WO1985000974A1 - Antibody compositions of therapeutic agents having an extended serum half-life - Google Patents

Antibody compositions of therapeutic agents having an extended serum half-life Download PDF

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Publication number
WO1985000974A1
WO1985000974A1 PCT/US1984/001389 US8401389W WO8500974A1 WO 1985000974 A1 WO1985000974 A1 WO 1985000974A1 US 8401389 W US8401389 W US 8401389W WO 8500974 A1 WO8500974 A1 WO 8500974A1
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WO
WIPO (PCT)
Prior art keywords
antibody
agent
composition according
fab
process according
Prior art date
Application number
PCT/US1984/001389
Other languages
French (fr)
Inventor
James M. Frincke
Barbara W. Unger
Karen G. Burnett
Evan Manuel Hersh
Michael Gordon Rosenblum
Jordan Udell Gutterman
Original Assignee
Hybritech Incorporated
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hybritech Incorporated filed Critical Hybritech Incorporated
Priority to JP59503388A priority Critical patent/JPH0717519B2/en
Publication of WO1985000974A1 publication Critical patent/WO1985000974A1/en
Priority to FI851635A priority patent/FI85441C/en
Priority to DK191985A priority patent/DK191985A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6875—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody being a hybrid immunoglobulin
    • A61K47/6879—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody being a hybrid immunoglobulin the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin

