WO2000016808A2 - Antibody directed enzyme prodrug therapy (edept) with glucoronidase - Google Patents
Antibody directed enzyme prodrug therapy (edept) with glucoronidase Download PDFInfo
- Publication number
- WO2000016808A2 WO2000016808A2 PCT/US1999/021308 US9921308W WO0016808A2 WO 2000016808 A2 WO2000016808 A2 WO 2000016808A2 US 9921308 W US9921308 W US 9921308W WO 0016808 A2 WO0016808 A2 WO 0016808A2
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- WO
- WIPO (PCT)
- Prior art keywords
- enzyme
- drug
- target site
- prodrug
- detoxified
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
- A61K47/6899—Antibody-Directed Enzyme Prodrug Therapy [ADEPT]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to an improved method for increasing the target- specific toxicity of a chemotherapy drug by pretargeting an enzyme to a mammalian target site and administering a cytotoxic drug known to act at the target site, or a prodrug thereof, which drug is also detoxified to form an intermediate of lower toxicity using the mammal's ordinary metabolic processes, whereby the detoxified intermediate is reconverted to its more toxic form by the pretargeted enzyme and thus has enhanced cytotoxicity at the target site.
- a prodrug is used, a further improvement is achieved by targeting a second enzyme to the target site that converts the prodrug to the active drug.
- Use of versatile bispecific antibodies that can bind more than one kind of enzyme to the target site facilitates efficient enzyme loading and further amplification of the target-specific activity.
- MAbs monoclonal antibodies
- a binary system for targeting prodrugs using a bispecific monoclonal antibody was described by Hansen U.S.S.N. 08/445,110 (hereinafter, "Hansen ⁇ 110"), the disclosure of which is incorporated herein in its entirety by reference.
- bsMAb with an anti-target arm and an anti-enzyme arm is given, followed later by an enzyme, e.g., glucuronidase, which is thus targeted to the disease site.
- an enzyme e.g., glucuronidase
- a prodrug e.g., a glucuronide prodrug, is administered and the free drug released by the tumor- targeted enzyme.
- this method has the further advantage of not requiring the coupling of relatively large MAb and enzyme structures, both of whose activities and pharmacokinetic properties can be affected adversely by such conjugations.
- bsMAb/prodrug invention As outlined above is the need for a specific antibody directed toward a specific enzyme. Thus, its adoption with different combinations of prodrugs and enzymes would require the preparation of new bsMAbs for each combination.
- One object of the present invention is to enable prodrug systems for enhancing chemotherapy of disease, either by using prodrugs as described previously, or by using commercially available drugs, with the knowledge that their detoxification pathways can be harnessed to improve their therapeutic profiles.
- Another object of the present invention is to provide agents useful for treatment of cancer by harnessing a drug's detoxification pathway for improved therapeutic profiles.
- a further object of the present invention is to provide multispecific antibodies that can target a variety of enzymes to a target site for significant target-specific amplification of a drug.
- the foregoing method is further enhanced by also localizing at the target site an enzyme that converts the prodrug to the active drug.
- the invention also provides kits for use in practicing the foregoing method.
- the prior art discloses the attachment of therapeutic or diagnostic agents directly to an antibody, or to a carrier attached to an antibody.
- Some of the problems associated with conjugating an agent to the antibody include cross-linking, loss of immunoreactivity, immunogenicity, insufficient loading of the agent on the antibody and inadequate deposition of the agent at the target site.
- the present invention overcomes these problems by pretargeting an enzyme to a target site and then administering a cytotoxic drug, or a prodrug form converted to its cytotoxic form, which is detoxified by ordinary metabolic processes and then reconverted to the toxic form by the pretargeted enzyme, resulting in a more concentrated cytotoxicity at the target site.
- the enzyme pretargeting can be accomplished by at least three different methods, each of which is described in detail in Hansen '110.
- the first method is to directly bind an enzyme to an antibody that selectively binds to at least one antigen present at the target site. The enzyme is thereby localized at the target site.
- the second method of pretargeting an enzyme to a target site is through a bispecific antibody or antibody fragment (bsMAb), with at least one binding site specific to an antigen at a target site and at least one other binding site specific to an enzyme.
- the enzyme can be injected in an amount and by a route which enables a sufficient amount of the enzyme to reach the localized antibody and bind to it to form the antibody-enzyme complex in situ.
- a mammal can be given a bsMAb, one arm of which specifically binds to a target site antigen, e.g., a tumor-associated antigen (TAA) and a second arm of which specifically binds to a low MW hapten, e.g., diethylenetriaminepentaacetic acid (DTPA) or one of its metal complexes.
