delivered to the circulatory system by administration * to the alimentary canal of a recipient animal, whereby the isolate is subjected to a digestive environment in the recipient prior to the absorption of biologically active fractions thereof through ali- mentary canal wail tissues. Example 1 Bovine fibroblast interferon was prepared as follows: _ Primary bovine fetal kidney (3FK) or bovine testicular (3T) cells were grown to confluency in cell culture. Stocks of bluetongue virus (international serotype 10) were prepared in baby hamster kidney (BHK) cells or VEEO cells and had titers of 10 δ to 10 8 PFTJ/ l. The 3FK or 3T cells were challenged with bluetongue virus (multiplicity of infection of greater than 1 was best) and supernatant fluids were harvested when the cytopathic effect (CPE) involved the entire cell sheet, i.e., about 24 hours. The supernatant fluids were dialyzed for 24 hours in a Kd-HCl buffer (pH 2.0) and 24 hours in a phosphate buffered saline (pH 7.4) before ultracentrifugation at 100,000 X g for 60 minutes. The interferon activity ( expressed as "units" as opposed to Iϋ) was assayed by a plaque reduction ■ l?l method using vesicular stomatitis virus (VSV) as a challenge virus on BFK cells [Hosenquist and Loan, "Interferon Production With Strain SF-4 of Parainfluenza-3 Virus" Am. J. Vet. Res., 28, pp. 619-628 (1967)3 . Example 2 Bovine nasal secretion interferon was prepared as f ollowss Calves were inoculated intranasally with a vaccinal strain of infectious bovine rhinotracheitis (IBS) virus and the nasal secretions were collected by tampon for 2-S days after virus inoculation. [McKercher, et aL, "A Simple Method For Obtaining- Undiluted Nasal Secretions From Cattle," Am. J. Vet. Res., 34, pp. 837-838 (1973)3 ; Cummins, et aL, "Protection of Calves Against Rhinovirus In ection by Nasal Secretions Interferon Induced by Infectious Bovine Rhinotracheitis Virus," Am. J. Vet. Res., 41, pp. 161-465 (1980); Todd, et aL, Infect. I mun. 5, pp. S99-706 (1972) . Nasal secretions were subjected to dialyzation and ultracentri- fugatioπ as described in Example L Example 3 This example illustrates therapeutic ef ectiveness of orally administered heterologous species interferon in treatment of benign • papillomas of probable viral origin in human patients. A. A male patient having a wart which was three milli¬ meters in diameter and which had been present for about ten years consumed 30,000 units of bovine interferon prepared according to Ex¬ ample 2. The single dose was incorporated in about 10 ml of tissue culture medium. The wart was completely resolved within three weeks after treatment and did not recur. B. A female patient complaining of two plantar warts and xanthalasma of several years duration was given an initial oral dose of bovine interferon of Example 1 totaling 10,000 units in nine equal portions on a twice-daily schedule. After about three weeks, the plantar warts were substantially reduced in size. Approximately eight weeks after the first dose, about 2500 units of interferon of Example 2 was orally administered in four equal doses, twice daily. Within a week, the warts exhibited a vascular response and had a reddened appearance. Approxi¬ mately 12 weeks a ter commencement of treatment, a single oral dose of 5250 units of interferon of Example 2 was given, followed one week later wit 21,000 units of Example 1 interferon, orally administered in ten, twice-daily doses. Within three weeks- thereafter, the plantar warts were somewhat painful upon application of pressure and "drier" as well as further reduced in size. No more interferon was given and no further improvements in the warts were noted. The. xanthalasma, which had been unchanged for two years, flattened and was reduced in size within a week a ter the first dose of interferon * The xanthalasma reappeared but partially regressed again after the second dose of interferon. The xanthalasma reappeared and has remained essentially unchanged since administration of the third dose. C A male patient with a plantar wart was given a single, 8600 units, oral dose of Example 2 interferon * Within three weeks, there appeared, to be ait increase in blood supply to the wart and a size reduction of about one-half. No further treatments were given nor were further improvements noted. Example 4 This Example relates to the therapeutic effectiveness of orally administered heterologous species interferon in treatment of malig¬ nant melanoma in human patients. A. A first female patient had experienced a two year history of malignant melanoma on the leg. Prior treatments included surgery (at about three months after diagnosis) which revealed metastases to the inguinal lymph nodes- Chemotherapy for one year after surgery proved ineffective, as did Laetrϋe treatments commencing five months prior to interferon therapy. At commencement of interferon therapy, approximately forty tumors were visible on the leg. With Laetrϋe therapy continuing, the patfent was given a total oral dose of 110,000 units of bovine interferon of Example 2 on the following dosage regimen Week 1 - 6600 units Week 3 - 27,000 units Week 4 - 36,600 units Week 5 - 39,300 units Within four months after initiation of treatment, all but one of the tumors had disappeared and the single remaining tumor regressed completely by eight months after treatment began. As of 22 months after therapy commencement, there were no recurrences of tumors or indica- ' tions of side