WO1991013633A1 - Improvements relating to immunoradiotherapy - Google Patents

Improvements relating to immunoradiotherapy Download PDF

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Publication number
WO1991013633A1
WO1991013633A1 PCT/GB1991/000383 GB9100383W WO9113633A1 WO 1991013633 A1 WO1991013633 A1 WO 1991013633A1 GB 9100383 W GB9100383 W GB 9100383W WO 9113633 A1 WO9113633 A1 WO 9113633A1
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Prior art keywords
antibody
hypoxic cell
tumour
labelled
sensitiser
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PCT/GB1991/000383
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French (fr)
Inventor
Richard Henry John Begent
Rosamund Barbara Pedley
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Cancer Research Campaign Technology Limited
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Priority claimed from GB909005535A external-priority patent/GB9005535D0/en
Priority claimed from GB919103784A external-priority patent/GB9103784D0/en
Application filed by Cancer Research Campaign Technology Limited filed Critical Cancer Research Campaign Technology Limited
Publication of WO1991013633A1 publication Critical patent/WO1991013633A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • 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
    • A61K2121/00—Preparations for use in therapy

Definitions

  • THIS INVENTION relates to improvements in the treatment of neoplastic diseases in man.
  • One of the major methods of therapy used in the treatment of neoplastic diseases is radiation therapy.
  • One form of radiation therapy involves irradiating, from an appropriate external source of radiation, that area of the patient's body believed to contain the neoplasia. This method is relatively unselective in that there is extensive and undesirable irradiation of healthy cells. More recently, this technique has been improved by the use of radionuclide labelled antibodies that will bind to tumour- associated antigens. Such labelled antibodies, normally monoclonal antibodies, are injected into the patient and tend to localise in the region of the tumour which becomes irradiated by the emission from the radionuclide attached to the antibody. This technique provides a much greater measure of selectivity than is obtainable with radiation generated outside the body.
  • the present invention provides the use of a combination of (i) a radionuclide labelled antibody that will bind to a tumour-associated antigen and (ii) a hypoxic cell radiosensitiser in the production of a medicament for the treatment of neoplastic diseases in man.
  • the present invention provides a method for bringing about tumour regression or the inhibition of tumour growth by the administration to a patient requiring such treatment of an effective amount of a radionuclide labelled antibody that will bind to a tumour-associated antigen and the administration to the patient, before and/or during and/or after administration of the antibody, of a hypoxic cell radiosensitiser.
  • references to antibodies includes whole antibodies or fragments thereof including the antigen binding region, eg an Fv, Fab or F(ab)2 fragment.
  • Antibodies may be produced by conventional methods or be altered antibodies produced by methods known to those of skill in the art. For example, whole antibodies may be humanized as described in EP-A-0125023 (Genentech) . The variable region may be altered by CDR-replacement, eg. as described in GB-A- 2188638 (Winter) . Antibodies may also be isolated from phage or bacterial libraries, eg. as described in Science, 246:1275-1281,1989.
  • hypoxic cell radiosensitisers are compounds which have the ability of increasing the susceptibility of the tumour cells to the radiation they are receiving from the externally generated source and their use permits a reduction in the general amount of radiation to which the patient is subjected and so reducing the extent of radiation damage to the healthy cells.
  • hypoxic cell radiosensitisers One of the most frequently used hypoxic cell radiosensitisers is misonidazole (3-methoxy-l-(2-nitro-imidazol-l-yl)- propane-2-ol) and this is one of the preferred compounds for use in the present invention.
  • Other hypoxic cell radiosensitisers such as analogues of misonidazole may also be used. Metronidazole and its analogues may also be used.
  • hypoxic cell radiosensitizer ⁇ examples include:
  • nitro aromatic heterocyclic cell sensitisers including, in addition to misonidazole, etanidazole (Stanford Reasearch no. SR2508) , 2- nitroimidazole-1-acetoxyhydroxymate (KIH-802) and pimonidazole (RO 03-8799) ;
  • quinione bioreductive alkylating agents such as mitomycin C, adriamycin, daunomycin and streptonigrin;
  • non-nitroimidazole hypoxic cell sensitisers such as 3-amirio-l,2,4-benzotriazine-l,4 dioxide (SR4233 (Stanford Research)) and (4)-morpholino-methyl-3,5,dioxypeperazynyl- 1,2-ethane (AT-1727) ; and
  • non-nitroimidazole glutathione depleters such as butathionine sulfoximine and diethyl maleate.
  • the radiolabelled antibody will be administered by injection, normally by the intravenous route to facilitate localisation of the labelled antibody in the tumour region as rapidly as possible.
  • the radiolabelled antibody may be administered intraperitoneally.
  • hypoxic cell radiosensitiser may be administered by conventional methods, this is normally by oral administration.
  • the compound may be dissolved/suspended in water and taken by mouth.
