Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,...
Reexamination Certificate
1999-09-17
2002-03-26
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
C424S009100, C424S179100, C424S181100, C530S391100
Reexamination Certificate
active
06361774
ABSTRACT:
BACKGROUND OF THE INVENTION
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. Where 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.
It is a continuing aim of chemotherapy to deliver a higher total dose of chemotherapeutic to a tumor target, and/or lower doses to sensitive non-target tissues. Direct attachment of drugs to specific targeting agents such as monoclonal antibodies (MAbs) has a number of drawbacks, including diminishing a drug's potency and changing the pharmacokinetic properties of the MAb for the worse. Despite this, impressive results have been seen in preclinical animal results using conjugates of MAbs and standard chemotherapy drugs such as doxorubicin (Trail et al.,
Science
261:212-215, 1993 &
Cancer Res.,
57: 100-105, 1997). A further problem in translating good animal results to the human situation is that in the latter, tumor target uptake of MAbs is often two to four orders of magnitude lower on a percent injected dose per gram basis.
In part to circumvent the above problems a novel approach was tried whereby an antibody enzyme conjugate was administered, followed sometime later by a precursor of an active drug, i.e. a prodrug. The enzyme localized to target by the tumor-specific antibody would act on the prodrug to release active drug at the target. The method has the advantages of not requiring coupling of drug to MAb, and by virtue of targeted enzyme activity the ability to produce large amounts of drug where it is needed. The latter advantage can overcome the issue of low absolute tumor accretion of MAbs in humans.
In a further modification, a binary system for targeting prodrugs using a bispecific monoclonal antibody (bsMAb) was described by Hansen U.S. Ser. No. 08/445,110 (hereinafter, “Hansen '110”), the disclosure of which is incorporated herein in its entirety by reference. In this system, a 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. Later still, a prodrug, e.g., a glucuronide prodrug, is administered and the free drug released by the tumor-targeted enzyme. In addition to addressing the issue of low levels of MAb accretion at human tumors, 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.
One limitation of the 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.
A need therefore continues to exist for a method for increasing the target-specific toxicity of a chemotherapy drug which is detoxified by normal metabolic processes to form an intermediate of lower toxicity, whereby the detoxified intermediate is reconverted to its more toxic form by the pretargeted enzyme and thus, has enhanced cytotoxicity at the target site.
OBJECTS OF THE INVENTION
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.
Other objects of the present invention will become more readily apparent to those of ordinary skill in the art in light of the following discussion.
SUMMARY OF THE INVENTION
These and other objects of the invention are achieved by providing a method for increasing the target-specific toxicity of a drug, comprising:
(1) pretargeting an enzyme to a mammalian target site; and
(2) administering a cytotoxic drug known to act at the target site, or a prodrug form thereof which is converted to the drug in situ, which drug is also detoxified to form an intermediate of lower toxicity using said 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.
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.
DETAILED DISCUSSION
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.
In a third alternative, 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. 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 crosslinked 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 th
Griffiths Gary L.
Hansen Hans J.
Foley & Lardner
Immunomedics Inc.
Webman Edward J.
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