effects from interferon therapy. B. A second female patient had experienced a two-year history of malignant melanoma on the leg with prior treatments including two surgical procedures. Amputation of the lower leg was refused. Laetrile treatments were begun but had not prevented tumors from increasing in number and size. Interferon therapy was commenced according to the following oral dosage schedule. Vβek T ES No. Doses Total Amount 1 Example 1 ^ 21 (BID) 8400 units 3 3 E Exxaammppllee _^1 2 211 ((BBIIDD)) 5900 units 5 Example 2 15 (BID) 3000 units 7 Example 1 15 (BID) 3000 units a Example 1 , 15 (BID) 15,400 units * 13 Example 1_ 19 (BID) 11,900 units 1 166 E Exxaammppllee 22__ 9 9 ( CTTΣ∑DD)) ' 25,400 units 19 Example 17 " (BID) 40,000 units 22 Example 2_ 16 (BID) 320,000 units Approximately 113,000 units was orally administered up through the 22nd week and the total treatment dosage was 433,000 units. Within one week of commencement of treatment the tumors were noticeably drier and required fewer changes of dressings. Seepage and oozing from the leg has nearly ceased. Over the following weeks the large tumors lost volume and' flattened and some of the smaller tumors regressed in size. Leg pain greatly subsided. No new tumors have developed during therapy and the largest of tumors appeared to be undergoing vascular changes. The patient complains of a "burning" sensation in her leg which is completely relieved during interferon treatment but returns upon completion of interferon dosages. Example 5 This Example relates to oral administration of bovine inter¬ feron to a human patient terminally ill with metastatic breast cancer. A total of 8400 units of interferon of Example 1 was administered in 21 equal 5 doses BID. The patient suffering from metastases to the brain and bone, expired two weeks after treatment was commenced. ExamDle 6 This- example relates to the therapeutic effectiveness of 10 orally administerd heterologous species interferon in the treatment of feline leukemia. A kitten showing clinical signs of chronic oral ulcers, non-regenerative anemia, enlarged lymph nodes, lymphocytosis, and a positive feline leukemia virus test (Leukassay from Pitman-Moore) was treated with 1.7 X 10 units of bovine fibroblast interferon (per Example 1) 15 orally. The oral ulcers have healed, the anemia has resolved, the lymph nodes appear normal, and the amount of feline leukemia viral antigen in the blood had declined (as measured by performing the Leukassay on serial dilutions of blood). The lymphocytosis has, however, continued. Another cat displaying clinical signs of anorexia, depression, 20 vomiting, and weight loss for about 6 weeks was found to be feline leukemia virus positive (Leukassay). A littermate had died of feline g leukemia 2 months before._ After treatment with 1 X 10 units of bovine inter eron (per Example 1) orally, the cat was clinically normal except the weight gain has not yet replaced the weight loss. The amount of feline 25. leukemia viral antigen in the blood has not declined in 3 weeks. A third cat with a leukocytosis, and anemia, severe depres¬ sion, and positive for feline leukemia virus (Leukassay) was treated for five days with a total of 5 x 1Q 3 units of bovine interferon of Example 1. Prednisolone was also administered. Within ten days after treatment the 30 cat appeared clinically normal, the white blood cell count returned to normal and the hematocrit improved from 12 to 18. Example 7 Three hamsters, four guinea pigs, and eight mice have been 35 treated orally with varying amounts of bovine interferon of Example 1. No clinical illness occurred during treatment, no weight loss was noted, and no signs of toxicity attributable to interferon were seen histopatho- logically after one week's therapy. Total dosages have ranged up to 400,000 units of interferon per kg of body weight. While the foregoing illustrative examples describe use of bovine interferon, and while bovine interferon is preferred on grounds of its easy availability in relatively large quantity, it will, be recognized that mammals may be ef ectively treated with heterologous species interferon of procine, equine, laprine, feline and human sources. Cross species in vitro antiviral activity of varying degree- is described for the bovine, porcine, equine, laprine, feline and human species. [See Tovey et al., ^ Gen. Virol. 36, pp. 341-344 (1977); Carter, Life Sciences 25, pp. 717-728 (1979); Babiuk and House, foterrirology, 8, pp. 250-256 (1977); Desmyter and Stewart, Virology, 7 , pp. 451-458 (1976); Stewart, The Interferon Systems, Springer Verlag, N.Y., N.Y., pp. 135-445 (1979).] Those species of inter eron which show some cross species antiviral protection may share a common-»sequeπce of a ino acids which, when freed from association in the entire inter eron molecule, exhibit similar antitumor activity. While phosphate buf ered saline or Eagles' Minimal Essential Medium was used as a carrier for interferon in the above Examples, other pharmaceutically acceptable diluents adjuvants and carriers such as are commonly employed in oral and parenterai therapy may be employed. While above Examples relate to therapeutic usage in humans and cats, horses, cattle, and rabbits are treatable in a similar manner. Dosage required for therapeutic ef ect are expected to vary widely depending on the mammal patient and condition treated, with from about 10 to about 1,000 units per kg in unit dosage form is