  • the exact sequence of treatment will be a matter of preference for the individual clinician. It is desirable that the effect of the hypoxic cell radiosensitiser be available immediately irradiation of the tumour cells occurs and consequently, it is usually preferred to administer the radiosensitiser before the antibody.
  • the radiosensitiser can and usually is administered on more than one occasion the first of which is preferably before the antibody is administered while the second and subsequent administrations are made simultaneously with or after administration of the antibody.
  • the first dose of the radiosensitiser may also be given after antibody administration when radioactivity is high in the tumour but has diminished in normal tissue and blood.
  • the second antibody or fragment thereof which is directed to the radionuclide labelled antibody, and is capable of forming a complex with the labelled antibody.
  • the complex formed is rapidly cleared from the blood. This will reduce further the levels of free radiolabelled antibody in normal tissues and blood. This is because formation of the complex will cause accelerated clearance of the labelled antibody from the blood, in a manner analogous to that described in WO89/10140.
  • the second, or clearance, antibody may be a monoclonal or polyclonal antibody directed against any portion of the radiolabelled antibody. For example, if the radiolabelled antibody is of the IgG class, an anti-IgG antibody may be used.
  • the second antibody may be attached to a acromolecule as described in W089/10140 in order that it is restrained from leaving the vascular compartment by virtue of the size of the resulting conjugate.
  • a further embodiment of the invention provides the use of a combination of (i) a radionuclide labelled antibody that will bind to a tumour-associated antigen, (ii) a hypoxic cell radiosensitiser, and (iii) a second antibody which is capable of forming a complex with the radiolabelled antibody, in the production of a medicament for the treatment of neoplastic diseases in man.
  • the present invention further provides a method for bringing about tumour regression or the inhibition of tumour growth by the administration to a patient requiring such treatment of an effective amount of a radionuclide labelled antibody that will bind to a tumour-associated antigen together with, before and/or during and/or after administration of the antibody, of a hypoxic cell radiosensitiser, and after administration of the labelled antibody and before and/or during and/or after the administration of the hypoxic cell sensitiser a second antibody which is able to bind to the radiolabelled antibody so as to accelerate clearance of the radiolabelled antibody from the blood.
  • A5B7 is a urine monoclonal antibody raised by conventional hybridoma technology using CEA as immunogen.
  • PK4S described in Begent et al, Brit. J. Surgery, 1986, 7_3 . : 64-67 is a polyclonal sheep antibody raised conventionally from the serum of sheep that have been immunised with CEA.
  • W14 is a monoclonal antibody raised by conventional hydridoma technology using human chorionic gonadotrophin (hCG) as immunogen and, for the purposes of this Example, is to be regarded as a non-specific antibody in relation to the tumour.
  • hCG human chorionic gonadotrophin
  • the Example was carried out using Balb/c nude mice (Nu/Nu) into which had been grafted a tumour, LS-174T, a moderately differentiated human colonic adenocarcinoma.
  • the tumours were measured in three dimensions and the volume estimated as LWH/2 in accordance with the technique of Looney et al.
  • Misonidazole was administered to the mice intraperitoneally at 500 g/kg per injection twice a day for 5 days commencing 1 hour before administration of the radiolabelled antibody.
  • the radiolabelled antibody was injected intravenously in a single dose to provide an amount of radiation of 0.5 mCi.
  • mice For comparative purposes, in addition to the use of the non-specific labelled W14 antibody, some mice remained untreated while others were treated with unlabelled antibody.
  • mice were injected intraperitoneally with IUdR at the rate of 50 mg/kg per dose 4 times over a 16 hour period with the radiolabelled antibody being injected 18 hours later.
  • the results were assessed by a comparison of survival between the various groups of treated mice taken at a time when the size of the tumour reached 4 cm 3 .
  • Figures 1 and 2 show that neither unlabelled antibody nor non-specific W14 antibody significantly affected survival when compared with untreated mice although labelled W14 did inhibit tumour growth for the first 6 days after administration.
  • Figures 1 and 2 also show that the single 0.5 mCi injection of the labelled specific monoclonal or polyclonal antibody delayed tumour growth for a mean period of 45 and 30 days respectively and significantly prolonged survival. Some temporary tumour regression was also seen.
  • misonidazole with 131 I-A5B7 further prolonged tumour growth inhibition by a mean of 15 days and significantly increased survival of mice when compared to 131 I-A5B7 alone.
  • a similar pattern of tumour growth inhibition resulted from the combination of misonidazole and 131 I-PK4S but the increase in survival time here was not statistically significant.
  • Figure 3 shows, interestingly, that not only does IUdR have no enhancing effect on the immunoradiotherapy but that it actually appears to have the opposite effect.

