JP2007528874A - Methods for improving the efficacy of therapeutic radiolabels - Google Patents

Abstract

  Disclosed is a radiosensitizer that uses a radiosensitizer such that the radiolabel and the radiosensitizer are part of the radiolabel by attaching the radiosensitizer directly to the radiolabel. A method for improving its efficacy by either producing a mixture of a labeling agent and a therapeutic agent analog having a radiosensitizer attached to the therapeutic agent instead of a radiolabel.

Description

The present invention relates to a method for improving the efficacy of radiolabeled therapeutic agents using radiosensitization.
The present invention relates to a radiolabeled drug and describes a method for improving its efficacy, wherein the radiosensitizer attaches the radiosensitizer directly to the radiolabeled drug. This produces a mixture of a radiolabeled drug and a drug analog having a radiosensitizer attached to the drug instead of the radiolabeled drug.

  Radiolabeled antibodies are valuable diagnostic and therapeutic reagents. They are particularly useful as cancer treatments. Administration of radiolabeled antibodies with binding specificity for tumor-specific antigens bound to radioisotopes with short-range, high-energy irradiation has the potential to deliver lethal doses of radiation directly to tumor cells.

  Yttrium 90-labeled Zevalin, which targets the CD20 epitope localized to B cells and is currently used to treat non-Hodgkin lymphoma, is an example for a radiolabeled antibody (C. Emmanouilides, Semin Oncol. 2003). ; 30 (4); 531-44). The radioisotope, yttrium 90, destroys cells with antibodies attached and cells within the irradiation range. The radiolytic activity of yttrium 90 has been well described (Salako et al. 1998, J. Nucl. Med. 39: 667; Chakrabarti et al., 1996, J. Nucl. Med. 37: 1384).

  Further examples for yttrium 90 labeled antibodies are Theragyn (Hird et al., Br. J. Cancer 1993, 68; 403) used in the treatment of ovarian cancer, and monoclonal antibody BC-1 conjugated through a linker to yttrium 90. AngioMab administered for the treatment of solid tumors.

  Methods for the synthesis of chelators and chelator complexes are known to those skilled in the art (eg, US Pat. No. 4,831,175, US Pat. No. 5,099,069, US Pat. No. 5,246,692, US Pat. No. 5,286,850 and US Pat. No. 5,124,471). An example of a radiolabeled antibody that uses an iodine isotope instead of yttrium 90 is Bexxar labeled with iodine-131. Bexxar also targets the CD20 epitope of B cells and is used for the treatment of non-Hodgkin lymphoma (BioDrugs. 2003; 17 (4): 290-5).

  Although these radiolabeled therapeutics are very effective in their indications, there is room for improvement. Its efficacy is except that an analogue of a radiolabeled therapeutic agent having a radiosensitizer moiety instead of a radiolabeled moiety attaches to the therapeutic agent or replaces the radiolabeled moiety with a radiosensitizer moiety. It has now been found that this can be increased by applying radiosensitization principles such as the synthesis of analogs that are the same as radiolabeled therapeutics. Radiosensitizers are well known in the art (eg, EP0316967, US Patent No. 2003166692, US Patent No. 2001051760, US Patent No. 66589981).

Dual drug compounds that combine the anti-tumor activity of an active therapeutic agent such as paclitaxel with the radiosensitizing potential of additional moieties attached to the therapeutic agent are described in WO9640091 and US Patent No. 5780653. However, these agents are still non-specific and require external radiation that is highly destructive to normal tissue. On the other hand, the present invention utilizes its own irradiation source and does not require external irradiation. Gd-containing complexes used as radiosensitizers are described in US Pat. No. 5,545,183 and US Pat. No. 2001051760 in which Gd-Texaphyrin or Gd-Photofrin is used. Instead of Gd, other metals with radiosensitivity potential such as Co (III) or Fe (III) as described in US Pat. No. 4727068 may be used.
Radiosensitizers attached to liposomes are described in WO0045845. Here, a radiosensitizer, such as 5-iodo-2′-deoxyuridine, is attached to the lipid of the liposome via a hydrophilic polymer chain.