Definitions

  • This invention relates to therapeutically active agents and the treatment of disease therewith. In another aspect, it relates to antibody complexes of a thera- Chamberically active agent. In a more specific aspect, it relates to complexes of a monoclonal antibody and a therapeutically active agent and their use in the treat ⁇ ment of disease.
  • the serum or plasma half-life of a therapeutically active agent can be extended by forming a complex of the agent with a selected antibody, preferably a monoclonal antibody, which binds to the agent at a site which does not substantially impair its therapeutic activity and which extends the serum half-life of the agent.
  • a selected antibody preferably a monoclonal antibody
  • the term "antibody” means a monoclonal antibody or polyclonal antibodies unless otherwise specified or required by the context.
  • the complex of the therapeutically active agent and the antibody may be formed in vitro and then administered. Alternatively, the agent and antibody may be administered at the same time. In yet another alterna- tive, the antibody may be administered first, and after an interval during which its distribution in the patient approaches equilibrium, the therapeutically active agent can be administered.
  • O agent can be maintained _in vivo for a longer interval. While monoclonal antibodies are preferred for use in the invention, it is also within the scope of the invention to use polyclonal antibodies against the therapeutically active agent which complex with the therapeutically active agent without materially impairing its therapeutic activity.
  • Another object of the invention is to provide com ⁇ positions which increase the effective lifetime of a therapeutic agent ⁇ n vivo after administration to a patient.
  • the present invention in one embodiment, is a complex between a therapeutically active agent with a monoclonal antibody selected to bind the therapeutic agent at a site which does not materially impair its therapeutic activity but which forms a complex with the agent to confer upon the agent a serum half-life -longer than that of the therapeutic agent alone and approaching the serum half-life of the antibody.
  • the invention comprises a similar complex of therapeutic agent with polyclonal antibodies selected to bind the antibody without materially impairing its thera ⁇ Chamberic activity and which form a complex having an extended serum half-life.
  • the invention is a process involving the administration to a host of a complex comprising the therapeutic agent and either a monoclonal antibody or polyclonal antibodies having the properties noted above.
  • the process of the present invention also includes either simultaneous administration of the thera- peutics agent and a suitable antibody preparation or an initial administration of the antibody preparation fol ⁇ lowed by administration of the therapeutic agent after the antibody has had an opportunity to distribute itself throughout the host.
  • the therapeutic agents useful in the invention are those which are or can be made immunogenic, i.e., those for which an immune response can be obtained either directly or, in the case of a hapten, by binding the agent to a molecule which is immunogenic.
  • Monoclonal antibodies against the therapeutic agent can be obtained by methods which are now well known to the art and which need not be described in detail. These methods generally involve immmunization of a mouse or other animal species, usually mammalian or avian, with the immunogen. Human lymphoid cells may also be obtained after, immunization (natural or induced) or may be sensitized JLn vitro. After an immune response is generated, spleen cells of the immunized mouse or other immune lymphoid cells are fused with cells of an established lymphoid tumor line using known techniques to form hybridomas which produce monoclonal antibodies. Clones of hybridomas are screened to select those which are producing monoclonal antibodies that are specific for the antigen of choice, in this case the therapeutic agent.
  • Monoclonal antibodies having the desired specif- icity are further screened to select those that form an antibody:agent complex in which the agent retains all, or substantially all, of its therapeutic activity. These complexes are further screened to select those which have an extended serum half-life. In certain cir ⁇ um- stances, it can be beneficial to use a mixture of two or more monoclonal antibodies. In some circumstances it may also be desirable to use a stoichiometric excess of antibody.
  • Polyclonal antibodies useful in the invention are obtained by well known techniques as well. These include stimulating an immune response against the therapeutic agent, or fragment thereof, in a suitable animal host such
  • OM as a rabbit or other mammal.
  • Chickens and other avian species can also be used.