Abstract

Use of a combination of (i) a radionuclide labelled antibody that will bind to a tumour-associated antigen and (ii) a hypoxic cell radiosensitiser, in the production of a medicament for the treatment of neoplastic diseases in man. The antibody may be a monoclonal antibody and/or an antibody fragment. The hypoxic cell sensitiser may be misonidazole or an analogue thereof.

Description

IMPROVEMENTS RELATING TO IMMUNORADIOTHERAPY
THIS INVENTION relates to improvements in the treatment of neoplastic diseases in man.
One of the major methods of therapy used in the treatment of neoplastic diseases is radiation therapy. One form of radiation therapy involves irradiating, from an appropriate external source of radiation, that area of the patient's body believed to contain the neoplasia. This method is relatively unselective in that there is extensive and undesirable irradiation of healthy cells. More recently, this technique has been improved by the use of radionuclide labelled antibodies that will bind to tumour- associated antigens. Such labelled antibodies, normally monoclonal antibodies, are injected into the patient and tend to localise in the region of the tumour which becomes irradiated by the emission from the radionuclide attached to the antibody. This technique provides a much greater measure of selectivity than is obtainable with radiation generated outside the body.
We have now found that tumour growth inhibition and tumour regression, brought about by the use of radionuclide labelled antibodies that will bind to a tumour-associated antigen can be improved if such therapy is carried out in combination with the administration to the patient of a hypoxic cell radiosensitiser. Accordingly, the present invention provides the use of a combination of (i) a radionuclide labelled antibody that will bind to a tumour-associated antigen and (ii) a hypoxic cell radiosensitiser in the production of a medicament for the treatment of neoplastic diseases in man.
Alternatively, the present invention provides a method for bringing about tumour regression or the inhibition of tumour growth by the administration to a patient requiring such treatment of an effective amount of a radionuclide labelled antibody that will bind to a tumour-associated antigen and the administration to the patient, before and/or during and/or after administration of the antibody, of a hypoxic cell radiosensitiser.
References to antibodies includes whole antibodies or fragments thereof including the antigen binding region, eg an Fv, Fab or F(ab)2 fragment. Antibodies may be produced by conventional methods or be altered antibodies produced by methods known to those of skill in the art. For example, whole antibodies may be humanized as described in EP-A-0125023 (Genentech) . The variable region may be altered by CDR-replacement, eg. as described in GB-A- 2188638 (Winter) . Antibodies may also be isolated from phage or bacterial libraries, eg. as described in Science, 246:1275-1281,1989.
For the demonstration of the effect of the present invention, we have worked primarily with antibodies labelled with 131ι but the use of other metallic or non- metallic -emitters or /3-emitters such as 90-Y or 211-AT can be used. Examples of other radionuclides inlcude 186- Re and 67-Cu. In principle, any α, β , S or Auger emitter that can be used in conventional immunoradiotherapy can be used in the practice of the present invention.
The development of radiation therapy has led to the recognition of a class of compounds identified as hypoxic cell radiosensitisers. These are compounds which have the ability of increasing the susceptibility of the tumour cells to the radiation they are receiving from the externally generated source and their use permits a reduction in the general amount of radiation to which the patient is subjected and so reducing the extent of radiation damage to the healthy cells. One of the most frequently used hypoxic cell radiosensitisers is misonidazole (3-methoxy-l-(2-nitro-imidazol-l-yl)- propane-2-ol) and this is one of the preferred compounds for use in the present invention. Other hypoxic cell radiosensitisers such as analogues of misonidazole may also be used. Metronidazole and its analogues may also be used.