Summary of the Invention The present invention relates to improving the efficacy of radiolabeled therapeutics by radiosensitization introduced via two possible routes. The first route consists of attaching or binding a radiosensitizer moiety to the radiolabeled therapeutic agent, while in the second route the radiolabeled therapeutic agent is radiosensitized in addition to or instead of the radiolabel. Mixed with a therapeutic analog containing agent.

Thus, in one aspect, the present invention is a method for improving the efficacy of a radiolabeled therapeutic agent comprising:
(i) combining a radiosensitizing component with the same molecule attached to the drug, or
(ii) co-administer a mixture of radiolabeled drug and radiosensitizer if the radiolabeled drug and radiosensitizer have substantially the same targeting properties;
A method comprising the above is provided.

In another aspect, the present invention relates to the following method,
Wherein the agent has two parts, a part containing a radiolabel attached thereto and another part containing a radiosensitizer; and / or wherein the therapeutic agent is preferably a radioisotope A labeled small molecule and / or wherein the agent is a chelate; and / or wherein the agent comprises a chelate; and / or

Wherein the agent is a protein; and / or wherein the agent is a macromolecule or binary polymer; and / or where the agent is an antibody or antibody construct; and / or where the agent is Is DNA or RNA or a constituent thereof; and / or where the drug is a carbohydrate; and / or where the drug is a multi-branched polymer; and / or where the drug is a liposome or micelle Contained within or on; and / or

If the radiolabeled drug and the radiosensitizer have substantially the same targeting properties, the drug comprises a mixture of the radiolabeled drug and an analog of the drug, and the analog The body functions as or contains a radiosensitizer; and / or wherein said agent is selected from alpha, beta and gamma emitters; and / or wherein said radiolabel is selected from the lanthanide group; and / Wherein said radioactive label is yttrium; and / or

Wherein said radiolabel is a radiohalogen; and / or wherein said radiolabel is iodine; and / or wherein said radiosensitizer is gadolinium, iodine or boron; and / or wherein said radiolabel is The label is attached or linked to the drug by a chelator bound to the drug via a bridge; and / or wherein the chelator or chelate comprises an EDTA, DTPA, or DOTA moiety, and / or

Wherein the linked or unbound chelator or chelate comprises MX-DTPA, phenyl-DTPA, benzyl-DTPA, or CHX-DTPA; and / or wherein the radiosensitizer is a triiodobenzene component And / or wherein the radiosensitizer comprises a borane or carborane component; and / or wherein the antibody is Zevalin; and / or

Including placing a mixture of a radioisotope and gadolinium, cobalt or iron on the chelator or chelate on the antibody; and / or a mixture of yttrium 90 and gadolinium, cobalt or iron on the chelator or chelate on the antibody And / or mixing a radioisotope-labeled therapeutic agent with a gadolinium, cobalt or iron-labeled therapeutic analog; and / or gadolinium with zevalin labeled with yttrium 90, Mixing with cobalt or iron labeled zevaline.

Detailed Description of the Invention Radiosensitization has heretofore been understood as the administration of a compound capable of increasing the damage potential of external radiation at a tumor site. This means that the radiosensitizer reaches the tumor site at a high concentration sufficient to act as a radiosensitizer and low enough to eliminate side effects, and damages normal tissue in the route to the tumor site This means that external radiation must be applied exactly to this site without. Since this objective has not yet been achieved satisfactorily, the use of radiosensitizers in therapy is very limited.

  We have now found a way to avoid these difficulties. With the new method, external irradiation is no longer necessary. Instead, the radiation is delivered to the tumor site via administration of a radiolabeled agent that accumulates at the tumor site and then destroys the tumor cells. The combined efficacy of targeted delivery of radiation and targeted delivery of a radiosensitizer that is part of a radiolabeled drug or delivered before or after administration of the radiolabeled drug further increases the efficacy of the treatment. .