  • Serum taken from the host is subjected to affinity purification to isolate poly ⁇ clonal antibodies against the therapeutic agent. These antibodies are subsequently fractionated, if necessary, to isolate a subpopulation which complexes with the thera ⁇ Chamberic agent without materially impairing its desirable activity.
  • human antibodies against the therapeutic agent produced by hybridomas which, for example, are the product of fusion of a human B-lympho ⁇ yte with an established mammalian lymphoid line, e.g., a human or mouse myeloma line.
  • a human B-lympho ⁇ yte with an established mammalian lymphoid line, e.g., a human or mouse myeloma line.
  • the term antibody includes fragments thereof such as Fab, Fab', and Fab'2 or mixtures thereof and including mixtures with whole antibody.
  • Such frac ⁇ tions may be less immunogenic in some patients and may also better allow better penetration of the agent to the target site.
  • the monoclonal antibody is preferably a hybrid antibody having a dual specificity, one against the therapeutically active agent and the other against another antigen, for example, an antigen asso ⁇ ciated with the disease which it is desired to treat with the agent.
  • tumor associated antigens such as carcinoembryonic antigen (CEA), prostatic acid phosphatase (PAP), ferritin and prostate specific antigen (PSA).
  • CEA carcinoembryonic antigen
  • PAP prostatic acid phosphatase
  • PSA prostate specific antigen
  • the other specificity could be selected to bind with an agent which has anti-tumor activity.
  • the second specificity could be against a toxin such as ricin or an interferon. Processes for obtaining such hybrids are disclosed in the pending patent application of J.
  • drugs such as adriamycin, vincristine, genomycin mitomycin C, and prostacyline; toxins such as abrin and ricin; and biological proteins such as the interferons (alpha, beta and gamma), the interleukins, hormones such as insulin, plasminogen activators such as urokinase, streptokinase and tissue plasminogen activator, growth factors such as nerve growth factors, and platelet activating factor.
  • drugs such as adriamycin, vincristine, genomycin mitomycin C, and prostacyline
  • toxins such as abrin and ricin
  • biological proteins such as the interferons (alpha, beta and gamma), the interleukins
  • hormones such as insulin
  • plasminogen activators such as urokinase, streptokinase and tissue plasminogen activator
  • growth factors such as nerve growth factors, and platelet activating factor.
  • interferon is used to include those agents having the characteristics attributed to inter ⁇ ferons as described in Interferon: An Overview, Ion Gresser, Ed., 4 (1982), p. 4, which is incorporated herein DNA technology which is identical to a naturally occurring interferon or which differs therefrom by one or more of the following: 1. a difference in amino acid sequence; 2. a difference in chain folding;
  • alpha-interferon a multi-species interferon
  • alpha-interferon a multi-species interferon
  • the maximum dose is limited because of high-dose toxic side effects.
  • the high doses used are very expensive and may elicit an immune response in a substantial number of patients treated.
  • Balb/c mice were immunized with partially purified leukocyte interferon. Spleen cells from immunized mice were fused with a myeloma line (either the NS-1 or SP2/0 lines) to produce hybridomas. The hybridomas were screened to select those reactive with interferon in a radioimmunoassay wherein the immune complexes were removed by horse anti-mouse IgG bound to sepharose beads. Interferon used in immunization and screening were from the same source. Antibodies were selected for positive reactivity with interferon. Hybri ⁇ domas producing the selected antibodies were cloned by limiting dilution to ensure homogeneity of the cell population.
  • a Fisher rat 250-260 g was lightly anesthetized with sodium thiopental. A plastic canula was then sur ⁇ gically inserted into the femoral artery of the other leg. A bolus dose of alpha-interferon (Clone A of Goeddel et al.. Nature, 290, 20-26 (1981), 7600 units total in 0.5 ml phosphate buffered saline) was administered over 2 seconds into the venous catheter. Blood samples (0.5 ml) were withdrawn at various times from the arterial catheter. After each blood withdrawal, 0.5 ml of PBS were injected via the venous catheter.
  • the volume of distribution is 20.8 ml.
  • a beta component to the plasma disappearance curve is identified with a 30 minute half-life.
  • the area under the curve was 7047 u/ml x min.
  • the half-life of this activity loss is 84 minutes. Twelve times longer than that observed for alpha-interferon itself, with a volume of distribution of 19.2 ml, essentially equivalent to that observed for alpha-interferon without added antibody.
  • the area under the curve was 50,000 u/ml x min, seven (7) times that for the free interferon.