- a target site antigen e.g., a tumor-associated antigen (TAA)
- TAA tumor-associated antigen
- DTPA diethylenetriaminepentaacetic acid
- the low MW hapten is in turn chemically bound to the enzyme to be used in the invention.
- the bsMAb can be an IgG with different functionalities (prepared from quadroma) an IgG-IgG cross- linked bsMAb ' , or Fab'-Fab', Fab'-F(ab') 2 , F(ab') 2 -Fab', F(ab') 2 -F(ab') 2 , IgG-Fab', IgG- F(ab') 2 bsMAbs or bispecific scFvs. All of these agents can be murine, chimeric, humanized or human in origin. Humanized or human antibodies are preferred.
- the bsMAb is administered and allowed to accrete to its maximum at the target.
- an enzyme conjugated to the low MW hapten recognized by the second arm of the bsMAb is then administered, whereby the enzyme-hapten conjugate is localized at the target site. Since the recognition is dependent only on the low MW hapten, any enzyme can be used within the scope of the invention. Indeed, a major strength of the approach is that it can be adopted for use with any enzyme-drug pair. Thus, using the bsMAb against DTPA as an example, facile substitution of DTPA onto any enzyme will allow use of an anti-tumor x anti-DTPA bsMAb with any enzyme-drug combination.
- MAbs have been raised to numerous low MW haptens including DTPA, biotin, p-nitrophenyl-, and fluorescein isothiocyanate groups. Such MAbs can be of various isotypes and isoforms and can be tested and used within the invention when the corresponding hapten is enzyme-linked.
- a further significant advantage of this method is that the substitution ratio of the recognition hapten attached to the enzyme can be varied at will. Manipulation of this ratio allows for design of agents with optimum recognition, enzyme activity and pharmacokinetic properties. Another advantage is that the substitution position of the recognition hapten on the enzyme can also be altered at will. Substitution sites such as protein lysyl amino groups, cysteinyl thiol groups and aspartyl/glutamyl carboxylate residues can be used by application of well-known linkage chemistries. Should the enzyme in question possess carbohydrate residues, it too can be used as a chemical attachment site in various well-known ways. The method and degree of hapten substitution onto an enzyme can therefore be chosen to minimize impact on enzymatic activity, an advantage not always possible when directly conjugating enzymes to MAbs or relying of MAb recognition of undefined enzyme epitopes.
- a primary targeting agent clearing composition can be given.
- This can be, for instance, a secondary antibody reactive with some part of the targeting molecule, i.e., the antibody-enzyme conjugate or the bsMAb, to remove it from circulation.
- the secondary MAb can be intact or a fragment, mono- or multi-valent and may be further substituted with agents to enhance circulatory clearance such as galactosyl residues.
- multiple galactose substitution directs serum- formed complexes of Mab- enzyme conjugate or bsMAb and secondary MAb to receptors on liver hepatocytes.
- the clearing agent can also be a high MW protein-bearing haptens recognized by one of the arms of the bsMAb.
- a conjugate of comprising human serum albumin and DTPA, optionally further substituted with galactose residues can be used as a bsMAb clearing agent.
- a hapten e.g. biotin
- a clearing agent is administered to remove non-targeted enzyme/hapten or enzyme/Mab conjugates from circulation prior to administration of said drug or prodrug.
- the clearing agent can be an antibody that binds the hapten.
- the clearing agent can be an anti-idiotypic antibody or anti-idiotypic antibody fragment which is directed to the paratope of the Mab. Clearance of enzyme/hapten or enzyme/Mab conjugates is more effective than clearance of bsMAb, since it limits residual enzyme activity in serum. High residual serum enzyme levels are a limiting factor in the success of targeted immunotherapy.
- a cytotoxic drug is injected, which is known to act at the target site, or a prodrug form thereof which is converted to the drug in situ.
- the drug is one which is detoxified to form an intermediate of lower toxicity, most commonly a glucuronide, using the mammal's ordinary detoxification processes.
- the detoxified intermediate e.g., the glucuronide, is reconverted to its more toxic form by the pretargeted enzyme and thus has enhanced cytotoxicity at the target site, in effect recycling the drug.
- a second enzyme that accelerates conversion of a prodrug into its cytotoxic drug product is also localized at the target site.
- This can be effected by any of the foregoing three mechanisms for enzyme localization. It is especially convenient to use a bsMAb whose second arm binds a hapten, and to conjugate the same hapten to each of the two different enzymes. After localization of the bsMAb at the target site, and optional clearance of non-targeted bsMAb, both enzyme conjugates are administered, in appropriate proportions and order, thereby loading the target with both enzymes. When the prodrug reaches the target site, it will be transformed by the enzyme into a product comprising the therapeutic agent.