  There are therefore two possible routes to increase the efficacy of radiolabeled therapeutics. The first route can be explained as follows. An additional component with the potential for radiosensitization is attached to the radiolabeled drug without affecting its targeting properties. One example of this approach is a monoclonal antibody to which a chelator is attached via a linker. Chelating agents can bind radioisotopes such as yttrium 90. The antibody is directed to an epitope on the tumor cell and carries the radioactive isotope directly to the tumor site where the tumor cell is destroyed by irradiation. Usually one or more chelating agents are attached to the antibody. This means that chelating agents can be used to bind not only radioisotopes, but also other metal ions that additionally function as radiosensitizers such as gadolinium, cobalt or iron. The advantage of this approach is that the irradiation and radiosensitizers are in close proximity—they are bound in the same molecule—and thus give a high photosensitive yield.

  Alternatively, the same type of drug—a monoclonal antibody with a chelator attached via a linker—can carry a radioactive isotope (eg yttrium 90) or a radiosensitized metal (eg gadolinium) and is preferably identical Two agents targeting the epitopes are delivered to the patient as a mixture or sequentially. Alternatively, two different targeting components, ie antibodies, can be used that localize to different epitopes in the same site, eg the same cell.

  Both drugs target the tumor and are therefore close to each other on the tumor so that effective irradiation and radiosensitization are possible. This proximity, however, in the first example, where the radiolabel and the radiosensitizer are bound in one molecule and therefore not only localize together on the tumor, but also attach to exactly the same tumor cells. Maybe not so close.

  Instead of using a chelating agent to bind the radiosensitizing component, other radiosensitizing moieties well known to those skilled in the art may be used. Examples for other radiosensitizing components that may be attached to the drug include iodine atoms or iodine containing moieties such as triiodobenzene derivatives, or boron atoms or boron containing moieties such as borane or carborane.

  However, any other radiation sensitizing component known in the art may be used as well, such as platinum-containing components, imidazoles, and the like. Instead of linking the radiosensitizing component directly to the radiolabeled drug, an analog of the radiolabeled drug is synthesized such that the moiety containing the radiolabel is exchanged for the component containing the radiosensitizer. Also good. That is, an analog in which the radiosensitizer is present at the position of the radiolabel. This means that the antibody of the above example will contain a radiosensitizer component bound to it.

  However, this principle does not work exclusively with antibodies, but with other carriers such as any biopolymer, polymer, liposome or micelle preparation. Even non-polymeric therapeutic agents large enough to carry additional components can be used for this principle. For example, paclitaxel may be modified to include a chelator bound through a linker. The chelator will then be able to bind a radiolabel, eg, a radiosensitized metal ion such as yttrium 90 and / or gadolinium.

  Further examples would include the chelate itself, which is itself a drug, although it does not bind to any other drug. In this example, the chelate will bind both radioisotopes and radiosensitized metal ions that are not necessarily in the same molecule, but in the same solution or separate preparations.

  Instead of using a radioisotope attached to the carrier drug via a chelate, the radioisotope may be attached directly to the carrier drug by, for example, radioiodination of the antibody. In this case, the same preparation means may be used as when non-radioactive iodine is bound to the antibody and then functions as a radiosensitizer. This can be done within the same molecule by simply adding non-radioactive iodine to the radioisotope used for radioiodination or by binding non-radioactive iodine to the antibody. Alternatively, the radiosensitization potential is increased not only by attaching a single iodine atom to the drug molecule, but also by attaching an iodine carrier such as a triiodobenzene derivative.

  The drug can be used at the same dose and in the same formulation as for non-sensitized drugs, but will also be used at lower doses as a result of sensitization. When two molecules are involved, they can be administered simultaneously or sequentially in any order. In the latter example 1, for example, the radiosensitizing agent is administered shortly before the other, eg, radiotherapeutic agent, eg, about 15-60 minutes. Longer and shorter times are also possible.