believed operative. According- to another aspect of the invention, a specific heterologous species interferon isolate may be efficaciously pretreated under digestive conditions and administered to the recipient animaTs circulatory system. Such practice involves "pre-digesting" the isolate in vitro in a suitable digestive environment comprising, e.g., a strongly acidic solution of pepsin and/or solutions or suspensions of the various enzymatic substances operative in digestive processes. If the digestive environment substantially duplicates that of a proposed recipient animal, the entire combination of reagents, reactants, and products may be administered to the alimentary canal of the recipient to ef ect delivery of the biologically active component of the isolate to the circulatory system. Alternatively, the resultant "digested" isolate containing the active fradon may be reclaimed, i.e., separated as smaller molecular weight components from the digestive environment (e.g. by dialysis, centrifuga- tion and chromatography), and administered orally or parenterally. In either event, the active component will be suitably rapidly incorporated into the recipient animal's circulatory system in a manner essentially eliminating the risks of adverse reaction which ordinarily accompany the administration of "foreign, **1 undergraded polypeptides. Upon consideration of the foregoing description and illustra¬ tive examples, numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art.

Claims: WHAT IS CLAL ED ISJ L. A method for delivery to a recipient mammal of a . biologically active fraction of interferon glycoprotein isolated from cells of heterologous mammalian species origin, said method comprising sub¬ jecting said interferon to treatment in a digestive environment to substantially free the non-species-speeific biologically active fraction therein from association with extranous polypeptide or carbohydrate materials ordinarily associated therewith and administering the biologic- ally active fraction of the interferon so treated to the circulatory system of the recipient animal. 2. The. method of claim 1 wherein said treatment and administration steps jointly comprise introduction of said iπter eron into the alimentary canal of the recipient mammal. 3. The method of claim 1 wherein said treatment step is carried out in vitro and the resultant treated interferon is reclaimed from said digestive environment prior to* said administration step. 4. The method of claim 3 wherein said administration step includes parenterai administration of said reclaimed, treated interferon. 5. The method of claim 1 wherein said interferon isolated from cells of heterologous species origin is isolated from ceils of human, feline, bovine, equine, laprine or procine species origin. 6. The method of claim 1 wherein the recipient mammal is of the human, feline, bovine, equine, laprine or porcine species. 7. The method of claim 1 wherein said interferon isolated from cells of heterologous species origin is isolated from cells of bovine species origin and the recipient animal is of the human or feline species. - 1S - 8. The method of claim 7 wherein said interferon is fibroblast interf eron. 9.. In the . method for enhancing the competence of a mammal^ response to viral and neoplastic disease states wherein exo¬ genous interferon glycoprotein is provided to the circulatory system of a mammal in need of such enhancement, the Improvement comprising: administering to the alimentary canal of the recipient mammal an ef ective amount of interferon isolated from cells of heter- ologous mammalian species origin, whereby said interferon is subjected to a digestive environment in the recipient mammal's digestive tract and the non-species-specific antiviral or antineoplastic fraction of said interferon is absorbed through digestive tract tissue and transported to the recipient mammal's circulatory system. 10. The improvement of claim 9 wherein the quantity of interferon administered to the alimentary canal comprises, in unit dosage form, from about 10 to about 1,000 units per kg of body weight in combination with a pharmaceutically acceptable diivent, adjuvant or carrier. ]_U The improvement of claim 9 wherein said iπterferon isolated from cells of heterologous species origin is isolated from cells of human, feline, bovine, equine, laprine or prociπe species origin. 12- The improvement of claim 9 wherein the recipient mammal is of the human, feline, bovine, equine, laprine or- procine species. 13. The improvement of claim 9 wherein said interferon isolated from cells of heterologous species origin is isolated from cells of bovine species origin and the recipient mammal is of the human species. 14. The improvement of claim 13 wherein said inter eron is fibroblast interferon. C ?I V _, IrO 15. The improvement of claim 13 wherein the response to be enhanced is a response to a benign papϋloma disease state. 16. The improvement of claim 13 wherein the response to be enhanced is a response to a malignant melanoma disease state. 17. The improvement of claim 9 wherein said interferon isolated from cells of heterologous species origin is isolated from cells of bovine species origin, the recipient animal is of the feline species and the response to be enhanced is a response to a feline leukemia disease state-

Inventors: CUMMINS J
Applicants: UNIV ILLINOIS
Application year: 1981
Main classification: A61K45
IPC codes: A61K38, C07K14, C12P21