- the enzyme can transform many molecules of prodrug to liberate many molecules of drug, which will accrete at the target site.
- the enzyme maximizes site- specific generation of the drug from its prodrug form and thereby minimizes systemic side effects.
- Further amplification of the site-specific activity of the drug is achieved by the second enzyme which converts a naturally detoxified form the drug, e.g., a glucuronide, which is circulating in the bloodstream and which will eventually be excreted, and reconverts it at the target site to its cytotoxic form.
- antibody herein will be understood to include antibody fragments and thus to be equivalent to the term “antibody/fragment” which is used interchangeably therefor in this discussion.
- Antibodies can be whole immunoglobulin of any class, e.g., IgG, IgM, IgA, IgD, IgE, or hybrid antibodies with dual or multiple antigen or epitope specificities, or fragments, e.g., F(ab')2, F(ab)2, Fab 1 , Fab and the like, including hybrid fragments.
- Antibodies include antiserum preparations, preferably affinity- purified, having a high immunoreactivity, e.g., a binding constant of at least about 107 1/mole, preferably at least about 109 1/mole, a high immunospecificity, e.g., at least about 40%, preferably at least about 60%, more preferably about 70-95%, and a low cross-reactivity with other tissue antigens, e.g., not more than about 30%, preferably not more than about 15% and more preferably not more than about 5%.
- a high immunoreactivity e.g., a binding constant of at least about 107 1/mole, preferably at least about 109 1/mole
- a high immunospecificity e.g., at least about 40%, preferably at least about 60%, more preferably about 70-95%
- a low cross-reactivity with other tissue antigens e.g., not more than about 30%, preferably not more than about 15% and more preferably not more than about 5%
- the antiserum can be affinity purified by conventional procedures, e.g., by binding antigen to a chromatographic column packing, e.g., Sephadex, passing the antiserum through the column, thereby retaining specific antibodies and separating out other immunoglobulins and contaminants, and then recovering purified antibodies by elution with a chaotropic agent, optionally followed by further purification.
- a chromatographic column packing e.g., Sephadex
- Monoclonal antibodies are also suitable for use in the present method, and are preferred because of their high specificities. They are readily prepared by what are now considered conventional procedures of immunization of mammals with an immunogenic antigen preparation, fusion of immune lymph or spleen cells with an immortal myeloma cell line, and isolation of specific hybridoma clones. More unconventional methods of preparing monoclonal antibodies are not excluded, such as interspecies fusions and genetic engineering manipulations of hypervariable regions, since it is primarily the antigen specificity of the antibodies that affects their utility in the present method.
- Antibody fragments can be made by pepsin or papain digestion of whole immunoglobulins by conventional methods such as those disclosed, inter alia, in U.S. Patent 4,331,647.
- the target sites can be, but are not limited to, cancers, infectious and parasitic lesions, fibrin clots, myocardial infarctions, atherosclerotic plaque, damaged normal cells, non-cancerous cells and lymphocyte autoreactive clones.
- Anti-fibrin antibodies are well known in the art. Antibodies that target myocardial infarctions are disclosed in, e.g., Haber, U.S. Patent 4,036,945, the disclosure of which is incorporated in its entirety herein by reference. Antibodies that target normal tissues or organs are disclosed in, e.g., U.S. Patent No. 4,735,210, the disclosure of which is incorporated in its entirety herein by reference. Anti-fibrin antibodies are well known in the art, as are antibodies that bind to atherosclerotic plaque and to lymphocyte autoreactive clones.
- antibodies can usually be raised to any antigen, using the many conventional techniques now well known in the art.
- Any targeting antibody to an antigen which is found in sufficient concentration at a site in the body of a mammal which is of therapeutic interest can be used to make the targeting antibody molecule for use in the method of the invention.
- Multispecific antibodies include but are not limited to bispecific antibodies.
- Bispecific antibodies can be made by a variety of conventional methods, e.g., disulfide cleavage and reformation of mixtures of whole IgG or, preferably, F(ab')2 fragments, fusions of more than one clone to form polyomas that produce immunoglobulins having more than one specificity, and by genetic engineering.
- the bispecific antibodies can bind to one or more epitopes on the enzyme but should not bind to a site that interferes with enzyme activity.
- the bispecific will have a non-targeting arm which binds specifically to a low MW hapten, e.g., a DPTA chelate or other convenient hapten.
- the recycling enzyme used in the present invention must be capable of transforming a detoxified, normally more serum-soluble drug, e.g., a glucuronide, to regenerate the drug.
- Glucuronidases are well known and are representative of suitable recycling enzymes.