Any of the molecules discussed herein can be routinely prepared by well-known techniques such as labeling, crosslinking, chelation and the like, eg, as described in the cited references and others.
Without further elaboration, it is believed that one skilled in the art will be able to make the most of the invention using the foregoing description. The following preferred specific embodiments are therefore merely illustrative and should not be construed as limiting the remainder of the disclosure in any way.
In the preceding and following examples, all temperatures are stated uncorrected in degrees Celsius, and all parts and percentages are by weight unless otherwise indicated.

Example 1.
Radiolabeling with ⁹⁰ Y of Ibritumomab tiuxetan (Zevalin) is performed according to the procedure described in WO0052031.
Gd-labeled Zevalin (Gd-Zevalin) is synthesized accordingly using a solution of GdCl ₃ instead of YCl ₃ . Alternative methods of reacting GdCl ₃ with chelating agents are described in the literature and those skilled in the art are familiar with these procedures.
Subsequently, both solutions are injected into the patient independently.

Example 2.
Radiolabeling of Zevalin with ⁹⁰ Y and Gd is performed according to the procedure described in Example 1.
Subsequently, both solutions are mixed with each other, and then the mixture is injected into the patient.

Example 3.
Radiolabeling of Zevalin with ⁹⁰ Y and Gd is performed by mixing a solution of YCl ₃ and GdCl ₃ with each other and using this mixture for the labeling of Zevalin. Optimal binding of Gd and ⁹⁰ Y is obtained when both lanthanides are present in equimolar amounts. YCl ₃ is usually used without a carrier and may add non-radioactive Y isotopes.
Subsequently, the solution is injected into the patient.

Example 4
Polymers with attached chelates are synthesized, for example, as described in US Patent No. 2003206865 or WO03013617. Labeling of these macromolecules with ⁹⁰ Y and Gd is performed according to the procedures described in the literature.

Example 5.
Liposomes with a radiosensitizer attached to the surface are prepared as described in WO0045845. ⁹⁰ Y-DTPA is present during preparation and is subsequently encapsulated within the liposome. Liposomes now contain a radiolabeled drug in their micelles and a radiosensitizer on the surface. US Patent No. 6475515 describes in detail the preparation of chelate-containing liposomes.

The entire disclosure of all applications, patents and literature cited herein and filed December 11, 2003 in the corresponding US Provisional Application Serial No. 60 / 528.473 are hereby incorporated by reference.
The foregoing examples can be reproduced with similar success by replacing those used therein with the reactants and / or operating conditions generally and specifically described in the present invention.
From the foregoing description, those skilled in the art can readily ascertain the substantial features of the present invention, and various modifications and alterations of the present invention to adapt to various uses and conditions without departing from the spirit and scope thereof. Can be done.

Claims (23)