Abstract

A complex of alpha-interferon with a monoclonal antibody complexes with the alpha-interferon without impairing its antiviral activity. The serum half-life of the interferon administered as the complex is substantially increased when compared to that of alpha-interferon administered alone.

Description

DESCRIPTION
ANTIBODY COMPOSITIONS OP THERAPEUTIC AGENTS HAVING AN EXTENDED SERUM HALF-LIFE
Field of the Invention
This invention relates to therapeutically active agents and the treatment of disease therewith. In another aspect, it relates to antibody complexes of a thera- peutically active agent. In a more specific aspect, it relates to complexes of a monoclonal antibody and a therapeutically active agent and their use in the treat¬ ment of disease.
Background It is almost a trite observation to note that the use of a broad spectrum of drugs to treat human and other mammalian disease is routine medical and veterinary practice. Therapeutically active agents, however, often suffer from a number of shortcomings which limit and complicate their use. A particular problem is that, after administration to the patient, a drug may be so rapidly cleared from the body by metabolic or other pathways or otherwise biologically inactivated so that only a relatively small percentage of the drug ad inis- tered actually has a therapeutic effect. To compensate for this problem, it is common practice to increase the dosag.e of the drug and/or to prolong its period of admin¬ istration and/or to shorten the interval between doses so that the therapeutically effective concentration of the drug in the patient is maintained for a period sufficient to achieve the desired result.
These procedures are useful but have their own limitations. Increasing the dosage may be limited, for example, in the case of intramuscular administration, by the bolus which can be tolerated. Many drugs have toxic side effects which may limit the dosage duration or interval which can be safely used. In some cases, promising drugs cannot be used because side reactions are so severe that an effective therapeutic dose cannot be safely administered. The need to administer multiple small doses of a drug or to use continuous infusion techniques increases the cost of treatment and the burden on hospital personnel, and, of course, adds to the patientrs discomfort. Accordingly, there exists a need for means by which the therapeutically active concentration of a drug, after administration, is maintained for a longer time.
Summary of the Invention
It is the normal and expected function of antibodies to complex with foreign substances to more rapidly clear them from the body. We, however, have unexpectedly found that the serum or plasma half-life of a therapeutically active agent can be extended by forming a complex of the agent with a selected antibody, preferably a monoclonal antibody, which binds to the agent at a site which does not substantially impair its therapeutic activity and which extends the serum half-life of the agent. Thus, as used herein, the term "antibody" means a monoclonal antibody or polyclonal antibodies unless otherwise specified or required by the context. According to our invention, the complex of the therapeutically active agent and the antibody may be formed in vitro and then administered. Alternatively, the agent and antibody may be administered at the same time. In yet another alterna- tive, the antibody may be administered first, and after an interval during which its distribution in the patient approaches equilibrium, the therapeutically active agent can be administered.
By selecting the proper antibody for forming the antibody: drug complex, the serum half-life and, thus, the effective concentration of the therapeutically active
O agent, can be maintained _in vivo for a longer interval. While monoclonal antibodies are preferred for use in the invention, it is also within the scope of the invention to use polyclonal antibodies against the therapeutically active agent which complex with the therapeutically active agent without materially impairing its therapeutic activity.
Accordingly, it is an object of the present invention to provide means by which the serum half-life of a thera- peutically active agent is extended.
Another object of the invention is to provide com¬ positions which increase the effective lifetime of a therapeutic agent ^n vivo after administration to a patient.
Detailed Description of the Invention
As indicated above, the present invention, in one embodiment, is a complex between a therapeutically active agent with a monoclonal antibody selected to bind the therapeutic agent at a site which does not materially impair its therapeutic activity but which forms a complex with the agent to confer upon the agent a serum half-life -longer than that of the therapeutic agent alone and approaching the serum half-life of the antibody. Alterna¬ tively, the invention comprises a similar complex of therapeutic agent with polyclonal antibodies selected to bind the antibody without materially impairing its thera¬ peutic activity and which form a complex having an extended serum half-life.