- Other forms of naturally detoxified drugs, such as sulfated or glycosylated (other than glucuronide) molecules can be regenerated at the target site by corresponding enzymes, e.g., sulfatases, glycosylases, and the like. Mutated or otherwise optimized forms of these enzymes also are suitable for use in the invention. Methods for mutation and optimization of enzymes are well known in the art.
- enzymes e.g., abzymes (catalytic antibodies), and the like
- enzymes e.g., abzymes (catalytic antibodies), and the like
- the prodrug cleaving enzyme also can be a mutated and/or optimized form of a natural enzyme or an enzyme mimic such as an abzyme or a synthetic or semisynthetic catalytic molecule.
- the prodrug cleaving enzyme and the prodrug itself can be one of those described in Hansen ' 110 or any other appropriate enzyme or enzyme mimic or prodrug that functions in the manner described herein for components of the inventive methods or compositions.
- the targeting molecule can be labeled with, or conjugated or adapted for conjugation to, a radioisotope or magnetic resonance image enhancing agent, to monitor its clearance from the circulatory system of the mammal and make certain that it has sufficiently localized at the target site, prior to the administration of the drug or prodrug.
- the targeting molecule can be tagged with a label, e.g., a radiolabel, a fluorescent label or the like, that permits its detection and quantitation in body fluids, e.g., blood and urine, so that targeting and/or clearance can be measured and/or inferred.
- Any conventional method of labeling proteins for in vivo use will be generally suitable for labeling the targeting molecule, e.g., those disclosed in Hansen ' 110 or others well known to the skilled artisan.
- the drug or prodrug must be soluble for purposes of administration and transport to the target site and the drug must also be capable of being converted to a detoxified form, e.g., a glucuronide, sulfate or glycoside, by the mammalian body.
- a detoxified form e.g., a glucuronide, sulfate or glycoside
- the term "soluble" means soluble in the fluid into which it is administered and by which it is transported to the target site, to a sufficient extent to permit transport of a therapeutically effective amount of the drug or prodrug to such site.
- drug administration will be into the bloodstream, by intravenous or intra-arterial infusion, and the drug will need to be soluble in serum and preferably sufficiently hydrophilic to be carried largely by the aqueous phase of serum and diffuse relatively easily through the walls of the blood vessels into interstitial fluid, for cases where such is necessary.
- Oral forms of a drug or prodrug, or other forms well known in the art, that permit transport of the drug or prodrug to the target site or that permit the prodrug to be converted to a drug which then can be transported to the target site also will be suitable for use in the invention.
- cytotoxic drugs that are useful for anticancer therapy are relatively insoluble in serum. Some are also quite toxic in unconjugated form and their toxicity is considerably reduced by conversion to prodrugs. Conversion of a relatively poorly soluble drug to a more soluble conjugate, e.g., a glucuronide, an ester of a hydrophilic acid, an amide of a hydrophilic amine, will improve its solubility in the aqueous phase of serum and its ability to pass through venous, arterial or capillary cell walls and reach the interstitial fluid bathing the tumor. Cleavage of the prodrug will deposit the less soluble drug at the target site. Many examples of such prodrug-todrug conversions are disclosed in Hansen ' 110.
- Conversion of certain toxic substances such as aromatic or alicyclic alcohols, thiols, phenols and amines to glucuronides in the liver is the body's method of detoxifying them and making them more easily excreted in the urine.
- One type of antitumor drug that can be converted to such a substrate is epirubicin, a 4-epimer of doxorubicin (Adriamycin), which is an anthracycline glycoside and has been shown to be a substrate for human beta-D- glucuronidase (Arcamone, Cancer Res., 45:5995, 1985,).
- Adriamycin 4-epimer of doxorubicin
- Other analogues with fewer polar groups would be expected to be more lipophilic and show greater promise for such an approach.
- Other drugs or toxins with aromatic or alicyclic alcohol, thiol or amine groups would also be candidates for such conjugate formation. These drugs, or other prodrug forms thereof, will
- Prodrug forms such as carrier polymer-loaded molecules also are suitable for use in the present methods. This latter example allows for the use of a multiply substituted prodrug in the prodrug administration step.
- loading with 5-flourouracil (5-FU) can be effected by oxidizing 5-flourouridine at the carbohydrate portion, e.g., using periodate, reacting this intermediate with an aminodextran, and reductively stabilizing the Schiff base adduct.
- Cycloheximide can be loaded by direct reaction of its cyclohexanone carbonyl with aminodextran amine groups, followed by reductive stabilization, or by reacting its side chain hydroxyl with an excess of a diisothiocyanate linker and reaction of the isothiocyanate derivative with amines on the aminodextran, or by reaction of the imide nitrogen with e.g., a haloacid or haloester, followed by activation of the resultant carboxyl derivative, e.g., with DCC, and condensation with amines on the aminodextran.