Examples of further hypoxic cell radiosensitizerε include:
(i) nitro aromatic heterocyclic cell sensitisers (nitroimidazoleε) including, in addition to misonidazole, etanidazole (Stanford Reasearch no. SR2508) , 2- nitroimidazole-1-acetoxyhydroxymate (KIH-802) and pimonidazole (RO 03-8799) ;
(ii) quinione bioreductive alkylating agents such as mitomycin C, adriamycin, daunomycin and streptonigrin;
(iii) non-nitroimidazole hypoxic cell sensitisers such as 3-amirio-l,2,4-benzotriazine-l,4 dioxide (SR4233 (Stanford Research)) and (4)-morpholino-methyl-3,5,dioxypeperazynyl- 1,2-ethane (AT-1727) ; and
(iv) non-nitroimidazole glutathione depleters such as butathionine sulfoximine and diethyl maleate.
The exact manner in which the combination therapy is to be carried out will depend, of course, upon the nature of the tumour being treated. In the normal course of events, the radiolabelled antibody will be administered by injection, normally by the intravenous route to facilitate localisation of the labelled antibody in the tumour region as rapidly as possible. Alternatively, particularly where the tumour is physically located near the peritoneal cavity, e.g. in the case of ovarian cancer, the radiolabelled antibody may be administered intraperitoneally.
The hypoxic cell radiosensitiser may be administered by conventional methods, this is normally by oral administration. For example, the compound may be dissolved/suspended in water and taken by mouth.
The exact sequence of treatment will be a matter of preference for the individual clinician. It is desirable that the effect of the hypoxic cell radiosensitiser be available immediately irradiation of the tumour cells occurs and consequently, it is usually preferred to administer the radiosensitiser before the antibody. The radiosensitiser can and usually is administered on more than one occasion the first of which is preferably before the antibody is administered while the second and subsequent administrations are made simultaneously with or after administration of the antibody. However, the first dose of the radiosensitiser may also be given after antibody administration when radioactivity is high in the tumour but has diminished in normal tissue and blood.
It is also possible to seek to enhance the therapeutic effect of the combination of the present invention by administering a second antibody (or fragment thereof) which is directed to the radionuclide labelled antibody, and is capable of forming a complex with the labelled antibody. The complex formed is rapidly cleared from the blood. This will reduce further the levels of free radiolabelled antibody in normal tissues and blood. This is because formation of the complex will cause accelerated clearance of the labelled antibody from the blood, in a manner analogous to that described in WO89/10140. The second, or clearance, antibody may be a monoclonal or polyclonal antibody directed against any portion of the radiolabelled antibody. For example, if the radiolabelled antibody is of the IgG class, an anti-IgG antibody may be used.
The second antibody may be attached to a acromolecule as described in W089/10140 in order that it is restrained from leaving the vascular compartment by virtue of the size of the resulting conjugate.
Thus a further embodiment of the invention provides the use of a combination of (i) a radionuclide labelled antibody that will bind to a tumour-associated antigen, (ii) a hypoxic cell radiosensitiser, and (iii) a second antibody which is capable of forming a complex with the radiolabelled antibody, in the production of a medicament for the treatment of neoplastic diseases in man.