In another embodiment, the invention is a process involving the administration to a host of a complex comprising the therapeutic agent and either a monoclonal antibody or polyclonal antibodies having the properties noted above. The process of the present invention also includes either simultaneous administration of the thera- peutics agent and a suitable antibody preparation or an initial administration of the antibody preparation fol¬ lowed by administration of the therapeutic agent after the antibody has had an opportunity to distribute itself throughout the host. The therapeutic agents useful in the invention are those which are or can be made immunogenic, i.e., those for which an immune response can be obtained either directly or, in the case of a hapten, by binding the agent to a molecule which is immunogenic. Monoclonal antibodies against the therapeutic agent can be obtained by methods which are now well known to the art and which need not be described in detail. These methods generally involve immmunization of a mouse or other animal species, usually mammalian or avian, with the immunogen. Human lymphoid cells may also be obtained after, immunization (natural or induced) or may be sensitized JLn vitro. After an immune response is generated, spleen cells of the immunized mouse or other immune lymphoid cells are fused with cells of an established lymphoid tumor line using known techniques to form hybridomas which produce monoclonal antibodies. Clones of hybridomas are screened to select those which are producing monoclonal antibodies that are specific for the antigen of choice, in this case the therapeutic agent. Monoclonal antibodies having the desired specif- icity are further screened to select those that form an antibody:agent complex in which the agent retains all, or substantially all, of its therapeutic activity. These complexes are further screened to select those which have an extended serum half-life. In certain cirσum- stances, it can be beneficial to use a mixture of two or more monoclonal antibodies. In some circumstances it may also be desirable to use a stoichiometric excess of antibody.
Polyclonal antibodies useful in the invention are obtained by well known techniques as well. These include stimulating an immune response against the therapeutic agent, or fragment thereof, in a suitable animal host such
OM as a rabbit or other mammal. Chickens and other avian species can also be used. Serum taken from the host is subjected to affinity purification to isolate poly¬ clonal antibodies against the therapeutic agent. These antibodies are subsequently fractionated, if necessary, to isolate a subpopulation which complexes with the thera¬ peutic agent without materially impairing its desirable activity.
Particularly preferred for use in the invention are human antibodies against the therapeutic agent produced by hybridomas which, for example, are the product of fusion of a human B-lymphoσyte with an established mammalian lymphoid line, e.g., a human or mouse myeloma line. As used herein, the term antibody includes fragments thereof such as Fab, Fab', and Fab'2 or mixtures thereof and including mixtures with whole antibody. Such frac¬ tions may be less immunogenic in some patients and may also better allow better penetration of the agent to the target site. In certain applications, the monoclonal antibody is preferably a hybrid antibody having a dual specificity, one against the therapeutically active agent and the other against another antigen, for example, an antigen asso¬ ciated with the disease which it is desired to treat with the agent. Among these may be mentioned tumor associated antigens such as carcinoembryonic antigen (CEA), prostatic acid phosphatase (PAP), ferritin and prostate specific antigen (PSA). In such cases, the other specificity could be selected to bind with an agent which has anti-tumor activity. For example, the second specificity could be against a toxin such as ricin or an interferon. Processes for obtaining such hybrids are disclosed in the pending patent application of J. Martinis et al.. Serial No. 367,784, filed April 12, 1983, assigned to Hybritech Inc., an assignee of this application, the disclosure of which is incorporated by reference. A ong the therapeutic agents which are useful in the invention may be mentioned drugs such as adriamycin, vincristine, genomycin mitomycin C, and prostacyline; toxins such as abrin and ricin; and biological proteins such as the interferons (alpha, beta and gamma), the interleukins, hormones such as insulin, plasminogen activators such as urokinase, streptokinase and tissue plasminogen activator, growth factors such as nerve growth factors, and platelet activating factor. Particularly useful are complexes of a monoclonal antibody and one of the interferons, for example, alpha-interferon. As used herein, the term "interferon" is used to include those agents having the characteristics attributed to inter¬ ferons as described in Interferon: An Overview, Ion Gresser, Ed., 4 (1982), p. 4, which is incorporated herein DNA technology which is identical to a naturally occurring interferon or which differs therefrom by one or more of the following: 1. a difference in amino acid sequence; 2. a difference in chain folding;
3. a difference in carbohydrate substitution.
The utility of the present invention is shown by the experiments described below with alpha-interferon. In that regard, alpha-interferon, a multi-species interferon, has been shown to have a therapeutic effect in the treat¬ ment of certain malignant tumors including breast cancer, multiple myeloma and malignant lymphoma. However, it has been shown to rapidly clear from the plasma of man and animals during clinical trials. This has been compensated for by giving a high dose intra-muscularly. However, the maximum dose is limited because of high-dose toxic side effects. Also, the high doses used are very expensive and may elicit an immune response in a substantial number of patients treated.
OMP Experimental Details