- the loaded aminodextran is stripped of drug by an amidase pretargeted to the target site. If the drug is detoxified as a glucuronide, the glucuronide of the drug can be cleaved by a glucuronidase which also has been pretargeted to the target site to regenerate and recycle the cytotoxic drug.
- antibiotic mitomycin C and its analogues This molecule has * an amine function and a cyclic imine, either of which can be reacted with an alkylating activating group, e.g., succinimidyloxy iodoacetate or sulfosuccinimidyloxy (4- iodoacetyl) aminobezoate (sulfo-SIAB), the resulting intermediate is then used to alkylate amine groups on an aminodextran.
- carboxyl groups can be introduced using, e.g., succinic anhydride, then activated, e.g., with DCC, and the activated intermediate coupled as before.
- a target-localized amidase will liberate the drug
- some drug molecules will be detoxified to form glucuronides, and targeted glucuronidase will regenerate the drug to amplify its target-specific activity.
- the prodrug CPT- 11 (irinotecan) is converted in vivo by carboxylesterase to the active metabolite SN-38.
- carboxylesterase is converted in vivo by carboxylesterase to the active metabolite SN-38.
- One application of the invention is to use a bsMAb targeted against a tumor and a hapten (e.g. DTPA) followed by injection of a DTPA-carboxyl esterase conjugate. Once a suitable tumor-to-background localization ratio has been achieved, the CPT11 is given and the tumor-localized carboxylesterase serves to convert CPT- 11 to SN-3 8 at the tumor.
- Etoposide is a widely used cancer drug that is detoxified to a major extent by formation of its glucuronide (Hande et al., Cancer Res., 48: 1829-1834, 1988), and could therefore be used within the scope of the invention.
- Glucuronide conjugates can be prepared from cytotoxic drugs and be injected as therapeutics for tumors pre-targeted with MAb- glucuronidase conjugates (Wang et al, Cancer Res., 52:4484-4491, 1992). Accordingly, such conjugates can also be used with the bsMAb approach described here.
- Designed prodrugs based on derivatives of daunomycin and doxorubicin have been described (Bakina et al., J.
- drugs and toxins which have a cytotoxic effect on tumor cells or microorganisms that may infect a human and cause a lesion, in addition to the specific illustrations given above. They are to be found in compendia of drugs and toxins, such as the Merck Index and the like.
- the ability to partially or completely detoxify a drug as a prodrug according to the invention, while it is in circulation, can reduce systemic side effects of the drug and permit its use when systemic admimstration of the drug would be unacceptable. For example, MTX and cycloheximide often are too toxic when administered systemically.
- Administration of the drug as a prodrug which is only converted to the toxic form at the target site by a pretargeted enzyme together with recycling and reactivation of the detoxified drug at the target site by a pretargeted second enzyme, permits use of a significantly reduced dose which is still effective for therapy at the target site while mitigating systemic toxicity.
- CPT- 1 1 clearance properties have been shown to be modulated by administration of cyclosporin A with the latter reducing the level of biliary clearance of SN-38 and its glucuronide (SN-38G) (Gupta et al., Cancer Res. 56: 1309-1314, 1996). In turn, this raised the plasma concentration of SN-38G. This would allow for greater contact with tumor- targeted DTPAglucuronidase in the present invention. Gupta et al. also showed a similar effect when using phenobarbitol (Cancer Chemother.
- valproic acid an inhibitor of uridine diphosphate glucuronosyl transferase (UDP-GT) inhibited the formation of SN-38G leading to a 270% AUC for SN-38 from subsequently-administered CPT-11.
- valproic acid an inhibitor of uridine diphosphate glucuronosyl transferase (UDP-GT) inhibited the formation of SN-38G leading to a 270% AUC for SN-38 from subsequently-administered CPT-11.
- the reagents are conveniently provided as separate injectible preparations for human therapeutic use.
- the first injectible preparation contains an effective amount of an antibody or antibody fragment conjugated to an enzyme, in a pharmaceutically acceptable injection vehicle, preferably phosphate-buffered saline (PBS) at physiological pH and concentration.
- PBS phosphate-buffered saline
- the second injectible preparation contains an effective amount of a soluble substrate conjugated to at least one therapeutic agent, in a pharmaceutically acceptable injection vehicle, generally similar to that used for the first preparation.
- the injectible preparations preferably will be sterile, especially if they are intended for use in humans.
- the reagents also can be conveniently provided in a therapeutic kit for antibody targeting to a target site, using suitable containers.