Alternatively, the present invention further provides a method for bringing about tumour regression or the inhibition of tumour growth by the administration to a patient requiring such treatment of an effective amount of a radionuclide labelled antibody that will bind to a tumour-associated antigen together with, before and/or during and/or after administration of the antibody, of a hypoxic cell radiosensitiser, and after administration of the labelled antibody and before and/or during and/or after the administration of the hypoxic cell sensitiser a second antibody which is able to bind to the radiolabelled antibody so as to accelerate clearance of the radiolabelled antibody from the blood.
The following Example is given to illustrate the invention.
Figure imgf000009_0001
EXAMPLE 1
The antibodies used are designated A5B7, PK4S and W14, all of which are in clinical use. A5B7 is a urine monoclonal antibody raised by conventional hybridoma technology using CEA as immunogen. PK4S described in Begent et al, Brit. J. Surgery, 1986, 7_3. : 64-67, is a polyclonal sheep antibody raised conventionally from the serum of sheep that have been immunised with CEA. W14 is a monoclonal antibody raised by conventional hydridoma technology using human chorionic gonadotrophin (hCG) as immunogen and, for the purposes of this Example, is to be regarded as a non-specific antibody in relation to the tumour.
The antibodies used in this Example were all labelled with 131i using the technique of Adam et al. Annals. Clin. Biochem. (1989) , 2_§. '• 244-245.
The Example was carried out using Balb/c nude mice (Nu/Nu) into which had been grafted a tumour, LS-174T, a moderately differentiated human colonic adenocarcinoma.
Misonidazole was used as the hypoxic cell radiosensitiser.
In the experiments, the size of the tumour, 10 to 14 days after transplant, was 0.1 to 0.2 cm3. As the experiments proceeded, the tumours were measured in three dimensions and the volume estimated as LWH/2 in accordance with the technique of Looney et al.
Misonidazole was administered to the mice intraperitoneally at 500 g/kg per injection twice a day for 5 days commencing 1 hour before administration of the radiolabelled antibody. The radiolabelled antibody was injected intravenously in a single dose to provide an amount of radiation of 0.5 mCi.
For comparative purposes, in addition to the use of the non-specific labelled W14 antibody, some mice remained untreated while others were treated with unlabelled antibody.
In a further comparative test, to demonstrate the importance of the hypoxic cell radiosensitiser, one group of mice were injected intraperitoneally with IUdR at the rate of 50 mg/kg per dose 4 times over a 16 hour period with the radiolabelled antibody being injected 18 hours later.
The results were assessed by a comparison of survival between the various groups of treated mice taken at a time when the size of the tumour reached 4 cm3.
The results are set out on Figures 1 to 3 of the accompanying Drawings.
Figures 1 and 2 show that neither unlabelled antibody nor non-specific W14 antibody significantly affected survival when compared with untreated mice although labelled W14 did inhibit tumour growth for the first 6 days after administration. Figures 1 and 2 also show that the single 0.5 mCi injection of the labelled specific monoclonal or polyclonal antibody delayed tumour growth for a mean period of 45 and 30 days respectively and significantly prolonged survival. Some temporary tumour regression was also seen.
The combination of misonidazole with 131I-A5B7 further prolonged tumour growth inhibition by a mean of 15 days and significantly increased survival of mice when compared to 131I-A5B7 alone. A similar pattern of tumour growth inhibition resulted from the combination of misonidazole and 131I-PK4S but the increase in survival time here was not statistically significant.
Figure 3 shows, interestingly, that not only does IUdR have no enhancing effect on the immunoradiotherapy but that it actually appears to have the opposite effect.