A method for improving the efficacy of the drug Ibritumomab tiuxetan labeled with yttrium 90,
(i) modify the drug by attaching a radiosensitized Gd component, or
(ii) The yttrium 90 labeled drug ibritumomab tiuxetane and the radiosensitized Gd component attached ibritumomab tiuxetane together to form a mixture,
A method comprising that. A method of administering yttrium 90-labeled Ibritumomab tiuxetan to a patient in need thereof,
(i) administering a modified yttrium 90-labeled ibritumomab tiuxetane to which a radiosensitized Gd component is attached, or
(ii) co-administering the drug ibritumomab / tiuxetane labeled with yttrium 90 and ibritumomab / tiuxetane to which the radiosensitized Gd component is attached, as a mixture or separately;
A method comprising that.   The method of claim 1, wherein the drug and / or the radiosensitized ibritumomab tiuxetane is contained within or on a liposome or micelle. A method for improving the efficacy of ibritumomab tiuxetan or Ibritumomab tiuxetan already labeled with yttrium 90,
(i) (a) labeling ibritumomab tiuxetane with a radiosensitized Gd component or preparing gd-labeled ibritumomab tiuxetane by providing an already Gd labeled ibritumomab tiuxetane;
(b) preparing yttrium 90-labeled ibritumomab tiuxetane by labeling ibritumomab tiuxetane with yttrium 90 or providing ibritumomab tiuxetane already labeled with yttrium 90; and
(c) co-administering Gd-labeled ibritumomab tiuxetane and yttrium 90-labeled ibritumomab tiuxetane to the patient as a mixture or separately; or
(ii) (a) preparing ibritumomab tiuxetane labeled with Gd and yttrium 90 by labeling ibritumomab tiuxetane with both a radiosensitized Gd component and yttrium 90; and
(b) administering to the patient ibritumomab tiuxetane labeled with said Gd and yttrium 90;
A method involving that. A method for improving the efficacy of a radiolabeled therapeutic agent comprising:
(i) (a) attaching the radiosensitizing component to the drug by combining the drug with the radiosensitizing component; and
(b) then administering the drug to the patient; or
(ii) (a) labeling a carrier having substantially the same targeting properties as the radiolabeled agent with a radiosensitizing component; and
(b) the radiolabeled drug and the carrier are then co-administered to the patient as a mixture or separately;
A method comprising that. A method of administering a radiolabeled therapeutic agent to a patient in need thereof
(i) administering a modified radiolabeled drug to which a radiosensitized Gd component is attached; or
(ii) co-administering the radiolabeled drug and a carrier having substantially the same targeting properties as the radiolabeled drug with the radiosensitized Gd component attached, as a mixture or separately;
A method comprising that.   The carrier and the radiolabeled drug have the same epitope as a target in the patient, or both the carrier and the radiolabeled drug are localized at the same site in the body, or the same cell 6. The method of claim 5, wherein the method attaches to different epitopes.   6. The method of claim 5, wherein the carrier is an antibody, biopolymer, polymer, liposome or micelle preparation or non-polymeric drug.   6. The method of claim 5, wherein the agent has at least two components attached thereto, at least one component comprising a radiolabel, and at least one component comprising a radiosensitizer.   6. The method of claim 5, wherein the therapeutic agent is or comprises a chelate.   6. The method according to claim 5, wherein the drug is a protein, a polymer or a biopolymer, an antibody or an antibody construct, DNA or RNA or a construct thereof, a carbohydrate, or a hyperbranched polymer compound.   If the radiolabeled drug and the radiosensitizer have substantially the same targeting properties, the drug comprises a mixture of the radiolabeled drug and an analog of the drug, the analog being 6. A method according to claim 5, which functions as or contains a radiosensitizer.   6. The method of claim 5, wherein the radioactive label is an alpha, beta or gamma emitter.   6. The method of claim 5, wherein the radiolabel is selected from the group of lanthanides.   6. The method of claim 5, wherein the radioactive label is yttrium.   6. The method of claim 5, wherein the radioactive label is a radioactive halogen or iodine.   6. The method of claim 5, wherein the radiation sensitizer is or includes gadolinium, iodine or boron, or is a triiodobenzene component or a borane or carborane component.   6. The method of claim 5, wherein the radioactive label is attached to the drug or is linked to the drug by a chelating agent attached to the drug via a bridge.   19. The method of claim 18, wherein the chelator or the chelate comprises an EDTA, DTPA, or DOTA component.   6. The agent is linked or not linked to a chelator or chelate, wherein the chelator or chelate comprises MX-DTPA, phenyl-DTPA, benzyl-DTPA, or CHX-DTPA. The method described in 1.   The chelator or chelate on the antibody is provided with a mixture of radioisotope and gadolinium, cobalt or iron, and / or the chelator or chelate on the antibody with a mixture of yttrium 90 and gadolinium, cobalt or iron. 21. The method of claim 20, wherein applying.   6. The method of claim 5, wherein the agent is ibritumomab tiuxetane.   Mixing a radioisotope-labeled drug with a drug analog labeled with gadolinium, cobalt or iron and / or yttrium 90-labeled ibritumomab tiuxetane and gritolinium, cobalt or iron-labeled ibritumomab tiuxetane. 6. The method of claim 5, wherein mixing is performed.