- a container holds an effective amount of a targeting molecule, such as an antibody, which specifically binds to the target site, conjugated to an enzyme capable of converting a detoxified drug to its more cytotoxic form
- the container has an effective amount of a targeting molecule which specifically binds to the target site and which is conjugated to a moiety which can directly or indirectly bind to an enzyme capable of converting a detoxified drug to its more cytotoxic form and, in a separate container, said enzyme in a form capable of binding directly or indirectly to said moiety.
- the reagents can be lyophilized for longer shelf stability or provided in the form of solutions, optionally containing conventional preservatives, stabilizers and the like.
- Other optional components of such kits would normally be containers of buffers, labeling reagents, radioisotopes, paramagnetic compounds, second antibody for enhanced clearance, and conventional syringes, columns, vials and the like.
- parenteral injection The various types of parenteral injections can be, but are not limited to intracavitary (e.g., intraperitoneal), intravenous, intraarterial, intrapleural, intrathecal, intramuscular, intralymphatic and regional intraarterial, intralesional, subcutaneous, catheter perfusion and the like.
- parenteral injections can be, but are not limited to intracavitary (e.g., intraperitoneal), intravenous, intraarterial, intrapleural, intrathecal, intramuscular, intralymphatic and regional intraarterial, intralesional, subcutaneous, catheter perfusion and the like.
- intravenous, intraarterial or intrapleural administration is normally used for lung, breast, and leukemic tumors.
- Intraperitoneal administration is advantageous for ovarian tumors.
- Intrathecal administration is advantageous for brain tumors and leukemia.
- Subcutaneous administration is advantageous for Hodgkin's disease, lymphoma and breast carcinoma.
- Catheter perfusion is useful for metastatic lung, breast or germ cell carcinomas of the liver.
- Intralesional administration is useful for lung and breast lesions.
- the enzyme will generally be administered as an aqueous solution in PBS, preferably a sterile solution, especially if it is for use in humans.
- dosage units of about 50 micrograms to about 5 mg of the enzyme will be administered, either in a single dose or in divided doses, although smaller or larger doses may be indicated in particular cases.
- An indication of the need for such cautionary procedures is an increase in human anti-mouse antibody (HAMA) production, which can be determined using an immunoassay.
- HAMA human anti-mouse antibody
- the corresponding localization and clearance time for F(ab)2 and F(ab')2 antibody fragments is from about 2 to 7 days and preferably 4 to 7 days, and from about 1 to 3 days and preferably 3 days for Fab and Fab 1 antibody fragments.
- Other antibodies may require different time frames to localize at the target site, and the above time frames may be affected by the presence of the conjugated enzyme. Again, it is noted that labeling the enzyme permits monitoring of localization and clearance.
- IgG is normally metabolized in the liver and, to a lesser extent, in the digestive system.
- F(ab)2 and F(ab')2 are normally metabolized primarily in the kidney, but can also be metabolized in the liver and the digestive system.
- Fab and Fab 1 are normally metabolized primarily in the kidney, but can also be metabolized in the liver and the digestive system.
- an effective amount of an antibody-enzyme conjugate is that amount sufficient to target the conjugate to the antigen at the target site and thereby bind an amount of the enzyme sufficient to transform enough of the glucuronide to its cytotoxic form to result in accretion of an effective therapeutic amount of the drug at the target site.
- the drug may be given in doses, and at times, that can be optimized empirically for a particular combination. It may be given as a single injection or infusion, or may be administered in repeat doses. It can most preferably be given from one to two hundred hours after the haptenenzyme is administered, and if given in multiple doses, can most preferably be given at intervals from every hour to every three days.
- the therapeutic drug will be generally administered as an aqueous solution in PBS. Again, this will be a sterile solution if intended for human use. The drug will be administered after a sufficient time has passed for the enzyme to localized at the target site and substantially clear from the circulatory system of the mammal.
- An effective amount of a prodrug is that amount sufficient to deliver an effective amount of the drug to the target site.
- An effective amount of a therapeutic drug is that amount sufficient to treat the target site.
- the therapeutic method of the invention can be accomplished by conjugating an effective therapeutic amount of a radioisotope such as Y-90 or 1-131 (which may be used for both localization and therapy depending on the amount injected) or a drug such as adriamycin for cancer or gentamycin for infection, an immunomodulatory substance such as poly-IC, or a biological toxin such as pokeweed mitogen to the substrate, and depositing a therapeutically effective amount of the agent at the target site.