Claims

1. Use of a combination of (i) a radionuclide labelled antibody that will bind to a tumour-associated antigen and (ii) a hypoxic cell radiosensitiser, in the production of a medicament for the treatment of neoplastic diseases in man.
2. Use of the combination according to claim 1 wherein the antibody is a monoclonal antibody.
3. Use of the combination according to claim 1 or 2 wherein the antibody is a whole antibody or a Fv, Fab or F(ab')2 fragment thereof.
4. Use of the combination according to any one of the preceding claims wherein the antibody is labelled with 131I, 90Y or 211AT.
5. Use of the combination according to any one of the preceding claims wherein the hypoxic cell sensitiser is a nitro aromatic heterocyclic cell sensitiser, a quinione bioreductive alkylating agent, a non-nitroimidazole hypoxic cell sensitiser or a non-nitroimidazole glutathione depleter.
6. Use of the combination according any one of the preceding claims wherein the hypoxic cell sensitiser is misonidazole or an analogue thereof.
7. Use of the combination of any one of the preceding claims wherein the combination additionally includes: (iii) a second antibody or fragment thereof which is capable of forming a complex with the radionuclide labelled antibody.
8. A kit comprising (i) a radionuclide labelled or labellable antibody that will bind to a tumour-associated antigen and (ii) a hypoxic cell radiosensitiser.
9. A kit according to claim 8 wherein the label, antibody and hypoxic cell sensitizers are as defined in any one of claims 2 to 6, and the kit optionally includes a second antibody or fragment thereof as defined in claim 7.
10. A method for bringing about tumour regression or the inhibition of tumour growth by the administration to a patient requiring such treatment of an effective amount of a radionuclide labelled antibody that will bind to a tumour-associated antigen and the administration to the patient, before and/or during and/or after administration of the antibody, of a hypoxic cell radiosensitiser.
11. A method according to claim 10 wherein the antibody is a monoclonal antibody.
12. A method according to claim 10 wherein the antibody is selected from the group consistion of whole antibodies and Fv, Fab and F(ab')2 fragments thereof.
13. A method according to claim 10 wherein the antibody is labelled with a radionuclide selected from the group consisting of: 131I, 90Y and 211AT.
14. A method according to claim 10 wherein the hypoxic cell sensitiser is selected from the group consisting of: nitro aromatic heterocyclic cell sensitisers; quinione bioreductive alkylating agents; non-nitroimidazole hypoxic cell sensitisers; and non-nitroimidazole glutathione depleters.
15. A method according to claim 10 wherein the hypoxic cell sensitiser is misonidazole or an analogue thereof.
16. A method according to claim 10 which additionally includes, after administration of the said labelled antibody and before and/or during and/or after the administration of the said hypoxic cell sensitiser a second antibody which is able to form a complex with the radiolabelled antibody.
17. A kit for use in the method of claim 10 which comprises (i) a radionuclide labelled antibody that will bind to a tumour-associated antigen and (ii) a hypoxic cell radiosensitiser.
18. A kit according to claim 17 which further includes a second antibody which is able to form a complex with the labelled antibody.
PCT/GB1991/000383 1990-03-12 1991-03-12 Improvements relating to immunoradiotherapy WO1991013633A1 (en)

Applications Claiming Priority (4)

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GB9005535.1 1990-03-12
GB909005535A GB9005535D0 (en) 1990-03-12 1990-03-12 Improvements relating to immunoradiotherapy
GB9103784.6 1991-02-22
GB919103784A GB9103784D0 (en) 1991-02-22 1991-02-22 Improvements relating to immunoradiotherapy

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011109387A1 (en) * 2010-03-01 2011-09-09 Intraop Medical Corporation Radiotherapy combined with hypoxic cell sensitizers
US8269197B2 (en) 2009-07-22 2012-09-18 Intraop Medical Corporation Method and system for electron beam applications

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0222617A2 (en) * 1985-11-13 1987-05-20 Ortho Pharmaceutical Corporation Monoclonal antibody therapy
EP0270340A2 (en) * 1986-12-05 1988-06-08 Cancer Biologics, Inc. Use of an antibody conjugate for the detection of necrotic malignant tissue and for the associated therapy
EP0282057A2 (en) * 1987-03-11 1988-09-14 The Board Of Regents Of The University Of Michigan Chemo-radio-immuno-conjugates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0222617A2 (en) * 1985-11-13 1987-05-20 Ortho Pharmaceutical Corporation Monoclonal antibody therapy
EP0270340A2 (en) * 1986-12-05 1988-06-08 Cancer Biologics, Inc. Use of an antibody conjugate for the detection of necrotic malignant tissue and for the associated therapy
EP0282057A2 (en) * 1987-03-11 1988-09-14 The Board Of Regents Of The University Of Michigan Chemo-radio-immuno-conjugates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Proceedings Eightieth Annual Meeting of the American Association for Cancer Research San Francisco, Calfornia, 24-27 May 1989, volume 30, March 1989, A.R. Fritzberg: "Antibody targeted radiotherapy: satus and efficacy issues", pages 648-650 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8269197B2 (en) 2009-07-22 2012-09-18 Intraop Medical Corporation Method and system for electron beam applications
WO2011109387A1 (en) * 2010-03-01 2011-09-09 Intraop Medical Corporation Radiotherapy combined with hypoxic cell sensitizers
US9393439B2 (en) 2010-03-01 2016-07-19 Intraop Medical Corporation Radiotherapy combined with hypoxic cell sensitizers
US9656098B2 (en) 2010-03-01 2017-05-23 Intraop Medical Corporation Radiotherapy combined with hypoxic cell sensitizers

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