1. Preparation of anti- -interferon monoclonal antibodies:
Balb/c mice were immunized with partially purified leukocyte interferon. Spleen cells from immunized mice were fused with a myeloma line (either the NS-1 or SP2/0 lines) to produce hybridomas. The hybridomas were screened to select those reactive with
Figure imgf000009_0001
interferon in a radioimmunoassay wherein the immune complexes were removed by horse anti-mouse IgG bound to sepharose beads. Interferon used in immunization and screening were from the same source. Antibodies were selected for positive reactivity with interferon. Hybri¬ domas producing the selected antibodies were cloned by limiting dilution to ensure homogeneity of the cell population.
2. Testing for Reactivity of an Antibody:Interferon Immune Complex in the Anti-Viral Protection Assay Approximately 40 anti-alpha interferon monoclonal antibodies were employed to make interferon:antibody immune complexes which were tested for retention of anti-viral activity using the standard method described, for example, in Rubinstein, et al. , J. Virology, 37, 755 (1981). The first step in this procedure was forma- tion of the immune complex by the addition of ascitic fluid to the anti-viral protection assay mixture which was monitored for inhibition of interferon activity. Ten of the forty antibodies were selected for further investiga¬ tion because they did not inhibit the viral protection properties of the interferon in this assay. These anti¬ bodies were then further concentrated with sodium sulfate and re-tested. In each case, non-inhibition of anti-viral activity as verified. To demonstrate whether complexes of interferon with these antibodies were actually formed, the reaction mixtures were adsorbed with solid phase sepharose bound sheep anti-mouse IgG to remove the antibody and complexed interferon. The supernatant from the sepharose adsorptions were then tested in the standard antiviral protection assay. In the case of one particular antibody, designated IFG 252.2 by us, the antiviral protection was almost completely removed from the supernatant during the adsorption. Controls were performed to ensure this phenomena was not due to non-specific absorption during the sepharose adsorption step. These data demonstrate that this antibody binds efficiently and avidly to inter¬ feron without inhibiting its antiviral activity. Another known biological property of alpha interferon is its inhibition of cellular proliferation. In an assay system using DAUDI cells, retention of anti-proliferative activity was demonstrated for alpha interferon in the presence of the IFG 252.2 antibody. These data demon- strate that IFG 252.2 also binds alpha-interferon without affecting its anti-proliferative activity. 3. Administration of Alpha-interferon:IFG 252.2
Complex to Laboratory Rats
A Fisher rat (250-260 g) was lightly anesthetized with sodium thiopental. A plastic canula was then sur¬ gically inserted into the femoral artery of the other leg. A bolus dose of alpha-interferon (Clone A of Goeddel et al.. Nature, 290, 20-26 (1981), 7600 units total in 0.5 ml phosphate buffered saline) was administered over 2 seconds into the venous catheter. Blood samples (0.5 ml) were withdrawn at various times from the arterial catheter. After each blood withdrawal, 0.5 ml of PBS were injected via the venous catheter. The samples were centrifuged, the plasma decanted and analyzed for inter- feron anti-viral activity by standard methods. In a second rat, the same amount of interferon was prein- cubated with IFG 252.2 (38 microgram/microliter = 190 micrograms antibody) and then administered through the venous catheter. Blood samples were taken and analyzed in the same way as for the first. The results of these experiements were then plotted and subjected to nonlinear regression analysis. These results indicate that the activity of alpha- interferon in the rat without added anti-interferon has a two phase disappearance curve. The alpha-phase has a 6.8 minute half-life with a two log reduction of interferon activity in the plasma at 30 minutes. The volume of distribution is 20.8 ml. At 30 minutes a beta component to the plasma disappearance curve is identified with a 30 minute half-life. At two hours essentially all of the interferon activity has been lost from the plasma. The area under the curve was 7047 u/ml x min. In contrast, when the IFG 252.2 antibody is utilized to extend the half-life, a single phase disappearance of activity from plasma is observed. The half-life of this activity loss is 84 minutes. Twelve times longer than that observed for alpha-interferon itself, with a volume of distribution of 19.2 ml, essentially equivalent to that observed for alpha-interferon without added antibody. The area under the curve was 50,000 u/ml x min, seven (7) times that for the free interferon. The foregoing experiments demonstrate that, by proper selection of an antibody, the serum half-life of a therapeutically active agent can be usefully extended without signficant impairment of therapeutic activity. Those skilled in the art will recognize that the invention, therefore, has application in veterinary medicine and for human health care. In that connection, it is within the scope of the invention to combine the therapeutic agent and/or the antibody or the antibody complex with the agent with other components such as a suitable vehicle. The foregoing description of the invention is exemplary only and modifications thereof may be made without departure from the scope of the invention which is to be limited only by the appended claims.