- a radioisotope such as Y-90 or 1-131 (which may be used for both localization and therapy depending on the amount injected) or a drug such as adriamycin for cancer or gentamycin for infection, an immunomodulatory substance such as poly-IC, or a biological toxin such as pokeweed mitogen
- Dosage units of substrate-agent conjugate will depend upon many factors, each of which can be determined in a relatively straightforward manner, so that optimal dosimetry can be effected. It will be helpful, in the initial dosimetric evaluation, to use a radiolabeled substrate-agent conjugate (if the agent is not itself a radioactive isotope) to determine the degree and rate of deposit of the agent at the target site, and the rate of clearance and biodistribution of non-targeted conjugate. Use of a labeled antibody-enzyme conjugate to estimate the amount of enzyme localized at the target site will also aid in dosimetric analysis.
- a substantially monoconjugated enzyme-antibody preparation is prepared by mildly oxidizing the carbohydrate portion of a humanized anti-lymphoma Fab' having a light chain glycosylation site with periodate, then contacting the oxidized Fab' with a dilute solution of glucuronidase (from bovine liver, Worthingon) to produce an antibody-enzyme conjugate, which is then stabilized by borohydride, in the usual manner.
- the conjugate can be radiolabeled with I- 131 , by conventional procedures.
- a human patient suffering from lymphoma is infused intravenously with a sterile, pyrogen-free PBS solution containing 5 mg each of the 1-13 1-labeled anti-lymphoma Fab'- glucuronidase and esterase conjugates prepared according to Example 1 hereof. After 3 days, the conjugates are well localized at the target site and substantially cleared from the circulatory system, as determined by gamma scanning.
- the patient is then infused intravenously with a sterile, pyrogen-free PBS solution containing 10 mg of epirubicin methyl ester.
- Subsequent radioimmunodetection shows significant reduction in the lymphoma, compared to a 10 mg dosage of epirubicin prior to targeting with the enzyme conjugates.
- IgG x Fab' bsMAb is made in the following manner. Humanized MIN-14 IgG (antiCEA) is treated with sodium periodate to specifically oxidize heavy chain carbohydrate residues. Formed aldehyde groups are reacted with an excess of the commercially available cross-linking agent MBPH ⁇ 4-(4-N-maleimidophenyl)butyric acid hydrazide; Pierce Chemical Co., Rockford, IL ⁇ .
- Non-reacted MBPH is removed from the modified hMN- 14 MAb by size-exclusion chromatography and the hMN- 14-(maleimide) n intermediate is reacted with a small molar excess of the Fab'-SH fragment of the anti-DTPA MAb ⁇ termed 734 ⁇ , generated from its IgG by standard pepsin digestion and thiol reduction.
- the desired bsMAb IgG x Fab' moiety is separated from unreacted proteins and non-1 : 1 conjugates by preparative size-exclusion HPLC. Further purification may be effected by affinity chromatography using a solid-phase-bound DTPA affinity column.
- Anti-idiotypic MAb to hMN-14 termed W12
- W12 Anti-idiotypic MAb to hMN-14, termed W12
- CTG cyanomethyl-2,3 ,4,6-tetra-O-acetyl- 1- thio- ⁇ -D- galactopyranoside
- the galactosyl- W12 thus formed is purified by size-exclusion chromatography. Fluorometric analysis of the product in comparison with unmodified MAb shows that approximately 80%o of the MAbs lysine residues are substituted with a galactose residue.
- the enzyme carboxylesterase (CE) is treated with a five-fold molar excess of DTP A- dianhydride (Sigma Chemical Co., St. Louis, MI). After stirring for one hour, the DTPA-CE is purified from free DTPA and aggregated enzyme by preparative size-exclusion HPLC. Approximately 1-2 DTPA units are appended per enzyme. Similarly, glucuronidase is conjugated to DTPA using the dianhydride.
- a patient with colorectal cancer is given an injection of the bsMAb comprised of an IgGhMN-14 cross-linked with an anti-DTPA Fab' fragment, prepared according to Example 3.
- an amount of galactose-W12, prepared according to Example 4 sufficient to clear nearly all non-target-bound MN-14-IgG x 734-Fab' from the circulation is administered. This amount is between 5 and 15 times the amount of primary bsMAb remaining in circulation at the time-point specified.
- a tumor-saturating amount of a mixture of the DTPA-CE and DTPA-glucuronide conjugates is given, and allowed to clear circulation and normal tissues.
- a standard chemotherapy dose of CPT- 11 is administered to the patient, generating free SN-38 specifically at the tumor target sites, regenerating free SN-38 at the target sites from the glucuronide, and destroying the tumors.
- a patient with colorectal cancer is given an injection of the bsMAb as in Example 6. After 48 h to allow for maximum accretion in tumors, an excess amount of same mixture of the DTPA-CE and DTPA-glucuronidase conjugates as in Example 6 is given. Three hours later an amount of galactose-W12 sufficient to clear nearly all non-target-bound M/N-14-IgG x 734-Fab'-DTPA-enzymes from the circulation is administered. This amount is between 5 and 15 times the amount of primary bsMAb complexes remaining in circulation at the time- point specified. Another three hours later, a standard chemotherapy dose of CPT- 11 is administered to the patient, generating free SN-38 specifically at the tumor target sites, recycling SN-38 glucuronide at the target site, and destroying said tumors.
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AU61475/99A AU763628B2 (en) | 1998-09-18 | 1999-09-17 | Methods and compositions for increasing the target-specific toxicity of a chemotherapy drug |
AT99948261T ATE499115T1 (en) | 1998-09-18 | 1999-09-17 | ANTIBODIES REFERRED ENZYME PRODRUG THERAPY WITH GLUCURONIDASE |
JP2000573769A JP4616991B2 (en) | 1998-09-18 | 1999-09-17 | Methods and compositions for increasing target specific toxicity of chemotherapeutic agents |
EP99948261A EP1113819B1 (en) | 1998-09-18 | 1999-09-17 | Antibody directed enzyme prodrug therapy (adept) with glucuronidase |
DE69943219T DE69943219D1 (en) | 1998-09-18 | 1999-09-17 | ANTIBODIES PROVIDED ENZYMPRODRUG THERAPY WITH GLUCURONIDASE |
CA002344440A CA2344440A1 (en) | 1998-09-18 | 1999-09-17 | Antibody directed enzyme prodrug therapy (edept) with glucoronidase |
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US10103998P | 1998-09-18 | 1998-09-18 | |
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WO2004045642A1 (en) * | 2002-11-15 | 2004-06-03 | Immunomedics, Inc. | Use of multi-specific, non-covalent complexes for targeted delivery of therapeutics |
US7833528B2 (en) | 1998-06-22 | 2010-11-16 | Immunomedics, Inc. | Use of multispecific, non-covalent complexes for targeted delivery of therapeutics |
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CN1767860A (en) * | 2003-01-31 | 2006-05-03 | 免疫医疗公司 | Methods and compositions for administering therapeutic and diagnostic agents |
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WO1997041898A1 (en) | 1996-05-03 | 1997-11-13 | Immunomedics, Inc. | Targeted combination immunotherapy of cancer |
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US5851527A (en) * | 1988-04-18 | 1998-12-22 | Immunomedics, Inc. | Method for antibody targeting of therapeutic agents |
DE4106389A1 (en) * | 1991-02-28 | 1992-09-03 | Behringwerke Ag | FUSION PROTEINS FOR PRODRUG ACTIVATION, THEIR PRODUCTION AND USE |
CA2069439A1 (en) * | 1989-12-15 | 1991-06-16 | Susumu Iwasa | Monoclonal antibodies, their production and use |
KR100270650B1 (en) * | 1994-12-23 | 2000-11-01 | 돈 리사 로얄 | Antibody directed enzyme prodrug therapy using mutated form of host enzymes |
GB9524942D0 (en) * | 1995-12-06 | 1996-02-07 | Aepact Ltd | Drug therapy |
US7018631B1 (en) * | 1998-02-19 | 2006-03-28 | St. Jude Children's Research Hospital | Compositions and methods for sensitizing and inhibiting growth of human tumor cells |
US7074405B1 (en) * | 1998-06-22 | 2006-07-11 | Immunomedics, Inc. | Use of bi-specific antibodies for pre-targeting diagnosis and therapy |
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HAISMA ET AL., BR. J. CANCER, vol. 66, 1992, pages 474 - 478 |
ROFFLER ET AL., BIOCHEM PHARMACOL., vol. 42, pages 2062 - 2065 |
Cited By (4)
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US7833528B2 (en) | 1998-06-22 | 2010-11-16 | Immunomedics, Inc. | Use of multispecific, non-covalent complexes for targeted delivery of therapeutics |
WO2004045642A1 (en) * | 2002-11-15 | 2004-06-03 | Immunomedics, Inc. | Use of multi-specific, non-covalent complexes for targeted delivery of therapeutics |
AU2003283599B2 (en) * | 2002-11-15 | 2008-11-20 | Immunomedics, Inc. | Use of multi-specific, non-covalent complexes for targeted delivery of therapeutics |
AU2003283599C1 (en) * | 2002-11-15 | 2009-06-25 | Immunomedics, Inc. | Use of multi-specific, non-covalent complexes for targeted delivery of therapeutics |
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WO2000016808A3 (en) | 2000-09-28 |
ATE499115T1 (en) | 2011-03-15 |
DE69943219D1 (en) | 2011-04-07 |
CA2344440A1 (en) | 2000-03-30 |
EP1113819B1 (en) | 2011-02-23 |
AU6147599A (en) | 2000-04-10 |
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