Claims

Claims:
1. A composition comprising a complex of a thera¬ peutically active agent and an antibody selected to bind said agent at a site which does not substantially impair its therapeutic activity and which extends the serum half-life of the therapeutically active agent.
2. A composition according to Claim 1 wherein the antibody is a monoclonal antibody.
3. A composition according to Claim 1 wherein the antibody comprises a population of polyclonal antibodies.
4. A composition according to Claims 2 and 3 wherein the antibody comprises an antibody fragment selected from the group consisting of Fab, Fab' and Fab'2.
5. A composition according to Claim 1 wherein the antibody is a hybrid monoclonal antibody having a dual specificity one of which is against the therapeuticcally active agent and the other against a disease associated antigen.
6. A composition according to Claims 1, 2, 3 or 5 wherein the therapeutically active agent is selected from drugs, toxins and biological proteins.
7. A composition according to Claim 5 wherein the hybrid antibody is an antibody fragment selected from Fab, Fab' and Fab'2.
8. A composition according to Claims 1, 2, 3, 5 or 7 wherein the therapeutically active agent is an inter¬ feron.
OMPI L. IPO £RNAΎ
9. A composition according to Claim 8 wherein the interferon is selected from alpha, beta and gamma inter¬ ferons.
10. A composition according to Claims 5 or 7 wherein one specificty of the hybrid antibody is directed against a tumor associated antigen and the other against an agent having anti-tumor activity.
11. A composition according to Claim 10 wherein the tumor associated antigen is selected from CEA, PAP, PSA or ferritin.
12. A composition according to Claim 10 wherein the second specificity is directed against an interferon.
13. A composition according to Claim 1, 2, 3 or 5 further comprising a pharmaceutical vehicle.
14. A process for treatment of disease comprising administering to a patient a therapeutically active agent and an antibody against said agent which binds the agent at a site which does not substantially impair its thera¬ peutic activity and which extends the serum half-life of the agent.
15. A process according to Claim 14 wherein the anti¬ body and agent are combined in vitro.
16. A process according to Claim 14 wherein the anti¬ body and agent are separately administered.
17. A process according to Claim 16 wherein the anti¬ body is allowed to distribute itself throughout the patient prior to administration of the agent.
18. A process according to Claims 14, 15, 16 or 17 wherein the antibody is a monoclonal antibody.
19. A process according to Claim 18 wherein the mono¬ clonal antibody is a hybrid antibody having a dual specificty one of which is directed against the thera¬ peutically active agent and the other against a disease associated antigen.
20. A process according to Claim 18 wherein the anti¬ body is a fragment selected from Fab, Fab* and Fab'2.
21. A process according to Claim 18 wherein the agent is an interferon.
22. A process according to Claim 21 wherein the inter¬ feron is selected from alpha, beta and gamma interferons.
23. A process according to Claim 19 wherein the antigen is a tumor associated antigen and the agent has anti-tumor activity.
24. A process according to Claim 23 wherein the agent is an interferon.
25. A process according to Claim 24 wherein the inter- feron is selected from alpha, beta and gamma interferons.
OMPI
PCT/US1984/001389 1983-09-01 1984-08-31 Antibody compositions of therapeutic agents having an extended serum half-life WO1985000974A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP59503388A JPH0717519B2 (en) 1983-09-01 1984-08-31 α-interferon therapeutic preparation complexed with antibody against α-interferon
FI851635A FI85441C (en) 1983-09-01 1985-04-25 FOERFARANDE FOER FRAMSTAELLNING AV EN TERAPEUTISKT ANVAENDBAR INTERFERON: ANTI-INTERFERON ANTIKROPP-KOMPLEX.
DK191985A DK191985A (en) 1983-09-01 1985-04-29 THERAPEUTIC ANTIBODY PREPARATIONS WITH EXTENDED SERUM Half-life

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB08323428A GB2148299B (en) 1983-09-01 1983-09-01 Antibody compositions of therapeutic agents having an extended serum half-life
GB8323428 1983-09-01

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DK191985D0 (en) 1985-04-29
GB2148299B (en) 1988-01-06
JPS60502104A (en) 1985-12-05
FI851635L (en) 1985-04-25
JPH0717519B2 (en) 1995-03-01
CA1249222A (en) 1989-01-24
EP0136835B1 (en) 1992-04-15
DE3485649D1 (en) 1992-05-21
AU3393584A (en) 1985-03-29
GB2148299A (en) 1985-05-30
FI851635A0 (en) 1985-04-25
US5055289A (en) 1991-10-08
EP0136835A3 (en) 1986-10-08
AU593208B2 (en) 1990-02-08
ATE74766T1 (en) 1992-05-15
FI85441B (en) 1992-01-15
EP0136835A2 (en) 1985-04-10
FI85441C (en) 1992-04-27
DK191985A (en) 1985-04-29
GB8323428D0 (en) 1983-10-05

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